Dr David B. Arciniegas, C. Alan Anderson, Christopher M. Filley-Behavioral Neurology & Neuropsychiatry-Cambridge University Press (2013)

more information - www.cambridge.org/9780521875011

Behavioral Neurology & Neuropsychiatry

Behavioral Neurology & Neuropsychiatry Edited by

David B. Arciniegas, MD The Michael K. Cooper Professor of Neurocognitive Disease, Director of the Neurobehavioral Disorders Program, and Associate Professor of Psychiatry and Neurology at the University of Colorado School of Medicine

C. Alan Anderson, MD Professor of Neurology, Emergency Medicine, and Psychiatry at the University of Colorado School of Medicine, and Staff Neurologist at the Denver Veterans Affairs Medical Center

and

Christopher M. Filley, MD Professor of Neurology and Psychiatry, and Director of the Behavioral Neurology Section at the University of Colorado School of Medicine, and Neurology Service Chief at the Denver Veterans Affairs Medical Center

Managing Editor

T. Angelita Garcia

CAMBRID GE UNIVERSIT Y PRESS Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo, Delhi, Mexico City Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/ 9780521875011 c Cambridge University Press 2013

This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 2013 Printed and bound in the United Kingdom by the MPG Books Group A catalog record for this publication is available from the British Library Library of Congress Cataloging in Publication data Behavioral neurology & neuropsychiatry / edited by David B. Arciniegas, C. Alan Anderson, Christopher M. Filley. p. ; cm. Behavioral neurology and neuropsychiatry Includes bibliographical references and index. ISBN 978-0-521-87501-1 (hbk.) – ISBN 0-521-87501-3 (hbk.) I. Arciniegas, David B. (David Brian), 1967– II. Anderson, C. Alan. III. Filley, Christopher M., 1951– IV. Title: Behavioral neurology and neuropsychiatry. [DNLM: 1. Brain Diseases – psychology. 2. Behavior – physiology. WL 348] 616.8 – dc23 2012030788 ISBN 978-0-521-87501-1 Hardback Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Contents List of contributors vii Foreword xi M. Marsel-Mesulam Preface xiii

1

Introduction 1 Christopher M. Filley, C. Alan Anderson, and David B. Arciniegas

Section I – Structural and Functional Neuroanatomy

184

14 Praxis 199 Kenneth M. Heilman 15 Visuospatial function 214 Doron Merims and Morris Freedman

2

Behavioral neuroanatomy 12 C. Alan Anderson, David B. Arciniegas, Deborah A. Hall, and Christopher M. Filley

3

Cerebellum 32 Jeremy D. Schmahmann

4

White matter 47 Christopher M. Filley

5

Frontal-subcortical circuits David G. Lichter

6

Arousal 88 C. Alan Anderson, Christopher M. Filley, David B. Arciniegas, and James P. Kelly

16 Executive function David B. Arciniegas

225

17 Comportment 250 Michael Henry Rosenbloom, Oliver Freudenreich, and Bruce H. Price 18 Emotion 266 David B. Arciniegas

59

7

Sleep 98 Martin L. Reite

8

Attention 115 Joshua Cosman and Matthew Rizzo

9

Motivation 134 Brian D. Power and Sergio E. Starkstein

10 Perception and recognition 144 Benzi M. Kluger and Gila Z. Reckess 11 Memory 161 Felipe DeBrigard, Kelly S. Giovanello, and Daniel I. Kaufer 12 Language 174 Mario F. Mendez

13 Affective prosody Elliott D. Ross

19 Personality 299 Sita Kedia and C. Robert Cloninger

Section II – Neurobehavioral and Neuropsychiatric Assessment 20 Neuropsychiatric evaluation Fred Ovsiew 21 Neurological examination Stuart A. Schneck

310 319

22 Assessment for subtle neurological signs 333 Igor Bombin, Celso Arango, and Robert W. Buchanan 23 Mental status examination David B. Arciniegas

344

24 Neuropsychological assessment C. Munro Cullum

394

v

Contents

25 Forensic assessment 406 Hal S. Wortzel and Robert L. Trestman 26 Structural neuroimaging 415 Robin A. Hurley, Deborah M. Lucas, and Katherine H. Taber 27 Advanced neuroimaging 430 Deborah M. Little, David B. Arciniegas, and John Hart, Jr. 28 Electroencephalography 442 Lauren C. Frey and Mark C. Spitz 29 Advanced electrophysiology Donald C. Rojas

459

30 Neurotoxicology 474 Christopher M. Filley 31 Neuropathological assessment 485 B. K. Kleinschmidt-DeMasters, Katherine L. Howard, Steven G. Ojemann, and Christopher M. Filley

Section III – Treatments in Behavioral Neurology & Neuropsychiatry 32 Principles of pharmacotherapy Jonathan M. Silver

vi

33 Rehabilitation and pharmacotherapy of cognitive impairments 511 David B. Arciniegas, Hal S. Wortzel, and Kimberly L. Frey 34 Pharmacotherapy of emotional disturbances 543 Steven L. Dubovsky 35 Pharmacotherapy of behavioral disturbances 566 Thomas W. McAllister and David B. Arciniegas 36 Psychotherapy 587 Lynne Fenton and Robert Feinstein 37 Environmental and behavioral interventions 604 Laura A. Flashman and Thomas W. McAllister 38 Procedural interventions 627 C. Alan Anderson and David B. Arciniegas

Index 649 498

The color plates are to be found between pp. 224 and 225.

Contributors

C. Alan Anderson, MD Professor of Neurology, Emergency Medicine and Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA; Staff Neurologist, Denver Veterans Affairs Medical Center, Denver, CO, USA Celso Arango, MD, PhD Head, Adolescent Unit, Department of Psychiatry, Hospital General Universitario Gregorio Maraño´ n, Madrid, Spain; Adjunct Associate Professor of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD, USA David B. Arciniegas, MD The Michael K. Cooper Professor of Neurocognitive Disease; Director, Neurobehavioral Disorders Program; Associate Professor of Psychiatry and Neurology, University of Colorado School of Medicine, Aurora, CO, USA

Joshua Cosman, PhD Postdoctoral Fellow, Department of Neuroscience, University of Iowa, Iowa City, IA, USA C. Munro Cullum, PhD Professor of Psychiatry and Neurology & Neurotherapeutics; Director of Neuropsychology; Pam Blumenthal Distinguished Professor of Clinical Psychology, The University of Texas Southwestern Medical Center, Dallas, TX, USA Felipe DeBrigard Graduate Student, Department of Philosophy and Coginitive Neuroscience of Memory Laboratory, The University of North Carolina at Chapel Hill, NC, USA Steven L. Dubovsky, MD Professor and Chair, Department of Psychiatry, The State University of New York at Buffalo, Buffalo, NY; Adjoint Professor of Psychiatry and Medicine, University of Colorado School of Medicine, Aurora, CO, USA

Igor Bombin Department of Psychology, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, University of Oviedo, Oviedo, Spain; Reintegra Foundation, Centro de Rehabilitación Neurológica, Spain

Robert Feinstein, MD Professor of Psychiatry and Vice Chairman for Clinical Education and Evidence Based Medicine, Integration, Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA

Robert W. Buchanan, MD Professor of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

Lynne Fenton, MD Assistant Professor, Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA

C. Robert Cloninger, MD Wallace Renard Professor of Psychiatry; Professor of Genetics and Psychology; Director, Center for Psychobiology of Personality, Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

Christopher M. Filley, MD Professor of Neurology and Psychiatry; Director, Behavioral Neurology Section, University of Colorado School of Medicine, Aurora, CO, USA; Neurology Service Chief, Denver Veterans Affairs Medical Center, Denver, CO, USA

vii

List of contributors

Laura A. Flashman, PhD Professor, Department of Psychiatry, Dartmouth Medical School, Hanover, NH, USA

Katherine L. Howard Coordinator, Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA

Morris Freedman, MD, FRCP Head, Division of Neurology and Director, Behavioural Neurology Program, Baycrest Hospital; Professor, Faculty of Medicine (Neurology) and Director, Behavioural Neurology Section, Division of Neurology, University of Toronto, Toronto, ON, Canada

Robin A. Hurley, MD Professor of Psychiatry & Behavioral Medicine and Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA

Oliver Freudenreich, MD Associate Professor of Psychiatry, Harvard Medical School; Director, First Episode and Early Psychosis Program, Massachusetts General Hospital, Boston, MA, USA Kimberly L. Frey, MS, CCC-SLP, CBIS Instructor, Neurobehavioral Disorders Program, Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA Lauren C. Frey, MD Assistant Professor, Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA Kelly S. Giovanello, PhD Assistant Professor, Department of Psychology Biomedical Research, Imaging Center, The University of North Carolina at Chapel Hill, NC, USA Deborah A. Hall, MD, PhD Assistant Professor, Department of Neurology, Rush University Medical Center, Chicago, IL, USA John Hart, Jr., MD Medical Science Director, Center for Brain Health, Jane and Bud Smith Distinguished Chair, Cecil Green Distinguished Chair, Professor, Behavioral and Brain Sciences, UT Dallas; Professor, Neurology & Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA Kenneth M. Heilman, MD The James E. Brooks Jr. Distinguished Professor of Neurology and Health Psychology, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA

viii

Daniel I. Kaufer, MD Assistant Professor, Department of Neurology, and Director, UNC Memory Disorders Program, University of North Carolina at Chapel Hill School of Medicine, NC, USA Sita Kedia, MD Assistant Professor, Department of Pediatrics, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA James P. Kelly, MD Director, National Intrepid Center of Excellence, Bethesda, MD, USA B. K. Kleinschmidt-DeMasters, MD Professor and Head of Neuropathology, Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA Benzi M. Kluger, MD, MS Assistant Professor, Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA David G. Lichter, MB, ChB, FRACP Clinical Professor of Neurology and Psychiatry, The State University of New York University at Buffalo, Buffalo, NY, USA Deborah M. Little, PhD Assistant Professor of Neurology and Rehabilitation Anatomy and Cell Biology, University of Illinois College of Medicine at Chicago, Chicago, IL, USA Deborah M. Lucas, MD Radiology Preceptor, W.G. “Bill” Hefner VA Medical Center, 1601 Benner Avenue, Salisbury, NC 28144, USA


Thomas W. McAllister, MD Millennium Professor of Psychiatry and Neurology; Vice Chair for Neuroscience Research, Department of Neurology, Dartmouth Medical School, Hanover, NH, USA Mario F. Mendez, MD, PhD Professor of Neurology and Psychiatry & Biobehavioral Sciences, UCLA School of Medicine; Director, Neurobehavior Unit, Greater Los Angeles VA Medical Center, Los Angeles, CA, USA Doron Merims, MD Neurologist, Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel Steven G. Ojemann, MD Associate Professor and Director, Stereotactic and Functional Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA Fred Ovsiew, MD Professor of Clinical Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago IL, USA Brian D. Power Clinical Lecturer, School of Psychiatry, University of Western Australia, Australia Bruce H. Price, MD Assistant Professor of Neurology, Harvard Medical School; Chief, Department of Neurology, McLean Hospital, Belmont, MA, USA Gila Z. Reckess Graduate Student, Department of Clinical and Health Psychology, University of Florida, FL, USA Martin L. Reite, MD Clinical Professor, Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA

Matthew Rizzo, MD Professor of Neurology, Engineering and Public Policy; Director, Division of Neuroergonomics; Director, University of Iowa Aging Mind and Brain Initiative, Department of Neurology, University of Iowa, Iowa City, IA, USA Donald C. Rojas, PhD Associate Professor, Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA Michael Henry Rosenbloom, MD Health Partner Specialty Center, Center for Dementia and Alzheimer’s Care, St. Paul, MN, USA Elliott D. Ross, MD Professor, Department of Neurology, The University of Oklahoma College of Medicine; Director, OKC VAMC Center for Alzheimer’s and Neurodegenerative Disorders, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Jeremy D. Schmahmann, MD Professor of Neurology, Harvard Medical School; Director, Ataxia Unit; Cognitive and Behavioral Neurology Unit; Laboratory for Neuroanatomy and Cerebellar Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Stuart A. Schneck, MD Professor Emeritus, Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA Jonathan M. Silver, MD Clinical Professor, Department of Psychiatry, NYU School of Medicine, New York, NY, USA Mark C. Spitz, MD Professor of Neurology, Director, Comprehensive Epilepsy Center, Medical Director, Clinical Neurophysiology Laboratory, University of Colorado School of Medicine, Aurora, CO, USA; Staff Neurologist, Denver Veterans Affairs Medical Center, Denver, CO, USA

ix


Sergio E. Starkstein, MD, PhD, FRANZCP Winthrop Professor, Fremantle Hospital, The University of Western Australia, Crawley, WA, Australia

Katherine H. Taber, PhD Research Health Scientist, Salisbury VAMC; Assistant Co-Director, MIRECC Education Component

x

Robert L. Trestman, PhD, MD Professor, Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, USA Hal S. Wortzel, MD Assistant Professor of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA; Director, Neuropsychiatric Consultation Services, Denver Veterans Affairs Medical Center, Denver, CO, USA

Foreword Practitioners of Behavioral Neurology & Neuropsychiatry should consider themselves privileged to have been assigned the uniquely challenging task of treating the most complex disorders of the most complex organ in the body. The facts and figures are quite daunting. The cerebral cortex alone contains 40 billion neurons crowded into 30 square feet of surface area. Each neuron makes thousands of contacts with other neurons. At these contact points, known as synapses, information flows from one neuron to another at a rate of approximately 100 times per second. The total number of neural contacts on the surface of the brain alone is 40 followed by 12 zeros, a number that is as large as the number of all the stars in our galaxy. This complexity is not devoid of order. A distinctive principle of brain function is the regional variation of specializations – different parts of the brain have different responsibilities. Some of these job descriptions defy common sense. What kind of engineering logic would have made memory for recent events, a faculty essential for all aspects of behavior, critically dependent on a tiny part of the temporal lobe known as the hippocampus? Why is language, a faculty that permeates all aspects of thought, critically dependent on only one hemisphere? The past 150 years have allowed us to accumulate mountains of facts at a continuously accelerating rate. The classic case reports of the late nineteenth and early twentieth centuries, the advent of new methods for tracing structural and chemical neuroanatomy, single cell recordings in behaving primates, and the modern revolution in neuroimaging are some of the engines that powered this growth. The next revolution will arise when these facts are linked to explanatory the-

ories of brain function, theories that can explain, in some principled way, how patterned synaptic activity can transform muscle contractions and sensory input into memories, words, and actions. While we wait for new insights to emerge, we have patients that need our help. In many instances, the diseases we see are irreversible. Few of our patients can be restored to former states of normalcy and many turn out to have relentlessly progressive neurodegenerative disorders. However, the practitioner in this field needs to understand (and believe) that “incurable” diseases are nonetheless “treatable.” Characterizing the neurobehavioral parameters of the disease, specifying the chief deficit that undermines daily activities, educating the patient and family, identifying appropriate resources for rehabilitation, and the judicious use of pharmacotherapy are some of the modalities that allow the informed practitioner to make a real difference in patient care. This volume covers key theoretical and practical topics in Behavioral Neurology & Neuropsychiatry. A special strength is the section on treatment. Edited by three leaders in this field, this volume will allow seasoned practitioners as well as novices to have a better understanding of this complex area of medicine and to take better care of their patients.

M. Marsel-Mesulam, MD Director, Cognitive Neurology and Alzheimer’s Disease Center; Ruth Dunbar Davee Professor of Neuroscience, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

xi

Preface

The recent merger of behavioral neurology and neuropsychiatry into a single medical subspecialty, Behavioral Neurology & Neuropsychiatry (BN&NP), represents a substantive rapprochement between the parent disciplines from whence its trainees and practitioners hail. This event occasions an approach to brain– behavior relationships that transcends the traditional perspectives of neurology and psychiatry, and creates an enduring context for the combined study of the psychiatry of neurology and the neurology of psychiatry. Most importantly, it identifies a cadre of clinicians dedicated to caring for persons and families affected by all manner of brain disorders producing cognitive, emotional, behavioral, and sensorimotor disturbances. The clinical approach of subspecialists in BN&NP reflects a materialist philosophy of mind that regards mental events as brain events and, by extension, mental disorders as brain disorders. Critical evaluation of the relationships between psychological and neurobiological phenomena is encouraged, as are revisions or elimination of concepts or theories that do not comport with modern neuroscience. Reciprocal interactions between neurobiological, psychological, social, and environmental factors and their influences on neuropsychiatric health are appreciated, and they are considered relevant to understanding brain–behavior disorders and their treatments to the extent that they affect brain structure and/or function. This philosophy precludes guild-based division of brain disorders into neurological and psychiatric types, and requires subspecialists in BN&NP to employ a comprehensive clinical approach that blends and adds to the historically distinct methods of neurology and psychiatry. For more than a decade, our BN&NP faculty group at the University of Colorado School of Medicine has applied this philosophy and approach to our daily practice. As BN&NP clinicians, teachers, and educators, we are an integrated transdisciplinary faculty group who bring a uniform body of subspecialty knowledge and skills to the clinic and bedside despite

differences in our primary training backgrounds. Our model informed the work of the Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association and the Society for Behavioral and Cognitive Neurology, their creation of the BN&NP training curriculum adopted by the United Council for Neurologic Subspecialties [1], and that organization’s development of BN&NP fellowship program accreditation standards and practitioner certification processes [2] – all endeavors to which the editors of this volume and many of its chapter authors contributed substantively. This book complements and extends those efforts by translating the philosophy and clinical approach used in our clinical and teaching efforts into a compendium of the concepts and principles of BN&NP. It draws naturally from information presented in the many volumes in this field that we have studied, and it extends and complements the writings of the many great teachers from whom we have learned. It is unique, however, in its specific focus on BN&NP and its organization around a peer-reviewed and nationally accepted curriculum for training in this subspecialty as well as its development by editors and authors committed to the growth of this area of clinical practice and study. Where material offered in this book imitates or critiques prior works, our aim – both as editors and as contributors – has been to ensure that its presentation honors the sources from which it derives, reflects the best traditions of scholarship, and serves to advance our field. Designed as a primer of concepts and principles in BN&NP, rather than an exhaustive survey of neurobehavioral disorders, the text divides into three parts: Structural and Functional Neuroanatomy (Section I), Clinical Assessment (Section II), and Treatment (Section III). Part I begins with an introduction to the history and current practice of BN&NP. Chapter 2 offers an overview of essential behavioral neuroanatomy, including brain–behavior

xiii

Preface

relationships associated with the brainstem, cerebellum, diencephalon, subcortical structures, limbic and paralimbic areas, white matter, and neocortex. The next several chapters provide detailed reviews of the neuroanatomy of frontal-subcortical and limbic-subcortical circuits, white matter, and the cerebellum and the neurobehavioral functions these systems support. Subsequent chapters in Section I discuss brain–behavior relationships from the vantage point of neurobehavioral functions (i.e., cognition, emotion, and behavior) and the neuroanatomy on which they are predicated. Given the importance of executive function and emotion in BN&NP, extended discussions of the history of ideas on these subjects and current views of their phenomenology and neuroanatomy are offered in Chapters 16 and 18. The principles of clinical assessment presented in Section II draw on the brain–behavior relationships described in Section I, and their application to everyday practice facilitates construction of subspecialty-relevant clinical histories and examinations. Chapter 20 outlines an approach to obtaining a neuropsychiatric history that is complemented by the bedside examination techniques and standardized assessments presented in Chapters 21–25. Recognizing that neuropsychiatric problems sometimes result in civil and criminal legal entanglements, special consideration is given to forensic neuropsychiatric assessment in Chapter 25. Current and emerging uses of neuroimaging, electrophysiologic, and other laboratory measures that may inform clinical evaluation and/or treatment planning are considered in Chapters 26–31. Throughout Section II, emphasis is placed on interpreting clinical symptoms, signs, and syndromes in terms of the neural processes underlying them, considering but not relying upon conventional (i.e., Diagnostic and Statistical Manual of Mental Disorders-based) psychiatric diagnoses, and avoiding dichotomization of clinical conditions into strict “psychiatric” or “neurological” types. The chapters comprising Section III of this volume describe treatments in BN&NP and the principles of their application to the care of patients and families affected by neurobehavioral disorders. The breadth of the clinical problems encompassed by BN&NP requires expertise in environmental, behavioral, rehabilitative, psychological, social, pharmacologic, and procedural interventions. The evidence base for the treatment of many neurobehavioral disorders is evolving rapidly, and their popularity often waxes and wanes

xiv

in short order. Nonetheless, the principles of treatment remain relatively stable and consistently applicable across the many conditions for which subspecialists in BN&NP are consulted and the various settings in which they practice. We therefore have limited consideration of condition-specific treatment issues throughout this volume and offer such only when their discussion illustrates the application of, or an exception to, a principle of treatment in BN&NP. We developed this volume over several years, constantly weighing the need to publish timely information against the necessity of producing a principlesfocused, stylistically coherent, and enduringly useful volume. The carefully selected group of international experts contributing to this work made these tasks easier. Their diverse training and practice backgrounds provide readers with a broad set of perspectives on the subjects addressed and their collective effort on this volume exemplifies the type of transdisciplinary collaboration that defines BN&NP. For chapters focused on subjects within the externally acknowledged expertise of our faculty groups, as well as for those topics on which we wanted to contribute a novel perspective, we functioned as both editors and authors. Thoughtfully approached and deliberately completed, we anticipate that this book will contribute usefully to the continued growth and development of BN&NP and will equip its readers to apply its principles to the study of neurobehavioral disorders and to the care of the individuals and families they affect. We appreciate deeply the time and effort offered by the authors who contributed the chapters comprising this volume as well as their patience and support during the editorial phase of its development. We also are grateful for the invaluable advice and consistent support for this project offered by the editorial group at Cambridge University Press, including Pauline Graham, Alison C. Evans, Katie James, Joanna Chamberlin, and Richard Marley, whose generosity and flexibility ensured that we were provided the time needed to develop this work according to its own requirements. We are thankful for the insights, feedback, and encouragement offered by colleagues, students, friends, family, and advisors who provided guidance on the development of this volume, including: Laura B. Arciniegas, JD, Marsha S. Anderson, MD, Richard L. Gallimore, PhD, Kimberly L. Frey, MS, Hal S. Wortzel, MD, Peter Wagner, MD, Donald C. Rojas, PhD, Jody Newman, MA, Jonathan M. Silver, MD, Thomas W. McAllister, MD, Stuart C. Yudofsky, MD, and Steven L.

Preface

Dubovsky, MD. We also acknowledge the support and contributions of the many other colleagues who provided the inspiration and support for the approach to BN&NP we established at the University of Colorado School of Medicine, including: Norman Geschwind, MD, Michael P. Alexander, MD, Jeffrey L. Cummings, MD, C. Edward Coffey, MD, Daniel I. Kaufer, MD, Tiffany Chow, MD, Robin A. Hurley, MD, Randolph B. Schiffer, MD, John Hart, Jr., MD, John J. Campbell, III, MD, Robert A. Bornstein, PhD, Sandra Bornstein, OT, C. Munro Cullum, PhD, Louis R. Caplan, MD, Harold P. Adams, MD, James P. Kelly, MD, Bruce H. Price, MD, Neill R. Graff-Radford, MD, Bruce L. Miller, MD, Jeremy D. Schmahmann, MD, Kenneth M. Heilman, MD, Kirk R. Daffner, MD, Antonio R. Damasio, MD, Hanna Damasio, MD, Thomas P. Beresford, MD, Lawrence E. Adler, MD, Martin L. Reite, MD, Robert Freedman, MD, James H. Austin, MD, Stuart A. Schneck, MD, Donald H. Gilden, MD, Kenneth L. Tyler, MD, Steven P. Ringel, MD, Hans E. Neville, MD, Roy R. Wright, MD, Edward Lewin, MD, Victoria S. Pelak, MD, Mark C. Spitz, MD, John R. Corboy, MD, Maureen A. Leehey, MD, Richard L. Hughes, MD, Patrick J. Bosque, MD, Jonathan H. Woodcock, MD, Ann H. Craig, MD, Elizabeth Kozora, PhD, Josette G. Harris, PhD, Bruce F. Pennington, PhD, Lisa A. Brenner, PhD, Catharine H. Johnston-Brooks, Brian D. Hoyt, PhD, Michael R. Greher, PhD, Yechiel Kleen, MD, William A. Locy, EdD, Cindy Kreutz, MBA, Estela Bogaert-Martinez, PhD, Jason Nupp, PsyD, Gail Ramsberger, PhD, Lise Menn, PhD, G. Vernon Wood, PhD, Robert B. Goos, MD, Lawrence Rodriguez, RN, James D. Hooker, MD, Al O. Singleton, III, MD, John DeQuardo, MD, Keith LaGrenade,

MD, Bruce D. Leonard, MD, Jack H. Simon, MD, David Rubinstein, MD, Jody Tanabe, MD, Bette K. Kleinschmidt-DeMasters, MD, Philip J. Boyer, MD, and Jonathan Filley, PhD. We are honored by the contributions of M.-Marsel Mesulam, MD, who reviewed the structure and content of this volume early in its development and generously offered its Foreword. Most importantly, we are thankful to our families for their support, encouragement, and tolerance of our efforts on this project and forbearance of its familial costs. We are especially indebted to T. Angelita Garcia, who served as the Managing Editor of this project at the University of Colorado School of Medicine. Ms. Garcia contributed to the review of every chapter included in this volume, constructed a master database containing its several thousand citations and ensured their uniform presentation, secured permissions for the use of materials reproduced from other works, assembled the final manuscript for submission to Cambridge University Press, and coordinated communication between the editors and publisher. Her efforts were essential to the successful completion of this work, and for her contributions we offer our most grateful acknowledgment and thanks. 1.

Arciniegas DB, Kaufer DI, , Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13.

2.

Silver JM. Behavioral Neurology & Neuropsychiatry is a subspecialty. J Neuropsychiatry Clin Neurosci. 2006;18(2):146–8.

xv

Chapter

1

Introduction Christopher M. Filley, C. Alan Anderson, and David B. Arciniegas

The writing of a new textbook in medicine presents both an exciting opportunity and a daunting challenge. Whereas any contemporary medical field witnesses timely new developments that call for rapid dissemination, it is uncertain how much time busy clinicians and investigators can devote to reading an entire textbook, especially when ready access to a range of online resources is increasingly available. We have ventured forth nonetheless, with the goal of creating a novel synthesis of the strong intellectual and academic traditions of Behavioral Neurology & Neuropsychiatry (BN&NP). The unification of the historically separate but parallel subspecialties of behavioral neurology and neuropsychiatry is a relatively recent event [1, 2]. These subspecialties were joined through the work of the American Neuropsychiatric Association and the Society for Behavioral and Cognitive Neurology to create the BN&NP subspecialty under the auspices of the United Council for Neurologic Subspecialties (UCNS). The goals of this effort included advancing and enriching this area of clinical practice and scientific research, in which the brain is recognized as the organ of the mind, as well as facilitating the continued growth of this subspecialty through standardization and accreditation of fellowship training programs and certification of its practitioners. This development reflects a broader re-engagement between neurology and psychiatry more generally [3–5]. Traditional academic boundaries are being reassessed from all sides as medical progress continues. As we have observed and contributed to this process of gradual rapprochement [2], and because we apply an integrated model of BN&NP in our daily work as clinicians, educators, and scientists, the idea of producing this volume arose naturally. This book thus

embodies a summary of our thoughts and practice in these fields – as well as those of our colleagues – as developed over more than two decades of clinical care, education, research, and reflection. As an overture to what follows, some preliminary information will help set the stage.

Historical background Neurology and psychiatry Neurology and psychiatry are securely established medical specialties with well-demarcated areas of clinical and research expertise. Although it seems natural that their common interest in focusing on the brain would foster interdisciplinary ties, close collaboration between these fields and their practitioners are the exception rather than the rule. Many physicians – past and present – have promulgated various degrees of separation between the two fields and rigidly maintained that neurologists study the brain and psychiatrists study the mind. This split fosters a strict dichotomy that keeps apart the professions and professionals most concerned with the myriad and often disabling problems of human behavior. Some argue that neurology will remain separated from psychiatry because each does something unique [6, 7] – the former being “objective” and the latter “humanistic” – while critics respond by chiding the simplistic gap between “mindless neurology” and “brainless psychiatry” [3, 8]. These fields share common origins in Western philosophical and medical traditions [9]. Many Renaissance-era physicians were committed to the thesis that mental states are brain states, and that aberrations of mental functioning are the products of

Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley. C Cambridge University Press 2013. Published by Cambridge University Press.

1


a disordered brain. Cullen (1710–1790) was the first among such physicians to include the mental disorders in his taxonomy of brain illnesses, and was the progenitor of the term “neuroses.” In his classification of disease, the neuroses included the comata, adynamiae, spasmi, and vesaniae, with this latter group consisting of many of the classic “psychiatric” illnesses (e.g., mania, depression, psychosis, and dementia). His work influenced Coombe (1797–1847) in his classification of brain diseases into two major categories, “organic” and “functional.” Coombe intended these terms to sort diseases of the brain into two categories based on the presence or absence of localizable abnormalities. It does not appear to have been his intention to establish a system in which some brain diseases are considered “real” brain problems and others are not considered brain problems at all. Griesinger (1817–1868) subsequently advanced the thesis that even normal mental processes are the direct result of brain activity alone, echoing Hippocrates’ view that mental illness has its origin in the brain [10]. Griesinger viewed psychiatry and neuropathology as a single field with one language and one set of operative laws, and advised physicians to “primarily and in every case of mental disease, recognize a morbid action of that organ [the brain]” [11]. In the following 50 years, a host of European physicians began in earnest to examine the brain with respect to mental processes. A common body of work by pioneering physician-scientists of the nineteenth and early twentieth centuries – among them Theodor Meynert, Jean-Martin Charcot, Sergei Korsakoff, John Hughlings Jackson, Henry Harlow, Eugen Bleuler, Emil Kraepelin, Arnold Pick, and Alois Alzheimer – whose efforts were neither guildspecific nor dominated by concerns regarding the primacy of one or another medical specialty. Their efforts steadily advanced knowledge of neuroanatomy, neurophysiology, and neuropathology as applied to behavioral phenomena in the quest to understand the mind as a function of the brain. This unity of purpose was so pervasive that these physicians were typically referred to as neuropsychiatrists, heralding more formal developments in this direction a century later. During this same period, however, neurology began to develop as an independent field of study, most notably after the formation of the National Hospital for the “Relief of Paralysis, Epilepsy, and Allied Diseases” in Britain in 1860. Concurrently, Charcot (1825–1893) and his students began concentrating on the “neuroses,” and pursuing a line of inquiry that turned the

2

interest of psychiatry at the beginning of the twentieth century toward introspection, reflection, and consideration of the person as a whole. Notably, as psychoanalysis became a more dominant force within psychiatry, this “person as a whole” became increasingly less whole with respect to a complete understanding of the neurology underlying neurotic conditions. As the twentieth century progressed, neurology and psychiatry became polarized with respect to the focus and content of their studies. Neurology was interested in localizable pathology, the “organic” problems, and psychiatry focused on the functioning of an individual’s psyche, internally and interpersonally. These “functional” problems, whose consideration was divorced of their neurological bases, became the province of psychiatry. Interestingly, this was not the initial objective of Sigmund Freud (1856–1939), the progenitor of psychoanalysis. A neurologist by training, Freud was committed to a form of substance materialism: “Research has afforded irrefutable proof that mental activity is bound up with the function of the brain as with no other organ. The discovery of the unequal importance of the different parts of the brain and their individual relations to particular parts of the body and to intellectual activities takes us a step further . . . ” [10]. Freud maintained that the science of his time could not establish clearly the relationship between the complex operations of mental processes and brain function. His theories therefore assumed a form of logical positivism in which he identified the concepts and mechanisms of mental operations from a purely psycho-philosophical perspective. Early in this endeavor, he offered cautionary notes on this approach: “Our mental topography has for the present nothing to do with anatomy . . . In this respect, then, our work is untrammeled and may proceed according to its own requirements. It will, moreover, be useful to remind ourselves that our hypotheses can in the first instance lay claim only to the value of illustrations” [10]. Freud (1895) [12] envisioned a future in which a scientific account of mental processes would be possible. However, de facto dualist perspectives on mind– body issues supplanted his early materialist positions on such matters and pervaded early and midtwentieth century psychiatric practice and popular culture. Indeed, when previously “functional” disorders like general paresis of the insane (a form of neurosyphilis) were discovered to have an “organic” basis,

Chapter 1: Introduction

they were quickly eschewed as proper subjects of psychiatric study and treatment and taken up by neurology. As a result, the early part of the twentieth century witnessed the progressive movement of a significant part of psychiatry away from its neuropsychiatric foundations, and facilitated the continued division of neurology and psychiatry into separate disciplines. As described by Hollender (1991) in American Board of Psychiatry and Neurology: The First Fifty Years [13], the unification of neurology and psychiatry under the American Board of Psychiatry and Neurology (ABPN) in 1934 had the potential to unify the fields. However, the manner in which the ABPN was created contributed substantially to the formal separation of psychiatry and neurology. In the early 1930s, a group of neuropsychiatrists within the Section on Nervous and Mental Disease of the American Medical Association (AMA) suggested that psychiatry and neurology be united under a common board of examiners for the purpose of establishing criteria and examinations for certification to practice in these medical specialties. Their explicit purposes were to recognize the common interests of these specialties in brain– behavior relationships, and to protect both the public and also the reputations of these fields by distinguishing qualified from unqualified practitioners. In order to develop a board that would be widely accepted by the practicing clinicians of that time, the AMA solicited the participation of representatives from the American Psychiatric Association (APA) and the American Neurological Association (ANA) in discussions regarding the development of a unified examining board. In recommending a unified board, the AMA made clear its position that the content and practice of psychiatry and neurology overlapped substantially, and that both fields would be best served by an examining board that acknowledged their similarity. Ongoing tensions between the fields with respect to public legitimacy and scientific dominance limited the ability of the participating psychiatrists and neurologists to work cooperatively on this task. Although the AMA representatives initiating these discussions were self-described neuropsychiatrists, the representatives from the APA and the ANA elected not to recognize neuropsychiatry as a field of practice. Instead, Hollender (1991) [13] notes that the APA and ANA representatives elected first to demarcate sharply the differences in training and certification between psychiatry and neurology and then argued over the order

in which the two fields should be represented in the Board’s official title. Despite their posturing, the ABPN administered the same examination to candidates in both areas for the first decade of its operations. Over time, and as a consequence of training differences driven by the ABPN guidelines, the examination became increasingly focused on the candidate’s field of training. Nonetheless, 25% or more of the board examination content for each remains based on the other specialty’s material. This continues to acknowledge, albeit implicitly, that much of what constitutes neurology and psychiatry is scientifically inseparable and the practice of both specialties requires a transdisciplinary knowledge base and skill set. Nonetheless, the creation of ABPN left a legacy of an uneasy, if not occasionally hostile, alliance between psychiatrists and neurologists. Its creation also effected an apparent amnesia within these specialties for the historical and philosophical background that resulted in their regulation under a combined board. As noted earlier in this chapter, thought leaders in both fields occasionally call for reunification of psychiatry and neurology [3–5]. However, attempts to unite these fields are met with skepticism, at best, outside of a small number of academic and private institutions. Similarly, requests to the ABPN for the establishment of Added Qualifications in Neuropsychiatry have not thus far been successful.

Behavioral Neurology & Neuropsychiatry The contemporary subspecialties of behavioral neurology and neuropsychiatry have taken separate but converging paths to their current positions. Behavioral neurology is widely held to have begun with the work of Norman Geschwind in the midtwentieth century [14], who established a fellowship program at the Boston Veterans Administration Hospital while rising to the position of James Jackson Putnam Professor of Neurology at Harvard Medical School. Geschwind reintroduced and expanded on observations of brain lesions and behavioral disturbances made by neurologists such as Paul Broca, Karl Wernicke, Hugo Liepmann, Hienrich Lissauer, and Jules Dejerine in the previous century, and wrote a seminal paper on disconnection syndromes in 1965 that inspired a generation of research on brain–behavior relationships [15, 16]. With this foundation, behavioral neurology firmly took

3


hold; the lesion method of studying brain–behavior relationships proved highly productive [17] and the idea of distributed neural networks subserving cognition appeared as a major organizing principle in the field [18]. Neuropsychiatry, on the other hand, flourished first as a discipline in the late nineteenth century as discussed above, but then fell into relative obscurity during the mid-twentieth century. Psychoanalytic theory and practice dominated psychiatry for the first half of the twentieth century, especially in the USA where psychoanalysts fleeing Hitler’s Germany exerted much influence [19], and neurobiological correlates of behavior were relatively neglected. This situation began to change with the introduction of modern psychopharmacology in the 1950s that ushered in the field of biological psychiatry – a powerful stimulus for adopting a neurobiological model of mental function. In this setting, a neuropsychiatric approach to patient care began to reemerge and steadily gain momentum as physicians increasingly appreciated the neurologic bases of psychiatric disease and the psychiatric aspects of neurologic disease [19–22]. The organization of a professional association for neuropsychiatrists and the development of neuropsychiatry as a medical subspecialty derive from the efforts of many physicians, most notably Jeffrey L. Cummings, Randall B. Schiffer, and Stuart C. Yudofsky. Two other factors also fueled the development of both behavioral neurology and neuropsychiatry; the rapid growth of neuropsychology, arising in large part from the influence of Alexander R. Luria in mid-century Russia [23], and the spectacular advances of neuroimaging from the 1970s onward that increasingly enabled precise structural [24] and later functional imaging of the brain [25]. These fields contributed cognitive measures and neuroradiologic techniques for detailed study of brain–behavior relationships that substantially augmented existing methods of clinical–pathologic correlation. With the advent of the twenty-first century, clinical neuroscience is flourishing, leading to thoughtful commentary advocating the closing, or at least narrowing, of the “great divide” that has existed between neurology and psychiatry [3].

Philosophical antecedents to Behavioral Neurology & Neuropsychiatry The fluctuating relationship between the previously separate subspecialties of behavioral neurology

4

and neuropsychiatry derives principally from the challenges of investigating the human mind and its disorders in a medical context. At the root of this conundrum is the ancient philosophical question of the relation of mind and body, recast in the modern formulation of the mind–brain debate. What is the source of human consciousness – an ineffable, immaterial mind that exists apart from any physical structure, or the collection of nerve cells and chemicals known as the brain that accounts for all behavior? To many, it is inconceivable that the “gray and white gook” inside the skull could actually be conscious [26], and thus responsible for such cherished capacities as intelligence, creativity, and altruism. The towering influence of the seventeenth-century dualist philosopher Rene Descartes [27] continues today in our society – and even to some extent in medicine. The era in which psychoanalysis dominated psychiatric practice created an intellectual environment in medicine that was sympathetic to dualistic thinking despite Freud’s early career as a neurologist. While not avowedly dualistic in the philosophical sense, mainstream psychiatry for much of the twentieth century contrasted “functional” with “organic” disorders as a way of establishing a group of mental disorders in which brain structure and function were essentially irrelevant [3]. Psychiatry focused primarily on symptoms rather than signs, and as the metaphors of psychoanalytic theory captured public and professional imagination, the use of neurological examination and laboratory data in studying behavior diminished [3]. Simultaneously, neurology chose to care for those patients in whom structural brain disease could be detected, eschewing the unavoidable subjectivity of behavioral analysis in favor of the “hard” scientific data of the neurological examination, cerebrospinal fluid analysis, electroencephalography, and neuropathology [3]. As the influence of psychoanalysis began to recede in the mid-twentieth century, strong proponents of mind–brain unity questioned the authority of Descartes [28–30], and the dichotomy of mind versus brain began to lose ground in medical thinking. Neurology and psychiatry gradually became more inclined to share the view that the brain is central to human behavior, and by 1987 the organic–functional distinction was explicitly discouraged by the influential Diagnostic and Statistical Manual of Mental Disorders [31]. Nonetheless, vestiges of philosophical dualism persist in medicine, in part because the


study of behavior and the vexing emotional disorders commonly considered “psychiatric” are so complex. To cite a clinical example, the floridly abnormal behavior of many psychotic patients with normal conventional clinical neuroimaging and laboratory studies seems to some critics to undermine arguments asserting that this illness is neurobiologically based – how can such abnormal behavior derive from a person whose brain is structurally normal? Perhaps it is not a surprise that lingering dualism sometimes still impacts clinical thinking [32]. Modern neuroscience notwithstanding, the fact remains that disorders of behavior are the most challenging and among the most difficult to describe objectively. The unifying foundation of BN&NP, however, is the shared philosophical position that brain and behavior are inseparable [2]. The organic–functional dichotomy cannot be maintained because all thought, emotion, and behavior are brain-based. Although traditionally trained behavioral neurologists tend to focus on brain disorders in which structural pathology is in some way demonstrable, and neuropsychiatrists hailing from general psychiatry are comfortable conceptualizing mental disorders as stemming from neurochemical deficits, all agree that higher functions – normal or abnormal – originate as neural events that involve the macro- or microstructure of the brain in the process of subserving mental operations. Thus, whereas the assessment and treatment of a person with Broca’s aphasia from an observable left inferior frontal lobe infarct differs markedly from that of an acutely psychotic schizophrenic individual with normal conventional neuroimaging, the underlying principle in dealing with both patients is the same: both syndromes involve an alteration of brain–behavior relationships that requires a thorough understanding of how the brain operates at all levels of analysis. The triage of patients into neurologic versus psychiatric settings should depend only on the evaluation and services required – such as a neurologic intensive care unit for emergent stroke treatment, or a locked psychiatric unit for acute agitated psychosis – and not on archaic notions of whether a patient has “organic” or “functional” disease. Individual temperament and interest will naturally influence the kind of clinical setting in which a physician may prefer to work, but the common principle that all patients in these settings have disorders of the brain must be honored if patient care is to be optimal and intellectual progress facilitated. Indeed, we

have described an integrated practice of BN&NP that fosters excellence in patient care, education, and research within a setting that explicitly avoids the arbitrary divisions that have often hampered collaboration between neurology and psychiatry [33].

The state of the field The prospect of behavioral neurology and neuropsychiatry drawing together finds considerable support in academia. Textbooks of behavioral neurology [34– 36] and neuropsychiatry [8, 37, 38] have proliferated in recent years. Annual scholarly meetings are held conjointly by the Society for Behavioral and Cognitive Neurology and the American Neuropsychiatric Association in order to disseminate new research findings and educate practitioners. Structural and functional neuroimaging, neuroanatomy, neuropsychology, neuropharmacology, neuropathology, clinical neurophysiology, and genetics are all receiving much-needed attention. Moreover, in a remarkable development, topics previously regarded as unapproachable for neuroscientists are being vigorously considered; accounts of the neural correlates of consciousness [39], ethics [40], and creativity [41], for example, are now regular reading for devotees of brain–behavior relationships. However, postgraduate training in neurology or psychiatry exerts a powerful socializing force, and fellowship experiences in the higher functions of the brain modify but do not undo these fundamental affiliations. The development of an integrated core curriculum for fellowship training [2] and the development of the UCNS fellowship accreditation processes may create a structure within which a professional identity and practice as a subspecialist in BN&NP becomes possible. This comprehensive curriculum is derived from the traditions of neurology, psychiatry, behavioral neurology, and neuropsychiatry, while drawing heavily from neuroanatomy, neurophysiology, neuroimaging, neuropsychology, neuropharmacology, and internal medicine. A range of supplementary topics is also included, including neurosurgery, neuropathology, neurorehabilitation, neurogenetics, sleep medicine, forensic psychiatry, epidemiology, and public policy. Fellowship training in this subspecialty requires the participation of faculty from both the psychiatry and the neurology departments at each institution, and requires that these faculties possess expertise in this area and the ability to provide clinical training in a transdisciplinary manner. A minimum of one year is

5


required for fellowship training in BN&NP, and more time can be arranged as indicated by the individual fellow’s interests and the availability of program resources. Although many fellowship trainees may work in academic settings upon completing their training, community practice opportunities are emerging rapidly. Among these are: (1) the need for physicians prepared to care for patients with complex, multifactorial disorders of behavior that call upon the expertise of both neurology and psychiatry; (2) the aging of the population in industrialized countries that will render more people at risk for common late-life neurodegenerative disorders such as Alzheimer’s disease (AD); (3) the continuing epidemic of traumatic brain injury (TBI) in times of peace as well as in war; and (4) astonishing advances in diagnosis and treatment of many neuropsychiatric disorders that formerly had mysterious etiologies, limited therapeutic options, and relatively poor prognoses. Certification in BN&NP will enhance opportunities by signifying special competence in these disciplines.

Future prospects While gazing ahead is always fraught with uncertainty, some speculations about where the future will lead are warranted as this combined subspecialty moves ahead. One prediction likely to be met is that the intellectual vigor of these fields will stimulate much continued discussion and steady development of concepts. A major goal of these two disciplines is the integration of structural and molecular paradigms in constructing a modern synthesis of brain–behavior relationships. As discussed above, those who think about structural brain lesions can learn from those whose emphasis is on abnormal neurotransmission, and surely the converse is true as well. How does the intricate neurochemistry of the brain map onto the familiar gyri, tracts, and nuclei to enrich our knowledge of distributed neural networks? Such a portrait will enable increasing sophistication of medical and surgical therapy based on manipulation of neuroanatomically localized neurotransmitter systems. A complete understanding of the brain as the organ of the mind requires the unification of knowledge from both traditions. This approach may plausibly lead to the reintegration of Freudian thinking into the mainstream of medicine. Freud himself harbored the belief

6

that the phenomena of psychoanalytic theory – the unconscious, the id, ego, and superego, repression, transference, dream analysis, and the like – would someday find correlates in the brain, and that a neurobiological model of the mind would develop [10]. Such a synthesis may become more feasible with modern investigative techniques [42]. Subspecialists in BN&NP do not see a need to vindicate Freudianism – indeed, difficulty establishing the neural basis of psychoanalytic theory and its clinical efficacy has been a major source of criticism – but the notion that complex psychological processes have a basis in brain function is fundamental. Freudian concepts may not readily be seen to correlate with brain structures as our understanding increases; however, the behaviors Freud observed in his patients – like any other – should result from the operations of neural systems. As Geschwind aptly wrote: “It must be realized that every behavior has an anatomy” [43]. The ultimate goal is to understand how the brain mediates behavior, whether investigators use a model of structural cortical damage affecting language, or examine altered neurotransmitter systems that influence personality. A topic sure to garner much attention is the continued application of functional imaging technology to understanding brain–behavior relationships. The lesion method has a time-honored tradition in behavioral neurology, and will continue to flourish, but what of functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and the like? Will these tools add significantly to the understanding of brain and behavior, or will they turn out to be no more than neo-phrenological instruments producing appealing but easily misinterpreted images? The impressive technique of fMRI has become the most promising of these modalities, about which thousands of research papers are now published every year, but fMRI remains limited by the extraordinary complexity of the brain’s functional organization [44]. SPECT scanning has the advantage of being readily available, but has proven disappointing when applied to clinical disorders [45]. At the same time, much excitement attends the advances of structural neuroimaging, which is now disclosing details of neuroanatomy and neuropathology as never before. Exploiting the remarkable success of MRI, investigators are pursuing more detailed volumetric quantitation of cerebral structures with voxelbased morphometry [46], and measurement of the


chemical composition of brain regions has become possible with magnetic resonance spectroscopy [47]. The study of white matter, long relegated to the background of cognitive neuroscience as the cerebral cortex has dominated thinking and research, will now be feasible with diffusion tensor imaging [48], which is generating elegant depictions of white matter tracts in health and disease. White matter disorders in general will stimulate wide-ranging investigation as the importance of white matter for human behavior is increasingly appreciated [49, 50]. All of these techniques create a context in which the study of the structure of distributed neural networks can be integrated with an understanding of their functional connectivity and role in neurobehavioral health and disease. Advances in genetics that are occurring at a rapid pace will also enhance understanding and clinical diagnosis of neurobehavioral disorders. Testing for autosomal dominant transmission in Huntington’s disease is a straightforward and well-known example of how genetic analysis can be applied clinically [51], and the list of genetic diseases in which such testing can be considered is quickly growing. Genetic testing for AD, while only exceptionally providing definitive results for patients and families, is gradually improving [52], and may be able to identify presymptomatic individuals in whom dementia can someday be prevented. While these developments are encouraging, the reality that genetic diseases are, presently, for the most part irreversible provides a strong impetus for further study of the pathogenesis of neurogenetic disorders. Nevertheless, treatment of patients with disorders of all types affecting behavior will surely come to be a major topic in the coming years. Many of the treatment options for patients with these disorders are based on scanty evidence, and convincing clinical trials are sorely needed. Randomized controlled trials for treatment of AD have been familiar to clinicians for decades, and serve as a model for large-scale investigation of treatments for a host of cognitive disorders. Traumatic brain injury occupies a major portion of the practice of many subspecialists in BN&NP and additional studies are needed to better define the best methods of neurorehabilitation. More study of neurosurgical interventions, such as for the treatment of neoplasms and hydrocephalus, will be helpful. More controversially, the oft-reviled area of psychosurgery may merit reconsideration as a treatment option for those with intractable and devastating disorders, particularly as modern surgical techniques permit

more precise procedures and research advances allow accurate evaluation of safety and efficacy [53]. The assessment of the efficacy of psychotherapy – recognized three decades ago to be a neurobiological phenomenon in which the brain undergoes synaptic change as in any other kind of learning [54] – is now feasible by functional neuroimaging [55], and is being further pursued. Evolving new modalities such as embryonic stem cell transplantation [56], gene therapy [57], deep brain stimulation [58], and transcranial magnetic stimulation [59] hold forth much promise. In the foreseeable future, basic science advances may disclose strategies for enhancing synaptic plasticity [60], stimulating remyelination [61], and promoting neurogenesis [62] – even in the brains of older adults. Lastly, a host of issues with public policy implications spring directly from the advances of BN&NP. Some examples will prove illustrative. What are the sociopolitical implications of the study of aggression, violence, and war as neurally based behaviors [63]? Which individuals with brain disorders should be held accountable for criminal behavior and punished, and which should be exonerated and treated as patients? How is the question of free will to be addressed in light of modern technology? What are the implications for individuals who will be found to have genetic diseases for which no cure is available? Will new treatments for cognitive disorders involving the activation of endogenous or surgically implanted stem cells produce cures for dreaded diseases, or might they possibly result in grossly aberrant behavior from novel and unpredictable neuronal connections? What are the implications of detecting residual cerebral activity with fMRI in patients diagnosed with vegetative or minimally conscious state? While not presuming to answer such imposing questions, subspecialists in BN&NP are ideally suited to illuminate the issues and inform public discourse so that society can more rationally adopt meaningful solutions.

Whither Behavioral Neurology & Neuropsychiatry? As this book goes to press, several clinical neuroscientific principles enjoy wide support: the constructs of mindless brain and brainless mind are outdated, the descriptors organic and functional are no longer meaningful, and human behavior is usefully conceptualized as no more, or less, than the product of brain activity. From these statements, hard won

7


through much effort over many years, all physicians dealing with neurobehavioral or neuropsychiatric disorders can legitimately aspire to be both objective and humanistic. Behavior is a measurable neural phenomenon, but its understanding also requires an exceptional degree of interpersonal sensitivity and interpretive skill. Nowhere is the art of medicine more critical – objective data such as mental status test scores and neuroimaging findings must be adroitly combined with subjective assessment of the person suffering with the disorder. The notion that only those in neurology can lay claim to neuroscience, while only those in psychiatry can appreciate the whole person, is confining, inaccurate, and unproductive. But there remains the issue of what exactly is the subject matter of BN&NP. A reasonable listing of the major disorders currently regarded as falling within the scope of this subspecialty includes the focal neurobehavioral syndromes (e.g., aphasia, apathy, orbitofrontal syndrome); delirium, dementia (e.g., AD), and major primary psychiatric disorders; neurological conditions with prominent cognitive, emotional, and behavioral features such as movement disorders, stroke, epilepsy, multiple sclerosis, and TBI [2]. Others can be added to or subtracted from this list, and physicians will naturally gravitate toward those disorders for which their training and inclination render them most suitable. Many subspecialists in BN&NP with primary training in neurology assume the care of dementia or stroke with focal syndromes, for example, while those with primary training in psychiatry take on schizophrenia, depression, obsessive-compulsive disorder, and the psychiatric sequelae of neurological conditions. Traumatic brain injury appears to be a special case, as subspecialists in BN&NP are increasingly committed to this common problem [64, 65]. As knowledge of brain–behavior relationships grows, these areas can be expected to evolve concomitantly, and with them practice patterns as well. Despite the enthusiasm generated by the development of BN&NP as a subspecialty [1], uncertainty persists about the future organization and direction of the combined field. Will a single name for this discipline come to replace the combined moniker? If so, what should it be? Perhaps “cognitive neuroscience” would suffice, but does this adequately capture the disorders traditionally considered to be “emotional?” An alternative is “medical neuroscience,” which serves to distinguish it from the surgical neurosciences but its

8

referents may be too broad. Will neurology and psychiatry residences modify their curricula to reflect a converging interest in brain–behavior relationships? Will there be combined clinical services where “neurologic” and “psychiatric” patients with cognitive disorders are evaluated and treated as a single group with altered brain function? Many influential opinions will doubtlessly line up on all sides of such questions. Whether some overarching category comes to encompass all the work in these fields remains to be disclosed, and we do not presume to make a prediction. For now, we believe this evolving alliance stands as a productive approach to bridge the gaps between neurology and psychiatry, body and mind, physical and mental. Whatever one’s perspective on the status of the subspecialty, continuing advances in understanding neuroscience as applied to patient care, education, and research demand attention. Given the powerful recent findings of neuroscience, adopting this attitude in clinical medicine seems eminently appropriate. Our attitude has always been that getting the work done is far more important than debating what to call ourselves.

About this book We have noted, as have many before us, that neurology and psychiatry suffer needlessly from arbitrary interdisciplinary barriers, maintained by the power of tradition, that often impede intellectual progress. While differences between these fields clearly exist and will not soon disappear, their commonalities promise to further understanding of brain–behavior relationships as never before. BN&NP represents the flagship subspecialty that aims to find and develop the intellectual common ground that beckons so strongly to students of human behavior. The mind and the brain are but two constructs describing the same entity, and medicine and society are best served by acknowledging this fundamental principle. This book reflects our view of the clinical neuroscience of behavior in the context of patients coping with a host of brain disorders, be they neurologic or psychiatric. Intended primarily for physicians and investigators entering the field or early in their careers, we hope the book can both inform and inspire its readers. Those farther along in their careers may also find information of value in these pages. We hope this book builds upon and extends the work of many previous volumes from which we have learned [8, 34–38] in a


comprehensive attempt to draw behavioral neurology and neuropsychiatry closer. We present this book in the spirit of promoting this effort for the good of our patients, our profession, and our world. The structure of the book follows the core curriculum for fellowship training discussed above [2]. Included are major sections on structural and functional neuroanatomy, assessment, and treatments, reflecting the primary topic areas for fellowship training [2]. The book is intended to convey principles of BN&NP rather than to present an exhaustive account of disease states. Accordingly, condition-specific chapters are not presented. Instead, disorders will be introduced when they serve to illustrate the principles under consideration. Readers may recognize points made in our previous work that have served to build a foundation for this text [66, 67], but this book offers something new: our combined approach to this intriguing area, including the expert contributions of many colleagues who have graciously devoted their time and effort to this project, that we hope will serve as a model for productive transdisciplinary collaboration.

12. Freud S, Strachey J, Freud A et al. The Standard Edition of the Complete Psychological Works of Sigmund Freud. London: Hogarth Press; 1953.

References

17. Damasio AR. Behavioral neurology – research and practice. Semin Neurol. 1984;4(2):117–19.

1. Silver JM. Behavioral neurology and neuropsychiatry is a subspecialty. J Neuropsychiatry Clin Neurosci. 2006;18(2):146–8. 2. Arciniegas DB, Kaufer DI, Joint Advisory Committee on subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13. 3. Price BH, Adams RD, Coyle JT. Neurology and psychiatry: closing the great divide. Neurology 2000;54(1):8–14. 4. Martin JB. The integration of neurology, psychiatry, and neuroscience in the 21st century. Am J Psychiatry 2002;159(5):695–704. 5. Yudofsky SC, Hales RE. Neuropsychiatry and the future of psychiatry and neurology. Am J Psychiatry 2002;159(8):1261–4. 6. Sachdev PS. Whither neuropsychiatry? J Neuropsychiatry Clin Neurosci. 2005;17(2):140–4. 7. Pies R. Why psychiatry and neurology cannot simply merge. J Neuropsychiatry Clin Neurosci. 2005;17(3): 304–9. 8. Cummings JL, Mega MS. Neuropsychiatry and Behavioral Neuroscience. Oxford: Oxford University Press; 2003.

9. Arciniegas DB. Neuropsychiatry – an introduction and brief history. In Arciniegas DB, Beresford TP, editors. Neuropsychiatry: An Introductory Approach. Cambridge: Cambridge University Press; 2001, pp. 3–12. 10. Encyclopaedia Britannica Inc., University of Chicago, Hutchins RM. Great Books of the Western World. Founders’ edition. Chicago, IL: W. Benton; 1952. 11. Griesinger W. Mental Pathology and Therapeutics. 2nd edition. New York, NY: William Wood & Company; 1882.

13. Hollender MH. American Board of Psychiatry and Neurology: The First Fifty Years. Deerfield, IL: American Board of Psychiatry and Neurology; 1991. 14. Schachter SC, Devinsky O. Behavioral Neurology and the Legacy of Norman Geschwind. Philadelphia, PA: Lippincott-Raven; 1997. 15. Geschwind N. Disconnexion syndromes in animals and man. I. Brain 1965;88(2):237–94. 16. Geschwind N. Disconnexion syndromes in animals and man II. Brain 1965;88(3):585–644.

18. Mesulam M (editor). Behavioral neuroanatomy. Large-scale neural networks, association cortex, frontal systems, the limbic system and hemispheric specializations. In Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 1–120. 19. Caine ED, Joynt RJ. Neuropsychiatry . . . again. Arch Neurol. 1986;43(4):325–7. 20. Yudofsky SC, Hales RE. The reemergence of neuropsychiatry: definition and direction. J Neuropsychiatry Clin Neurosci. 1989;1(1):1–6. 21. Trimble MR. Neuropsychiatry or behavioral neurology. Neuropsychiatry Neuropsychol Behav Neurol. 1993;6(1):60–4. 22. Benson DF. Neuropsychiatry and behavioral neurology: past, present, and future. J Neuropsychiatry Clin Neurosci. 1996;8(3):351–7. 23. Luria AR. Higher Cortical Functions in Man. 2nd edition. New York, NY: Basic Books; 1980. 24. Turner R. Magnetic resonance imaging of brain function. Ann Neurol. 1994;35(6):637–8. 25. Raichle ME. Visualizing the mind. Sci Am. 1994; 270(4):58–64. 26. Searle JR. Minds, Brains, and Science. Cambridge, MA: Harvard University Press; 1984.

9


27. Descartes R. Discourse on Method. 2nd (rev.) edition. New York, NY: Liberal Arts Press; 1956. 28. Damasio AR. Descartes’ error and the future of human life. Sci Am. 1994;271(4):144.

44. Logothetis NK. What we can do and what we cannot do with fMRI. Nature 2008;453(7197):869–78.

29. Churchland PS. Neurophilosophy: Toward a Unified Science of the Mind–Brain. Cambridge, MA: MIT Press; 1986.

45. Wortzel HS, Filley CM, Anderson CA, Oster T, Arciniegas DB. Forensic applications of cerebral single photon emission computed tomography in mild traumatic brain injury. J Am Acad Psychiatry Law 2008;36(3):310–22.

30. Dennett DC. Consciousness Explained. 1st edition. Boston, MA: Little, Brown and Co.; 1991. 31. American Psychiatric Association. Work Group to Revise DSM–III. Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised: DSM–III–R. Washington, DC: American Psychiatric Association; 1987. 32. Miresco MJ, Kirmayer LJ. The persistence of mind–brain dualism in psychiatric reasoning about clinical scenarios. Am J Psychiatry 2006;163(5): 913–18. 33. Filley CM, Arciniegas DB, Wood GV et al. Geriatric treatment center: a contemporary model for collaboration between psychiatry and neurology. J Neuropsychiatry Clin Neurosci. 2002;14(3):344–50. 34. Devinsky O. Behavioral Neurology: 100 Maxims. 1st edition. New York, NY: Mosby-Year Book; 1992. 35. Feinberg TE, Farah MJ. Behavioral Neurology and Neuropsychology. New York, NY: McGraw-Hill; 1997. 36. Rizzo M, Eslinger PJ. Principles and Practice of Behavioral Neurology and Neuropsychology. Philadelphia, PA: W.B. Saunders; 2004. 37. Yudofsky SC, Hales RE. The American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neurosciences. 4th edition. Washington, DC: American Psychiatric Publishing; 2002. 38. Schiffer RB, Rao SM, Fogel BS. Neuropsychiatry. 2nd edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2003. 39. Crick F. The Astonishing Hypothesis: The Scientific Search for the Soul. New York, NY: Scribner and Maxwell Macmillan International; 1994. 40. Gazzaniga MS. The Ethical Brain. New York, NY: Dana Press; 2005. 41. Heilman KM. Creativity and the Brain. New York, NY: Psychology Press; 2005. 42. Carhart-Harris RL, Mayberg HS, Malizia AL, Nutt D. Mourning and melancholia revisited: correspondences between principles of Freudian metapsychology and empirical findings in neuropsychiatry. Ann Gen Psychiatry 2008;7:9. 43. Geschwind N. The borderland of neurology and psychiatry: some common misconceptions. In Benson DF, Blumer D, editors. Psychiatric Aspects of

10

Neurological Disease. New York, NY: Grune & Stratton; 1975, pp. 1–8.

46. Ashburner J, Friston KJ. Why voxel-based morphometry should be used. Neuroimage 2001; 14(6):1238–43. 47. Ross B, Michaelis T. Clinical applications of magnetic resonance spectroscopy. Magn Reson Q. 1994;10(4): 191–247. 48. Assaf Y, Pasternak O. Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review. J Mol Neurosci. 2008;34(1):51–61. 49. Filley CM. The Behavioral Neurology of White Matter. 2nd edition. New York, NY: Oxford University Press; 2012. 50. Schmahmann JD, Pandya DN. Fiber Pathways of the Brain. Oxford: Oxford University Press; 2006. 51. Myers RH. Huntington’s disease genetics. NeuroRx. 2004;1(2):255–62. 52. Howard KL, Filley CM. Advances in genetic testing for Alzheimer’s disease. Rev Neurol Dis. 2009;6(1): 26–32. 53. Anderson CA, Arciniegas DB. Neurosurgical interventions for neuropsychiatric syndromes. Curr Psychiatry Rep. 2004;6(5):355–63. 54. Kandel ER. Psychotherapy and the single synapse. The impact of psychiatric thought on neurobiologic research. N Engl J Med. 1979;301(19): 1028–37. 55. Linden DE. How psychotherapy changes the brain – the contribution of functional neuroimaging. Mol Psychiatry 2006;11(6):528–38. 56. Khanna A, Shin S, Rao MS. Stem cells for the treatment of neurological disorders. CNS Neurol Disord Drug Targets 2008;7(1):98–109. 57. Okada T, Shimazaki K, Nomoto T et al. Adeno-associated viral vector-mediated gene therapy of ischemia-induced neuronal death. Methods Enzymol 2002;346:378–93. 58. Schiff ND, Fins JJ. Deep brain stimulation and cognition: moving from animal to patient. Curr Opin Neurol 2007;20(6):638–42. 59. Rossini PM, Rossi S. Transcranial magnetic stimulation: diagnostic, therapeutic, and research potential. Neurology 2007;68(7):484–8.


60. Wieloch T, Nikolich K. Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol. 2006;16(3):258–64. 61. Franklin RJ, Kotter MR. The biology of CNS remyelination: the key to therapeutic advances. J Neurol. 2008;255(Suppl. 1):19–25. 62. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008;132(4):645–60. 63. Filley CM, Price BH, Nell V et al. Toward an understanding of violence: neurobehavioral aspects of unwarranted physical aggression: Aspen Neurobehavioral Conference consensus statement. Neuropsychiatry Neuropsychol Behav Neurol. 2001; 14(1):1–14.

64. Kelly JP, Nichols JS, Filley CM et al. Concussion in sports. Guidelines for the prevention of catastrophic outcome. J Am Med Assoc. 1991;266(20): 2867–9. 65. Arciniegas D, Adler L, Topkoff J et al. Attention and memory dysfunction after traumatic brain injury: cholinergic mechanisms, sensory gating, and a hypothesis for further investigation. Brain Inj. 1999;13(1):1–13. 66. Filley CM. Neurobehavioral Anatomy. 3rd edition. Boulder, CO: University Press of Colorado; 2011. 67. Arciniegas DB, Beresford TP. Neuropsychiatry: An Introductory Approach. Cambridge: Cambridge University Press; 2001.

11

Section I

Structural and Functional Neuroanatomy

Chapter

Behavioral neuroanatomy

2

C. Alan Anderson, David B. Arciniegas, Deborah A. Hall, and Christopher M. Filley

Understanding human behavior in health and disease begins with structural and functional neuroanatomy. The two major divisions of the human nervous system are the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and the spinal cord. The PNS includes the cranial and spinal nerves, the distal branches of which form efferent and afferent connections carrying information between the CNS and the entire body. The autonomic nervous system includes components of both the CNS and the PNS, and serves to regulate many aspects of visceral function that provide homeostatic balance and the capacity to adjust to the ever-changing demands of both internal and environmental needs. There are approximately 100 billion neurons in the human brain, and these are supported by, and interact with, as many as ten times that number of glial cells [1]. Each neuron makes contact with thousands of other neurons as well as with a large number of glial cells. The vast majority of brain neurons are classified as interneurons, which are thought to participate in the processing of information rather than with sensory input or motor output. This enormous degree of connectivity is the basis of the computational power that produces human arousal, awareness, consciousness, and behavior. While our knowledge of the full complement of mechanisms by which the brain produces consciousness and other neuropsychiatric functions remains incomplete, it is clear that all aspects of human behavior are firmly grounded in brain function. From the meticulous dissections performed by generations of neuroanatomists through the information obtained through advanced functional imaging techniques, our knowledge and understanding of the structure of the

brain as well as the functional relationship between its components has advanced substantially. In this chapter, we focus on those aspects of structural and functional neuroanatomy that are most relevant to Behavioral Neurology & Neuropsychiatry (BN&NP). We consider the general structure of the brain from the brainstem through the cerebral cortex (Figure 2.1), including a review of white matter anatomy, the cerebral vasculature, and the ventricular system. With this background, we then discuss the interactions of cortical, subcortical, and white matter regions, and cerebral lateralization. This approach leads us to the general concept of distributed neural networks, which will serve as a comprehensive organizing principle for understanding the neurobiology of cognition, emotion, and behavior. In the chapters that follow, in-depth consideration is given to several aspects of specific brain structures and functional systems. For those interested in a more detailed review of general and behavioral neuroanatomy, several excellent resources are available [2–5]. As a general principle, normal function at any level depends in part on normal function at lower levels. The CNS includes (in ascending order) the spinal cord, brainstem, cerebellum, hypothalamus, thalamus, and the paired cerebral hemispheres. The neuroanatomy relevant to BN&NP therefore begins with the brainstem.

Brainstem and cerebellum The brainstem comprises the medulla oblongata (myelencephalon), pons and cerebellum (metencephalon), and midbrain (mesencephalon). Each of these areas and the neurobehaviorally salient structures they


12

Chapter 2: Behavioral neuroanatomy

(A)

(B)

(C)

(D)

(E)

Figure 2.1. General structure of the brain (A). Major areas considered in this chapter include the brainstem and cerebellum (B), diencephalon (C), limbic and paralimbic structures (D), basal ganglia (see Figure 2.5), and cerebral cortex (E). This figure is presented in color in the color plate section.

contain are reviewed briefly in this section. The reticular formation (which is contributed to by several brainstem substructures) and the cranial nerves (some, but not all, of which are located within the brainstem) also are discussed in this section.

Myelencephalon The medulla oblongata is the most caudal part of the brain, forming the junction of the brain with the spinal cord [6]. Anteriorly the medulla lies against the basilar portion of the occipital bone and posteriorly it abuts the ventral surface of the cerebellum. Descending pyramidal (motor) tracts and ascending spinothalamic tracts (pain and temperature sensation) decussate as they pass through the medulla. Cranial nerve (CN) nuclei located in the medulla include the inferior portions of CN V (trigeminal), and VIII (vestibulocochlear), IX (glossopharyngeal), X (vagus), XI (accessory), and XII (hypoglossal). The medulla also contains the nuclei for a variety of modulatory ascending and descending pathways including serotonergic, adrenocorticotropic, ␤-endorphin, melanocyte stimulating hormone, and adrenergic fibers. These systems are

involved in modulating ascending and descending tracts, and also provide input into the reticular activating system more rostrally.

Metencephalon Pons The word pons means “bridge” in Latin, which is appropriate given the extensive motor, sensory, and other pathways between the cerebrum, the cerebellum, and the spinal cord that pass through it. The pons has extensive connections with the cerebellum, forming bundles of transversely oriented fibers that link pontine nuclei and the cerebellum via the middle cerebellar peduncles. The ventral surface of the pons abuts the occipital bone and its dorsal surface lies along the ventral surface of the cerebellum. The pons contains the nuclei for CN VI (abducens), VII (facial), and the superior portions of the nuclei for CN V (trigeminal), and VIII (vestibulocochlear). The pons also contains the locus ceruleus, a noradrenergic nucleus with diffuse projections throughout the cerebral hemispheres [7], and serotonergic nuclei (the pontine raphe nuclei) providing modulatory input into the reticular formation [6, 8].

13

Section I: Structural and Functional Neuroanatomy

14

Cerebellum

Mesencephalon

The cerebellum also is a portion of the metencephalon. Together with the brainstem, the cerebellum occupies the posterior cranial fossa and is separated from the cerebrum rostrally by the tentorium cerebelli. For practical purposes, the cerebellum has three major functional subdivisions [3]. The first is the archicerebellum (flocculonodular lobe). It is the oldest part of the cerebellum phylogenetically, which includes the nodules and flocculi of the vermis, and connects extensively to the vestibular system. The second subdivision is the paleocerebellum, which includes portions of the anterior lobe, the lingula, the central lobule and portions of the lower vermis, the paraflocculus, and the cerebellar tonsils. This subdivision of the cerebellum receives its principal input from spinocerebellar pathways. The third subdivision is the neocerebellum, which includes the remainder of the vermis and the cerebellar hemispheres. It is the youngest subdivision phylogenetically and the largest. The neocerebellum receives its major input from the pons, and is involved in the maintenance of posture, motor coordination, and the cerebellar contributions to higher cognitive and emotional processing. Dense bidirectional cerebellar connections to the brainstem are carried by the paired peduncles to the medulla (inferior cerebellar peduncles or corpora restiformia), the pons (middle cerebellar peduncles or brachia pontis), and the midbrain (superior cerebellar peduncles or brachia conjunctiva). The surface of the cerebellum forms small parallel convolutions called folia, separated by fissures into various subdivisions. At a microscopic level, the cerebellar cortex is divided into three layers: the molecular layer, the Purkinje cell layer, and the granular layer. The Purkinje cells provide the output of the cortical layers to deeper cerebellar nuclei. Input into the cerebellum includes afferent fibers originating in the cerebral cortex, the brainstem (including the reticular formation, vestibular nuclei, and inferior olive), and the spinal cord [3]. The cerebellum possesses tremendous processing power and plays a role in the integration of motor and sensory information coordinating movement, posture, motor learning, memory, and other higher-order cognitive functions [9, 10]. The role of the cerebellum in cognitive and emotional function, as well as the neurobehavioral consequences of cerebellar injury or disease, is discussed in detail in Chapter 3.

The mesencephalon is the midbrain, and comprises the tectum (corpora quadrigemina), tegmentum, the cerebral peduncles, multiple nuclei and fasciculi, and the ventricular mesocoelia (or iter, which refers to the passage between the third and fourth ventricles, or the aqueduct of Sylvius). Ventral to the midbrain lies the basilar portion of the occipital bone, and the dorsal surface of the midbrain forms an isthmus between the cerebrum and the cerebellum. Rostrally, the midbrain adjoins the pons and caudally it adjoins the diencephalon. CN nuclei located in the midbrain include cranial nerves III (oculomotor), IV (trochlear), and the most superior portions of cranial nerves V and VIII. The midbrain connections with the cerebrum are carried by the cerebral peduncles, which contain the afferent and efferent connections between the spinal cord, brainstem, and the neocortex. The most dorsal portion of the midbrain is the tectum, with its quadrigeminal plate formed by the paired inferior and superior colliculi. The colliculi are relay stations for auditory information (the inferior colliculi) and visual information (the superior colliculi). The superior colliculi receive inputs from fibers of the optic tract, the occipital cortex, the inferior colliculi, and the spinal cord; these nuclei play a role in sensory processing and integration, reflex responses to visual threat including eye closure, aversive movements, and defensive posturing [3]. The upper brainstem, including the mesencephalon and upper pons, also contain several of the major ascending modulatory neurotransmitter nuclei (see Figures 2.2 and 2.3). Within the midbrain are the substantia nigra and the ventral tegmental area. The substantia nigra provides much of the dopaminergic innervation of the basal ganglia and plays a critical role in the modulation of “extrapyramidal” motor function. In addition, afferent fibers from dopaminergic nuclei in the ventral tegmental area project to the limbic system through the mesolimbic pathway, and to the neocortex via the mesocortical pathway. The midbrain also provides serotonergic innervation to the cerebrum from the dorsal raphe nucleus. Like other brainstem nuclei, these collections of serotonergic neurons extend caudally into the pons and medulla. Serotonergic afferent fibers from these nuclei project diffusely to the cerebral cortex and modulate arousal through the reticular activating system.


Figure 2.2. Modulatory neurotransmitter nuclei. A major input to the relay and reticular nuclei of the thalamus originates from cholinergic (ACh) cell groups in the upper pons, the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT). These inputs facilitate thalamocortical transmission. A second pathway activates the cerebral cortex to facilitate the processing of inputs from the thalamus; this arises from neurons in the monoaminergic cell groups, including the tuberomammillary nucleus (TMN) containing histamine (His), ventral periaqueductal gray (vPAG) dopamine-containing cell groups (DA), the dorsal and median raphe nuclei containing serotonin (5-HT), and the noradrenergic locus coeruleus (LC) containing noradrenaline (NA, also known as norepinephrine). This pathway also receives contributions from peptidergic neurons in the lateral hypothalamus (LH) containing orexin (ORX) or melanin-concentrating hormone (MCH), and from basal forebrain (BF) neurons that contain gamma-aminobutyric acid (GABA) or ACh. Reproduced from Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437(7063):1257–63, with permission from Nature Publishing Group.

The serotonergic system provides largely inhibitory modulation to the activity of frontal–subcortical and limbic circuits [8]. The pedunculopontine tegmental cholinergic nuclei (Ch5 and Ch6, commonly abbreviated as Ch5–6) also are located predominantly in the mesencephalon [11, 12]. This group of cells provides cholinergic innervation to the thalamus, cerebellum, globus pallidus, subthalamic nucleus, substantia nigra (pars compacta); medullary reticular formation and spinal cord; and, to a lesser extent, the striatum (caudate nucleus and putamen). The periaqueductal gray (PAG) is the gray matter surrounding the cerebral aqueduct in the midbrain tegmentum and is a behaviorally relevant structure.

Figure 2.3. Modulatory neurotransmitter nuclei. A schematic drawing to show the key projections of the ventrolateral preoptic nucleus (VLPO) to the main components of the ascending arousal system. It includes the monoaminergic cell groups such as the tuberomammillary nucleus (TMN), the A10 cell group, the raphe cell groups and the locus coeruleus (LC). It also innervates neurons in the lateral hypothalamus, including the perifornical (PeF) orexin (ORX) neurons, and interneurons in the cholinergic (ACh) cell groups, the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT). Additional abbreviations: 5-HT – serotonin; GABA – gamma-aminobutyric acid; Gal – galanin; NA – noradrenaline; His – histamine. Reproduced from Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437(7063):1257–63, with permission from Nature Publishing Group.

This collection of nuclei is connected to multiple cortical, limbic, diencephalic, and brainstem areas and also is connected extensively with the reticular formation. Functionally, the periaqueductal gray area is part of the limbic system, participating in the modulation of pain, arousal in the face of threat, emotional expression, sexual and feeding behaviors, and the regulation of metabolism. It may also have a role in modulating attention for salient internal and external stimuli related to survival, emotion, and memory [8].

Reticular formation The reticular formation is the collective term for a group of brainstem nuclei along with their projections that are spread throughout the brainstem from the medulla through the midbrain. Its name derives from its net-like organization (from the Latin reticulum for

15


“little net”). The reticular formation extends rostrally from the brainstem into the intralaminar nuclei of the thalamus and certain aggregations of subthalamic cells (the zona incerta). These are discrete nuclei with specific interconnections involved in the modulation of arousal and associated autonomic functions [13, 14]. The nuclei of the reticular formation can be divided into three zones with distinct anatomy and function. First is the median and paramedian zone formed by the serotonergic raphe nuclei. Second is a medial zone that appears to integrate signals from ascending sensory and descending motor pathways. The third group is the lateral zone that includes cholinergic, noradrenergic, and adrenergic nuclei. Nuclei in the more rostral portion of all three zones contribute to the maintenance and modulation of arousal, wakefulness, and thus consciousness. Nuclei in the more caudal portion of all three zones support respiratory drive, and modulate reflex mechanisms involving the gastrointestinal, genitourinary, cardiopulmonary, and vestibular systems. The reticular formation’s role in arousal can be divided into an ascending reticular activating system (ARAS) and (providing homeostatic balance) an ascending reticular inhibiting system (ARIS). The ARAS is a collection of nuclei including the noradrenergic nuclei in the locus coeruleus in the pons, dopaminergic nuclei in the ventral tegmental area in the midbrain and Ch5–6 cholinergic nuclei, with widely distributed projections including the thalamus, subthalamic nuclei, limbic system, and widespread regions of the cerebral cortex. The ARAS integrates both bottom-up and top-down input to modulate levels of general and specific arousal and attention based on internal and external stimuli and circumstances [13]. We find it useful to use the construct of a corresponding ARIS as the opposing system to the ARAS, reducing arousal and modulating attention when appropriate [8]. This system is composed of the ascending serotonergic projections of the raphe nuclei providing an inhibitory balance to the activating influence of the cholinergic, noradrenergic, and dopaminergic systems. The system modulates wakefulness, promoting sleep. Thus, sleep is not simply the loss of activation from the ARAS, but rather an active process with input from these inhibitory fibers originating largely in the medullary portions of the reticular formation. Ascending serotonergic projections

16

III

IV

V.

V V (Motor root) VI VII XII Nucleus ambiguus IX and X XI

Cervical nerves

Figure 2.4. Lateral view of the brainstem showing the relative positions of the nuclei of cranial nerves III to XII. Adapted from Gray’s Anatomy of the Human Body originally published in 1918.

from the dorsal raphe and central superior nuclei in the midbrain influence behavior through their modulation of frontal-subcortical circuits. The complex interaction of these fundamental systems regulating arousal and awareness will be described further in later chapters.

Cranial nerves The 12 cranial nerves (CNs) provide motor and sensory innervation to the head and neck. All but CN I and II connect to the brain via the brainstem (Figure 2.4). The CNs each exist in pairs, and their crossed and uncrossed connections with other structures in the CNS are important in understanding the anatomy of the brain [3]. The olfactory nerve (CN I) mediates the sense of smell. The collected axons of olfactory receptor cells in the roof of the nasal cavity form the olfactory nerve. These fibers pass through the cribriform plate of the ethmoid bone, and terminate in the olfactory bulb at the base of the frontal lobe. From there, the olfactory tract projects to the olfactory cortex in the medial temporal lobe.


The optic nerve (CN II) carries visual information from the eye to the rest of the brain. The optic nerve is actually a tract of the brain. More than any other sensory modality, the sense of vision is of central importance in human life. Light signals are initially processed in the eye, where photoreceptor cells in the retina transduce the patterns of light into electrochemical signals carried by the optic nerves. The optic nerve splits in the optic chiasm with the result that each hemisphere receives input from the contralateral visual field. Thus the right hemisphere receives input from the left visual field and vice versa. The bulk of the visual information generated by the retina goes to the lateral geniculate nucleus (LGN) of the thalamus. Efferent connections from the LGN form the optic radiations coursing through the temporal and parietal lobes carrying visual information to the primary visual cortex in the occipital lobes. Other areas of the brain receiving retinal input include the superior colliculus, suprachiasmatic nucleus, medial, lateral and dorsal terminal accessory optic nuclei, olivary nucleus, and the inferior pulvinar [15]. These projections play a role in visual targeting and visual processing, and may serve as alternate routes for visual information when the LGN pathway is injured. The oculomotor (CN III), trochlear (CN IV), and abducens (CN VI) nerves are considered together because of their role in conjugate eye movements. CN III also provides the afferent limb of the pupillary light reflex, and mediates eyelid opening. The trigeminal nerve (CN V) has both motor and sensory functions. The trigeminal nerve mediates somatic sensation from the face via its three divisions: ophthalmic (V1), maxillary (V2), and mandibular (V3). Afferent fibers from the three divisions form the trigeminal ganglion outside the brainstem, and then coalesce to enter the pons as a single nerve. Facial somatosensory information then projects to the ventral posterior medial nucleus of the thalamus and on to primary sensory cortex. The motor nuclei of CN V supply the muscles of mastication. The facial nerve (CN VII) originates from the facial nucleus in the pons and is primarily motor in its function, innervating the ipsilateral muscles of the face. Facial weakness related to CN VII dysfunction is frequently seen in clinical neurology. In addition to its motor component, CN VII also has one notable sensory function, carrying taste sensation from the anterior two-thirds of the tongue, via a branch named the

chorda tympani, to the solitary tract extending from the pons into medulla. The vestibulocochlear nerve (CN VIII) has two sensory components, the vestibular and cochlear divisions. These mediate the vestibular (balance) system and the sense of audition (hearing), respectively. Mechanoreceptors located in the inner ear respond to physical stimulation with the cells that form the vestibular division responding to positional head movements, and those of the cochlear division responding to sound stimuli. CN VIII carries auditory and positional sensory input to the vestibular and cochlear nuclei in the pons. This information is extensively processed in the brainstem and cerebellum, with auditory input relayed on to the medial geniculate nucleus of the thalamus and then on to the primary auditory cortex in the temporal lobe (Heschl’s gyrus). The glossopharyngeal nerve (CN IX) mediates motor, sensory, and autonomic functions of the face. Its motor fibers innervate the muscles of the pharynx, and its sensory fibers mediate somatic sensation of the tongue, nasopharynx, and middle and external ear as well as taste from the posterior one-third of the tongue. Autonomic fibers carried by CN IX supply parasympathetic input to the parotid gland. The vagus nerve (CN X) is the most widely distributed of the CNs, carrying parasympathetic signals to thoracic and abdominal organs, as well as motor and sensory innervation to the larynx, pharynx, and external ear. The accessory nerve (CN XI) arises from the lower medulla and upper spinal cord supplying motor innervation to the ipsilateral sternocleidomastoid and trapezius muscles. The hypoglossal nerve (CN XII) originates in the medulla and provides ipsilateral motor innervation to the muscles of the tongue.

Diencephalon The diencephalon includes the thalamus, metathalamus (medial and lateral geniculate nuclei), epithalamus (habenula, stria medullaris, and pineal body), and subthalamus (often referred to as the prethalamus by developmental neurobiologists, of which the major part is the subthalamic nucleus). Of these, we will consider briefly the thalamus, hypothalamus (and pituitary), and the epithalamus; the subthalamic nucleus is discussed in the context of frontal-subcortical circuits (see Chapter 5).

17


Table 2.1. Thalamic nuclei, their afferent and efferent connections, and their major functions.

Region

Nucleus

Afferent(s)

Efferent(s)

Function(s)

Motor

Ventroanterior

Globus pallidus

Frontal cortex

Modulation of motor function

Ventrolateral

Cerebellum

Frontal cortex

Modulation, coordination, and learning of movements

Ventral posterolateral

Sensory tracts from body

Parietal cortex

Somatosensation

Ventral posteromedial

Sensory tracts from body

Parietal cortex

Facial sensation

Solitary tract

Cortical gustatory area, anterior insula

Taste

Lateral geniculate

Optic tracts

Occipital cortex

Vision

Medial geniculate

Inferior colliculi

Temporal cortex

Hearing

Medial dorsal

Globus pallidus, amygdala, temporal cortex, frontal cortex

Prefrontal cortices

Executive function, memory, social cognition, emotion

Lateral nuclear group (pulvinar)

Frontal, parietal, temporal, and occipital cortices

Frontal, parietal, temporal, and occipital cortices

Coordination of intra- and cross-modal cortical information processing

Limbic

Anterior and laterodorsal

Mammillary bodies

Posterior cingulate, retrosplenial area, entorhinal-hippocampal complex

Learning and memory

Non-specific

Midline

Hypothalamus

Amygdala, cingulate, hypothalamus

Visceral function

Intralaminar

Reticular formation, precentral and premotor cortex

Striatum, cortex

Activation

Reticular

Thalamic nuclei, cortex

Dorsal thalamic nuclei

Sampling, gating, and focusing thalamocortical outputs

Sensory

Association

Thalamus The thalamus relays and integrates ascending information from arousal networks in the brainstem and sensory pathways from the visual system, olfactory system, brainstem, and spinal cord with connections traversing between cortical and subcortical structures [8]. The thalamus is not a unitary structure but rather a collection of smaller nuclei that are topographically related to the parts of the brain to which they are connected (Table 2.1). The anterior thalamus has bidirectional connections to frontal cortical regions, the superior and posterior thalamus are interconnected with parietal and occipital cortex, the inferior tier of thalamic nuclei is connected to the orbitofrontal, insular, and temporal regions, and the ventral thalamus is connected with limbic structures. The various subgroups of nuclei of the thalamus are interconnected as well. As such, the thalamus plays an integral

18

role in arousal systems, sensory and motor processing, attention, language, visuospatial function, and memory [16, 17].

Hypothalamus The hypothalamus rests inferior to the thalamus and superior to the pituitary gland. It is composed of nuclei involved in the integration and the expression of higher cerebral functions (in particular the limbic system) through autonomic, endocrine, and emotional systems (Table 2.2). The hypothalamus monitors and modulates fluid electrolyte balance, body temperature, sexual function, circadian rhythms, satiety and appetitive behaviors, and arousal in the setting of environmental threat. Anterior regions of the hypothalamus innervate the parasympathetic autonomic nervous system with posterior regions affiliated with the sympathetic branch.


Table 2.2. Selected nuclei of the hypothalamus and their key functions.

Region

Zone

Preoptic

Anterior

Medial

Nucleus

Function(s)

Periventricular

Thirst and hunger Thyroid releasing hormone production Somatostatin, leptin, and gastrin production

Paraventricular

Corticotropinreleasing hormone Oxytocin release Vasopressin release Thermoregulation Thyrotropin inhibition Vasopressin release Circadian rhythms Oxytocin release Vasopressin release Thirst and hunger

Anterior Suprachiasmatic Lateral

Supraoptic Lateral

Tuberal

Medial

Lateral Mammillary Medial

Lateral

Ventromedial

Satiety Neuroendocrine control Dorsomedial Blood pressure Heart rate Gastrointestinal stimulation Lateral Thirst and hunger Tuberomammillary Histamine release Mammillary Dorsal premammillary Posterior

Memory Thirst and hunger

Blood pressure control Pupillary dilation Temperature control Ventral Reproductive premammillary control Tuberomammillary Histamine release Lateral Thirst and hunger

The hypothalamus governs endocrine functions through its innervation and vascular connections with the pituitary gland. The hypothalamus is closely linked to the limbic system, contributing to emotional function and matching the autonomic response to internal drive states and the response to environmental needs. A dramatic example of this is the change in autonomic function seen as part of the flight or fight response.

Epithalamus This portion of the diencephalon comprises the pineal body, habenula, and stria medullaris. The pineal body is a midline structure located in the posterior portion

of the diencephalon, rostral and dorsal to the superior colliculus and beneath the stria medullaris. It produces a variety of neurotransmitters (serotonin, melatonin, norepinephrine, luteinizing hormone, thyrotropinreleasing hormone, and somatostatin), is connected to the visual system and the suprachiasmatic nucleus of the hypothalamus, and plays a role in sleep–wake cycles and the maintenance and regulation of circadian rhythms [18]. The habenula (also referred to as the habenular nuclei or habenular complex) refers to a cell mass embedded in the posterior end of the stria medullaris, through which they receive their principal afferents from limbic structures (e.g., hypothalamus, septum [11]). The medial habenula includes, among other components, the Ch7 cholinergic nucleus [19]. It, along with the other medial and lateral habenular subnuclei, projects to the interpeduncular nucleus (located at the base of the midbrain between the cerebral peduncles) via the retroflex fasciculus (i.e., habenulointerpeduncular tract) [11]. The interpeduncular nucleus, in turn, projects to the serotonergic mesencephalic raphe nuclei, as well as the PAG. The habenula is involved in multiple neurobehaviorally important functions, including pain processing, stress responses, sleep regulation, appetitive and reproductive behaviors, and learning (including encoding of negative reward signals) [20, 21].

Basal ganglia Basal ganglia include several subcortical gray matter nuclei deep in the cerebral hemisphere (Figure 2.5). The structures included under the umbrella term basal ganglia vary, but typically include the caudate nucleus, the putamen, and globus pallidus. The caudate nucleus is contiguous with the putamen in its ventral portions, and is divided into three parts: head, body, and tail. The caudate head bulges into the anterior horn of the lateral ventricle, the body extends along the thalamus, and the tail ends in the temporal lobe. The putamen is the largest nucleus of the basal ganglia; its dorsal and lateral portions surround the medial elements of the basal ganglia (hence the name putamen, meaning shell in Latin). The globus pallidus, also called the pallidum, lies medial to the putamen and is divided into external (lateral) and internal (medial) components. The caudate and putamen comprise the striatum. The striatum also may be divided into dorsal and ventral components; the dorsal striatum (neostriatum)

19


decision-making. These networks have the same general anatomy as the motor circuit with reciprocal connections between specific regions of cortex, specific thalamic nuclei, and the basal ganglia. These networks are discussed in more detail in Chapter 5. The close relationship between these networks serving motivation, attention, cognition, visuospatial function, and voluntary movement help us understand the frequent existence of cognitive problems, visuospatial disturbances, motivational disturbances, and movement disorders across a variety of illnesses including Parkinson’s disease, Huntington’s disease, Wilson’s disease, and schizophrenia.

Figure 2.5. Subcortical structures (coronal view). Labeled areas are: A – caudate nucleus; B – thalamus; C – putamen; D – globus pallidus; E – hypothalamus; F – mammillary body.

refers to the combination of the caudate and putamen, and the ventral striatum (limbic striatum) consists of the nucleus accumbens and olfactory tubercle. The putamen and the globus pallidus (which is anatomically a component of the prethalamus) comprise the lenticular nucleus. The basal ganglia are functionally connected to several other brain structures, including the substantia nigra (pars compacta and reticulata), subthalamic nucleus, thalamus, raphe nuclei, and cerebral cortex (motor and premotor). The basal ganglia “bias” the automatic manner in which sensory inputs are interpreted and movements selected. These nuclei serve to integrate and modulate cerebral cortical control with sensory feedback for the generation of voluntary movement. The basal ganglia serve as a component of parallel loops, in combination with the cortex and the thalamus via connections mediated through internal and external capsules forming the extrapyramidal motor system [22]. The system is distinguished from the pyramidal motor system that includes the corticobulbar and corticospinal tracts. The extrapyramidal system links the globus pallidus to the ventroanterior and ventrolateral thalamic nuclei with connections to motor cortex which then connects back to the globus pallidus completing the loop. The basal ganglia are thought to modulate the initiation, cessation, and timing of voluntary movement. More recently recognized is the basal ganglia’s role in frontal-subcortical circuits involved in attention and visuospatial function, executive function, motivation, and the modulation of social behavior and

20

Limbic system The French neurologist Paul Broca initially described the limbic system in 1878 as a collection of structures at the junction of the cerebral hemispheres and the diencephalon (Figure 2.6). The term limbic, derived from the Latin term limbus (“edge,” “border,” ‘band,” or “girdle”), reflects both the location and orientation of the structures as well as the extensive connections between the limbic system and the thalamus, hypothalamus, and cortex. In 1937, James Papez wrote a paper hypothesizing that a network of cerebral structures that included the parahippocampal gyrus, hippocampus, fornix, mammillary bodies, mammillothalamic tract, anterior nucleus of the thalamus and the cingulate gyrus formed the neuroanatomic substrate for emotion [23] (described subsequently as the Papez circuit). Although the neuroanatomy of emotion is considerably more extensive than suggested by this early formulation (see Chapter 18), the structures in this circuit are intimately involved in the processing of episodic memory (memory with spatial and temporal context such as specific events), survival functions (eating, fighting, fear, sexual desire/mating, grooming, nurturing), and the complex interplay between these cerebral functions. As currently conceived, the fundamental components of the limbic system include the cingulate and orbitofrontal gyri, hippocampus, parahippocampal gyrus, hypothalamus, anterior and dorsomedial nuclei of the thalamus, amygdala, medial temporal cortex, and the periaqueductal gray area (the limbic midbrain) [1, 24]. Several major pathways (including the fornix, medial forebrain bundle, and the stria terminalis) form reciprocal connections to other areas


Corpus callosum Cingulate gyrus

Orbital and medial prefrontal cortex

Cut edge of midbrain Parahippocampal gyrus

Temporal lobe

Mammillothalamic tract

Figure 2.6. Limbic and paralimbic areas (green shading) viewed parasagittally. The top panel depicts these areas as if viewed through the left hemisphere. The bottom panel illustrates these areas in greater detail. Reprinted from Purves D, Augustine GJ, Fitzpatrick D et al. (editors), Neuroscience, 2nd edition; 2001, with permission from Sinauer Associates. This figure is presented in color in the color plate section.

Anterior nucleus of the thalamus

Fornix

Medial dorsal nucleus of the thalamus

Anterior commissure

Ventral basal ganglia

Hypothalamus

Optic chiasm Amygdala

Mammillary body

Hippocampus

of the brain including the frontal-subcortical circuits, tightly linking these areas as well as the reticular activating system described above. The limbic system plays a central role in assessing the importance of incoming sensory information with high emotional and survival value, evaluating the current situation with reference to past experience, decision-making, and directing the behavioral response. The limbic system thus monitors and regulates internal emotional states, and integrates that information with the response to the external environment [24]. The connections to the ARAS modulate the

overall level of arousal to meet the needs of the behavioral response [13]. The cingulate gyrus, septal nuclei, and other frontotemporal areas contribute to the experience of positive emotions while the amygdala, in connection with other frontotemporal areas, plays a prominent role in the experience of negative emotions. The external manifestations of emotion involve both hypothalamic modulation of autonomic (e.g., visceral) function through sympathetic and parasympathetic pathways (via the hypothalamus) and the corresponding automatic motor responses (via the basal ganglia). The amygdala, a collection of

21


nuclei located in the anterior temporal lobe adjacent to the hippocampus, is centrally involved in emotional learning, and in processing sensory input so as to link emotional valence with new information. As an adaptive phenomenon, it makes teleological sense that the limbic system evolved to integrate emotion and new learning (episodic memory) where emotional associations with high survival value are best remembered so they may be repeated (or avoided). It also makes sense that the type of memory mediated by limbic structures should include episodic memory, with spatial and temporal components evoking memories of prior similar situations in response to current sensory input [25]. Just as our understanding of the role of the amygdala in emotion has advanced, so has our appreciation of the role of the hippocampus in memory. The hippocampus is a curved structure in the medial temporal lobe, comprised of three-layered archicortex divided into the dentate gyrus, hippocampus proper, and the subiculum. The hippocampus has an integral role in the learning of facts and events (declarative memory). The acquisition of new memories also includes other structures, tightly connected to the hippocampus, including the basal forebrain and the dorsal medial nucleus of the thalamus [26, 27]. A long history of clinical experience demonstrates that bilateral injury to any of these structures produces severe impairment of recent declarative memory. In summary, the limbic system is integrally involved with episodic memory and emotion. Key structures including the amygdala and hippocampus process sensory input, assign an emotional valance, and initiate the process encoding new events into memory. This is an active process with the “emotional” elements of the circuit (e.g., extended amygdala and cingulate areas) modulating the focus of attention and the priority with which memories are created. A potent emotional valence (either positive or negative) attached to a candidate input for memory serves as strong internal reinforcement (i.e., has high survival value) for learning and the eventual formation of permanent memories; conversely, input with limited emotional impact (i.e., low survival value) is less likely to be encoded and retained for later recall.

Cerebral cortex (telencephalon) The cerebral cortex varies from 1.5 to 4.5 mm in depth and consists of a thin sheet of neurons and supporting

22

Figure 2.7. Drawings of cortical lamination by Santiago Ramon y Cajal. Each shows a vertical cross-section of the cortex, the surface of which is at the top. Left: Nissl-stained visual cortex of a human adult. Middle: Nissl-stained motor cortex of a human adult. Right: Golgi-stained cortex of a 1.5-month-old infant. The Nissl stain shows the cell bodies of neurons; the Golgi stain shows the dendrites and axons of a random subset of neurons.

glial cells that form the outermost layer of the brain. It has been estimated that there are 14 billion neurons in the cerebral cortex with as many as 300 trillion synapses [18]. An appreciation of the structure and function of the cerebral cortex is key to understanding brain–behavior relationships. More than 90% of the cerebral cortex is classified as neocortex, recognized for its recent arrival in the course of brain evolution. Microscopically, the neocortex is formed as a horizontally laminated structure with six layers: the outermost molecular layer, the external granular cell layer, the external pyramidal cell layer, the internal granular cell layer, the internal pyramidal cell layer, and deepest, the multiform layer (Figure 2.7). Functionally, columns of cells arranged perpendicular to the surface of the cortex respond as a unit, both receiving and processing incoming stimuli and then generating efferent signals. Traditionally, the neocortex has been divided into the frontal, temporal, parietal, and occipital lobes based on the gross anatomy of the cortical surface


Table 2.3. Traditional brain–behavior relationships.

Frontal

Temporal

Parietal

Occipital

Motor planning

Audition

Somatosensation

Vision

Voluntary movement

Auditory association

Somatosensory association

Visual perception

Language (fluency)

Language (comprehension)

Cross-modal sensory association

Motor prosody

Sensory prosody

Visuospatial function

Motivation

Visual recognition

Praxicon

Working memory

Declarative memory

Derivative language functions (reading, writing, calculation)

Executive function

Emotional generation

Comportment

Olfaction

Figure 2.8. Lobar divisions of the cerebral hemispheres (left lateral view). This figure is presented in color in the color plate section.

(Figure 2.8); these areas are associated traditionally with specific neurobehavioral functions (Table 2.3). The frontal lobe is the most rostral portion of the brain, with its boundaries defined posteriorly by the Rolandic fissure and inferiorly by the Sylvian fissure. The temporal lobe is demarcated superiorly by the Sylvian fissure with its posterior boundary defined by the junction of two lines: the first a line from the parieto-occipital sulcus to the pre-occipital notch and the second a continuation extending posteriorly from the Sylvian fissure. The parietal lobe has the Rolandic fissure as its anterior boundary, and its inferior and posterior extent are determined by the lines that demarcate the temporal and occipital lobes. The occipital lobe is located posterior to the temporal and parietal lobes. The insula, a small neocortical region of neurobehavioral relevance, lies deep in the Sylvian fissure beneath the overlying cortex of the frontal, temporal, and parietal lobes [18]. While the surface of the brain is commonly divided into the frontal, parietal, temporal, and occipital lobes, a more detailed and functionally

relevant mapping of the cerebral cortex comes from Korbinian Brodmann, a German neurologist and neuroanatomist who based his cortical maps on the cytoarchitectonic arrangement of neurons established with meticulous dissections using the Nissl stain [28]. These histologically based areas described by Brodmann remain useful (and in use) today for neurobehavioral localization (Figure 2.9). Another way of classifying the functional areas of the neocortex is to divide it into primary and association (secondary, tertiary, or quaternary) cortices based on the level of information processing (Figure 2.10). The primary motor cortex is located in the precentral gyrus of the frontal lobe. Secondary motor association cortex (supplementary motor cortex) generates the impulses that are then developed into motor output by the primary motor cortex. Primary motor cortex generates afferent signals that directly control voluntary movement. The majority of ascending sensory tracts project to primary sensory cortex. The assorted primary cortical areas project to adjacent secondary association cortices where sensory input (e.g., visual, auditory, tactile, olfactory, gustatory) is compared with previously experienced (encoded) sensory inputs. This processed information from the sensory association cortex is then further communicated to tertiary and quaternary association areas for further elaboration, identification, comparison, and integration into cognitive, emotional, and behavioral networks. Primary sensory processing is subserved by the postcentral gyrus (tactile and proprioceptive), the medial and superior temporal lobe (olfactory/gustatory and auditory, respectively), and the occipital lobe (visual). These sensory areas are unimodal (serving only one sensory type), and project to unimodal secondary association areas associated with and adjacent to them. These unimodal association

23


Figure 2.9. Brodmann’s areas in the human brain. Reprinted with permission from Mark Dubin, PhD, Department of Molecular, Cellular & Developmental Biology, University of Colorado at Boulder (http://spot.colorado.edu/∼dubin/talks/brodmann/brodmann.html). This figure is presented in color in the color plate section.

areas project to higher-order areas for cross-modal processing and integration of sensory information into memory, cognitive, and emotional networks. Two of the higher-order association areas are integral to the function of the human brain, and therefore warrant additional description. First, the inferior parietal lobule (including the supramarginal and angular gyri) receives input from all of the secondary association areas, and is classified as a cross-modal (heteromodal) or tertiary association cortex. This area of cortex serves to integrate sensory information across modalities, giving humans the ability to associate sights with sounds, sight with touch, smell with sight, and so on. This tertiary association cortex has reciprocal connections with the reticular formation, the limbic system, and the frontal lobes, which both modulate and integrate arousal, attention, and emotion with sen-

24

sory experiences, based in large part on their relative emotional valence and/or survival value. Second, the frontal lobes serve as quaternary association areas integrating extensively processed information from four areas, the tertiary sensory association cortices (heteromodal cortex), the secondary association cortices, and limbic-subcortical and reticular areas, for the highest level of synthesis, elaboration, and regulation of emotional, cognitive, and behavioral/motor processes. The frontal lobes are the most phylogenetically recent addition to the brain, and the slowest to mature during human development. Their connections with the rest of the brain are dense and richly reciprocal. Input to the frontal lobes is segregated, with sensory information largely projecting to the lateral convexities of the prefrontal cortices, and limbic information projecting


2º M 1º M

1º S

2º S 2º V 3º

4º

1º V

1º A 2º A

2º V

heteromodal cortices with efferents back to tertiary and secondary association cortices [24]. This system modulates directed attention to sensory and emotional information with high survival value. These reciprocal cortico-cortical circuits control and determine where internal and external attentional systems are directed, and determine which mental processes will be continued, and when and how any changes in mental direction will occur.

White matter Motor Output Ascending Input

Figure 2.10. Schematic diagram of the information flow between the primary, secondary, tertiary, and quaternary cortical areas. The ascending input and motor outputs are simplified in order to highlight the cortical elements through which representational information processing networks are developed. Abbreviations: M – motor; S – somatosensory; A – auditory; V – visual; 1◦ – primary cortical area; 2◦ – secondary association cortex; 3◦ – heteromodal cortex; and 4◦ – prefrontal cortex.

to the basilar (orbitomedial) surface of the frontal lobes. Subcortical structures (striatum, globus pallidus, subthalamic nucleus, and thalamus) form five major circuits with various frontal gyri, including primary motor cortex, frontal eye fields, dorsolateral prefrontal cortex (made up of the middle and superior frontal gyri), orbitofrontal cortices (gyrus rectus and medial orbital gyrus medially and lateral orbital gyrus and medial inferior frontal gyrus laterally), and the anterior cingulate gyrus [29]. The five major frontalsubcortical circuits subserve key functions including motor (voluntary motor function), frontal eye fields (eye movements), dorsolateral prefrontal (executive function), lateral orbitofrontal (“social cognition”), and anterior cingulate (motivation and emotional experience) and are discussed in detail in Chapter 5. Reticular formation afferents project diffusely throughout the frontal lobes, modulating arousal and attention in response to sensory and limbic inputs. Output from the frontal lobes is essentially reciprocal to these same structures, as well as to frontal motor areas for the final step of generating a motor response. The dorsolateral, orbitofrontal, and anterior cingulate areas integrate cognitive, emotional, and motivational information with somatosensory information received from the secondary sensory association and

While much of the focus of neuroanatomy is on gray matter and the relationships between and within the cerebral cortex and subcortical structures, we should emphasize that cerebral white matter occupies nearly one half the total volume of the brain, serving to link cortical and other gray matter regions [30]. The white matter is formed by collections of CNS axons ensheathed with myelin that are most commonly called tracts, but that may also be termed fasciculi, bundles, lemnisci, funiculi, and peduncles based on their location and the structures they connect. A detailed discussion of the structural and functional anatomy of white matter is presented in Chapter 4. The myelin sheath surrounding axons dramatically increases conduction velocity allowing for the rapid transfer of information along white matter tracts that is necessary for efficient communication in sensory and motor systems, as well as the integration of higher functions mediated by other cortical and subcortical networks subserving cognition, emotion, and attention. These tracts connect widely dispersed gray matter regions, linking cortical and subcortical areas to form unified neural networks. These networks in turn subserve the many unique functions of the brain, from basic sensation and motor function to cognition and emotion. In particular, the commissural and association fibers play a major role in the mediation of higher cerebral functions. Commissural fibers are white matter tracts that link the left and right cerebral hemispheres via the cerebral commissures. The corpus callosum, the largest of these commissures, is a massive tract that connects all four lobes of the brain with the homologous regions in the contralateral hemisphere. The anterior and hippocampal commissures are much smaller commissural fiber systems serving a similar function on a much smaller scale.

25


Association tracts link gray matter regions within each hemisphere. Neuroanatomists have distinguished two types of association fibers: short (arcuate or U fibers) and long association fibers. The short association fibers connect adjacent cortical gyri throughout the cerebrum in contrast to the long association fiber systems that are longer and link cerebral lobes within the ipsilateral cerebral hemisphere. Examples of the long association fibers include the superior occipitofrontal fasciculus, the inferior occipitofrontal fasciculus, the arcuate fasciculus, the uncinate fasciculus, and the cingulum. An interesting neuroanatomic feature of these tracts, and a measure of the central role of the frontal lobes, is that they all have one terminus in a frontal lobe, while the other terminus is variably in more posterior regions. Given their relevance to BN&NP, two other white matter tracts are particularly relevant to neuropsychiatry and merit special mention: the fornix and the medial forebrain bundle. The fornix is a prominent arched tract that connects the hippocampus with the mammillary bodies as part of the Papez circuit, playing a key role in attention and memory formation. The medial forebrain bundle joins the hypothalamus with both caudal and rostral brain regions and participates in the hypothalamic control of the autonomic nervous system. These examples emphasize the essential role of white matter in the operations of all distributed neural networks [30].

Vascular supply Normal brain function requires a steady delivery of well-oxygenated blood. Brain ischemia or anoxia causes neurologic symptoms within seconds, and irreversible neuronal and glial damage and ultimately cell death occurs if the interruption lasts more than a few minutes. The clinical effects of hypoxic-ischemic injury comprise an important area of BN&NP [31] and the effects of focal ischemic injury inform much of what we know about brain–behavior relationships [3]. A working knowledge of the complex system of arteries and veins supplying the brain is necessary for understanding the neurobehavioral effects of many neurologic disorders, including one of the most common, ischemic stroke. At the microscopic level, numerous cerebral capillaries serve as the bridging vessels between the arterial and venous systems. These capillaries consist of tightly packed endothelial cells mediating the

26

exchange of oxygen, glucose and other critical nutrients and removing the byproducts of metabolism. These capillaries regulate the interchange between the CNS and the blood supply, forming a major part of the blood–brain barrier and protecting the brain from the entry of pathogens and toxins from the bloodstream. Four large arteries, sometimes called great vessels of the neck, provide the blood supply to the brain (Figures 2.11 and 2.12). The right and left common carotid arteries usually arise from the right subclavian artery and the ascending aorta, respectively, and midway through their course through the neck they bifurcate into the external carotid artery supplying the face and other extracranial structures, and the internal carotid artery (ICA) irrigating a substantial portion of the brain. The paired vertebral arteries, typically somewhat smaller than the common carotids, usually arise from the subclavian arteries and ascend in parallel to a level just below the pons, where they merge to form the single basilar artery. The basilar artery links with the paired internal carotid arteries to form the Circle of Willis, a vascular loop at the base of the brain from which arise all the arteries supplying the cerebrum. The Circle of Willis is formed by the paired posterior cerebral arteries (PCAs) that bifurcate from the top of the basilar artery and proceed on to supply posterior and basal cerebral regions, the paired posterior communicating arteries (PCoAs) that connect the PCAs with the ICAs, the paired anterior cerebral arteries (ACAs) that arise from the ICAs and go on to irrigate anterior and dorsal regions of the cerebrum, and a single anterior communicating artery (ACoA) that joins the two ACAs. The largest vessels arising from the Circle of Willis are the two middle cerebral arteries (MCAs), each ascending to supply a substantial portion of the ipsilateral cerebral hemisphere. Whereas vascular disease of many kinds can affect any of the cerebral vasculature and dramatically disrupt neurologic function, occlusions of the MCA, ACA, and the PCA are most important in terms of neurobehavioral function because of the key cortical and subcortical structures they supply. It is important to note the variability of the vascular anatomy and region of distribution of these vessels in normal individuals. There are a variety of normal anatomical variants of the origin of the great vessels from the aorta, the anatomy of the Circle of Willis, and the specific territory and volume of brain irrigated by any given vessel [32].


A richly anastomosed system of cerebral veins provides the venous drainage of the cranium [32]. These venous systems are conventionally divided into superficial and deep groups, both of which drain into a network of dural sinuses. Superficial veins near the brain surface typically drain into the superior sagittal sinus, a long, tubular structure that runs along the inner table of the skull in the interhemispheric fissure at the top of the brain. Deep veins draining subcortical structures including the basal ganglia and thalamus empty into the straight sinus that courses superior to the cerebellum. The major deep and superficial dural venous sinuses coalesce at the confluence of sinuses, and then empty into the bilateral transverse sinuses and on to the internal jugular veins returning blood to the heart via the superior vena cava. Vascular disorders involving the cerebral venous system are less common than those of the arterial system, but the neurological and neuropsychiatric outcomes can be equally catastrophic.

Ventricular system Figure 2.11. Orthogonal frontal projection of the cerebral and cerebellar arteries in situ, together with some bony landmarks and the lateral ventricles. Labeled structures include: 1 – Calvaria (inner border). 2 – Medial occipital artery, parieto-occipital branch. 3 – Trunk of the corpus callosum. 4 – Lateral ventricle. 5 – Insula. 6 – Medial occipital artery. 7 – Superior cerebellar artery, medial branch. 8 – Lateral occipital artery. 9 – Free margin of the lesser wing of the sphenoid bone. 10 – Middle meningeal artery, intraosseous part (in-constant). 11 – Middle meningeal artery, frontal branch. 12 – Middle meningeal artery, parietal branch. 13 – Superior margin of petrous part of the temporal bone. 14 – Superior cerebellar artery, lateral branch. 15 – Posterior cerebral artery. 16 – Superior cerebellar artery. 17 – Basilar artery. 18 – Anterior inferior cerebellar artery. 19 – Posterior inferior cerebellar artery, medial branch. 20 – Posterior inferior cerebellar artery, lateral branch. 21 – Posterior inferior cerebellar artery. 22 – Vertebral artery, intracranial part. 23 – Maxillary artery, pterygoid part. 24 – Middle meningeal artery. 25 – Superficial temporal artery. 26 – Maxillary artery, manidibular part. 27 – Vertebral artery, atlantal part. 28 – External carotid artery. 29 – Facial artery. 30 – Vertebral artery, cervical part. 31 – Paracentral artery. 32 – Pericallosal artery. 33 – Callosomarginal artery. 34 – Middle cerebral artery, terminal part. 35 – Middle cerebral artery, insular part. 36 – Anterior cerebral artery, post-communicating part. 37 – Anterior communicating artery. 38 – Anterior cerebral artery, pre-communicating part. 39 – Middle cerebral artery, sphenoid part. 40 – Internal carotid artery, cavernous part. 41 – Internal carotid artery, petrous part. 42 – Internal carotid artery, cervical part. 43 – Common carotid artery. Reprinted from Nieuwenhuys R, Voogd J, Huijzen CV. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008, with permission from Springer Science+Business Media. This figure is presented in color in the color plate section.

Four internal cavities called ventricles sit in the center of the brain. These cavities are filled with cerebrospinal fluid (CSF), a colorless liquid produced by the choroid plexuses within the ventricles and that surrounds and bathes the entire CNS (Figure 2.13). The ventricular system together with the production and reabsorption of the CSF are important in governing the intracranial pressure and fluid dynamics of the brain. The CSF plays a supportive role in normal CNS function, and abnormalities of the CSF may reflect the presence of infection, malignancies, inflammatory processes, and many other neurologic disorders. The two largest ventricles are the lateral ventricles, one in each cerebral hemisphere, and deep within the frontal, temporal, parietal, and occipital lobes. Both lateral ventricles communicate with a single third ventricle, a narrow cavity located on the midline between the right and left thalami, via an opening in each lateral ventricle called the foramen of Monro. The tent-shaped fourth ventricle lies on the dorsum of the brainstem and is connected to the third ventricle by a small conduit through the midbrain known as the cerebral aqueduct. Finally, the fourth ventricle empties into the cisterna magna through three apertures, the midline foramen of Magendie and the two lateral foramina of Luschka. From there the CSF then circulates through the spinal canal, irrigating and supporting the spinal cord to its

27


Figure 2.12. Orthogonal lateral projection of the cerebral and cerebellar arteries, together with external and bony landmarks. Some neural structures are illustrated in outline; in the center, two lines tangential to the anterior and posterior commisures (AC and PC, respectively) are seen: the one passing above the AC and beneath the PC is part of the bicommissural line of Talairach (BC); the other tangent is part of the ¨ upper horizontal line of Kronlein (CH). Additional abbreviations include: CM – canthus-meatus line; FH – horizontal line of Frankfurt; GI – glabella-inion line; VCA – vertical tangent to anterior commissure; and VCP – vertical tangent to posterior commissure. Labeled structures include: 1 – Central sulcus. 2 – Pericallosal artery. 3 – Callosomarginal artery. 4 – Corpus callosum. 5 – Outline of ventricles. 6 – Outline of insula. 7 – Anterior cerebral artery. 8 – Middle cerebral artery, frontal trunk. 9 – Anterior commissure. 10 – Middle cerebral artery, parietal trunk. 11 – Middle cerebral artery, temporal trunk. 12 – Posterior commissure. 13 – Medial occipital artery. 14 – Lateral occipital artery. 15 – Superior cerebellar artery, medial branch. 16 – Superior cerebellar artery, lateral branch. 17 – Superior cerebellar artery. 18 – Posterior cerebral artery. 19 – Posterior communicating artery. 20 – Internal carotid artery, cerebral part. 21 – Internal carotid artery, cavernous part. 22 – Siphon point. 23 – Middle cerebral artery, sphenoid part. 24– Ektocanthion (Canthus externus). 25 – Glabella. 26 – Orbital (on infraorbital margin). 27 – Internal carotid artery, petrous part. 28 – Basilar artery. 29 – Superior margin of petrous part of the temporal bone. 30 – Anterior inferior cerebellar artery. 31 – Porion (on supramental margin). 32 – Fourth ventricle. 33– Posterior inferior cerebellar artery, medial branch. 34 – Posterior inferior cerebellar artery, lateral branch. 35 – Posterior inferior cerebellar artery. 36 – Vertebral artery, intracranial part. 37 – Vertebral artery, atlantal part. 38 – Internal carotid artery, cervical part. 39 – Maxillary artery. 40 – Middle meningeal artery. 41 – External carotid artery. 42 – Vertebral artery, cervical part. 43 – Common carotid artery. 44 – Spinal cord. 45 – Inion (external occipital protuberance). Reprinted from Nieuwenhuys R, Voogd J, Huijzen CV. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008, with permission from Springer Science+Business Media. This figure is presented in color in the color plate section.

lower end and then recirculating rostrally to the convexities of the brain, where it is eventually absorbed into the cerebral venous sinuses through structures called the arachnoid villi. The choroid plexus in all four ventricles steadily produces CSF at a rate of about 450 ml per day. Thus the total CSF volume turns over about three times daily. The total volume of CSF in and around the CNS

28

is approximately 140 ml, whereas the volume of CSF contained within the ventricles at any given time is a small fraction of this, about 25 ml. The neuroanatomic importance of the CSF is twofold: physically, it serves a supportive role in providing buoyancy that cushions the brain from the rigid bony protuberances of the inner aspect of the skull, and functionally, the CSF takes part in regulating the chemical environment of


Figure 2.13. The ventricular system, including the lateral ventricles (dark blue, rostral), third ventricle (purple), cerebral aqueduct (green), fourth ventricle (light blue, caudal), and choroid plexus (red). Adapted from 3D Brain from G2C Online (www.g2conline.org), produced by the Dolan DNA Learning Center, Cold Spring Harbor Laboratory. This figure is presented in color in the color plate section.

brain neurons. Directly related to these roles, the ventricular system and the CSF have many important clinical implications. Enlargement of the ventricular system, known as hydrocephalus, results from an excess of CSF production, disturbed circulation, or impaired absorption, and can have major neurologic consequences. Analysis of the constituents of the CSF after lumbar puncture is crucial for diagnosis of many neurologic disorders, such as meningitis and encephalitis.

Conclusion Our understanding of the neuroanatomy of cognition, emotion, behavior, and sensorimotor function is an amalgam of traditional neuroanatomic dissection, the information gleaned from the clinical study of neurologic patients, and the methods of modern neuroscience, all of which are expanding our insights into brain–behavior relationships as never before. The localization of higher function in the brain is a central goal of neuroscience, and with our expanding knowledge of the relationships between brain structure and function, the neurobiological basis of human behavior becomes ever more clear. How the brain generates cognitive and especially emotional function has long been the subject of vigorous debate. Accepting the premise that all behavioral function originates in brain activity was the first step,

but the understanding of the specific localization and nature of higher functions within the brain requires more work. Much of our knowledge of the relation between specific regions and structures in the brain and specific cognitive functions was obtained through careful clinical description combined with detailed post-mortem study. The advent of modern neuroimaging techniques has expanded and refined our understanding. However, even with this large body of knowledge, uncertainty remains about how any given brain region generates a specific cognitive function. Reduced to its simplest formulations, theories about the cerebral representation of higher mental function fall into two camps: localization and equipotentiality. The foundation of the localizationist’s conception of brain function originated in the time-honored practice of neurologists and neuropsychiatrists that emphasizes a detailed understanding of neuroanatomy and the localization of functions within it. The lesion method, the study of focal brain injury and the resultant disturbance of function, produced a relatively secure, and clinically useful map of brain–behavior relationships. While the lesion method has proved highly effective in demonstrating the anatomy of elemental neurologic deficits such as CN deficits and hemiparesis, it has been less helpful in identifying the sites, or explaining the underlying mechanism of higher functions. While the description of the effects of frontal, temporal, and parietal lesions has advanced our general understanding of the anatomic underpinnings of language, visual processing, and memory, it is increasingly clear that there is no simple correspondence between a given gyrus and a discrete cognitive domain. At the other end of the spectrum were the equipotential theorists, who contended that any specific localization of higher functions in the brain is impossible, and that all cerebral cortical areas are capable of supporting the operations of higher functions [1]. The cortex was considered to be essentially undifferentiated with respect to cognitive function and the effect of any lesion, anywhere in the cerebral hemispheres, would impair neurobehavioral function in proportion to the amount of tissue damaged. This notion, originally supported by experimental studies in higher primates, was then countered by evidence from a century of clinical and decades of neuroimaging studies that confirmed the specialization of cerebral areas with regard to higher functions. Thus, like strict

29


localization, pure equipotentiality is insupportable in light of current knowledge. Rather than either of these extremes, the current formulation of brain function is based on the idea of distributed neural networks [24]. The central concept of neural networks is that integrated ensembles of interconnected cerebral structures subserve specific neurobehavioral domains. Thus there is no exclusive relationship between any single brain structure and a corresponding mental function, but rather, a neuroanatomically linked network operating as a functional unit subserves a given function. Examples of these distributed networks include the left perisylvian language zone and medial temporal, frontal, and thalamic contributions to memory formation, storage, and retrieval. Higher-order brain function is predicated on the structures and function of lower and more fundamental regions of the brain. Thus, the reticular activating system in the brainstem supports and modulates higher functions through its modulation of the diencephalon, basal ganglia, and cerebral cortex. The interaction of these structures as components of distributed neural networks provides the fundamental organization of cognition and emotion. Throughout the following chapters, the concept of distributed neural networks will serve as a foundation for brain–behavior relations and their clinical relevance.

9. Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci. 2004;16(3):367–78. 10. Schmahmann JD, Caplan D. Cognition, emotion and the cerebellum. Brain 2006;129(Pt 2):290–2. 11. Nieuwenhuys R, Voogd J, Huijzen CV. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008. 12. Mesulam M. Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus of the human brain. In Bloom FE, Kupfer DJ, American College of Neuropsychopharmacology, editors. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995, pp. 135–146. 13. Pfaff D. Brain Arousal and Information Theory. Cambridge, MA: Harvard University Press; 2006. 14. Posner JB, Plum F. Plum and Posner’s Diagnosis of Stupor and Coma. 4th edition. Oxford: Oxford University Press; 2007. 15. Stoerig P, Cowey A. Blindsight in man and monkey. Brain 1997;120 (Pt 3):535–59. 16. Taber KH, Wen C, Khan A, Hurley RA. The limbic thalamus. J Neuropsychiatry Clin Neurosci 2004;16(2): 127–32.

1. Filley CM. Neurobehavioral Anatomy. 3rd edition. Boulder, CO: University Press of Colorado; 2011.

17. Benarroch EE. The midline and intralaminar thalamic nuclei: anatomic and functional specificity and implications in neurologic disease. Neurology 2008; 71(12):944–9.

2. Nauta WJH, Feirtag M. Fundamental Neuroanatomy. New York, NY: Freeman; 1986.

18. Carpenter MB. Core Text of Neuroanatomy. 3rd edition. Baltimore, MD: Williams & Wilkins; 1985.

3. Duus P. Topical Diagnosis in Neurology: Anatomy, Physiology, Signs, Symptoms. 2nd rev. edition. Stuttgart: Thieme Medical Publishers; 1989.

19. Herkenham M, Nauta WJ. Efferent connections of the habenular nuclei in the rat. J Comp Neurol. 1979; 187(1):19–47.

4. Filley CM. Neurobehavioral Anatomy. 2nd edition. Boulder, CO: University Press of Colorado; 2000.

20. Matsumoto M, Hikosaka O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 2007;447(7148):1111–15.

References

5. Snell RS. Clinical Neuroanatomy. 7th edition. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. 6. Hurley RA, Flashman LA, Chow TW, Taber KH. The brainstem: anatomy, assessment, and clinical syndromes. J Neuropsychiatry Clin Neurosci. 2010; 22(1):iv, 1–7. 7. Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009;10(3):211–23.

30

8. Arciniegas DB, Beresford TP. Neuropsychiatry: An Introductory Approach. Cambridge: Cambridge University Press; 2001.

21. Andres KH, von During M, Veh RW. Subnuclear organization of the rat habenular complexes. J Comp Neurol. 1999;407(1):130–50. 22. Tisch S, Silberstein P, Limousin-Dowsey P, Jahanshahi M. The basal ganglia: anatomy, physiology, and pharmacology. Psychiatr Clin North Am. 2004;27(4): 757–99. 23. Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry 1937;38(4):725–43.


24. Mesulam M (editor). Behavioral neuroanatomy. Large-scale neural networks, association cortex, frontal systems, the limbic system and hemispheric specializations. In Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 1–120.

28. Brodmann K. Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues, Barth, Leipzig (1909). Translated by Garey LJ as Localisation in the Cerebral Cortex. London: Smith-Gordon; 1994. New edition: London: Imperial College Press; 1999.

25. Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 2005;48(2):175–87.

29. Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol. 1993;50(8):873–80.

26. Squire LR. Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem. 2004;82(3):171–7. 27. Squire LR, Knowlton B, Musen G. The structure and organization of memory. Annu Rev Psychol. 1993; 44:453–95.

30. Filley CM. The Behavioral Neurology of White Matter. Oxford: Oxford University Press; 2001. 31. Anderson CA, Arciniegas DB. Cognitive sequelae of hypoxic-ischemic brain injury: a review. NeuroRehabilitation 2010;26(1):47–63. 32. Morris P. Practical Neuroangiography. Baltimore, MD: Williams & Wilkins; 1997.

31

Section I


Chapter

Cerebellum

3

Jeremy D. Schmahmann

The inclusion of a chapter on the cerebellum in a textbook devoted to Behavioral Neurology & Neuropsychiatry (BN&NP) reflects a paradigm shift in understanding the role of the cerebellum and the neural substrates of cognition. The cerebellum has long been recognized as important for motor control. Clinical evidence reveals, however, that some cerebellar lesions do not produce motor incapacity, and that cerebellar lesions can impair a number of higher-order functions. The focus of this chapter is to present an overview and practical approach to conceptualizing these manifestations of cerebellar lesions, and to outline the principles that govern the cerebellar contribution to cognition and emotion as well as to sensorimotor function.

The cerebellum and cognition – the underlying neurobiology Distributed neural circuits Understanding how the cerebellum contributes to cognition is key to developing a clinical approach to evaluation and management. Central to this concept is the notion of distributed neural circuits, the idea that all behaviors are subserved by neural systems comprising anatomic regions, or nodes, each displaying unique architectural properties, distributed geographically throughout the nervous system, and linked anatomically and functionally in a precise and unique manner [1]. These nodes are not exclusive to the cerebral cortex, but include subcortical regions – striatum, thalamus, and cerebellum. The clinical manifestations of cerebellar lesions may thus be viewed as disconnection syndromes – focal disruptions of distributed cortical and subcortical neural circuits that are the basis of all neurological function [2–4].

Essential cerebellar anatomy Situated in the posterior fossa, the cerebellum is comprised of two hemispheres joined across the midline, or vermis. It contains cerebellar cortex, white matter, and deep nuclei (Figure 3.1). Cerebellar fissures (equivalent to cerebral sulci) separate the cerebellar folia (equivalent to cerebral gyri) to form ten lobules identified by the roman numerals I through X, grouped into three lobes. Lobules I through V constitute the anterior lobe, lobules VI through IX the posterior lobe, and lobule X is the flocculonodular lobe [5–7]. The histology of the deeply folded cerebellar cortex is essentially uniform throughout [8]. It has three layers: the Purkinje cell monolayer situated between the granule cell layer beneath and the molecular layer above. Purkinje cells (PCs) provide the sole axonal efferent from the cortex to the deep nuclei. The flattened arbor of the PC dendritic tree extends up into the molecular layer. Granule cells receive mossy fiber afferents from the spinal cord and brainstem including basis pontis, and send their axons into the molecular layer where they divide to form parallel fibers running along the long axis of the folium, synapsing with the distal dendrites of hundreds of PCs. Climbing fiber (CF) axons from the neurons of the inferior olivary nucleus in the medulla entwine themselves around the proximal dendrites of PCs in a one-CF-to-one-PC relationship, terminating in the cerebellar cortex in discretely organized parasagittal zones. Cortical interneurones include stellate and basket cells in the molecular layer that inhibit the PCs, and Golgi cells in the granule cell layer that inhibit the granule cells.


32

Chapter 3: Cerebellum

(A)

(B)

(C)

(F)

(D)

(G)

(E)

(H)

Figure 3.1. A, Posterior, and B, right lateral surface reconstructions of the human cerebellum derived from MRI images. The named fissures are demarcated in color, and the fissures and lobules are identified. C, Surface reconstruction of the cerebellum seen from the oblique posterior view, with lobules demarcated. Parasagittal images of human cerebellum on MRI 2 mm lateral to midline in D, and 18 mm lateral to midline in E. Fissures are color coded according to the convention used in A and B, and the lobules are designated. F, Superior (SCP), middle (MCP), and inferior (ICP) cerebellar peduncles in human identified with diffusion spectrum imaging, overlaid on diffusion-weighted image of cerebellum and brainstem. G, Cryosection image of post-mortem human cerebellum in the coronal plane 52 mm behind the anterior commissure – posterior commissure (AC-PC), with deep cerebellar nuclei identified: D – dentate nucleus, E – emboliform nucleus, F – fastigial nucleus, G – globose nucleus. H, Diagram of a single cerebellar folium is shown sectioned in its longitudinal axis (diagram right) and transversely (left) to depict the histology of the cerebellar cortex. Purkinje cells are red; superficial and deep stellate, basket, and Golgi cells are black; granule cells and ascending axons and parallel fibers are yellow; mossy and climbing fibers are blue. Also shown are the glomeruli with mossy fiber rosettes, claw-like dendrites of granule cells, and Golgi axons. (A, B, D, E, G reproduced from Schmahmann JD, Doyon J, Toga A, Evans A, Petrides M. MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; Copyright Elsevier, 2000, with permission from Elsevier; C from Makris N, Schlerf JE, Hodge SM et al. MRI-based surface-assisted parcellation of human cerebellar cortex: an anatomically specified method with estimate of reliability. Neuroimage 2005;25(4):1146–60, with permission from Academic Press; F reproduced from Granziera C, Schmahmann JD, Hadjikhani N et al. Diffusion spectrum imaging shows the structural basis of functional cerebellar circuits in the human cerebellum in vivo. PLoS One 2009;4(4):e5101, with permission; H reproduced from Williams PL, Bannister LH, Berry MM et al. (editors). Gray’s Anatomy. 38th edition. New York, NY: Churchill Livingstone; 1995; Copyright Elsevier, 1995, with permission from Elsevier. Redrawn from Eccles JC, Ito M, Szentágothai J. The Cerebellum as a Neuronal Machine. Berlin: Springer-Verlag; Copyright Elsevier, 1967. This figure is presented in color in the color plate section.

33


The cerebellar nuclei are, from medial to lateral, the fastigial, globose, emboliform, and dentate nuclei; these are supplemented by the lateral vestibular nucleus in the medulla that has direct connections with cerebellar lobule X cortex. Three peduncles link the cerebellum to the neuraxis. The inferior cerebellar peduncle conveys afferents from the spinal cord (spinocerebellar tracts) and the climbing fiber inputs from the inferior olivary nucleus, as well as cerebellar efferents to the inferior olive and to vestibular nuclei. The middle cerebellar peduncle is the conduit of mossy fiber afferents from the pontine nuclei in the massively expanded ventral part of the pons. The superior cerebellar peduncle carries efferents from the cerebellar nuclei to the cerebral hemispheres, as well as some spinocerebellar afferents to cerebellum. Three pairs of blood vessels derived from the posterior circulation (vertebrobasilar system) irrigate the cerebellum. These are relevant in understanding the consequences of stroke. The posterior inferior cerebellar arteries (PICAs) irrigate the medial and lateral aspects of the posterior lobe, the ventral aspect of the cerebellar nuclei, and the medulla. The anterior inferior cerebellar arteries irrigate the anterior aspects of the posterior lobe, part of the anterior lobe, the middle cerebellar peduncle and the inferior aspect of the lateral pons. The superior cerebellar arteries supply the anterior lobe and rostral part of the posterior lobe, the superior aspect of the deep nuclei, the superior cerebellar peduncle, and the rostral part of the lateral pons.

Cerebrocerebellar connections The anatomical connections of the cerebellum with spinal cord, brainstem and cerebral hemispheres are discretely organized in parallel anatomic subsystems (or loops) that provide the structural basis for the role of the cerebellum in movement, cognition, and emotion. Its connections with the cerebral hemispheres are via a two-stage feedforward projection from cerebral cortex through the nuclei of the basis pontis and a two-stage feedback system from the cerebellar nuclei through thalamus to cerebral cortex. Sensorimotor information reaches the cerebellum from the spinal cord via the spinocerebellar tracts, the spinal-recipient parts of the inferior olivary complex, and the motor recipient nuclei in the basis pontis [9–13]. Sensorimotor projections to cerebellar cortex terminate in the anterior lobe (lobules I–V), adjacent

34

parts of lobule VI, and lobule VIII. The sensorimotorrelated corticonuclear complexes engage the interpositus nucleus (globose and emboliform in the human) and the dorsal part of the dentate nucleus [14, 15] and project back to motor-related areas of the cerebral cortex [16]. The cerebrocerebellar link is predominantly contralateral, so that the right cerebellum communicates mostly with the left cerebral hemisphere, and vice versa. Cerebellar control of movement is overwhelmingly ipsilateral; i.e., the right cerebellum coordinates movements of the right side of the body. Higher-order information gains access to the cerebellum via the corticopontine pathway, transmitted from the pons through the middle cerebellar peduncle to the cerebellum. These inputs are derived from association areas in the prefrontal, posterior parietal, superior temporal, and dorsal parastriate cortices; and from paralimbic areas in the posterior parahippocampus, limbic regions of the cingulate gyrus and the anterior insular cortex [12, 17, 18]. The cerebellar cortical destinations of these afferents are predominantly in lobules VI and VII (Crus I and II being hemispheric extensions of lobule VIIA; and lobule VIIB). The more recently evolved ventral parts of the dentate nucleus [19] convey information from these cerebellar regions via thalamus back to the cerebral cortical association areas, thus closing the loop [17, 20]. Limbic and paralimbic cortices are interconnected with the cerebellar vermis and fastigial nucleus [21].

Cerebellar functional topography Physiological studies in cat [22] and human [23, 24] reveal cerebellar somatotopy confined to the anterior lobe, parts of lobule VI, and lobule VIII. Resting-state functional connectivity magnetic resonance imaging (fcMRI) in humans shows that activity in the anterior lobe, lobules VI and VIII, correlates with sensorimotor regions of the cerebral cortex, whereas activity in the posterior lobe (mostly Crus I and II of lobule VII) correlates with prefrontal, parietal, and temporal association areas and the cingulate gyrus [25]. Functional MRI (fMRI) studies indicate that whereas the cerebellar anterior lobe, adjacent parts of lobule VI, and lobule VIII are activated in sensorimotor tasks, lobules VI and VII in the posterior lobe are active during language, spatial, and executive function tasks, and affective processing engages the posterior lobes including the vermis [26, 27] (Figures 3.2 and 3.3).


(A)

(D)

(B)

(C)

Figure 3.2. Activation Likelihood Estimation (ALE) activation maps for the domains of A, spatial cognition, B, motor tapping with the right hand, and C, language tasks drawn from a meta-analysis of functional imaging studies [26]. The right cerebellum is depicted on the right. The results are overlaid upon an image of the cerebellum in the coronal plane at y = −70 from the MRI Atlas of the Human Cerebellum [7], and the cerebellar fissures and lobules at this level are identified in D. Reproduced from Schmahmann JD, Doyon J, Toga A, Evans A, Petrides M. MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; Copyright Elsevier, 2000, with permission of Elsevier; and with permission of Academic Press from Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage 2009;44(2):489–501. This figure is presented in color in the color plate section.

The recognition that sensorimotor control is topographically separate and distinct from cognitive and emotional regulation in the cerebellum represents a major departure from earlier conventional wisdom [28]. It now appears that the anterior lobe and parts of medial lobule VI, together with lobule VIII of the posterior lobe and the globose and emboliform nuclei (or, more accurately the interpositus nucleus in the experimental animal) constitute the sensorimotor cerebellum. Lobule VII (that includes crus I and crus II of lobule VIIA, and lobule VIIB), parts of lobule VI, and the ventral part of the dentate nucleus, constitute the anatomical substrate of the cognitive cerebellum. The limbic cerebellum appears to have an anatomical signature in the fastigial nucleus and the cerebellar vermis, particularly the posterior vermis. Little is known of the possible cognitive role of lobule IX, although early fcMRI data provide some insights into its potential incorporation into the default mode network [29]. [As discussed in Chapter 5, Frontal-subcortical circuits] Lobule X is an essential node in the vestibular system.

Clinical manifestations of cerebellar lesions The cerebellar motor syndrome Lesions of the cerebellum have traditionally been regarded as producing motor impairments only. The cerebellar motor syndrome is characterized by widebased and unsteady, or ataxic, gait; incoordination, or dysmetria, of the arms and legs; articulation impairment, or dysarthria; and eye movement abnormalities that disturb vision, among other problems [30, 31]. These deficits are present in patients with neurodegenerative ataxias involving the entire cerebellum, but in stroke patients they arise following lesions principally in the anterior lobe [32, 33]. Oculomotor abnormalities and vestibular symptoms (vertigo, nausea, emesis) result from lesions of lobules IX and X, but lesions in the hemispheres that avoid the anterior lobe do not result in the cerebellar motor syndrome. Indeed, when these patients are examined a few days after stroke

35


Figure 3.3. Representative rostral (y = −44) to caudal (y = −76) coronal sections through a human cerebellum showing activation patterns in a functional magnetic resonance imaging experiment in a single subject [28]. Tasks investigated sensorimotor function (finger tapping, red), language (verb generation, blue), spatial cognition (mental rotation, green), working memory (n-back task, purple), and emotional processing (viewing images from the International Affective Picture System, yellow). Lobules V, VI, Crus I (Cr I), Crus II (Cr II), VIIB and VIII are labeled. The right and left cerebellar hemispheres are as indicated. Reproduced with permission of Masson Spa from Stoodley CJ, Schmahmann JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex 2010;48(7):831–844. This figure is presented in color in the color plate section.

when the vestibular symptoms have subsided, it can be difficult to detect any sign of a motor disorder [33].

The cerebellar cognitive affective syndrome The importance of the cerebellum for non-motor function was highlighted by the description of the cerebellar cognitive affective syndrome (CCAS) [34]. The CCAS results from lesions of the posterior lobe, characterized by clinically relevant deficits in executive function, visual spatial performance, linguistic processing, and dysregulation of affect (Table 3.1). In the original report of 20 patients, 18 demonstrated problems with executive functions, including poor working memory (in 11 of 16 tested), motor or ideational set shifting (in 16 of 19), and perseveration of actions or drawings (in 16 of 20). Verbal fluency was impaired in 18 patients, presenting as telegraphic speech, occasionally so limited as to resemble mutism. Decreased verbal fluency was unrelated to dysarthria. Visuospatial disintegration was found in 19 patients,

36

who were disorganized in their sequential approach to drawing, and the conceptualization of the figures was disorganized. Four patients demonstrated simultanagnosia. Naming was impaired in 13 patients, generally being spared in those with smaller lesions. Six with bilateral acute disease had agrammatic speech, and elements of abnormal syntactic structure were noted in others. Prosody was abnormal in eight patients, with tone of voice characterized by a high-pitched, whining, childish, and hypophonic quality. Mental arithmetic was deficient in 14 patients. Verbal learning and recall were mildly abnormal in 11, and visual learning and recall were impaired in four (of 13 patients tested). Ideational apraxia was evident in two individuals. Difficulty modulating behavior and personality style was a prominent feature of the bedside mental state examination in 15 patients, particularly those with large or bilateral PICA territory infarcts, and in one with surgical excision of the vermis and paravermian structures. Flattening of affect or disinhibition were manifested as overfamiliarity, flamboyant and


Table 3.1. Deficits that characterize the cerebellar cognitive affective syndrome (CCAS). The net effect of these disturbances in cognitive functioning is a general lowering of overall intellectual function.

Neurobehavioral domain Deficits characterizing CCAS Executive function

Spatial cognition

Deficient planning, motor or ideational set-shifting, abstract reasoning, working memory and multi-tasking; decreased verbal fluency, sometimes to the point of telegraphic speech or mutism; perseverative ideation in thought and/or action Visuospatial disintegration with impaired attempts to draw or copy a diagram; disorganized conceptualization of figures; impaired visual-spatial memory; in some cases, simultanagnosia may be present

Language

Anomia, agrammatic speech, abnormal syntactic structure, abnormal prosody

Personality

Aberrant modulation of behavior and personality with posterior lobe lesions that involve midline structures; flattening or blunting of affect alternates or coexists with disinhibited behaviors such as overfamiliarity, flamboyant and impulsive actions, and humorous but inappropriate and flippant comments; regressive, childlike behaviors and obsessive-compulsive traits can be observed

impulsive actions, and humorous but inappropriate and flippant comments. Behavior was regressive and childlike, and obsessive-compulsive traits were occasionally observed. Autonomic changes were a central feature in a patient with stroke involving the fastigial nucleus and paravermian cortex. This manifested as spells of hiccupping and coughing, which precipitated bradycardia and syncope. Neuropsychological testing confirmed the observations from the bedside evaluation (Table 3.2). Deficits were more pronounced and generalized in patients with large, bilateral, or pancerebellar disorders, and particularly in those with acute onset cerebellar disease. Lesions of the posterior lobe were particularly important in the generation of the CCAS; the vermis was consistently involved in patients with pronounced affective presentations; and the anterior lobe seemed to be less involved in the generation of these cognitive and behavioral deficits. Patients with stroke improved over time, although executive function remained abnormal.

Table 3.2. Neuropsychological findings in the cerebellar cognitive affective syndrome reported by Schmahmann and Sherman, 1998 [34]. These findings are grouped according to major functional category. Abbreviations: WAIS: Wechsler Adult Intelligence Scale; WAIS–R: Wechsler Adult Intelligence Scale–Revised; WMS–R: Wechsler Memory Scale–Revised; n = number of patients who received each test. ∗∗∗ P ⬍ 0.001; ∗∗ P ⬍ 0.01; and ∗ P ⬍ 0.05. Reprinted from Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain 1998;121(Pt 4):561–79, by permission of Oxford University Press.

Test

Z-score Mean SD

Intellectual functioning WAIS – Full-scale IQ WAIS–R Verbal IQ WAIS–R Performance IQ

−1.0 −0.93 −1.3

0.123 0.0002∗∗∗ 13 0.145 ⬍0.0001∗∗∗ 15 ∗∗∗ 0.127 0.0006 13

Executive functioning Word Association Animal Naming Trails A Trails B Wisconsin Card Sorting Test

−2.7 −1.5 −1.2 −0.89 −0.83

1.8 0.77 1.3 0.76 1.7

⬍0.0001∗∗∗ 0.0002∗∗∗ 0.0067∗∗ 0.0030∗∗ 0.2205

16 10 12 11 8

Reasoning and abstraction Similarities Comprehension Picture Completion Arithmetic Picture Arrangement

−0.42 −0.79 −0.77 −0.86 −1.4

0.99 0.67 0.98 1.1 0.74

0.1141 0.0120∗ 0.0150∗ 0.0112∗ ⬍0.0001∗∗∗

16 8 13 13 14

Visuospatial/visual construction Rev Complex Figure: Copy WAIS–R Block Design WAIS–R Object Assembly Hooper Visual Orientation

−5.9 −1.2 −0.81 −0.42

3.2 0.90 0.84 0.89

0.0002∗∗∗ 0.0006∗∗∗ 0.0431∗ 0.3038

13 12 7 6

−1.4 −0.40

1.4 1.4

0.0047∗∗ 0.6097

13 4

−0.13 −0.51

1.3 0.93

0.7448 0.0501

10 15

Attention and orientation Digit Span – forward Digit Span – backward Tapping Span – forward Tapping Span – backward Digit Symbol Stroop

−0.51 −0.61 −0.78 −0.85 −1.3 0.07

1.3 1.2 1.0 0.84 0.67 0.95

0.1501 0.0644 0.0844 0.0571 0.0004∗∗∗ 0.8769

15 15 7 7 9 4

Memory WMS–R Logical Memory I Logical Memory II Visual Reproduction I Visual Reproduction II Rey Complex Figure: Memory

−0.40 −0.42 −1.1 −1.4 −1.7

1.1 0.89 1.1 0.84 0.76

0.1756 0.1046 0.0038∗∗ 0.0001∗∗∗ 0.0012∗∗

14 14 12 12 7

Language Boston Naming Test Peabody Picture Vocab. PPVT-R WAIS–R Vocabulary WAIS–R Information

P-value

n

The principal features and clinical relevance of the CCAS have been emphasized and elaborated upon in subsequent clinical reports (cerebellar stroke [35–39]; mass lesions [40]; and superficial siderosis [41, 42]).

37


Cerebellar stroke patients have been reported to show deficits in executive function as revealed by poor performance on phonemic and alternate categorical fluency, naming with and without interference, and a paced auditory serial addition task; and visual spatial deficits with low scores on the Wechsler Adult Intelligence Scale–Revised (WAIS–R) Block Design subtest [43]. These deficits are clinically relevant; young adults (ages 18–44) with cerebellar strokes producing impaired working memory, visuospatial skills, and cognitive flexibility have delayed return to the work force because of cognitive limitations, not motor incapacity [44]. Our understanding of the manifestations of the CCAS continues to evolve, as exemplified by cerebellar patients who report problems with multi-tasking, organizing their thoughts, sustaining their level of concentration and energy, and being somewhat forgetful. One with post-infectious cerebellitis developed impaired judgment, diminished insight, and inability to predict consequences of his actions. An artist with a PICA territory infarct reported loss of creativity that persisted for almost a year, no longer able to experience the flow of visual images that premorbidly characterized his artistic process. Another suffered bilateral cerebellar strokes – one in the left anterior lobe that resulted in left-sided dysmetria, and the other in the right posterior lobe and vermis. His chief complaints were post-stroke executive impairments, irritability, poor impulse control, and depression. The CCAS occurs in children as well. Children who had undergone resection of cerebellar tumors but who did not receive radiation therapy or methotrexate achieved poor scores on tests of expressive language, word finding, and digit span, visual-spatial functions and verbal memory, and they showed perseveration and difficulties establishing set [45]. More than half of these children with vermis involvement experienced the posterior fossa syndrome (PFS) [46, 47], which was described initially as mutism without behavioral impairment [48, 49]; pseudobulbar palsy [50]; cerebellar speech syndrome [51]; and mutism and subsequent dysarthria [52]. In our series [45], this phenomenon developed after a 1–2-day latent period of normal behavior following surgery, and was characterized by the development of mutism followed by recovery over months with dysarthria, and buccal and lingual apraxia. Children also exhibited behavioral changes including regressive personality, apathy, and poverty

38

of spontaneous movement. Emotional lability was marked, with rapid fluctuation of emotional expression gravitating between irritability with inconsolable crying and agitation, to giggling and easy distractibility. The PFS generally follows a surgical approach to tumor resection through the cerebellar vermis, occurring in about 15–50% of patients according to different studies. The relationship between PFS and CCAS in the post-operative population has been specifically considered [53], although it should be noted that PFS, the hallmark feature of which is post-operative mutism following a delay, is not a prerequisite for the development of the intellectual and emotional deficits that comprise the CCAS, either acutely (as in stroke or tumor patients) or more chronically as occurs in destructive or degenerative lesions of the cerebellum. Subsequent analyses of children following cerebellar tumor resection reveal auditory sequential memory and language deficits following right-sided tumors, and deficient spatial and visual sequential memory with left hemisphere tumors [54]. Impaired executive functions have been reported, including impaired planning, sequencing, mental flexibility and hypothesis generation and testing, visual-spatial function, expressive language, and verbal memory [55–60]. Behavioral changes have been noted, with apparent increased thoughtfulness, anxiety and aggression [61], hyperspontaneous, disinhibited behavior, and hypospontaneous, flattened affect [62]. Vermal lesions in particular lead to post-surgical mutism and agrammatism, and behavioral disturbances include irritability, decreased ability to tolerate the company of others, and autistic features such as avoidance of physical and eye contact, complex repetitive and rhythmic rocking movements, stereotyped linguistic utterances, and lack of empathy [63]. Attention deficit disorder, addiction, anorexia, uncontrolled temper tantrums and phobias have also been described in the post-tumor resection pediatric population [64], and the posttumor CCAS deficits in children may be persistent [65, 66].

The cerebellar cognitive affective syndrome – the emotional deficits Emotional dysregulation can be a striking aspect of the CCAS [34, 45]. Behavioral aberrations in children following cerebellar tumor resection include disinhibition, impulsivity and irritability [67], dysphoria,


inattention and irritability [57], anxiety and aggression [61], and stereotypies and aberrant interpersonal relations that meet criteria for the diagnosis of autism [63]. The immune-mediated syndrome of opsoclonus– myoclonus–ataxia that occurs in children [68] and adults [69] produces a psychiatric constellation of mood changes and inconsolable irritability with lability, aggression, and night terrors. Dysphoric mood, disinhibition and poor affect regulation, disruptive behaviors and temper tantrums occur together with the cognitive and language impairments typically seen in the CCAS. Further, these behavioral changes have a predilection for lesions involving the vermis and paravermian regions, findings that are consistent with earlier clinical [70] and electrophysiological studies in experimental animals [71] and patients [72] that led to the first indication of the cerebellum as an “emotional pacemaker” [73]. Pathological laughing and crying (PLC), a manifestation of disordered voluntary control of emotional expression, occurs following lesions of the pontocerebellar circuit [74, 75] including post-infectious cerebellitis [76] and stroke in the basis pontis [13, 77], and it is described in patients with the cerebellar form of multiple system atrophy (MSA) [78]. These findings provide support for the notion that the cerebellum is engaged in the voluntary control of emotional expression. PLC may occur in the absence of a mood disorder, but some MSA patients also report true depression, suggesting that the cerebellum may influence the feeling state as well as the affective display. In our continuing observations of adults and children with cerebellar lesions we have noted altered regulation of mood and personality, psychotic thinking, and behaviors that meet criteria for diagnoses of attention-deficit hyperactivity disorder, obsessivecompulsive disorder, depression, bipolar disorder, disorders on the autism spectrum, anxiety, panic, and often, “atypical psychosis.” Other features include a lack of initiation, apathy, and irritability. We have conceptualized these behaviors as either excessive or reduced responses to the external or internal environment. The exaggerated, positive, released, or hypermetric responses may be regarded as analogous to the overshoot in the motor domain resulting from cerebellar lesions (akin to “cognitive overshoot” [79]). The diminished, negative, restricted or hypometric responses may be likened to hypotonia [80], or to hypometric movements (undershoot) in the motor

Table 3.3. Neuropsychiatric manifestations in patients with cerebellar disorders, arranged according to major neurobehavioral domains, each with positive and negative symptoms. Adapted from Schmahmann JD, Weilburg JB, Sherman JC. The neuropsychiatry of the cerebellum – insights from the clinic. Cerebellum 2007;6(3):254–67 and reproduced with permission from Taylor & Francis Ltd.

Positive (exaggerated) symptoms

Negative (diminished) symptoms

Attentional control

Inattentiveness Distractibility Hyperactivity Compulsive and ritualistic behaviors

Ruminativeness Perseveration Difficulty shifting focus of attention Obsessional thoughts

Emotional control

Impulsiveness Disinhibition Lability Unpredictability Incongruous feelings Pathological laughing and crying Anxiety Panic Agitation

Anergy Anhedonia Dysphoria Sadness Depression Hopelessness

Autism Stereotypical behaviors Avoidant behaviors spectrum Self-stimulation Tactile defensiveness behaviors Easy sensory overload Psychosis Illogical thought spectrum Paranoia Hallucinations

Lack of empathy Muted affect Emotional blunting Apathy

Social skill set

Passivity Immaturity Childishness Difficulty with social cues and interactions Unawareness of social boundaries Overly gullible and trusting

Anger Aggression Irritability Overly territorial Oppositional behavior

system following cerebellar lesions. Further, we conceptualize these manifestations as falling into five neuropsychiatric domains – attentional control, emotional control, social skill set, autism spectrum disorders, and psychosis spectrum disorders [66] (Table 3.3). Certain manifestations, such as the social skill set negative symptoms, are reminiscent of observations regarding the cerebellar role in theory of mind studies [81, 82], providing a clinical underpinning to this observation from experimental psychology. Some patients with acquired cerebellar lesions develop panic disorder, perhaps reflecting overshoot of anticipatory fear [83] resulting from cerebellar-induced emotional dyscontrol.

39


Effect of cerebellar lesions on development The developing nervous system appears to require an intact cerebellum for normal intellectual and social/emotional function as well as for motor skill. The cerebellum has a protracted developmental trajectory: it reaches its peak volume later than the cerebrum and more phylogenetically recent cerebellar regions (engaged in cognitive processing) mature particularly late [84]. This renders the cerebellum vulnerable to environmental influences, and is clinically relevant in infants born prematurely, as the rapid rate of growth of the cerebellum during late gestation is impeded by the premature birth [85]. Thus, adolescents who had been born very pre-term (⬍33 weeks’ gestation) have reduced cerebellar volumes and testing reveals deficits in executive, visual-spatial, and language skills including impaired reading [86]. Malformations, agenesis, and hypoplasia of the cerebellum are associated with a range of motor, linguistic, intellectual, and emotional manifestations [61, 87–89]. Children with cerebellar hypoplasia and nonprogressive cerebellar ataxia struggle with cognitive and emotional deficits conforming to the description of the CCAS [90]. Indeed, autistic features and speech delay, together with ataxia, hypotonia, and ocular signs correctly predict 86% of children with cerebellar hypoplasia [91]. Early damage to the cerebellar vermis is particularly relevant for the later emergence of neuropsychiatric phenomena. Vermal regions are among the brain areas showing structural differences in autism spectrum disorders [92–94]; pre-term infants with cerebellar hemorrhage in the vermis have pervasive developmental disorder and diagnostic scores on autism screening questionnaires [95]; the vermis has been implicated in psychoneurotic symptoms following early childhood trauma, and in addictive behaviors that underlie substance abuse [96, 97]; and morphometric studies reveal reduced size of the posterior vermis (lobules VIII through X) in attention-deficit hyperactivity disorder [98–100]. The recognition that cerebellum appears to have a trophic influence on the development of interconnected brain systems subserving higher-order function is of great interest and also has practical implications for diagnosis and management. Even at the level of gross morphology, early damage to cerebellar hemispheres results in volume loss in the contralateral cerebral hemisphere [101, 102], a phenomenon

40

that harks back to the early descriptions by Gudden and von Monakow of sustaining projections [103], and which appears to be clinically significant.

The cerebellar component of primary psychiatric disease Reports in the 1800s noted deviant and aberrant behaviors in individuals with cerebellar anomalies. Later clinical observers [70, 104] noted a relationship between the cerebellum and personality, aggression, and emotion, suggesting a casual link between cerebellar structural abnormalities and psychosis. The connections of the cerebellum with brain circuits implicated in psychiatric illness, and notably in schizophrenia, are particularly important in this regard [21, 105–109]. There is now a sizeable literature examining structural and functional imaging observations in cerebellum in early infantile autism, schizophrenia, depression, bipolar disorder, panic and obsessivecompulsive disorder (for more recent reviews, see [110–113]). These observations build upon early reports suggesting that the vermis and fastigial nucleus in humans and monkeys play a role in emotion, aggression, and psychosis [73, 104, 114–116]. The definition of the five domains of neuropsychiatric impairments arising from lesions of the cerebellum – attentional control, emotional control, social skill set, autism spectrum disorders, and psychosis spectrum disorders, provides a clinical framework within which to consider the role of the cerebellum in psychiatric illness. The implications of a cerebellar role in the pathophysiology of mental illness are far-reaching, and include new approaches to treatment.

Cognition in ataxic disorders To develop an understanding of the cerebellar role in non-motor function, it has been necessary to study patients with lesions confined to the cerebellum. Disorders such as the hereditary spinocerebellar ataxias (SCAs) are noteworthy for at least two opposing reasons. Whereas the neuropathology in some like SCA 5, SCA 6, and SCA 8 involves cerebellum exclusively or overwhelmingly, in many others like SCA 1, SCA 2, SCA 3, and SCA 17 the brainstem, basal ganglia, and cerebral cortex are also affected. In these cases it is prudent to be cautious about ascribing to cerebellum functional impairments, including dementia, which may arise in these patients from lesions of cerebral cortex,


cerebral white matter tracts, or other subcortical areas including striatum and thalamus. Patients with SCA 17, for example, may present with cognitive decline and psychiatric manifestations resembling the phenotype of Huntington’s disease [117]. From the perspective of clinical diagnosis and management, however, it is important to recognize that patients with the inherited ataxias may have cognitive and/or neuropsychiatric impairments, and to treat these clinical symptoms no matter the precise location of the pathology.

Mechanisms of the cerebellar contribution to cognition and emotion Earlier investigators regarded the cerebellum as the “great modulator of neurologic function” [73, 114]. The fundamental mechanism by which the cerebellum modulates movement, intellect, and emotion remains a matter of debate [118–121]. Our dysmetria of thought theory [4, 17, 34, 108, 109] is based upon two complementary facts of anatomical organization. First, cerebellar histology is essentially uniform throughout. This enables a computation we have termed the Universal Cerebellar Transform (UCT), allowing the cerebellum to modulate behavior, acting as an oscillation dampener maintaining function in equilibrium around a homeostatic baseline and smoothing out performance, modifying it according to context. It does so automatically, and without conscious awareness. Second, the specificity of the anatomical connections between cerebellum and the spinal cord and brainstem, and the feedforward (cortico-ponto-cerebellar) and feedback (cerebellar-thalamic-cortical) connections with sensorimotor as well as association areas of the cerebral hemispheres facilitates functional topography within the cerebellum. Thus, in the same way that the cerebellum regulates the rate, force, rhythm, and accuracy in the motor domain, so does it regulate the speed, capacity, consistency, and appropriateness of cognitive and emotional processes. If the UCT is the essential functional contribution that the cerebellum makes to the distributed neural system, then by corollary, there should be a Universal Cerebellar Impairment – namely, dysmetria (the Greek term originally used to designate motor incoordination). When the motor cerebellum is damaged the dysmetria manifests as ataxia of extremity movements, eye movements, speech and equilibrium. When the lesion is in the cognitive cerebellum, the result is dysmetria of thought (or, more recently, cognitive dysmetria

[122]), which manifests as the various components of the CCAS. When the limbic (midline) cerebellum is damaged, the dysmetria of emotional control manifests predominantly as neuropsychiatric impairments. Studies employing the contemporary methods of cognitive neuroscience are under way in a number of centers to attempt to define whether the UCT indeed exists, and the precise nature of the computation that defines the transform.

Implications for therapy Appreciation of the cerebellar contribution to higher function has relevance for understanding the neural bases of intellect and emotion and the role of cerebellum in neuropsychiatric diseases. Knowledge of the characteristic features of the CCAS provides an opportunity for counseling and education, thus fulfilling the patient’s “need-to-know-imperative.” It facilitates therapeutic intervention by cognitive and behavioral therapy for previously unrecognized emotional disturbances in the cerebellar patient population. It opens the way to the use of available pharmacologic agents that treat the presenting neurobehavioral and neuropsychiatric symptoms. There is already considerable anecdotal experience from our Ataxia Unit and elsewhere that treatment of the neuropsychiatric symptoms resulting from cerebellar lesions can be effective, regardless of which node in the distributed circuit is disturbed. Prospective studies of the pharmacologic treatment of the CCAS have not yet been performed. The role of cerebellar–vestibular interactions in dyslexia has been proposed previously [123–125], and we have postulated that cross-model therapies may be useful in disorders of higher function [126]. Some have claimed success in the management of attention deficit disorder and dyslexia by maneuvers that emphasize cerebellar motor control [127] but this approach is controversial and requires further empirical study. Earlier investigators [73, 128] reported that electrical stimulation of the cerebellum resulted in successful treatment of behavioral disorders including aggression and psychosis. We have suggested that applying repetitive transcranial magnetic stimulation (TMS) to the limbic cerebellum in the vermis may improve psychiatric disorders such as schizophrenia by upregulating cerebellar modulation of cerebrocerebellar circuits engaged in cognition and emotion [66, 112]. Our preliminary results using intermittent theta burst stimulation in eight patients with refractory

41


schizophrenia provide support for this contention, resulting in improvements in mood as well as working memory, attention, and visual-spatial ability [129].

Conclusion The recognition that the cerebellum is a key element in the neural substrates of cognition is a relatively recent development, and there are many outstanding questions still to be answered. Among the most interesting is why some patients with cerebellar disorders appear cognitively intact despite a prominent cerebellar motor syndrome. A ready explanation may be that in these patients with focal lesions the non-motor cerebellum is spared. In patients with cerebellar neurodegenerative disease, however, widespread degeneration throughout the cerebellum and a prominent cerebellar motor syndrome may be accompanied by only subtle cognitive impairments. It remains to be shown whether this is a result of such factors as time course and age of onset of the illness, and variations in the neuronal elements of the cerebrocerebellar circuit involved, or whether this is simply a reflection of insufficiently sensitive testing in these cases. We have shown, for example, that language deficits do occur in nondemented patients with degeneration confined to the cerebellum [130]. These and other aspects of the relationship between cerebellum and higher function need further investigation.

Acknowledgments Supported in part by R01 MH67980, the Birmingham Foundation, and the MINDLink Foundation. Valuable assistance was provided by Jason MacMore.

References 1. Mesulam MM. A cortical network for directed attention and unilateral neglect. Ann Neurol. 1981; 10(4):309–25. 2. Geschwind N. Disconnexion syndromes in animals and man. II. Brain. 1965;88(3):585–644. 3. Geschwind N. Disconnexion syndromes in animals and man. I. Brain. 1965;88(2):237–94. 4. Schmahmann JD, Pandya DN. Disconnection syndromes of basal ganglia, thalamus, and cerebrocerebellar systems. Cortex 2008;44(8): 1037–66. 5. Larsell O, Jansen J. The Comparative Anatomy and Histology of the Cerebellum. The Human Cerebellum,

42

Cerebellar Connections, and Cerebellar Cortex. Minneapolis, MN: The University of Minnesota Press; 1972. 6. Schmahmann JD, Doyon J, McDonald D et al. Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space. Neuroimage 1999; 10(3 Pt 1):233–60. 7. Schmahmann JD, Doyon J, Toga A, Evans A, Petrides M. MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; 2000. 8. Eccles JC, Ito M, Szentágothai J. The Cerebellum as a Neuronal Machine. Berlin: Springer-Verlag; 1967. 9. Oscarsson O. Functional organization of the spinoand cuneocerebellar tracts. Physiol Rev. 1965;45: 495–522. 10. Brodal A, Walberg F. The olivocerebellar projection in the cat studied with the method of retrograde axonal transport of horseradish peroxidase. IV. The projection to the anterior lobe. J Comp Neurol. 1977;172(1): 85–108. 11. Brodal P. The corticopontine projection in the rhesus monkey. Origin and principles of organization. Brain 1978;101(2):251–83. 12. Schmahmann JD, Pandya DN. The cerebrocerebellar system. Int Rev Neurobiol. 1997;41:31–60. 13. Schmahmann JD, Ko R, MacMore J. The human basis pontis: motor syndromes and topographic organization. Brain 2004;127(Pt 6):1269–91. 14. Jansen J, Brodal A. Experimental studies on the intrinsic fibers of the cerebellum. II. The cortico-nuclear projection. J Comp Neurol. 1940;73: 267–321. 15. Haines DE. HRP study of cerebellar corticonuclearnucleocortical topography of the dorsal culminate lobule – lobule V – in a prosimian primate (Galago): with comments on nucleocortical cell types. J Comp Neurol. 1989;282(2):274–92. 16. Middleton FA, Strick PL. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 1994;266(5184): 458–61. 17. Schmahmann JD. From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Human Brain Mapp. 1996;4: 174–98. 18. Schmahmann JD, Pandya DN. Anatomic organization of the basilar pontine projections from prefrontal cortices in rhesus monkey. J Neurosci. 1997;17(1): 438–58. 19. Leiner HC, Leiner AL, Dow RS. Does the cerebellum contribute to mental skills? Behav Neurosci. 1986; 100(4):443–54.


20. Kelly RM, Strick PL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci. 2003;23(23):8432–44.

36. Exner C, Weniger G, Irle E. Cerebellar lesions in the PICA but not SCA territory impair cognition. Neurology 2004;63(11):2132–5.

21. Schmahmann JD. The cerebrocerebellar system: anatomic substrates of the cerebellar contribution to cognition and emotion. Int Rev Psychiatry. 2001; 13:247–60.

37. Yang Y, Kim JE, Lee JS, Kim S. Akinetic mutism and cognitive-affective syndrome caused by unilateral PICA infarction. J Clin Neurol. 2007;3(4):192–6.

22. Snider RS, Stowell A. Receiving areas of the tactile, auditory, and visual systems in the cerebellum. J Neurophysiol. 1944;7:331–57. 23. Bushara KO, Wheat JM, Khan A et al. Multiple tactile maps in the human cerebellum. Neuroreport 2001; 12(11):2483–6. 24. Grodd W, Hulsmann E, Lotze M, Wildgruber D, Erb M. Sensorimotor mapping of the human cerebellum: fMRI evidence of somatotopic organization. Hum Brain Mapp. 2001;13(2):55–73. 25. Krienen FM, Buckner RL. Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity. Cereb Cortex. 2009;19(10):2485–97. 26. Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage 2009;44(2): 489–501. 27. Stoodley CJ, Valera EM, Schmahmann JD. An fMRI case study of functional topography in the human cerebellum. Behav Neurol. 2010; 23(1): 65–79. 28. Stoodley CJ, Schmahmann JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex 2010;46(7):831–844. 29. Habas C, Kamdar N, Nguyen D et al. Distinct cerebellar contributions to intrinsic connectivity networks. J Neurosci. 2009;29(26):8586–94. 30. Babinski J. De l’asynergie cérébelleuse. Revue Neurologique 1899;7:806–16. 31. Holmes G. The cerebellum of man (Hughlings Jackson memorial lecture). Brain 1939;62:1–30. 32. Schoch B, Dimitrova A, Gizewski ER, Timmann D. Functional localization in the human cerebellum based on voxelwise statistical analysis: a study of 90 patients. Neuroimage 2006;30(1):36–51. 33. Schmahmann JD, MacMore J, Vangel M. Cerebellar stroke without motor deficit: clinical evidence for motor and non-motor domains within the human cerebellum. Neuroscience 2009;162(3):852–61. 34. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain 1998;121(Pt 4): 561–79. 35. Paulus KS, Magnano I, Conti M et al. Pure post-stroke cerebellar cognitive affective syndrome: a case report. Neurol Sci. 2004;25(4):220–4.

38. Baillieux H, De Smet HJ, Dobbeleir A et al. Cognitive and affective disturbances following focal cerebellar damage in adults: A neuropsychological and SPECT study. Cortex 2010;46(7):869–79. 39. Marien P, Baillieux H, De Smet HJ et al. Cognitive, linguistic and affective disturbances following a right superior cerebellar artery infarction: a case study. Cortex 2009;45(4):527–36. 40. Akil H, Statham PF, Gotz M, Bramley P, Whittle IR. Adult cerebellar mutism and cognitive-affective syndrome caused by cystic hemangioblastoma. Acta Neurochir (Wien). 2006;148(5):597–8. 41. van Harskamp NJ, Rudge P, Cipolotti L. Cognitive and social impairments in patients with superficial siderosis. Brain 2005;128(Pt 5):1082–92. 42. Uttner I, Tumani H, Arnim C, Brettschneider J. Cognitive impairment in superficial siderosis of the central nervous system: a case report. Cerebellum 2009;8(1):61–3. 43. Neau JP, Arroyo-Anllo E, Bonnaud V, Ingrand P, Gil R. Neuropsychological disturbances in cerebellar infarcts. Acta Neurol Scand. 2000;102(6):363–70. 44. Malm J, Kristensen B, Karlsson T et al. Cognitive impairment in young adults with infratentorial infarcts. Neurology 1998;51(2):433–40. 45. Levisohn L, Cronin-Golomb A, Schmahmann JD. Neuropsychological consequences of cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a paediatric population. Brain 2000;123(Pt 5):1041–50. 46. Pollack IF, Polinko P, Albright AL, Towbin R, Fitz C. Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery 1995;37(5):885–93. 47. Sadeh M, Cohen I. Transient loss of speech after removal of posterior fossa tumors – one aspect of a larger neuropsychological entity: the cerebellar cognitive affective syndrome. Pediatr Hematol Oncol. 2001;18(7):423–6. 48. Rekate HL, Grubb RL, Aram DM, Hahn JF, Ratcheson RA. Muteness of cerebellar origin. Arch Neurol. 1985;42(7):697–8. 49. Catsman-Berrevoets CE, van Dongen HR, Zwetsloot CP. Transient loss of speech followed by dysarthria after removal of posterior fossa tumour. Dev Med Child Neurol. 1992;34(12):1102–9.

43


50. Wisoff JH, Epstein FJ. Pseudobulbar palsy after posterior fossa operation in children. Neurosurgery 1984;15(5):707–9. 51. Kingma A, Mooij JJ, Metzemaekers JD, Leeuw JA. Transient mutism and speech disorders after posterior fossa surgery in children with brain tumours. Acta Neurochir. (Wien) 1994;131(1–2):74–9. 52. van Dongen HR, Catsman-Berrevoets CE, van Mourik M. The syndrome of ‘cerebellar’ mutism and subsequent dysarthria. Neurology 1994;44(11): 2040–6. 53. Wells EM, Walsh KS, Khademian ZP, Keating RF, Packer RJ. The cerebellar mutism syndrome and its relation to cerebellar cognitive function and the cerebellar cognitive affective disorder. Dev Disabil Res Rev. 2008;14(3):221–8. 54. Riva D, Giorgi C. The neurodevelopmental price of survival in children with malignant brain tumours. Childs Nerv Syst. 2000;16(10–11):751–4. 55. Karatekin C, Lazareff JA, Asarnow RF. Relevance of the cerebellar hemispheres for executive functions. Pediatr Neurol. 2000;22(2):106–12.

64. Steinlin M, Imfeld S, Zulauf P et al. Neuropsychological long-term sequelae after posterior fossa tumour resection during childhood. Brain 2003;126(Pt 9):1998–2008. 65. Baillieux H, De Smet HJ, Lesage G et al. Neurobehavioral alterations in an adolescent following posterior fossa tumor resection. Cerebellum 2006;5(4): 289–95. 66. Schmahmann JD, Weilburg JB, Sherman JC. The neuropsychiatry of the cerebellum – insights from the clinic. Cerebellum 2007;6(3):254–67. 67. Maryniak A, Roszkowski M. Cognitive and affective disturbances in children after surgical treatment of cerebellar tumors. Neurol Neurochir Pol. 2005;39(3): 202–6. 68. Turkel SB, Brumm VL, Mitchell WG, Tavare CJ. Mood and behavioral dysfunction with opsoclonusmyoclonus ataxia. J Neuropsychiatry Clin Neurosci. 2006;18(2):239–41.

56. Grill J, Viguier D, Kieffer V et al. Critical risk factors for intellectual impairment in children with posterior fossa tumors: the role of cerebellar damage. J Neurosurg. 2004;101(2 Suppl):152–8.

69. Ohara S, Iijima N, Hayashida K, Oide T, Katai S. Autopsy case of opsoclonus-myoclonus-ataxia and cerebellar cognitive affective syndrome associated with small cell carcinoma of the lung. Mov Disord. 2007; 22(9):1320–4.

57. Turkel SB, Shu Chen L, Nelson MD et al. Case series: acute mood symptoms associated with posterior fossa lesions in children. J Neuropsychiatry Clin Neurosci. 2004;16(4):443–5.

70. Heath RG, Franklin DE, Shraberg D. Gross pathology of the cerebellum in patients diagnosed and treated as functional psychiatric disorders. J Nerv Ment Dis. 1979;167(10):585–92.

58. Berger A, Sadeh M, Tzur G et al. Task switching after cerebellar damage. Neuropsychology 2005;19(3): 362–70.

71. Heath RG, Harper JW. Ascending projections of the cerebellar fastigial nucleus to the hippocampus, amygdala, and other temporal lobe sites: evoked potential and histological studies in monkeys and cats. Exp Neurol. 1974;45(2):268–87.

59. Ronning C, Sundet K, Due-Tonnessen B, Lundar T, Helseth E. Persistent cognitive dysfunction secondary to cerebellar injury in patients treated for posterior fossa tumors in childhood. Pediatr Neurosurg. 2005;41(1):15–21. 60. Vaquero E, Gomez CM, Quintero EA, Gonzalez-Rosa JJ, Marquez J. Differential prefrontal-like deficit in children after cerebellar astrocytoma and medulloblastoma tumor. Behav Brain Funct. 2008;4:18. 61. Richter S, Dimitrova A, Maschke M et al. Degree of cerebellar ataxia correlates with three-dimensional MRI-based cerebellar volume in pure cerebellar degeneration. Eur Neurol. 2005;54(1):23–7. 62. Aarsen FK, Van Dongen HR, Paquier PF, Van Mourik M, Catsman-Berrevoets CE. Long-term sequelae in children after cerebellar astrocytoma surgery. Neurology 2004;62(8):1311–16. 63. Riva D, Giorgi C. The cerebellum contributes to higher functions during development: evidence from a series

44

of children surgically treated for posterior fossa tumours. Brain 2000;123(Pt 5):1051–61.

72. Nashold BS, Jr., Slaughter DG. Effects of stimulating or destroying the deep cerebellar regions in man. J Neurosurg. 1969;31(2):172–86. 73. Heath RG. Modulation of emotion with a brain pacemaker. Treatment for intractable psychiatric illness. J Nerv Ment Dis. 1977;165(5):300–17. 74. Gondim FA, Parks BJ, Cruz-Flores S. “Fou rire prodromique” as the presentation of pontine ischaemia secondary to vertebrobasilar stenosis. J Neurol Neurosurg Psychiatry 2001;71(6):802–4. 75. Parvizi J, Anderson SW, Martin CO, Damasio H, Damasio AR. Pathological laughter and crying: a link to the cerebellum. Brain 2001;124(Pt 9): 1708–19. 76. Dimova PS, Bojinova VS, Milanov IG. Transient mutism and pathologic laughter in the course of cerebellitis. Pediatr Neurol. 2009;41(1):49–52.


77. Tei H, Sakamoto Y. Pontine infarction due to basilar artery stenosis presenting as pathological laughter. Neuroradiology 1997;39(3):190–1. 78. Parvizi J, Joseph J, Press DZ, Schmahmann JD. Pathological laughter and crying in patients with multiple system atrophy-cerebellar type. Mov Disord. 2007;22(6):798–803. 79. Schmahmann JD. Dysmetria of thought. Clinical consequences of cerebellar dysfunction on cognition and affect. Trends Cogn Sci. 1998;2:362–70. 80. Holmes G. The symptoms of acute cerebellar injuries due to gunshot wounds. Brain 1917;40: 461–535. 81. Brunet E, Sarfati Y, Hardy-Bayle MC, Decety J. A PET investigation of the attribution of intentions with a nonverbal task. Neuroimage 2000;11(2):157–66. 82. Calarge C, Andreasen NC, O’Leary DS. Visualizing how one brain understands another: a PET study of theory of mind. Am J Psychiatry 2003;160(11): 1954–64.

92. Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci. 2005;23(2–3): 183–7. 93. Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL. Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med. 1988;318(21):1349–54. 94. Penn HE. Neurobiological correlates of autism: a review of recent research. Child Neuropsychol. 2006;12(1):57–79. 95. Limperopoulos C, Bassan H, Gauvreau K et al. Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics 2007;120(3):584–93. 96. Anderson CM, Teicher MH, Polcari A, Renshaw PF. Abnormal T2 relaxation time in the cerebellar vermis of adults sexually abused in childhood: potential role of the vermis in stress-enhanced risk for drug abuse. Psychoneuroendocrinology 2002;27(1–2):231–44.

83. Weilburg JB, Bear DM, Sachs G. Three patients with concomitant panic attacks and seizure disorder: possible clues to the neurology of anxiety. Am J Psychiatry 1987;144(8):1053–6.

97. Anderson CM, Maas LC, Frederick B et al. Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacology 2006;31(6):1318–26.

84. Tiemeier H, Lenroot RK, Greenstein DK et al. Cerebellum development during childhood and adolescence: a longitudinal morphometric MRI study. Neuroimage 2010;49(1):63–70.

98. Berquin PC, Giedd JN, Jacobsen LK et al. Cerebellum in attention-deficit hyperactivity disorder: a morphometric MRI study. Neurology 1998;50(4): 1087–93.

85. Limperopoulos C, Soul JS, Gauvreau K et al. Late gestation cerebellar growth is rapid and impeded by premature birth. Pediatrics 2005;115(3):688–95.

99. Mostofsky SH, Reiss AL, Lockhart P, Denckla MB. Evaluation of cerebellar size in attention-deficit hyperactivity disorder. J Child Neurol. 1998;13(9): 434–9.

86. Allin M, Matsumoto H, Santhouse AM et al. Cognitive and motor function and the size of the cerebellum in adolescents born very pre-term. Brain 2001;124(Pt 1): 60–6. 87. Chheda M, Sherman J, Schmahmann JD. Neurologic, psychiatric and cognitive manifestations in cerebellar agenesis. Neurology 2002;58(Suppl. 3):356. 88. Gross-Tsur V, Ben-Bashat D, Shalev RS, Levav M, Sira LB. Evidence of a developmental cerebellocerebral disorder. Neuropsychologia 2006;44(12): 2569–72. 89. Tavano A, Grasso R, Gagliardi C et al. Disorders of cognitive and affective development in cerebellar malformations. Brain 2007;130(Pt 10):2646–60. 90. Steinlin M, Zangger B, Boltshauser E. Non-progressive congenital ataxia with or without cerebellar hypoplasia: a review of 34 subjects. Dev Med Child Neurol. 1998;40(3):148–54. 91. Wassmer E, Davies P, Whitehouse WP, Green SH. Clinical spectrum associated with cerebellar hypoplasia. Pediatr Neurol. 2003;28(5):347–51.

100. Castellanos FX, Giedd JN, Berquin PC et al. Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2001;58(3):289–95. 101. Dow RS, Moruzzi G. The Physiology and Pathology of the Cerebellum. Minneapolis, MN: University of Minnesota Press; 1958. 102. Limperopoulos C, Soul JS, Haidar H et al. Impaired trophic interactions between the cerebellum and the cerebrum among preterm infants. Pediatrics 2005;116(4):844–50. 103. Schmahmann JD, Pandya DN. Fiber Pathways of the Brain. Oxford: Oxford University Press; 2006. 104. Cooper IS, Riklan M, Amin I, Cullinan T. A long-term follow-up study of cerebellar stimulation for the control of epilepsy. In Cooper IS, editor. Cerebellar Stimulation in Man. New York, NY: Raven Press; 1978, pp. 19–38. 105. Watson PJ. Nonmotor functions of the cerebellum. Psychol Bull. 1978;85(5):944–67.

45


106. Frick RB. The ego and the vestibulocerebellar system: some theoretical perspectives. Psychoanal Q. 1982; 51(1):93–122.

118. Ivry R. Cerebellar timing systems. In Schmahmann JD, editor. Cerebellum and Cognition. San Diego, CA: Academic Press; 1997, pp. 555–73.

107. Snider SR. Cerebellar pathology in schizophrenia – cause or consequence? Neurosci Biobehav Rev. 1982; 6(1):47–53.

119. Bower JM. Control of sensory data acquisition. In Schmahmann JD, editor. Cerebellum and Cognition. San Diego, CA: Academic Press; 1997, pp. 489–513.

108. Schmahmann J. An emerging concept. The cerebellar contribution to higher function. Arch Neurol. 1991; 48(11):1178–87.

120. Molinari M, Chiricozzi FR, Clausi S et al. Cerebellum and detection of sequences, from perception to cognition. Cerebellum 2008;7(4):611–15.

109. Schmahmann JD. The role of the cerebellum in affect and psychosis. J Neurolinguistics 2000;13: 189–214.

121. Ito M. Cerebellar microcomplexes. In Schmahmann JD, editor. Cerebellum and Cognition. San Diego, CA: Academic Press; 1997, pp. 475–89.

110. Konarski JZ, McIntyre RS, Grupp LA, Kennedy SH. Is the cerebellum relevant in the circuitry of neuropsychiatric disorders? J Psychiatry Neurosci. 2005;30(3):178–86.

122. Andreasen NC, Paradiso S, O’Leary DS. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr Bull. 1998;24(2):203–18.

111. Picard H, Amado I, Mouchet-Mages S, Olie JP, Krebs MO. The role of the cerebellum in schizophrenia: an update of clinical, cognitive, and functional evidences. Schizophr Bull. 2008;34(1):155–72.

123. Frank J, Levinson H. Dysmetric dyslexia and dyspraxia. Hypothesis and study. J Am Acad Child Psychiatry. 1973;12(4):690–701.

112. Hoppenbrouwers SS, Schutter DJ, Fitzgerald PB, Chen R, Daskalakis ZJ. The role of the cerebellum in the pathophysiology and treatment of neuropsychiatric disorders: a review. Brain Res Rev. 2008;59(1): 185–200. 113. Wolf U, Rapoport MJ, Schweizer TA. Evaluating the affective component of the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci. 2009;21(3):245–53. 114. Snider RS. Recent contributions to the anatomy and physiology of the cerebellum. Arch Neurol Psychiat. 1950;64(2):196–219. 115. Reis DJ, Doba N, Nathan MA. Predatory attack, grooming, and consummatory behaviors evoked by electrical stimulation of cat cerebellar nuclei. Science 1973;182(114):845–7. 116. Berman AF, Berman D, Prescott JW. The effect of cerebellar lesions on emotional behavior in the rhesus monkey. In Cooper IS, Riklan M, Snider RS, editors. The Cerebellum, Epilepsy and Behavior. New York, NY: Plenum Press; 1974, pp. 277–84. 117. Mariotti C, Alpini D, Fancellu R et al. Spinocerebellar ataxia type 17 (SCA17): oculomotor phenotype and clinical characterization of 15 Italian patients. J Neurol. 2007;254(11):1538–46.

46

124. Levinson HN. The cerebellar-vestibular basis of learning disabilities in children, adolescents and adults: hypothesis and study. Percept Mot Skills 1988; 67(3):983–1006. 125. Nicolson R, Fawcett AJ, Dean P. Dyslexia, development and the cerebellum. Trends Neurosci. 2001;24(9): 515–16. 126. Schmahmann JD. Therapeutic and research implications. In Schmahmann JD, editor. Cerebellum and Cognition. San Diego, CA: Academic Press; 1997, pp. 637–47. 127. Reynolds D, Nicolson RI, Hambly H. Evaluation of an exercise-based treatment for children with reading difficulties. Dyslexia 2003;9(1):48–71; discussion 46–7. 128. Riklan M, Marisak I, Cooper IS. Psychological studies of chronic cerebellar stimulation in man. In Cooper IS, Riklan M, Snider RS, editors. The Cerebellum, Epilepsy and Behavior. New York, NY: Plenum Press; 1974, pp. 285–342. 129. Demirtas-Tatlidede A, Freitas C, Cromer J et al. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr Res. 2010;124:91–100. 130. Stoodley CJ, Schmahmann JD. The cerebellum and language: evidence from patients with cerebellar degeneration. Brain Lang. 2009;110(3):149–53.

Section I


Chapter

White matter

4

Christopher M. Filley

The white matter of the brain has recently assumed a prominent role in the study of brain–behavior relationships. Although recognized by neuroanatomists for centuries, and long understood by clinicians as crucial for elemental neurologic function, white matter has come to be appreciated as a major contributor to higher function by virtue of its key position within the distributed neural networks that subserve all aspects of cognition, emotion, and behavior [1–3]. Clinical and basic neuroscience advances have offered new insights into the structure and function of myelinated systems that promise to enhance our understanding of the normal brain and the many disorders that may disturb its operations and produce neurobehavioral dysfunction. This chapter presents a summary of current knowledge in this field and its implications for the future of Behavioral Neurology & Neuropsychiatry (BN&NP).

Historical background White matter was first depicted as a neuroanatomic structure by the great anatomist Andreas Vesalius (1514–1564) in 1543 [1]. In his monumental work De Humani Corporis Fabrica, a treatise that still stands as a landmark in the history of science, Vesalius clearly demarcated the white matter from the gray in drawings of the brain made from cadavers. In the spirit of the Renaissance – the first era in which dissection of the human body was fully explored – the drawings of this book display impressive artistic as well as scientific merit, reflecting the influence of the great painter Titian on Vesalius and his co-workers [1]. Progress on the function of white matter was slower to come, but in the seventeenth century Thomas Willis (1621–1675) proposed that white matter areas including the corpus callosum elaborated sensory signals

into perceptions destined to be stored in the cerebral cortex [1]. Anticipating modern systems neuroscience, Franz Joseph Gall (1758–1828), who was a highly competent neuroanatomist despite his unfortunate forays into phrenology, established in the early 1800s that white matter was comprised of fascicles that connected cortical gray matter areas devoted to mental activity [1]. Later in the nineteenth century, the neurologist Jean-Martin Charcot (1825–1893) gained well-deserved fame for advancing the understanding of white matter and its functions through the study of multiple sclerosis (MS) and similar diseases [1]. In the mid-twentieth century, Norman Geschwind (1926–1984) emphasized the importance of white matter tracts in behavioral neurology in a classic treatise on disconnection syndromes that inspired a generation of clinicians and investigators [4, 5]. Geschwind’s Harvard Medical School associate M-Marsel Mesulam then advanced the influential notion of distributed neural networks by which cognitive operations are organized, leading to the concept that higher functions are subserved by gray and white matter structures integrated within widespread regions of the brain [6]. Today, as the twenty-first century begins, the understanding of white matter structure and function is rapidly advancing as increasingly sophisticated methods of study build on the steady accomplishments of the past [3, 7].

Neuroanatomy The anatomy of white matter is fundamental to understanding its role in brain–behavior relationships, and the bridging of structure and function is the principal goal of current investigations. Despite the bewildering array of fiber tracts coursing throughout the


47


brain, progress is being made in sorting out the location and connectivity of these myelinated systems, as well as their functional affiliations. White matter makes up nearly one-half the brain volume [1], and it has been estimated that 135,000 km of myelinated fibers can be found interconnecting the roughly 100 billion neurons of the brain whose cell bodies reside in cortical and subcortical gray matter [8]. Organized in tracts, fasciculi, funiculi, lemnisci, peduncles, and bundles, white matter travels within and between the cerebral hemispheres and links these regions with the brainstem, cerebellum, and spinal cord [9]. Convenient distinctions between the projection, commissural, and association tracts are familiar from neuroanatomy textbooks, and it is recognized that the latter two categories are most important for the mediation of higher functions [9]. However, with few exceptions, the role of individual tracts is not well characterized in BN&NP, and even the identification of most tracts is impossible in routine clinical practice. Radiologists as well as clinicians tend to consider the cerebral white matter as an undifferentiated whole because the homogeneity of white matter on clinical imaging prohibits visualization of all but the largest tracts. Descriptive terms such the centrum semiovale and the corona radiata are used for clinical purposes, but reflect limited understanding of the tracts lying within the amorphous areas implied by these terms. The microstructure of brain white matter plays a complementary, and equally important, role in the organization of cognition and emotion. The defining neuroanatomical feature is myelin, the fatty insulation that invests most axons in the brain and dramatically increases neuronal conduction velocity [10]. Myelin, a complex mixture of about 70% lipid and 30% protein, encircles axons in a circumferential manner after being laid down by oligodendrocytes, glial cells in the brain responsible for myelination [11]. The white hue of the brain sectioned at autopsy in fact derives from myelin. At the neuronal level, myelin forms a concentric sheath along the length of the axon, leaving bare small unmyelinated segments called nodes of Ranvier [10]. These nodes permit saltatory conduction, by which the action potential “jumps” from one node to the next as it rapidly traverses the length of the axon to the terminal dendrites and synapses [10]. Traditional teaching on the anatomy of white matter systems relevant to brain–behavior relationships is founded on the knowledge of tracts established with gross brain dissection, myelin-staining, and

48

degeneration techniques developed in the centuries after the seminal observations of Vesalius [12]. A standard current formulation is that of Nolte [9], in which tracts within the association, commissural, and projection systems are distinguished (Table 4.1). Best understood is the corpus callosum, by far the largest single tract in the brain and easily recognized as the primary interhemispheric connection. The association tracts are divided into the short association fibers, also known as uncinate or U fibers, linking adjacent cortical gyri, and the long association tracts that connect intrahemispheric regions: the superior occipitofrontal fasciculus, the inferior occipitofrontal fasciculus, the arcuate fasciculus (superior longitudinal fasciculus), the cingulum bundle, and the uncinate fasciculus [9]. While this classification can still be productively used, advances in neuroimaging and experimental neuroanatomy are revising our understanding of the complexity of white matter systems. The burgeoning field of tractography with the use of diffusion tensor imaging (DTI) [13] is moving swiftly to clarify and expand knowledge of white matter tracts, and recent investigations of the rhesus monkey brain using autoradiography [12, 14] have introduced markedly different conceptualizations of previously accepted classifications. Table 4.1 lists three classifications of cerebral white matter systems based on the knowledge that is rapidly accumulating from these advances. Much uncertainty remains, as different tracts are apparent from the various methods employed, and the correspondence between monkey and human white matter systems is not fully established. Based on detailed studies of the rhesus monkey brain, for example, Schmahmann and colleagues have raised the possibility that the arcuate fasciculus may not in fact be related to language, potentially overturning neurologic teaching of the past century [12, 14]. As the field progresses, it can be anticipated that controversies such as this will be addressed and increasing consensus gained on the anatomy of white matter tracts by the combined application of complementary techniques. In parallel with this process, the functional affiliations of these tracts are likely to become more evident as well.

Neurophysiology The major function of white matter can be conceived as the transfer of information within the nervous system, in contrast to the processing of information that

Chapter 4: White matter

Table 4.1. Evolving formulations of cerebral white matter pathways. The white matter pathways identified by anatomical examination of the human brain (gross dissection, myelin staining of human brain, lesion degeneration) as described in [9] are listed in the column on the left; those identified with diffusion tensor imaging of human brain, as described by [13], are listed in the center column; and those identified with autoradiography and diffusion spectrum imaging of rhesus monkey brain [12, 14] are listed in the column on the right. These pathways are organized in the table as association, commissural, and projection types.

Anatomical examination of human brain

Diffusion tensor imaging of human brain

Autoradiography and diffusion spectrum imaging of rhesus monkey brain

Short association (U) fibers

Short association (U) fibers

Local (U) fiber system Neighborhood fiber system

Arcuate fasciculus

Superior longitudinal (arcuate) fasciculus

Arcuate fasciculus Superior longitudinal fasciculus 1 Superior longitudinal fasciculus 2 Superior longitudinal fasciculus 3 Middle longitudinal fasciculus Extreme capsule

Association pathways

Superior occipitofrontal fasciculus Superior fronto-occipital (subcallosal) fasciculus

Fronto-occipital fasciculus

Inferior occipitofrontal fasciculus

Inferior fronto-occipital fasciculus Inferior longitudinal fasciculus

Inferior longitudinal fasciculus

Uncinate fasciculus Cingulum

Uncinate fasciculus Cingulum

Uncinate fasciculus Cingulum bundle Striatal pathways External capsule Subcallosal fasciculus of Muratoff (Muratoff bundle)

Corpus callosum

Corpus callosum

Corpus callosum

Anterior commissure

Anterior commissure

Anterior commissure

Hippocampal commissure

Hippocampal commissure Habenular commissure Posterior commissure Tectal commissure

Hippocampal commissure

Internal capsule

Internal capsule

Internal capsule

Optic radiation

Optic radiation

Optic radiation (within the sagittal stratum)

Thalamocortical radiation

Acoustic radiation Fornix

Thalamic peduncles

Commissural pathways

Projection pathways

is the responsibility of gray matter [15]. The myelination of white matter enables the rapid transfer of information within distributed neuronal networks that subserve all higher functions of the brain [1–3, 15]. By virtue of the myelin sheath and critically placed nodes of Ranvier permitting saltatory conduction, myelinated fibers conduct impulses up to 100 times faster that unmyelinated fibers, vastly increasing the speed of information transfer. It is not surprising, therefore, that one of the most salient, albeit non-specific, neurobehavioral features of white matter disorders is cognitive slowing [1, 2, 15]. Myelination also enhances the timing and synchronization of neuronal arrays

that are thus enabled to engage in highly integrative operations such as executive function, sustained attention, and working memory. Myelinated systems confer efficiency to the operations of neural networks so that the cognitive processing within cortical and subcortical gray matter structures can be optimized. In clinical practice, neurophysiological assessment using short latency evoked potentials has long been used for quantitating the integrity of primary sensory tracts, but the more challenging study of higher function has been limited to the research arena, where longer latency potentials such as the P50 and P300 have been employed to investigate cognitive systems [1].

49


White matter makes another unique contribution to function of large-scale distributed neural networks. The faster electrical conduction enabled by myelinated systems appears to have evolutionary importance. Myelin, a recent development in phylogeny, is almost exclusively confined to the nervous systems of vertebrate species [10]. Recent findings indicate a selective increase in prefrontal white matter volume in humans compared with non-human primates, whereas gray matter volume is not significantly different [16]. These observations suggest that the myelin within white matter has a special role not only in enhancing neuronal conduction velocity within the brain as a whole, but specifically within frontal networks subserving the most highly evolved human behaviors.

Development and aging While the expansion and then reduction of cortical gray matter has long been assumed as crucial in normal cognitive development and aging, there is increasing recent evidence for a role of white matter in these processes. Since the early twentieth century, white matter systems in the forebrain have been known to continue developing into adolescence, with myelination generally regarded as an index of cerebral maturation [1]. More recent data suggest that, whereas gray matter development peaks at age four, myelination continues well into midlife [17] and even the sixth decade [18]. The implications of this protracted developmental course are notable, as it may be that cerebral myelination plays an essential role in normal cognitive and behavioral maturation, and conversely, white matter disorders during the multi-decade process of development may exert a profound effect on the transition to adulthood [1]. In the later decades of life, conversely, considerable support exists for a decline of white matter integrity [1]. The contribution of cortical gray matter loss to cognitive aging may have been overestimated in the past, as estimates of cortical neuronal loss were likely excessive, and in fact loss of white matter volume may actually be more significant [1, 17, 19]. Thus, whereas the dementia of Alzheimer’s disease (AD) features cortical volume loss in medial temporal and other areas, normal aging is characterized by prominent loss of white matter volume, especially in anterior cerebral regions [20, 21]. These structural differences have clinical correlates that implicate the oft-noted differences between the “cortical” cognitive features of AD and the

50

contrasting cognitive changes of normal aging: in AD, the familiar syndromes of amnesia, aphasia, apraxia, and agnosia result from widespread cortical involvement, whereas in the latter, slowed cognition, impaired vigilance, and executive dysfunction may represent the effects of progressive white matter decline most evident in the frontal lobes [1, 20–22].

Neuroimaging The development of magnetic resonance imaging (MRI) in the early 1980s has proven to be a pivotal event in the understanding of white matter and its impact on higher brain function [1]. As a clinical tool, MRI offered a major advance over computed tomography; not only did MRI improve the visualization of white matter in known myelin diseases such as MS, it enabled the identification of previously unrecognized white matter disorders such as the syndrome of dementia, ataxia, and other neurologic deficits in longterm solvent abusers who develop toluene leukoencephalopathy (TL) [1, 2]. Perhaps the most familiar discovery made possible by MRI was the unexpectedly high prevalence of cerebral white matter hyperintensities (Figure 4.1), seen to some degree in approximately 95% of community-dwelling older people [23]. The origin and consequences of these abnormalities remain incompletely understood, but many believe they represent ischemic white matter damage, and that Binswanger’s disease (BD) or subcortical ischemic vascular dementia (SIVD) can result if the lesion burden becomes sufficiently severe [1]. White matter hyperintensities have thus stimulated much interest in the possibility that millions of people have subtle brain lesions that may potentially be addressed by medical intervention before any clinical manifestations appear. As MRI grew more sophisticated, additional techniques were introduced to improve still further the neuroimaging of white matter tracts. One such technique is magnetic resonance spectroscopy (MRS), which enables measurement of the chemical composition of white matter to assess the integrity of axons and myelin [1]. MRS has the potential to be “noninvasive biopsy” of white matter that may significantly improve diagnosis since it can detect changes in the so-called “normal-appearing white matter” [1]. Another method attracting much attention is DTI, which allows the characterization of individual tracts – tractography – with unprecedented detail (Figure 4.2). Advances in understanding the connectivity of white


Figure 4.2. Diffusion tensor image showing the arcuate fasciculus. Note the additional fascicle extending to Geschwind’s territory in the inferior parietal cortex, not recognized by traditional neuroanatomic investigation. Reproduced from Catani M, Jones DK, Ffytche DH. Perisylvian language networks of the human brain. Ann Neurol. 2005;57(1):8–16, with permission from John Wiley & Sons, Inc. This figure is presented in color in the color plate section.

Figure 4.1. Brain MRI scan (FLAIR sequence) showing periventricular white matter hyperintensities in an older man with hypertension and cognitive impairment.

matter appear most promising with DTI, which brings a new level of precision to the study of disconnection syndromes in a host of clinical disorders [24]. Combined with functional neuroimaging techniques such as positron emission tomography (PET) and functional MRI (fMRI), DTI promises to help define the distributed neural networks subserving higher function by identifying the white matter components of these networks that interact with cortical and subcortical gray matter structures [15].

Disorders of white matter Well over 100 white matter disorders of the brain have been described by neurologists, neuropathologists, and most recently, neuroradiologists [1]. Many of these disorders are classic neurologic diseases such as MS, but some, such as TL, have only become apparent with the routine application of MRI to clinical populations. Remarkably, despite the traditional emphasis on non-cognitive aspects of white matter disorders such as impaired vision, weakness, spasticity, ataxia, gait disorder, and sensory loss, close reading of clinical reports describing patients with cerebral white matter

disorders reveals evidence of cognitive or emotional dysfunction in every one of these afflictions [1]. Ten categories of white matter disorder can be considered: genetic, demyelinative, infectious, inflammatory, toxic, metabolic, vascular, traumatic, neoplastic, and hydrocephalic [1]. Table 4.2 provides a listing of entities within these categories; additional entries are likely as knowledge accumulates. A brief consideration of representative disorders will serve to highlight the diversity of white matter pathology, and standard neurology textbooks can be consulted for more information. Metachromatic leukodystrophy (MLD), an autosomal recessive leukodystrophy that typically causes a devastating and rapidly fatal illness in infants or, in older children and adults, psychosis or dementia in association with extensive cerebral dysmyelination, is the prototype genetic white matter disorder [25]. MS is the most familiar demyelinative disorder, the neurobehavioral effects of which have been known since the time of Charcot but are now better appreciated as correlating with cerebral plaque burden and associated cerebral atrophy [26]. Among the infectious diseases, the acquired immumodeficiency syndrome dementia complex involves prominent leukoencephalopathy as well as subcortical gray matter involvement [27]. Systemic lupus erythematosus illustrates the growing recognition of the impact of inflammatory white matter disease on cognition [28]. TL is the best example of white matter neurotoxicity producing impaired

51


Table 4.2. Cerebral white matter disorders.

52

Genetic

Leukodystrophies (e.g., metachromatic leukodystrophy) Aminoacidurias (e.g., phenylketonuria) Phakomatoses (e.g., neurofibromatosis) Mucopolysaccharidoses Muscular dystrophy Callosal agenesis

Demyelinative

Multiple sclerosis Acute disseminated encephalomyelitis Acute hemorrhagic encephalomyelitis Schilder’s disease Marburg’s disease Balo’s concentric sclerosis

Infectious

HIV-associated dementia Progressive multifocal leukoencephalopathy Subacute sclerosing panencephalitis Progressive rubella panencephalitis Varicella zoster encephalitis Cytomegalovirus encephalitis Lyme encephalopathy

Inflammatory

Systemic lupus erythematosus Behcet’s disease ¨ Sjogren’s syndrome Wegener’s granulomatosis Temporal arteritis Polyarteritis nodosa Scleroderma Isolated angiitis of the central nervous system Sarcoidosis

Toxic

Cranial irradiation Therapeutic drugs Drugs of abuse (e.g., toluene) Environmental toxins (e.g., carbon monoxide)

Metabolic

Vitamin B12 (cobalamin) deficiency Folate deficiency Central and/or extra-pontine myelinolysis Hypoxia Hypertensive encephalopathy Eclampsia High altitude cerebral edema

Vascular

Binswanger’s disease CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) Leukoaraiosis Cerebral amyloid angiopathy White matter disease of prematurity Migraine

Traumatic

Traumatic brain injury Shaken baby syndrome Corpus callosotomy

Neoplastic

Gliomatosis cerebri Diffusely infiltrative gliomas Lymphomatosis cerebri Focal white matter tumors

Hydrocephalic

Early hydrocephalus Normal pressure hydrocephalus

cognition [29], and one of the most convincing examples of white matter dementia (see below). Among the metabolic disorders, vitamin B12 (cobalamin) deficiency has been documented to produce reversible dementia related to white matter involvement [30]. White matter ischemia and infarcts lead to BD, the form of SIVD in which cerebral white matter damage gradually erodes cognitive function [31]; the vascular disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is similar neuropathologically and clinically [32]. Among the many neuropathological insults of traumatic brain injury (TBI), diffuse axonal injury (DAI) within the white matter is arguably the most common and devastating [33]. Neoplastic white matter results from the propensity of gliomas to originate and spread in myelinated regions of the brain, and gliomatosis cerebri vividly illustrates these features [34]. Finally, hydrocephalus, either in children or in adults, exerts its most prominent effects on white matter; in older adults, dementia as a result of normal pressure hydrocephalus (NPH) is a common sequel [35]. Many other examples can be found, including diseases, injuries, and intoxications occurring at all ages and presenting in any medical or surgical setting [1].

Neurobehavioral syndromes While the diversity of white matter disorders is surely impressive, common clinical patterns of cognitive and emotional dysfunction can nevertheless be discerned that cut across all etiological and neuropathological categories. From a comprehensive consideration of these unifying phenomena, it is possible to establish a coherent classification of neurobehavioral syndromes – a behavioral neurology of white matter [1–3]. Three major groups of syndromes emerge that capture the variety of cognitive and emotional impairments related to cerebral white matter disorders: focal neurobehavioral syndromes, white matter dementia, and neuropsychiatric syndromes [1–3].

Focal syndromes Focal neurobehavioral syndromes are well known to subspecialists in BN&NP from the classic literature beginning in late nineteenth century Europe that produced the first modern descriptions of aphasia, apraxia, agnosia, and related syndromes [1]. In 1965, Geschwind reintroduced these syndromes in the context of cerebral disconnection and revitalized


Table 4.3. Focal neurobehavioral syndromes.

Table 4.4. The profile of white matter dementia.

Amnesia

Cognitive slowing

Aphasia Broca’s Wernicke’s Conduction Global Transcortical motor Transcortical sensory Anomic Mixed transcortical

Executive dysfunction

Apraxia Ideomotor Callosal

Normal extrapyramidal function

Alexia Pure alexia Alexia with agraphia Developmental dyslexia Gerstmann’s syndrome Agnosia Visual Auditory Neglect Visuospatial dysfunction Akinetic mutism Executive dysfunction Callosal disconnection

behavioral neurology after decades of relative neglect [4, 5]. In some cases, these disconnections involve lesions in gray matter regions, but most imply white matter pathology, and examples of stroke, neoplasia, and demyelinative plaques interrupting neural networks to produce focal syndromes constitute a growing literature (Table 4.3). Today these syndromes remain foundational to behavioral neurology and continue to attract interest with the evolving neuroimaging that is further clarifying the underlying neuroanatomy of cognition [13].

White matter dementia White matter dementia is a term introduced in 1988 to call attention to the cognitive loss that can occur in patients with white matter disorders [36]. Examples such as MS [37] and TL [38] leave no doubt that cognitive impairment, often reaching the level of dementia, can occur with widespread white matter involvement. In individuals with early white matter pathology, symptoms are relatively mild and nonspecific – forgetfulness, lassitude, personality changes,

Sustained attention (vigilance) deficit Memory retrieval impairment Visuospatial dysfunction Psychiatric disturbance Normal language

Normal procedural memory

and the like – and at the most severe end of the spectrum, the profound disturbances of the persistent vegetative and minimally conscious states can result from white matter destruction. Most patients fall between these extremes, where a need for defining the neurobehavioral profile of white matter dementia has been apparent. Whereas caution is advisable when attempting to compile a cognitive profile of white matter dementia, there are striking cognitive similarities among the disorders that may cause white matter dementia [1], and evidence suggests that white matter dementia can be differentiated phenomenologically from both cortical and subcortical dementia. Table 4.4 summarizes neurobehavioral features that emerge from preliminary compilation of the deficits encountered in white matter dementia, irrespective of the specific neuropathology involved [1, 15, 39, 40]. This profile, which should be regarded as a common but not invariant description, is most useful in the early stages of white matter dementia; clinical differentiation of various dementias becomes more difficult as neuropathology of any type advances and erases subtle distinctions based on relative involvement or sparing of critical cerebral areas. Table 4.4 is based on an initial consideration of subcortical (more recently frontal-subcortical) dementia, and like subcortical dementia, white matter dementia involves cognitive slowing, executive dysfunction, sustained attention (vigilance) deficits, memory retrieval impairment, visuospatial dysfunction, and psychiatric disturbance while memory encoding and language are spared [1, 15, 39]. Unlike subcortical dementia, however, white matter dementia features normal extrapyramidal function and, importantly, procedural memory [1, 15, 40]. Both these dementia syndromes are to be distinguished from cortical dementia, in which amnesia (memory encoding deficit), aphasia, apraxia, and

53


agnosia are typical [1, 15, 39, 40]. More work is needed on refining these distinctions, but they point the way toward better recognition of the neurobehavioral deficits of patients whose white matter disorders might be identified and treated before dementia worsens. Milder forms of this syndrome may even serve to call attention to unrecognized cerebral white matter disease that has not yet caused dementia, as can be seen in SLE patients with cognitive impairment but normal conventional MRI who have MRS abnormalities consistent with early myelinopathy [28]. Indeed, one of the most useful aspects of pursuing such diagnostic distinctions is the opportunity to identify cognitive loss from white matter disorders when the potential for reversibility is at its highest. Further support for the concept of white matter dementia comes from both clinical and experimental laboratory studies. Mendez and colleagues reviewed 28 patients with white matter disorders causing dementia and found a neuropsychological profile similar to that depicted in Table 4.4 [41]. Studies of braininjured monkeys demonstrated DAI identical to that seen in humans after TBI, and the duration of coma and neurologic outcome were directly proportional to the degree of DAI [42]. Using a vascular disease model, Shibata and colleagues found that mice with bilateral carotid stenosis for 30 days had white matter ischemia sparing the hippocampus and cortices, and developed selective impairment in working memory [43]. The concept of white matter dysfunction producing a unique dementia syndrome has merit as a clinical model and a framework for brain–behavior research. However, overlap of white and gray matter pathology is often observed neuropathologically and complicates analysis. A particularly illustrative example of this complexity can be seen with AD, in which white matter is implicated in several ways. While indisputably a cortical neurodegenerative disorder, the neuropathology of AD often includes white matter changes related to three phenomena – cerebral ischemia [31], cerebral amyloid angiopathy [44], and Wallerian degeneration [45]. An intriguing hypothesis has also been advanced proposing that oligodendrocyte injury and myelin breakdown are core pathogenetic events in AD [46]. While certain disorders can be usefully conceptualized as white matter disorders – TL is an excellent example – in many others a commingling of gray and white matter pathology cannot be avoided and poses a major challenge for the study of higher function and its dissolution. Such complexity is in fact typical of

54

Table 4.5. Neuropsychiatric syndromes associated with white matter abnormalities.

Psychiatric syndromes in white Psychiatric disorders with matter disorders white matter abnormalities Depression

Schizophrenia

Mania

Depression

Psychosis

Bipolar disorder

Pathologic affect

Attention-deficit hyperactivity disorder

Euphoria

Autism

Fatigue

Aggression

brain function, and while humbling, should encourage rather than deter a comprehensive effort to further explicate brain–behavior relationships.

Neuropsychiatric syndromes Neuropsychiatric syndromes associated with white matter disorders prove to be the most difficult to describe because many uncertainties linger with regard to correlating psychiatric symptoms with any neuropathology, whether in white or gray matter. However, the frequent complaints of personality change, depression, inattention, fatigue, and similar non-specific symptoms heard in clinical settings often herald the onset of white matter disorders that will later produce more disabling deficits [1, 47]. From a nosologic perspective, it is useful to consider (1) the psychiatric syndromes that arise in patients with known white matter disorders, and (2) the evidence for white matter involvement in known psychiatric disorders [47]. To summarize a large and diverse literature, the white matter disorders have been noted to produce a variety of syndromes with prominent psychiatric features, whereas many established psychiatric disorders have been theorized to have a basis in white matter pathology [1, 25, 47]. Table 4.5 presents a sampling of entities within each of these categories, and many others are likely to be added to these lists. A recurring theme is that neuropsychiatric dysfunction in white matter disorders may be produced by microstructural injury that is more subtle than the neurologic lesions leading to focal neurobehavioral syndromes and dementia [1, 25, 47, 48]. By implication, neuropsychiatric dysfunction may reflect primary circuitry disturbances and “higherorder” disconnection syndromes [4, 5, 47, 48]. However, it must be acknowledged that these notions are


largely speculative, and much work will be necessary to establish the precise contribution of white matter dysfunction or damage in the pathogenesis of many neuropsychiatric syndromes. At the same time, recognition of the possibility that study of the white matter may offer clues to understanding baffling diseases such as schizophrenia may be central to major advances that lie ahead.

Treatment and prognosis The treatment of cerebral white matter disorders depends on the specific problem disclosed by the diagnostic search. Therapeutic options are well covered in standard textbooks of neurology, and may be (1) preventive, as in the case of reduction of cerebrovascular risk, prevention of TBI, or avoidance of leukotoxins; (2) pharmacologic, as with MS, various infectious and inflammatory diseases, metabolic disorders, or stroke; or (3) neurosurgical, as in neoplasia, NPH, and some cases of cerebrovascular and genetic disease. The range of medical and surgical interventions varies greatly, reflecting the diverse neuropathology of these disorders, but the goal from the perspective of BN&NP is the alleviation of suffering related to the often disabling cognitive and emotional effects of these disorders. In most cases, complete recovery cannot be expected, although with such a range of neuropathology, this generalization has exceptions. Symptomatic treatment, however, can often be provided with salutary effect. Non-pharmacologic approaches may be invaluable, offering patients much-needed explanation of their illness, counseling about future prospects, and specific psychotherapy as indicated. Antidepressant, antipsychotic, mood-stabilizing, anxiolytic, cholinesterase-inhibiting, stimulant, corticosteroid, immunomodulatory, antiepileptic, and anti-fatigue medications may all have a role in these patients. Caution is in order, however, since many patients are particularly vulnerable to adverse effects of treatment because of advanced age and concurrent medical problems. It is also well to keep in mind that few adequately controlled studies of the efficacy or safety of these drugs are available to guide treatment in this context. The prognosis of white matter disorders is as varied as the etiologies of these conditions. In some patients, a cure is possible, as in B12 deficiency that is recognized early and treated promptly. In many others, such as those with MS, lingering symptoms

will typically be expected. In still others, including many with TBI, lifelong disability is inevitable. As a general rule, however, the prognosis for white matter disorders is more favorable than that of gray matter disorders such as AD, the best-recognized dementia that serves as a useful contrast to the white matter disorders. As the inexorable neuronal loss of AD does not necessarily occur in many white matter disorders, they are often preventable, partially reversible, or even curable. In addition, many white matter disorders only involve myelin loss or injury while sparing the axon – this phenomenon leaves intact the cellular apparatus supporting remyelination and preserves some potential for spontaneous recovery [1]. When the axons are damaged, the prognosis clearly worsens [49], but it has long been known in MS, for example, that remyelination can occur [1]. Even the renewal of axons has been proposed as a possible mechanism of recovery. Intriguing recent DTI data in post-TBI minimally conscious patients have suggested axonal regrowth in white matter that correlates with clinical improvement [50]. Another exciting possibility is the application of evolving stem cell techniques that propose the use of oligodendrocyte progenitor cells as precursors to remyelination [51]. Finally, the concept of plasticity has recently come to be applied to the white matter. The concept of activity-dependent myelination has been shown in several animal models, and it is likely that electrical activity within axons enhances the number of both oligodendrocytes and myelinated axons [52]. In humans, data consistent with this idea have been presented in piano players who developed increased white matter organization in the pyramidal tract that was proportional to the number of hours spent practicing [53]. The notion that “experience changes white matter” has far-reaching implications both for the development and maintenance of normal white matter structures and for the rehabilitation of patients with white matter disorders [52].

Conclusion White matter has become a crucial component of the study of higher brain function. The disorders of white matter that present to the subspecialist in BN&NP are common, often diagnostically difficult, and still more therapeutically challenging. These conditions are often unrecognized or underappreciated, leaving many patients undiagnosed and untreated. White matter

55


dementia merits particular attention as a frequent and problematic syndrome for large numbers of patients at all ages. Treatment of white matter disorders and their neurobehavioral syndromes is not well understood, but prognosis may be favorable in many cases, especially when axons are spared and myelin can be restored. Despite these intriguing possibilities, the understanding of the behavioral neurology of white matter is in its infancy, reflecting a long-standing tradition of studying cortical and subcortical gray matter as the most prominent neurobehavioral substrate. From a theoretical perspective, white matter and its disorders offer an extraordinary opportunity to expand our appreciation of brain–behavior relationships by combining the lesion method of behavioral neurology with increasingly impressive neuroanatomical techniques, neuroimaging methods, and neuropathological examination to establish the neuroanatomical basis of white matter syndromes. The study of white matter is a natural outgrowth of prior investigations highlighting the importance of brain connectivity, and promises to fill an enormous gap in our understanding of the brain and its many complex operations. Allied with the study of microconnectivity in the cerebral cortex and subcortical gray matter, a focus on the macroconnectivity provided by white matter tracts promises to expand our understanding of the distributed neural networks that subserve all aspects of cognition, emotion, and behavior. The modern appreciation of white matter as fundamental to BN&NP began with Geschwind’s ideas on disconnection in 1965 [4, 5], but uncertainty persisted then about the role of myelinated tracts in higher function, and lingers to some extent today [54]. However, white matter is steadily receiving increased neuroscientific attention. In 2009, for example, the Human Connectome Project was launched by the US National Institutes of Health to compile functional (i.e., fMRI) and structural (i.e., DTI) imaging from hundreds of participants into a circuitry map of the human brain [55, 56]. The intent is to develop a large, publically accessible database derived from normal and abnormal brains, with the goals of improving knowledge of brain–behavior relationships and exploring network causes of brain disorders such as AD, schizophrenia, and autism. This project offers more evidence that the time has come to modify the familiar but overly narrow “corticocentric” approach to higher function [57] by focusing on the connectome as much as the synaptome [58, 59].

56

References 1. Filley CM. The Behavioral Neurology of White Matter. 2nd edition. New York, NY: Oxford University Press; 2012. 2. Filley CM. The behavioral neurology of cerebral white matter. Neurology 1998;50(6):1535–40. 3. Schmahmann JD, Smith EE, Eichler FS, Filley CM. Cerebral white matter: neuroanatomy, clinical neurology, and neurobehavioral correlates. Ann N Y Acad Sci. 2000;1142:266–309. 4. Geschwind N. Disconnexion syndromes in animals and man. I. Brain. 1965;88(2):237–94. 5. Geschwind N. Disconnexion syndromes in animals and man. II. Brain. 1965;88(3):585–644. 6. Mesulam MM. Large-scale neurocognitive networks and distributed processing for attention, language, and memory. Ann Neurol. 1990;28(5):597–613. 7. Schmahmann JD, Pandya DN. Cerebral white matter – historical evolution of facts and notions concerning the organization of the fiber pathways of the brain. J Hist Neurosci. 2007;16(3):237–67. 8. Saver JL. Time is brain-quantified. Stroke 2006;37(1): 263–6. 9. Nolte J. The Human Brain: An Introduction to its Functional Anatomy. 6th edition. Philadelphia, PA: Mosby/Elsevier; 2009. 10. Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev. 2001;81(2):871–927. 11. Benarroch EE. Oligodendrocytes: susceptibility to injury and involvement in neurologic disease. Neurology 2009;72(20):1779–85. 12. Schmahmann JD, Pandya DN. Fiber Pathways of the Brain. Oxford: Oxford University Press; 2006. 13. Aralasmak A, Ulmer JL, Kocak M et al. Association, commissural, and projection pathways and their functional deficit reported in literature. J Comput Assist Tomogr. 2006;30(5):695–715. 14. Schmahmann JD, Pandya DN, Wang R et al. Association fibre pathways of the brain: parallel observations from diffusion spectrum imaging and autoradiography. Brain 2007;130(Pt 3):630–53. 15. Filley CM. White matter: organization and functional relevance. Neuropsychol Rev. 2010;20(2):158–73. 16. Schoenemann PT, Sheehan MJ, Glotzer LD. Prefrontal white matter volume is disproportionately larger in humans than in other primates. Nat Neurosci. 2005; 8(2):242–52. 17. Wozniak JR, Lim KO. Advances in white matter imaging: a review of in vivo magnetic resonance methodologies and their applicability to the study of


development and aging. Neurosci Biobehav Rev. 2006;30(6):762–74. 18. Benes FM, Turtle M, Khan Y, Farol P. Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood. Arch Gen Psychiatry 1994;51(6):477–84. 19. Peters A. The effects of normal aging on myelin and nerve fibers: a review. J Neurocytol. 2002;31(8–9): 581–93. 20. Head D, Buckner RL, Shimony JS et al. Differential vulnerability of anterior white matter in nondemented aging with minimal acceleration in dementia of the Alzheimer type: evidence from diffusion tensor imaging. Cereb Cortex. 2004;14(4):410–23. 21. Head D, Snyder AZ, Girton LE, Morris JC, Buckner RL. Frontal-hippocampal double dissociation between normal aging and Alzheimer’s disease. Cereb Cortex 2005;15(6):732–9. 22. Filley CM, Cullum CM. Attention and vigilance functions in normal aging. Appl Neuropsychol. 1994; 1(1–2):29–32. 23. Launer LJ. Epidemiology of white matter lesions. Top Magn Reson Imaging 2004;15(6):365–7. 24. Catani M. Diffusion tensor magnetic resonance imaging tractography in cognitive disorders. Curr Opin Neurol. 2006;19(6):599–606. 25. Filley CM, Gross KF. Psychosis with cerebral white matter disease. Neuropsychiatry Neuropsychol Behav Neurol. 1992;5:119–125. 26. Ghaffar O, Feinstein A. The neuropsychiatry of multiple sclerosis: a review of recent developments. Curr Opin Psychiatry 2007;20(3):278–85. 27. Boisse L, Gill MJ, Power C. HIV infection of the central nervous system: clinical features and neuropathogenesis. Neurol Clin. 2008;26(3): 799–819. 28. Filley CM, Kozora E, Brown MS et al. White matter microstructure and cognition in non-neuropsychiatric systemic lupus erythematosus. Cogn Behav Neurol. 2009;22(1):38–44. 29. Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N Engl J Med. 2001;345(6): 425–32. 30. Stojsavljevic N, Levic Z, Drulovic J, Dragutinovic G. A 44-month clinical-brain MRI follow-up in a patient with B12 deficiency. Neurology 1997;49(3):878–81. 31. Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol. 2002;1(7):426–36. 32. Harris JG, Filley CM. CADASIL: neuropsychological findings in three generations of an affected family. J Int Neuropsychol Soc. 2001;7(6):768–74.

33. Alexander MP. Mild traumatic brain injury: pathophysiology, natural history, and clinical management. Neurology 1995;45(7):1253–60. 34. Filley CM, Kleinschmidt-DeMasters BK, Lillehei KO, Damek DM, Harris JG. Gliomatosis cerebri: neurobehavioral and neuropathological observations. Cogn Behav Neurol. 2003;16(3):149–59. 35. Del Bigio MR, Wilson MJ, Enno T. Chronic hydrocephalus in rats and humans: white matter loss and behavior changes. Ann Neurol. 2003;53(3): 337–46. 36. Filley CM, Franklin GM, Heaton RK, Rosenberg NL. White matter dementia: clinical disorders and implications. Cogn Behav Neurol. 1988;1(4):239–54. 37. Franklin GM, Nelson LM, Filley CM, Heaton RK. Cognitive loss in multiple sclerosis. Case reports and review of the literature. Arch Neurol. 1989;46(2):162–7. 38. Filley CM, Heaton RK, Rosenberg NL. White matter dementia in chronic toluene abuse. Neurology 1990;40(3 Pt 1):532–4. 39. Filley CM, Heaton RK, Nelson LM, Burks JS, Franklin GM. A comparison of dementia in Alzheimer’s disease and multiple sclerosis. Arch Neurol. 1989;46(2):157–61. 40. Lafosse JM, Corboy JR, Leehey MA, Seeberger LC, Filley CM. MS vs. HD: can white matter and subcortical gray matter pathology be distinguished neuropsychologically? J Clin Exp Neuropsychol. 2007; 29(2):142–54. 41. Mendez MF, Perryman KM, Bronstein YL. White matter dementias: neurobehavioral aspects and etiology. J Neuropsychiatry Clin Neurosci. 2000;12(1): 133. 42. Gennarelli TA, Thibault LE, Adams JH et al. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol. 1982;12(6):564–74. 43. Shibata M, Yamasaki N, Miyakawa T et al. Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke 2007;38(10): 2826–32. 44. Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm. 2002;109(5–6): 813–36. 45. Bozzali M, Falini A, Franceschi M et al. White matter damage in Alzheimer’s disease assessed in vivo using diffusion tensor magnetic resonance imaging. J Neurol Neurosurg Psychiatry 2002;72(6):742–6. 46. Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging 2004;25(1):5–18; author reply 49–62. 47. Filley CM. White matter: beyond focal disconnection. Neurol Clin. 2011;29(1):81–97.

57


48. Kumar A, Cook IA. White matter injury, neural connectivity and the pathophysiology of psychiatric disorders. Dev Neurosci. 2002;24(4): 255–61. 49. Medana IM, Esiri MM. Axonal damage: a key predictor of outcome in human CNS diseases. Brain 2003;126(Pt 3):515–30. 50. Voss HU, Uluc AM, Dyke JP et al. Possible axonal regrowth in late recovery from the minimally conscious state. J Clin Invest. 2006;116(7): 2005–11. 51. Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008;9(11):839–55. 52. Fields RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 2008;31(7): 361–70.

58

53. Bengtsson SL, Nagy Z, Skare S et al. Extensive piano practicing has regionally specific effects on white matter development. Nat Neurosci. 2005;8(9):1148–50. 54. Miller BL. A commentary on “disconnexion syndromes in animals and man”. Neuropsychol Rev. 2010;20(2):126–7. 55. Williams R. The human connectome: just another ‘ome’? Lancet Neurol. 2010;9(3):238–9. 56. Kennedy DN. Making connections in the connectome era. Neuroinformatics 2010;8(2):61–2. 57. Parvizi J. Corticocentric myopia: old bias in new cognitive sciences. Trends Cogn Sci. 2009;13(8):354–9. 58. Biswal BB, Mennes M, Zuo XN et al. Toward discovery science of human brain function. Proc Natl Acad Sci USA 2010;107(10):4734–9. 59. DeFelipe J. From the connectome to the synaptome: an epic love story. Science 2010;330(6008):1198–201.

Section I


Chapter

Frontal-subcortical circuits

5

David G. Lichter

A series of parallel segregated frontal-subcortical circuits (FSCs) connect specific regions of the frontal cortex (including paralimbic frontal areas) to the striatum, the globus pallidus (GP) and substantia nigra (SN), and the thalamus [1–3]. Together, these constitute an important effector mechanism that allows the individual to interact adaptively with the environment. This chapter reviews the neuroanatomy and neurochemistry of FSCs, and outlines the signature syndromes of FSC circuit dysfunction. The similarity of cognitive and behavioral changes that accompany cortical and subcortical lesions is discussed within this framework. Select neuropsychiatric disorders that appear linked to FSC dysfunction are then presented. Finally, we explore the manner in which these insights may better inform clinical management of patients with relevant neuropsychological, behavioral, and neuropsychiatric disorders.

Frontostriatal systems The frontal lobe may be viewed as comprising two distinct anatomical/functional systems, which reflect its dual developmental origin [4]. The sequential processing of sensory, spatially related, and motivational information is mediated by a dorsal system, which comprises dorsolateral and medial portions of the frontal lobes, interconnected with the posterior parietal lobe and cingulate gyrus. Emotional tone is mediated by a second, ventral system, which involves the orbital surface of the frontal lobes. The architectonic organization of the prefrontal cortex [5, 6] is reflected in the pattern of prefrontostriatal projections [7]. Thus, the dorsal architectonic trend, which originates in the rostral cingulate gyrus and culminates in the dorsal portion of the frontal eye field, maps onto

the dorsal caudate nucleus. In contrast, the ventral architectonic trend, which originates in the ventral orbital region and extends to the ventral portion of the frontal eye field, maps onto the ventro-medial portion of the caudate and adjacent portion of nucleus accumbens (NAc). Closely connected cortical areas send converging projections into the striatum [8, 9]. Early experimental observations supported a role for discrete dorsal and ventral frontostriatal systems in cognition and behavior. Thus, lesions or electrical stimulation of the dorsolateral prefrontal (DLPF) cortex or of the anterodorsal head of the caudate nucleus, to which this region projects, produce deficits in delayed response and delayed alternation tasks [10, 11]. In contrast, lesions or electrical stimulation of either the orbitofrontal (OF) cortex or of the ventrolateral head of the caudate result in deficits in object alternation or response inhibition paradigms [12]. Disruption to discrete cognitive processes following striatal injury can be interpreted as the “downstream” interruption of anatomically congruent outflow from the frontal cortex [12–14].

Frontal-subcortical circuits: shared anatomy Basic circuit structure The following principal circuits may now be recognized: a motor circuit that originates in the supplementary motor area (SMA), an oculomotor circuit originating in the frontal eye fields, and three primary circuits/circuit networks mediating cognitive, behavioral, and affective functions [1–3]. Of these, the DLPF


59


Frontal cortex

Figure 5.1. The general structure shared by all frontal-subcortical circuits (direct connections).

Striatum

Globus pallidus/ substantia nigra

Thalamus

circuit mediates “executive functions,” i.e., the organization of information to facilitate a response. The lateral OF (LOF) circuit is involved with integration of limbic and emotional information into goal-directed and contextually appropriate behavioral responses. Finally, the rostromedial limbic network consists of the medial OF (MOF) circuit, which facilitates integration of information pertaining to emotions, and the linked anterior cingulate (AC) circuitry. The AC network is involved primarily in motivational mechanisms but also, through the activity of its subgenual portion, in mood regulation. All circuits share a basic anatomy, with an origin in the frontal lobes and sequential projections to the striatum (caudate, putamen, or ventral striatum), GP/SN, and then to specific thalamic nuclei, with a final link back to the frontal lobe (Figure 5.1). The circuits have two pathways: (1) a direct pathway, featuring a monosynaptic link between the striatum and GP interna (GPi)/SN pars reticulata (SNr) complex, and (2) an indirect pathway that projects from striatum to GP externa (GPe), linking to GPi/SNr via the subthalamic nucleus [3] (Figure 5.2). Both direct and indirect circuits project to the thalamus; the direct pathway disinhibits the thalamus, whereas the indirect pathway inhibits it. The relative influence of the two pathways therefore determines the final output of the circuit. All circuits thus share common structures and are parallel and contiguous, but remain largely segregated anatomically, despite the progressive focusing of succeeding projections onto smaller numbers of neurons. Thus, the DLPF cortex projects to the dorsolateral region of the caudate nucleus, the LOF cortex projects to the ventral

60

Figure 5.2. The general anatomy of the direct and indirect frontal-subcortical pathways. 1 – Excitatory cortico-striatal fibers. 2 – Direct loop’s inhibitory striato-pallidal (GPi) fibers. 3 – Indirect loop’s inhibitory striato-pallidal (GPe) fibers. 4 – Indirect loop’s inhibitory GPe-subthalamic nucleus fibers. 5 – Indirect loop’s excitatory subthalamic-GPi/SNr fibers. 6 – Inhibitory outflow from GPi/SNr to specific thalamic regions. 7 – Excitatory fibers returning from thalamus to cortex (shown for convenience in contralateral hemisphere). Excitatory fibers are glutaminergic, inhibitory fibers mediated via GABA. Note: these circuits are unilateral: each set of projections from cortex to subcortical structures to cortex remains within a single hemisphere. In this figure, projection from cortex to subcortical structures as well as projections between subcortical structures are illustrated on the left half of the figure whereas projections from thalamus to cortex are illustrated on the right side of the figure. This does not suggest that these circuits cross from one hemisphere to the other; instead, they are diagrammed in this manner here in order to preserve readability of the figure.

caudate area, and the MOF and AC circuitry connects to the medial striatal/NAc region. Similar anatomic arrangements are maintained in the GP and thalamus (Figure 5.3).

Open-loop elements While each circuit comprises a closed loop of anatomically segregated dedicated neurons, open-loop elements support the functional connectivity of FSCs. Circuit structures receive projections from non-circuit cortical areas, thalamic and amygdaloid nuclei, and also project to regions outside the circuits. Brain regions linked by these afferent or efferent projections are functionally related [15, 16]. Circuits mediating limbic functions, for example, have connections to other limbic areas whereas those involved with executive functions (EFs) interact with brain structures involved with cognition. In this manner, circuits integrate information from anatomically disparate but

Chapter 5: Frontal-subcortical circuits

cortex [1, 3]. These areas project principally to the putamen and thence to ventrolateral GPi, GPe, and caudolateral SNr. The GP connects to ventral lateral, ventral anterior, and centromedian nuclei of the thalamus whose major efferents are to the SMA, premotor cortex, and motor cortex, completing the circuit. Throughout the circuit, the discrete somatotopic organization of movement-related neurons is maintained, although information processing in the circuits is not strictly sequential [3].

The oculomotor circuit The oculomotor circuit originates in the frontal eye field, Brodmann’s area (BA) 8, as well as prefrontal and posterior parietal cortex and connects sequentially to the central body of the caudate nucleus, dorsomedial GPi and ventrolateral SNr, ventral anterior and medial dorsal thalamic nuclei, and back to the frontal eye field [1–3].

The dorsolateral prefrontal circuit

Figure 5.3. The segregated anatomy of the frontal-subcortical circuits: dorsolateral prefrontal (horizontal stripes), lateral orbitofrontal (stippling), and anterior cingulate/medial orbitofrontal (cross-hatched) circuits in the striatum (top), pallidum (center), and mediodorsal thalamus (bottom).

functionally related brain regions, the cascade of the closed circuit constituting the eventual effector mechanism [17].

Organization of individual frontal-subcortical circuits The motor circuit The motor circuit originates from neurons in the SMA, premotor cortex, motor cortex, and somatosensory

Figure 5.4 illustrates the anatomy of the direct pathways of two of the behaviorally relevant FSCs. The DLPF circuit originates in BA 9 and 10 (areas reciprocally connected with adjacent BA 46) on the lateral surface of the anterior frontal lobe. Neurons in these regions project to the dorsolateral head of the caudate nucleus [18], thence to the lateral aspect of the mediodorsal GPi and rostrolateral SNr via the direct pathway [19]. The indirect pathway projects sequentially to the dorsal GPe, lateral subthalamic nucleus [20] and GPi/SNr. Output from the basal ganglia projects to the ventral anterior and mediodorsal (parvocellular portion) thalamic nuclei [21–23]. The circuit is closed by projections from these thalamic regions back to the dorsolateral frontal lobe [24, 25].

The lateral orbitofrontal circuit The LOF circuit originates in the lateral orbital gyrus of BA 11 and the medial inferior frontal gyrus of areas 10 and 47 [26]. Multiple sensory inputs, including olfactory, gustatory, visceral, somatic, and visual afferents converge on this region. Projections are to the ventrolateral caudate and dorsal edge of the NAc [27] with subsequent links to the most medial portion of the mediodorsal GPi and to the dorsomedial SNr [28]. The ventrolateral caudate also sends an indirect loop through the dorsal GPe to the lateral subthalamic

61


The anterior cingulate and subgenual cingulate circuits

Figure 5.4. The anatomy of the direct pathways of the dorsolateral prefrontal and lateral orbitofrontal circuits. NAc, nucleus accumbens; GPi, globus pallidus, internal segment; SNr, substantia nigra, pars reticulata; VAmc, ventral anterior nucleus, magnocellular portion; VApc, ventral anterior nucleus, parvocellular portion; MDpc, mediodorsal nucleus, parvocellular portion; MDmc, mediodorsal nucleus, magnocellular portion; MDpl, mediodorsal nucleus, paralaminar portion.

nucleus, thence to GPi and SNr [20]. Neurons are sent from the GPi and SNr to the medial section of the magnocellular division of the ventral anterior thalamus as well as the paralaminar portion and inferomedial sector of the magnocellular division of the mediodorsal thalamus [18, 21, 29]. The circuit then closes with projections from these thalamic regions to the LOF cortex (Figure 5.4).

The rostromedial limbic circuitry Emotional, motivational, and affective information processed by the basal ganglia is represented in the rostromedial limbic circuitry arising from the orbital and medial prefrontal cortex. Closely integrated anatomically and functionally, this comprises AC circuitry (including that related to the subgenual cingulate) and the MOF circuit (Figure 5.5).

62

There are two major subdivisions of the AC cortex, which subserve distinct functions (Figure 5.6). The dorsal cognitive division (BA 24, 24a’–b’ and 32’), also referred to as the cognitive effector region [26], is more developed in its cytoarchitecture than the rostral-ventral division, and is part of a distributed attentional network which has reciprocal interconnections with DLPF cortex (BA 46/9), parietal cortex (BA 7), and premotor and supplementary motor areas [30– 32]. This region is connected via the Muratoff bundle to dorsal and medial portions of the head and body of the caudate nucleus [7, 18, 33], with succeeding projections to the GPi/SNr and thence to the parvocellular mediodorsal thalamus as well as the ventral anterior and midline/intralaminar thalamic nuclei [25, 34]. These thalamic regions then reconnect with the cognitive division of AC via the inferior thalamic peduncle and anterior internal capsule (Figure 5.5). Functions of the cognitive effector region include modulation of attention or executive functions by influencing sensory or response selection; monitoring competition, complex motor control, motivation, novelty, error detection and working memory; and anticipation of cognitively demanding tasks [35]. The rostral-ventral affective division of the AC cortex comprises the subgenual cingulate (BA 25), adjacent (caudal) portions of BA 32 (pregenual cingulate), area 33, and the rostral portions of AC cortex, subcallosal areas 24a and 24b (Figure 5.6). These regions project to the medial part of the ventral striatum [18, 36], which includes the ventromedial caudate, ventral putamen [37], and core and shell of the NAc (the shell region receiving projections especially from the subgenual cingulate [38]). Projections from the ventral striatum and NAc core innervate the rostromedial GPi and ventral pallidum (VP, the portion of the globus pallidus inferior to the anterior commissure) as well as the rostromedial SNr and ventral tegmental area (VTA) [39–41]. The NAc shell projects to the VP, VTA and SNpc, allowing this region to influence dopaminergic inputs to other parts of the striatum [41]. The VP and GPi then project to the dorsal portion of the magnocellular mediodorsal thalamus, midline and intralaminar (parafascicular) thalamic nuclei [23, 40, 42–44], with closed-loop projections back to the anterior and subgenual cingulate (Figure 5.5) [25, 34].


Figure 5.5. The anatomy of the direct pathways of the rostromedial limbic circuits. VP, ventral pallidum; Pf, parafascicular nucleus. Other abbreviations follow Figure 5.4. The pale arrows indicate open-loop connections between engaged thalamic nuclei and the lateral orbitofrontal and dorsolateral prefrontal cortices.

While the OF cortex mediates information concerning the internal environment, the AC circuitry facilitates the intentional selection of environmental stimuli based on their internal relevance [45], thereby mediating motivated behavior. Through both its dorsal and rostral-ventral divisions and their connections with motor pathways, lateral PFC, and afferents from the midline thalamus and brainstem (including arousal systems), the AC cortex is ideally positioned to participate in the willed control of behavior [46]. The subgenual cingulate component of AC circuitry (Figures 5.5 and 5.6) includes substantial predominantly ipsilateral connections with the amygdala [44], MOF cortex (see below), other portions of both anterior and posterior cingulate, anterior insula, medial temporal lobe, hypothalamus,

periaqueductal gray and dorsal brainstem [47]. The strong projections to the dorsal raphe suggest a role in regulating the overall function of the serotonergic system [44]. With its major outflow to autonomic, visceromotor, and endocrine systems [30, 35, 48], this circuit has been implicated in salience monitoring of emotional and motivational information, mediation of emotional and autonomic response to socially significant or provocative stimuli, affective processing, and inhibitory control [35, 49, 50].

The medial orbitofrontal circuit Arising from the gyrus rectus (areas 14r, 14c) and related areas on the medial orbital surface, including BA 11m, 13a and 13b, the MOF cortex is integrated anatomically and functionally with the

63


Figure 5.7. The direct and indirect frontal-subcortical pathways. Filled arrows represent inhibitory (GABAergic) pathways; open arrows, excitatory (glutamatergic) pathways. Note that dopaminergic input from the substantia nigra pars compacta and ventral tegmental area is inhibitory, via D2 receptors, to GABA/enkephalin neurons projecting to the indirect pathway, and excitatory, via D1 receptors, to GABA/substance P neurons projecting to the direct pathway.

Figure 5.6. The medial surface of the right hemisphere (anterior towards the left), showing a schematic representation of cytoarchitectural areas of the anterior cingulate cortex. The areas forming the dorsal cognitive division and the skeletomotor effector region (striped) are outlined by solid lines, the rostro-ventral affective division areas being outlined by dotted lines.

specialized connections with the amygdala, the MOF circuit may serve both as an integrator of visceral drives as well as a sensor of information pertaining to emotions [51, 58].

Neurochemical organization Shared neurochemical organization

infracallosal AC and subgenual cingulate (“visceral effector region”) [27, 51], with which it shares subcortical projections (Figure 5.5). Sequentially, these links are to the ventromedial caudate and NAc (core); ventromedial pallidum and dorsomedial SNr; magnocellular portions of the ventral anterior and medial mediodorsal thalamic nuclei, with a closed-loop projection back to the MOF cortex [18, 23, 38–40, 52, 53]. In addition to its connections with the infracallosal cingulate, the MOF cortex has strong reciprocal connections with the medial portion of the basal and magnocellular division of the accessory basal amygdala, as well as with the ventromedial temporal pole and rostral (agranular) insula [51, 54– 57]. The subgenual cingulate provides motivational input to gustatory, olfactory and alimentary information from anterior insular processing converging on the MOF cortex. Considering its robust connections with high-order sensory association cortices and

64

Common to all circuits is an origin in the frontal lobes with excitatory glutamatergic fibers that terminate in the striatum (caudate, putamen, and ventral striatum). These striatal cells then project inhibitory gammaaminobutyric acid (GABA) fibers both to neurons in the GPi/SNr (direct loop connection) and to the GPe (indirect loop connection). Via the indirect loop, the GPe projects inhibitory GABA fibers to the subthalamic nucleus which then connects with the GPi/SNr through excitatory glutamatergic fibers [2, 59]. The direct pathway expresses dopamine (DA) D1 receptors and utilizes substance P with its GABA projection to the pallidum while the indirect loop receives its dopaminergic influence via D2 receptors and combines GABA with enkephalin [60]. The GPi/SNr then project inhibitory GABA fibers to specific thalamic targets, which complete the circuit by sending a final excitatory connection to the cortical site of the circuit’s origin in the frontal lobe (Figure 5.7).


Circuit-discrete neurochemical organization The striatum is organized as two separate systems, the striosomes and the matrix. These elements are differentiated by their distinct ontological, connectional, and chemical characteristics [61]. Relative to matrix neurons, striosomal cells mature earlier, have lower concentrations of DA, serotonin and acetylcholine, and have high concentrations of limbic-associated membrane protein [62, 63]. Striosomes receive dense orbitofrontal and insular input and have high levels of D1 receptors, with dopaminergic projections from the ventral tier of the substantia nigra pars compacta (SNpc). In contradistinction, matrix cells receive afferents predominantly from the sensorimotor cortex and express primarily D2 receptors, with dopaminergic input from the dorsal tier of the SNpc [64]. The matrix stains selectively for adenylate cyclase whereas the phosphoinositide system is selectively concentrated in the striosomes of the medial and ventral striatum [65]. GABAergic output from the striosomes is to the medial portion of the SNpc, dedicated to the OF circuit, whereas the GABAergic output of the matrix is to the GPe, GPi, and SNr. Mirroring the circuit-discrete neurochemical organization of the striatum, the NAc region of the ventromedial striatum is also divided into two functionally distinct components with discrete histochemistries. Thus, the core or dorsolateral portion of the NAc, which receives projections from the MOF and AC cortex, is distinguished by a lower concentration of mu opiate receptors and a higher concentration of calcium-binding proteins. This region is virtually identical histologically to the ventromedial caudate. In distinction, the shell or ventromedial portion of NAc, which receives a segregated pool of projections from the subgenual cingulate (BA 25) and pregenual cingulate (BA 32), is inversely devoid of calcium-binding proteins and replete with mu opiate receptors [38].

Neurotransmitter systems influencing frontal-subcortical circuits Processing of the detailed information contained in the FSCs is modulated by input from dopaminergic, cholinergic, noradrenergic, and serotonergic systems.

The dopamine system Dopaminergic projections from the SNpc (primarily cell group A9), the caudal extension of SNpc into the

retrorubral region (cell group A8) and the VTA (A10 cell group) innervate the entire striatum, thereby influencing each of the FSCs. This provides an anatomic basis for the multifaceted effects of dopaminergic agents on motor activity, motivation, thought, and behavior. Reflecting DA’s modulatory function, DAcontaining axon terminals synapse directly on striatal output neurons, many on the necks of dendritic spines. The VTA is the primary source of DA for the ventral striatum, prefrontal cortex, and limbic targets. The nigra has inhibitory connections, via D1 receptors, with the indirect portions of the FSCs and excitatory connections, via D2 receptors, with the direct circuits (see Figure 5.2). Representing an important convergence within the otherwise segregated FSCs, the SNpc receives diffuse input from the limbic circuits, providing a means for limbic emotional input to influence both motor activity and cognition.

The cholinergic system Cholinergic input to the basal ganglia and most of the thalamus is derived from the pedunculopontine nucleus and laterodorsal tegmentum of the brainstem. Second, portions of the mediodorsal, ventroanterior, and reticular nuclei of the thalamus, as well as limbic structures and neocortex, receive cholinergic input from the basal forebrain, which includes the septum, diagonal band of Broca, and the nucleus basalis of Meynert [66]. Acetylcholine facilitates thalamic activation of the cortex and also assists in the septal hippocampal pathway supporting mnemonic function. Within the striatum, there are important interactions between the cholinergic and dopaminergic systems. Activation of D2 DA receptors, located on cholinergic interneurons, inhibits acetylcholine release, whereas D1 receptor agonists enhance acetylcholine release. Conversely, acetylcholine enhances DA release via nicotinic and muscarinic receptors located on presynaptic DA terminals [67].

The norepinephrine system Noradrenergic neurons from the locus coeruleus project to the entire cortex and hippocampus as well as cerebellum and spinal cord. A ventral pathway originating below the locus coeruleus innervates the brainstem and hypothalamus. Beta 1 receptors are present in the cerebral cortex while beta 2 receptors predominate in the cerebellum. Electrophysiologic studies suggest

65


that a balance between norepinephrine and DA levels may set the signal-to-noise ratio of the attentional system [68, 69], which incorporates a distributed network involving the cingulate, DLPF, and inferior parietal cortices [70].

The serotonergic system The serotonin 5-HT1 receptor is the most abundant serotonin receptor in the basal ganglia. 5-HT1C receptors are very dense in the globus pallidus and moderately dense in the caudate, putamen, and accumbens regions, which also contain intermediate levels of the 5-HT2 receptor. The highest densities of 5-HT1D receptors are found in the basal ganglia and SN. 5-HT3 is enriched in the striatal matrix and is the most abundant receptor in the ventral striatum [62, 71] and other areas functionally related to the AC circuit, including hippocampus, septum, and amygdala. This receptor is linked to a ligand-gated cation channel that also modulates the release of acetylcholine and DA.

Mechanisms for interactions between motor and behavioral circuits Although the FSCs remain largely segregated throughout their course, several mechanisms may allow for complex interactions between motor and behavioral systems [52]. At higher levels, thalamic relay nuclei form not only reciprocal but also non-reciprocal cortical connections, linking multiple frontal cortical areas, allowing for information flow between cortical circuits [23] (see Figure 5.5 as an example). At the level of the striatum, striosomes interdigitate with the surrounding matrix, so that matrix-striosome borders may serve as interfaces where the sensorimotor systems of the matrix interact with the striosomal processing of prefrontal and limbic inputs [72]. Linkage between the sensorimotor and limbic related regions of the striatum can also occur through corticonigral influences on the striatum and through the overlapping efferent striatal projections to the SN. Whereas the main output from the striatal matrix is to the GPi and SNr, striosomes project primarily to the dopaminergic SNpc. In this manner, the ventral striatum is able to exert a global regulatory influence on the dopaminergic input to the entire striatum. This provides an important mechanism for limbic “motivational” input to modulate motor behavior and provides for the “anchoring” or reinforcement of successful experience.

66

A recent re-evaluation [41] supports the original concept of the NAc part of the ventral striatum as a functional interface between the limbic and motor systems [73]. Thus, its afferent connections position this region as a site for integration of signals with emotional content (amygdala); contextual information (hippocampus); motivational significance (dopaminergic inputs); information about the state of arousal (midline thalamus); and executive/cognitive information (prefrontal cortex) [41]. Outputs of the ventral striatum include projections to the brainstem dorsal raphe, the midbrain parabrachial region and to the habenula, which may also play an important role in integration of the motor and behavioral circuits [74]. The habenula, which receives input from the anterior thalamic nuclei and GP, projects to the rostral midbrain with connections to the dopaminergic VTA and to the serotonergic dorsal raphe. Both of these cell groups project diffusely to multiple tiers of the FSCs. In particular, the limbic ventral striatal and habenular input to the dorsal raphe suggests another important mechanism for cross-talk between circuits and for limbic modulation of motor function [75]. Also providing for circuit linkage between limbic and motor systems are the cholinergic interneurons of the caudate and putamen and somatostatin/neuropeptide Y-containing interneurons that ramify between compartments [76]. Differences in peptide cotransmitters and in monoaminergic, GABAergic and glutamatergic synaptic receptor expression at subcortical sites (see above) provide other mechanisms for differential response within FSCs and for a complex interplay between these circuits [75]. From a neurophysiologic perspective, integration of the temporal coincidence of processing in FSCs, occurring particularly at the level of the thalamus [74], may also contribute importantly to linkage and synthesis of information between FSCs.

Prototypical frontal-subcortical circuit syndromes Three principal frontal lobe symptom complexes are recognizable: a medial frontal-AC syndrome with apathy and diminished initiative; an OF syndrome with prominent disinhibition and irritability; and a DLPF syndrome, with neuropsychological deficits involving


EFs. Supporting the concept of circuit-specific behavioral syndromes, similar disorders have been observed with lesions of subcortical structures of these circuits.

The anterior cingulate syndrome: akinetic mutism and abulia Akinetic mutism (AM) [77] represents a wakeful state of profound apathy, with indifference to pain, thirst, or hunger, and absence of motor or psychic initiative, manifested by lack of spontaneous movement, absent verbalization, and failure to respond to questions or commands. The term abulia, derived from the Greek boul, or will [78] refers to a similar but less severe psychomotor syndrome, encompassing lack of spontaneity, apathy, and paucity of speech and movement. Akinetic mutism has been described with AC lesions, craniopharyngiomas, obstructive hydrocephalus, tumors in the region of the third ventricle, and other conditions involving the ventral striatum (NAc and ventromedial caudate), ventral GP, and medial thalamus [79]. Although reports of the clinical consequences of lesions restricted to limbic structures of the basal ganglia are scarce [57], larger lesions that include both ventral striatum and more dorsal areas of the basal ganglia are associated with severe apathetic states. In a review of patients with focal lesions of the basal ganglia [80], abulia occurred in 18 of 64 (28%) small and large caudate lesions sparing the lentiform nucleus, 15 of which were unilateral. Abulia was also seen in six of 22 (27%) restricted GP lesions, all bilateral, but did not accompany isolated lesions of the putamen (a link in the motor circuit). Lesions of the mediodorsal and anterior nuclei of the thalamus may also result in apathy [81–83]. Unilateral lesions of the AC cortex produce transient AM [84] while the most dramatic examples of AM follow bilateral AC lesions [85], particularly lesions that extend from the cognitive effector region posteriorly into the skeletomotor effector division of the cingulate [51], a region connected with primary motor and SMA [29, 86]. There are non-overlapping representations for hand movements and speech within the AC cortex, reflecting separate AC motor channels [29]. While there are no published reports of isolated speech deficits with restricted cingulate lesions, bilateral lesions in monkeys to the rostral AC cortex, located around the genu of the corpus callosum, significantly impair spontaneous vocalization whereas deficits involving limb movements in

humans have been associated with lesions affecting both rostral and caudal cingulate motor areas [46]. Reflecting reciprocal connections between the AC cortex and the MOF cortex [51], orbito-medial prefrontal cortical lesions may also result in severe forms of apathy [46, 57]. Data suggest a functional continuum along the rostral-caudal axis of medial frontal lobe regions from cognitive and emotional functions to motor functions devoted to self-initiation of action and thought [57]. Reflecting this continuum, a similar disorder affecting the “drive” for willed movement and speech (“motor neglect”) has been seen in patients with lesions of the SMA [87–89]. Such patients exhibit initial global akinesia and neglect, which then lateralizes in unilateral cases. Primarily part of the motor circuit, the SMA also receives reciprocal projections from the AC (area 24c’). Positron emission tomography (PET) studies in humans have shown that regional cerebral blood flow in the rostral SMA and adjacent mesial frontal cortex is associated with the self-generation of motor actions but not with externally cued ones [90]. Conceptually distinct, DLPC circuit lesions may produce a “cognitive” rather than “emotionalaffective” form of apathy, cognitive inertia resulting from difficulties in elaborating the plan of actions necessary for ongoing or forthcoming behavior [57]. This reflects links between layer V of the dorsal cingulate cortex and superficial layers of the DLPF cortex (see Figure 5.5), a powerful avenue of communication between cognitive and motor systems [31]. Thus, while the AC can be considered broadly as the cortical gateway for limbic motivation to influence goal-directed behavior [26], subtypes of apathy may be defined based on the connections of the cingulate with other regions [30, 91].

The orbitofrontal syndrome: personality and emotional changes The OF cortex is the neocortical representation of the limbic system [92] and is involved in the determination of the appropriate time, place, and strategy for environmentally elicited behavioral responses. Lesions in this area disconnect frontal monitoring systems from limbic input [93]. In particular, visceral sensory input to OF cortex is normally used to provide information about the internal milieu and guide bodily reactions to that status (“somatic marker hypothesis”) [94]. Lesions of the LOF may then result in an “interoceptic

67


agnosia,” which may provide the basis for the variety of emotional and social deficits commonly observed with such lesions. Impulsivity and behavioral disinhibition are the hallmark symptoms of OF lesions. Common manifestations include lack of judgment and social tact, improper sexual remarks or gestures and other antisocial acts [95, 96]. Patients may exhibit inappropriate jocularity (witzelsucht) or emotional lability and irritability, trivial stimuli often resulting in abrupt outbursts of anger [97]. Inattention, distractibility, and increased motor activity may be seen, as well as hypomania or mania. MOF lesions are associated with abnormal autonomic responses to socially meaningful behavior and difficulty extinguishing unreinforced behavior, which correlate with antisocial acts [98]. Large bilateral OF lobe lesions may result in enslavement to environmental cues, with automatic imitation of the gestures of others, or enforced utilization of environmental objects [99]. Typically, however, patients with OF dysfunction exhibit a dissociation between impairment of behavior necessary for activities of daily living and normal performance on psychological tests sensitive to frontal lobe dysfunction, such as the Wisconsin Card-Sorting Test (WCST) [93, 100, 101]. Although the OF syndrome usually follows bilateral OF cortex injury [93, 101], unilateral lesions may produce a similar disorder [102]. Patients with ventral caudate lesions may also appear disinhibited, euphoric, impulsive and inappropriate, reproducing the corresponding OF lobe syndrome [103]. It is likely that the early appearance of comparable personality alterations in Huntington’s disease (HD) reflects the involvement of medial caudate regions receiving OF and AC circuit projections [104]. Similarly, mania (see below) may result not only from injury to MOF cortex and caudate nuclei but also from lesions to the right thalamus [105–108]. Mixed behavioral syndromes commonly accompany focal lesions of the GP and thalamus, reflecting the progressive spatial restriction of the parallel circuits at these levels [109].

The dorsolateral prefrontal syndrome: executive function deficits Both experimental and clinical data link the DLPF cortex and its subcortical connections with EFs. Executive functions incorporate anticipation, goal selection, planning, monitoring, and use of feedback to

68

adjust task performance. Patients with restricted DLPF cortex lesions have difficulty focusing and sustaining attention, generating hypotheses, and maintaining or shifting sets in response to changing task demands, as required by the WCST [110]. Associated features include reduced verbal and design fluency, impairment of memory search strategies and of organizational and constructional strategies on learning and copying tasks, and motor programming disturbances. Similar syndromes have been reported in patients with lesions of subcortical structures of the DLPF circuit [109]. Thus, impairment on tests of memory and EF, including the WCST, have been noted in patients with dorsal caudate lesions [103], bilateral GP hemorrhages [111] and bilateral or left paramedian/medio-dorsal thalamic infarction [112, 113]. Executive functions deficits and other features of “subcortical” dementia [114] in such conditions as HD, Parkinson’s disease (PD), progressive supranuclear palsy (PSP), Wilson’s disease, neuroacanthocytosis and other subcortical disorders are believed to reflect involvement of the DLPF circuit as it projects through the basal ganglia [109, 115–117].

Movement disorders and frontal-subcortical circuits Basal ganglia dysfunction frequently results not only in disorders of movement, but also in alterations in intellectual function, mood, personality, and behavior. The nature and severity of such changes reflect the extent of involvement of the behaviorally relevant FSC structures, which project through the caudate and ventral striatum, rather than the motor circuit, which projects to the putamen. Diseases affecting primarily the putamen, such as PD, thus exhibit less striking intellectual and emotional alterations than diseases that affect primarily the caudate, such as HD. In PD, executive dysfunction and dementia is associated with involvement of the medial substantia nigra and VTA, which project to the caudate nucleus and medial frontal cortex, and is not present when changes are confined to the lateral nigral neurons, which project to the putamen [118]. While patients with PSP, a hypokinetic disease, exhibit hypoactive behaviors such as apathy, patients with HD, a hyperkinetic syndrome, exhibit predominantly hyperactive behaviors, such as agitation, irritation, euphoria, or anxiety. Such behaviors may result from an excitatory subcortical output through the medial and OF cortical circuits [119].


Subcortical dementia and amnestic syndromes Subcortical dementia is generally characterized by neuropsychological deficits typical of DLPF circuit lesions [114, 120]. Such deficits may be combined with amnesia, however, when subcortical lesions involve the thalamus [109]. The thalamus is poised at the interface of the FSCs and the medial temporal-limbic circuit (incorporating the hippocampus, fornix, hypothalamus, and thalamus). While the FSCs mediate memory activation and search functions, the medial temporalthalamic circuit mediates memory storage (both recall and recognition) [113]. A related syndrome involving amnesia, fluctuating inattention, apathy and psychomotor retardation, may occur with capsular genu infarction. It has been inferred that such lesions interrupt the inferior and anterior thalamic peduncles, functionally deactivating the ipsilateral frontal cortex [121]. The anterior thalamic peduncle conveys reciprocal connections between the thalamic dorsomedial nucleus and the cingulate gyrus, as well as the prefrontal and OF cortex; the inferior thalamic peduncle carries fibers which connect with the OF, insular and temporal cortices, and amygdala. Injury to these tracts thus produces a thalamocortical disconnection syndrome combining amnesia with FSC circuit deficits.

Frontal-subcortical circuit dysfunction associated with neuropsychiatric disorders Obsessive-compulsive disorder and Tourette syndrome Convergent data, including ethological and experimental observations [122, 123], clinicopathologic findings [124, 125], behavioral observations [126], magnetic resonance imaging (MRI) [127–129] and PET studies [130–133] have implicated the basal ganglia and related cortical and thalamic structures in the pathobiology of both obsessive-compulsive disorder (OCD) and Gilles de la Tourette syndrome (TS). The neurobiologic substrates for these disorders include both corticostriatothalamocortical circuits and monoaminergic pathways that modulate the activity of these circuits [134–139].

In OCD, functional imaging studies have shown increased glucose metabolism or blood flow in the medial and OF cortex and AC gyrus, in the caudate nucleus, and, to a lesser extent, in the thalamus. This has suggested aberrant OF and limbic circuits as pathophysiologic mechanisms in OCD [130, 140, 141]. The prevailing theory is that the observed cortical, striatal, and thalamic overactivity in OCD results from a relative imbalance favoring the direct versus indirect pathways within this circuitry, leading to failed striatothalamic inhibition [140, 142, 143]. In TS, studies have suggested both anatomical and functional disturbances in basal gangliathalamocortical circuits. Diffusion-tensor (DT)-MRI has shown smaller left caudate and bilateral thalamic volumes in TS children compared with controls, tic severity being positively correlated with group differences in radial water perfusion in the right thalamus [144]. Resting state fluorodeoxyglucose (FDG)–PET has suggested reduced activity in a limbic basal ganglia-thalamocortical network, with covariate decreases in caudate and thalamic metabolism associated with smaller reductions in lentiform and hippocampal activity. The expression of this metabolic pattern correlated closely with ratings on the Tourette Syndrome Global Scale [133]. Tic severity in TS has also been correlated with hypoperfusion of the left caudate and cingulate gyrus [145] and differences in D2 DA receptor binding in the head of the caudate nucleus has predicted differences in tic severity within monozygotic twin pairs [146]. The preceding observations link tics to the “associative” (non-motor) neural circuits in which the caudate nucleus (not the putamen) is a key node, and has suggested that dopaminergic dysfunction in the caudate may underlie the integrated ideational-motor symptomatology of TS and the “compulsive” quality of tics [146]. Other studies have supported the importance of sensory elements in tic pathophysiology. Thus, functional MRI (fMRI) has identified a brain network of paralimbic and sensory association areas which are activated before tic onset, analogous to movements triggered internally by unpleasant sensations, such as itch and pain [147]. It has been hypothesized that discrete sets of striatal neurons may become overactive in TS, and that the production of simple tics (via motor circuit activation), complex tics (via activation of premotor areas, SMAs, and cingulate motor areas), and compulsions (with OF circuit involvement) might be determined

69


by the specific FSC that is impacted [148]. Consistent with this hypothesis, increasing complexity of cognitive and behavioral symptoms in TS has been associated with increasing, apparently dysfunctional synaptic activity within the medial, lateral, and caudal OF cortices on FDG-PET scans [149]. PET data have also suggested an alteration of cortical–subcortical interactions in TS, with increased metabolic rates in frontal motor regions and decreases in glucose utilization in paralimbic prefrontal cortices and in the ventral striatum [131]. Ventral striatal dysfunction has also been shown with PET using [11C] dihydrotetrabenazine (DTBZ) to label the type 2 vesicular monoamine transporter, TS patients showing increased DTBZ binding in the ventral striatum relative to controls [150]. Pertinent to such findings, and by analogy with animal models of stereotypy, it has been postulated that the pathophysiology of TS may be related to an imbalance between dorsal and ventral striato-pallidal systems, perhaps arising from striosomal dysfunction [148, 151, 152].

Attention-deficit hyperactivity disorder Characterized by inattention, impulsivity and hyperactivity, attention-deficit hyperactivity disorder (ADHD) shares clinical features with other neuropsychiatric conditions, including the OF and DLPF syndromes. It has been hypothesized that the neural substrates of ADHD involve disturbances in frontal-subcortical interactions involving arousal and reward systems [153] which are driven primarily by dopaminergic activity and modulated by adrenergic and serotonergic mechanisms. Dysfunction of fronto-striatal type in ADHD has been inferred from neuropsychological studies [154–156], the pattern of cognitive deficits resembling those found in “striatal” disorders such as TS [157] and HD [158]. Both MRI and quantitative morphologic studies have shown smaller caudate volumes in ADHD patients compared with controls [159, 160]. Xenon inhalation and emission tomography have revealed striatal hypoperfusion in childhood ADHD, partially reversible by methylphenidate [161], and fMRI has also shown differences between ADHD children and controls in frontal-striatal function and its modulation by methylphenidate [162]. Performance on response inhibition tasks have correlated significantly with fMRI measures of the prefrontal cortex and caudate nuclei, predominantly in the right hemisphere

70

[163]. Comparable PET studies have shown caudate hypofunction in response-inhibition paradigms [164]. The relevance of these findings may relate to the integration of the caudate nuclei not only in the DLPF (executive function) circuit but also in the OF circuit, which subserves delayed responding in primates. Impaired signaling of delayed rewards is also integral to ADHD and has been linked to disturbances in motivation processes. This implicates the AC circuit [165], which links the ventral striatum, especially NAc [166] to both AC and OF cortex [167]. Dysfunction in NAc in ADHD is consistent with the observed variability in response to psychostimulant therapy in affected children [168]. A dual pathway hypothesis [169, 170] proposes that alterations within the DLPF circuit, modulated by mesocortical DA, and the AC/reward circuit, modulated by mesolimbic DA, constitute discrete neuropsychologic bases for dissociable psychological processes in ADHD, leading to executive/inhibitory deficits and delay aversion, respectively. It is likely that both DA and norepinephrine actions contribute to the therapeutic effects of stimulants in patients with ADHD. Electrophysiologic studies in animals suggest that DA decreases “noise” through modest levels of stimulation of D1 receptors, abundantly present in prefrontal cortex, while norepinephrine enhances “signals” through post-synaptic alpha2A-adrenoceptors in prefrontal cortex [70, 171]. Alpha2-receptor stimulation increases delay-related neuronal firing [172], the cellular measure of working memory and behavioral inhibition.

Depression Both structural and functional brain-imaging studies have supported an association between lesions disrupting frontostriatal or paralimbic pathways and depressed mood. OF-inferior prefrontal cortex metabolism is lower in depressed when compared with non-depressed HD patients [173], and PD patients with depression show significantly lower metabolic activity both in the orbital-inferior frontal cortex and head of the caudate nucleus compared with those without depression [174]. This is consistent with pathological evidence in depressed, cognitively impaired parkinsonian patients of disproportionate degeneration of DA neurons in the VTA, a system that is linked to motivation and reward (see below) [152] and which projects to OF and prefrontal cortex.


Frontolimbic DA deficiency may underlie clinical similarities between the anhedonia and “psychomotor retardation” (PsR) of major depression and the lethargy of thought, affect, and movement that constitutes “bradyphrenia” in PD [175]. Anhedonia has been linked with novelty reward, mediated by dopaminergic projections to the ventral striatum, and reward scores in response to a dopaminergic challenge correlate with activity changes in ventrolateral prefrontal cortex and caudate/putamen on fMRI in major depression [176]. Depressed patients with PsR show decreased presynaptic DA function in the left caudate [177] and elevated putaminal D2 receptor binding [178]. The DA metabolite homovanillic acid (HVA) is diminished in depressed patients with PsR [179] and levodopa improves the PsR of major depression [180]. Furthermore, clinical improvement in depressed patients with PsR parallels the dopamimetic specificity of the antidepressants administered [181]. However, DA agonists alone have limited effect on depressive symptoms in PD [182] and cerebrospinal fluid (CSF) HVA levels do not correlate with mood in PD [183]. Based on convergent findings from patients with primary and secondary depression, a model of depression has been proposed which implicates failure of the coordinated interactions of a distributed network of cortical-limbic pathways [184]. In this model, a dorsal (“attention-cognition”) compartment which includes both neocortical (DLPF) and superior limbic (AC) elements is postulated to regulate attentional and cognitive aspects of depression, such as apathy, psychomotor slowing, and impaired attention and EF. A ventral (“vegetative-circadian”) compartment, which is composed of limbic, paralimbic, and subcortical regions (anterior insula, hippocampus, subgenual cingulate, and hypothalamus) is recognized as mediating circadian and vegetative aspects of the illness, including sleep, appetite, libidinal, and endocrine disturbances. Both PET and fMRI studies have revealed decreased function of dorsal regions, such as the ventral AC cortex, and increased limbic metabolism and activation in depression [185], while fMRI has shown reciprocal effects of antidepressant treatment on activity and connectivity in these regions [186]. The rostral anterior (pregenual) cingulate is isolated from both the ventral and dorsal compartments based on its cytoarchitectural characteristics and its reciprocal connections to both compartments and may serve an important regulatory role in mediating interactions between them [187].

An important role for the subgenual cingulate (BA 25) in depression was first provided by the observation of metabolic change (overactivity) in this region in treatment-resistant depression, which uniquely predicted antidepressant response [184, 185]. Deep brain stimulation (DBS) of white matter tracts adjacent to the subgenual cingulate was subsequently shown to effectively reverse symptoms in otherwise treatmentresistant depression [188, 189] (see below). Disturbances in the subgenual cingulate circuit have been linked also with the rapid mood shifts in bipolar disorder, and may have a role in the pathophysiology of OCD [190, 191].

Mania and the lateralization of emotional behavior Affective response to brain injury may reflect the hemisphere involved. Thus, crying is more common in patients with left hemispheric lesions, while laughter occurs with right-sided lesions [192]. Left frontal and left basal ganglia infarctions are most likely to be associated with depression [103, 193] and in PD depression is more common with right hemiparkinsonism (left striato-frontal dysfunction) [194]. Conversely, mania frequently results from right-sided thalamic or right medial diencephalic lesions that may disrupt hypothalamic circuits or disturb modulating transmitters traversing the medial forebrain bundle [106, 107]. Mania has also been observed in patients with MOF cortex lesions and caudate dysfunction in basal ganglia disorders such as HD [193, 195]. The increase in appetite drives that often accompanies mania has suggested underlying hyperfunctioning of the paleocortical paralimbic belt [51]. Whereas depressed patients show bilateral temporal hypometabolism on FDG-PET scans, patients with mania exhibit unilateral, right-sided temporal hypometabolism [194]. A differential biochemical response to injury in the two hemispheres may contribute to the polarity of the expressed mood disorder. Thus, right but not left frontolateral cortical lesions in rat models produce hyperactivity, widespread depletion of brain norepinephrine, and an increased turnover of DA in the NAc. Correspondingly, right but not left hemispheric stroke in humans leads to an increase in 5-HT-2 serotonin receptor binding in both temporal and parietal cortex [194].

71


Bipolar disorder Vulnerability to bipolar disorder (BD) is linked with the gene coding for diacylglycerol (DAG) kinase eta, an enzyme that metabolizes DAG, inhibiting phosphatidylinositol-protein kinase C intracellular signaling [196–198]. The phospho-inositol second messenger system is concentrated in striosomes in limbic brain regions. This chemoarchitectural disorganization in BD is consistent with a disease model that involves dysfunction within both striato-thalamoprefrontal networks and limbic modulating regions [199–202]. Support for this model includes MRI abnormalities in prefrontal cortical areas, striatum and amygdala, and activation differences in anterior limbic regions shown by functional imaging studies. Specifically, reduced ventral and orbital prefrontal activity and increased amygdala activity has been noted, both during episodes and in remission. This suggests that dysregulation of mood in BD may result from diminished prefrontal modulation of subcortical limbic structures [199, 203].

Schizophrenia Failures of stimulus filtering and gating in schizophrenic patients have been linked with abnormalities of cortico-striato-pallido-thalamic circuitry [204–206]. Evidence implicating the DLPF circuit in schizophrenia includes the similarity of observed neuropsychological deficits to symptoms associated with DLPF lesions, decreased regional metabolism and blood flow activation, disruption of cortical subplate activity (required for connectivity of thalamocortical neurons), and decreases in major components of the GABA cortical inhibitory system [207–209]. The DLPF cortex is part of a task-related frontoparietal neuronal network, the activity of which is anticorrelated with a “default” network that is normally active at rest. The latter network, which includes medial prefrontal and posterior cortices, has been linked with internally generated “stimulusindependent” thought as well as self-monitoring and salience monitoring [210]. Using a brain-imaging technique based on low-frequency fluctuations of the blood oxygen level-dependent (BOLD) signal, schizophrenic patients exhibited striking deficits in regions associated with the default network, including the posterior cingulate and medial prefrontal regions [211]. This supports earlier data showing deficits in

72

small interneurons in cingulate and prefrontal cortices in schizophrenic patients [212]. It has been suggested that if the default network in schizophrenia is associated with decreased communication between the medial prefrontal and posterior cingulate regions, self-monitoring systems may become split, leading to the perception that auditory thoughts are externally produced [213].

Substance abuse disorders and impulse control disorders The principal components of the drug reward circuit are the A10 dopaminergic cell group of the VTA, limbic structures of the basal forebrain (OF cortex, AC cortex and ventral striatum, particularly NAc) and the dopaminergic connection between the VTA and basal forebrain limbic system (mesocorticolimbic DA system). This network links substance addiction to brain motivational and reward systems. Linked brain regions include the amygdala, which provides affective salience, and the hippocampus, relaying contextual memories. While early phases of drug-seeking behavior and addiction are probably characterized by interactions between these systems, the dorsal striatum appears to become involved in later phases when drugtaking has become a habit [214–218]. Other components of the drug reward circuit are the opioid peptide, GABA, glutamate, and serotonin systems, and other neural inputs that interact with the VTA and basal forebrain [219–221]. Impulse control disorders (ICDs), including pathological gambling, compulsive sexual behavior, and compulsive buying, are characterized by a failure to resist an impulse, drive, or temptation to perform a typically pleasurable activity. A range of ICDs occur at a greater frequency in PD than in the general population and are linked particularly with the use of direct DA agonist drugs [222]. Compared with levodopa, DA agonists have significantly greater occupation of D3 DA receptors which are concentrated in limbic brain regions, including ventral striatum, with highest concentrations in the shell of the NAc [223]. Even within the dorsal striatum, the D3 receptor is primarily localized to the patch/striosome compartment that is anatomically connected to limbic structures [224, 225]. This and other evidence suggests that pathological gambling and other ICDs in PD may result from dopaminergic overstimulation of a relatively preserved


mesocorticolimbic DA pathway in predisposed individuals [226]. Although considered by some as OCD-spectrum disorders, there is broader support for categorizing ICDs as behavioral addictions [227–230]. Supporting such a model, a single photon emission computed tomography (SPECT) study of PD patients with pathological gambling showed resting state overactivity in a right hemisphere network that included the OF cortex, hippocampus, amygdala, insula, and ventral pallidum [226]. The ventral pallidum is part of the limbic circuitry (see above) and is implicated in the modulation of hedonic responses to natural and drug rewards, and subsequent reward seeking-motivated drive [231].

Therapeutic interventions for frontal-subcortical circuit disorders Pharmacologic interventions The dorsolateral prefrontal syndrome: executive dysfunction In PD, specific executive functions, including working memory, cognitive sequencing, and attention shifting, may respond at least partially to dopaminergic therapies [232, 233]. This reflects the combined impact in PD of caudate nuclear DA deficiency, which creates a partial “disconnection syndrome” of subcortical origin [234] and a lesser reduction of DA in the DLPF cortex [235]. However, incomplete reversal of cognitive deficits with DA agonists is typically noted in PD [233, 236], reflecting the importance of non-dopaminergic neuronal dysfunction, especially cholinergic dysfunction, in PD dementia. Executive dysfunction in PD may also be ameliorated by the selective norepinephrine reuptake inhibitor atomoxetine [237]. This is consistent with psychopharmacologic and anatomical studies, which implicate the noradrenergic as well as the dopaminergic system as an important modulator of frontal lobe function [172, 238, 239]. Noradrenergic agents may also ameliorate executive dysfunction in a variety of other clinical states. The alpha-2 adrenergic agonists clonidine and guanfacine both enhance working memory performance in aged monkeys [240, 241] and cognitive tasks mediated by prefrontal cortex, such as Trails B, Word Fluency and Stroop tasks, are improved

by clonidine in patients with schizophrenia and Korsakoff ’s syndrome [242–244]. In patients with dementia of the frontal lobe type, EF may be selectively enhanced by the alpha-2 adrenergic antagonist idazoxan [245]. In ADHD and TS, a variety of agents having important effects on the noradrenergic system, dopaminergic system, or both, may ameliorate features of both DLPF (attentional/executive) and OF (inhibitory) dysfunction (see below). Such drugs include selegiline, stimulant medications, low-dose tricyclic antidepressants, clonidine, and guanfacine [246–251].

The anterior cingulate syndrome: akinetic mutism and apathy In animals, a syndrome similar to akinetic mutism (AM) was first demonstrated by bilateral or unilateral injection of 6-hydroxydopamine into the SN, VTA, or nigrostriatal tract within the medial forebrain bundles of the lateral hypothalamus [252–254]. These behavioral deficits could be reversed by the direct DA agonist apomorphine [255, 256], and blocked by pretreatment with the DA receptor antagonist spiroperidol [257]. Similarly, in an early clinical report, AM following surgical removal of a tumor from the anterior hypothalamus responded to the DA receptor agonists lergotrile and bromocriptine but not to the presynaptic dopaminomimetics carbidopa/levodopa or methylphenidate [258]. This suggested that akinesia in this setting resulted from loss of dopaminergic input to AC or other corticolimbic structures rather than to the striatum. Clinico-pathologic correlations have subsequently suggested that isolated damage to any of the projections of brainstem dopaminergic nuclear groups may result in AM [259]. Chronic AM secondary to mesencephalic infarction, destroying ventral tegmental DA neurons at their site of origin, may also be reversed with DA agonists [260]. Where DA receptors have been lost, however, as in patients with lesions involving the AC gyri, response to direct DA agonists is typically poor. While requiring confirmation, a recent report suggests that AM may respond successfully to intramuscular olanzapine [261], a drug which may also ameliorate negative symptoms in schizophrenia. In addition to blockade of DA D2-receptors in the mesolimbic pathway, olanzapine blocks serotonin 5HT2A receptors, leading to disinhibition of D2 receptors and enhanced DA release in the mesocortical pathway.

73


A preponderance of the latter action might explain observed increases in levels of DA in the medial prefrontal cortex in response to olanzapine administration [261]. Dopaminergic agents may also afford a clinically significant and sustained improvement in apathetic states encountered in a variety of neuropsychiatric disorders including Wilson’s disease, PD and human immunodeficiency virus (HIV)-associated dementia, subcortical strokes and anterior communicating artery aneurysm [209, 262–266]. Effective agents in such conditions may include direct DA agonists, particularly pramipexole and ropinirole, which have some selectivity for D3 receptors, amantadine, selegiline, bupropion, amphetamine, and methylphenidate. Apathy is the most commonly observed behavioral disturbance in Alzheimer’s disease (AD) and is associated with AC hypoperfusion [267]. The documented improvement in AD-related apathy with cholinesterase inhibitor therapy [268] may reflect partial correction of cholinergic disconnection of AC structures. The latter include the basal nucleus of the amygdala [51], innervated by cholinergic projections from basal forebrain structures, and the midline thalamic nuclei which receive input both from the basal forebrain and from cholinergic pedunculopontine projections that form part of the ascending reticular activating system. Cholinesterase inhibitors may also ameliorate apathy in traumatic brain injury [269, 270].

The orbitofrontal syndrome: personality change A variety of pharmacologic agents may ameliorate, at least partially, the disinhibited behavior of the patient with OF circuit dysfunction [271]. Such drugs include the major and minor tranquilizers, propranolol, buspirone, carbamazepine, sodium valproate, lithium, clonidine, and selective serotonin reuptake inhibitors (SSRIs). Robust data, including studies using 5HT1B receptor gene knockout mice [272], link behavioral disinhibition with central serotonergic deficiency [273–276]. The efficacy of serotonergic agonists, including fluoxetine and clomipramine, for impulsive, aggressive, or sexually disinhibited behaviors [275, 277, 278] may relate to the density of serotonin receptors in the ventral striatum and other limbic brain regions. Certain 5-HT1A agonists (“serenics”) exert a dose-dependent decrease in aggression with a concomitant increase in social interest in animal

74

paradigms [279]. In man, both propranolol and pindolol have agonist effects at limbic somato-dendritic 5-HT1A receptors at dosages used in the treatment of aggressive behavior [280–282] and the partial 5-HT1A agonist buspirone may also be effective in the treatment of aggression in a variety of neuropsychiatric conditions. In addition to their dopaminergic activity, neuroleptics may have a serotonergic mode of action in the treatment of impulsive aggression by binding to and down-regulating the 5-HT2 receptor [274], which is represented in intermediate levels in the NAc and striatum. Lithium’s mood-stabilizing action may be mediated by effects both on the serotonin system and on phosphoinositide [283, 284], which is selectively concentrated in striosomes of the medial and ventral striatum [64], regions which receive dense OF input. Clonidine is an alpha-2 noradrenergic agonist, which reduces central noradrenergic transmission by stimulating presynaptic autoreceptors [285, 286]. Its efficacy for OF syndrome is exemplified by the report of a patient with OF dysfunction including mania secondary to bilateral OF contusions [105]. The rapid response to clonidine in this case was attributed to reduction of noradrenergic overactivity induced by lesions of prefrontal areas projecting to noradrenergic systems [287] which, in turn, innervate and modulate prefrontal cortex [238, 239, 288]. Clonidine may also successfully ameliorate symptoms characteristic of OF circuit dysfunction, including distractibility, impulsivity and emotional lability, in children with ADHD and TS [246, 248, 289]. Several classes of drugs thus have the potential to favorably influence symptoms of OF circuit dysfunction, reflecting serotonergic, dopaminergic, and noradrenergic modulation of functions of the OF cortex and connected brain regions.

Obsessive-compulsive disorder Serotonin is robustly implicated in the pathophysiology of OCD and SSRIs are effective treatments for this condition [290, 291]. The serotonergic innervation of the striatum is dense and is localized to those basal ganglia regions which receive input from the OF and AC cortices, via the ventromedial caudate nucleus head and ventral striatum, respectively [62]. Glucose metabolic rates in the head of the caudate nucleus diminish when OCD is treated successfully with SSRIs, a result that may be attributable to the action of serotonin afferents from the dorsal raphe on


caudate interneurons [130, 292]. The thalamofrontal pathways, lesioned at different sites in anterior capsulotomy and subcaudate tractotomy (see below), contain both serotonergic and dopaminergic tracts [293]. The improvement in OCD that may be observed with adjunctive DA receptor blockers, particularly in TS [294], reflects the functionally coupled interactions between brain 5-HT and DA systems [295].

Neurosurgical interventions Obsessive-compulsive disorder and Tourette syndrome Anterior cingulotomy or limbic leucotomy have been used successfully in the past to treat disabling ritualistic behaviors in selected patients with OCD [296] and TS [297–299]. The rationale for lesioning the anterior cingulate in these disorders derives from its role as the conduit for frontal cortex input to the Papez circuit and limbic system [300, 301], while limbic leucotomy selectively targets both anterior cingulate cortex and frontothalamic projections. The beneficial effect of anterior capsulotomy in OCD [302] would also be predicted by the proposed models, as this procedure severs a pathway for reciprocal tracts interconnecting the OF cortex with the dorsomedial and related thalamic nuclei [143, 303]. More recently this has been replaced effectively by DBS of the ventral anterior internal capsule [304], a procedure which has been shown to modulate activity in the dorsal and ventral striatum, subgenual cingulate cortex, MOF cortex, and thalamus [191, 305, 306]. This demonstrates how the stimulation of a single region can generate complex changes throughout the interconnected network [303]. Electrode placements in ventral caudate, STN, zona incerta (near the STN), and ventral striatum have also been effective for refractory OCD [98]. Deep brain stimulation of several targets has been used effectively to treat severe pharmacologically refractory TS. These include the nucleus ventralis oralis, the motor and limbic portions of GPi [307–311], NAc/anterior limb of the internal capsule [312], and the centromedian parafascicular complex of the median and intralaminar thalamic nuclei [311, 313–317], a unit which has significant projections into motor striatum as well as limbic and associative areas of the subthalamic nucleus [318]. Targeting of these sites often results in at least 70% long-term reductions in vocal or motor tics, with accompanying disappearance of the preceding sensory urge.

Depression Five potential targets have been identified in the literature as potential surgical targets for DBS in treatmentresistant depression: (1) ventral striatum/NAc; (2) subgenual cingulate cortex (area 25); (3) inferior thalamic peduncle; (4) rostral cingulate cortex (area 24a); and (5) lateral habenula [319]. Although it has been suggested that the subgenual cingulate region may prove to be most effective, based on its anatomic connectivity [189], further studies are required in larger patient groups to assess both the safety and efficacy of these targets.

Addiction In the past, procedures such as cingulotomy, hypothalamotomy, and resection of the substantia innominata and NAc have been recommended as treatments for severe addictive disorders. With expansion of knowledge concerning its neurobiology, refractory addictive states might also prove amenable to DBS of relevant brain targets [320].

Conclusion Frontal-subcortical circuits (FSCs) are effector mechanisms that allow the organism to act on the environment. The DLPF circuit allows the organization of information to facilitate a response; AC circuitry is required for motivated behavior; the LOF circuit allows the integration of limbic and emotional information into contextually appropriate behavioral responses; and mood regulation and integration of information pertaining to emotions are functions, respectively, of the subgenual cingulate and MOF circuits. Correspondingly, impaired EFs, apathy, impulsivity, and depression are hallmarks of FSC dysfunction. Movement disorders typically involve not only the motor circuit but also other FSCs as they project through the basal ganglia. A variety of other neuropsychiatric disorders may result from disturbances that impact directly or indirectly on the integrity or functioning of these circuits. Examples of such conditions include OCD and TS, ADHD, substance abuse and impulse control disorders, BD and schizophrenia. The circuits involve a number of transmitters, receptor subtypes, and second messengers that can be manipulated pharmacologically. In addition, for an increasing number of conditions, such as disabling OCD, TS and depression, discrete neurosurgical approaches to

75


specific FSC dysfunctions are being explored more actively, with advances in DBS showing particular promise.

Acknowledgments Special thanks are offered to John Nyquist for preparation of the figures.

References 1. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–81. 2. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 1990;13(7):266–71. 3. Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res. 1990;85:119–46. 4. Pandya D, Barnes CL. Architecture and connections of the frontal lobe. In Perecman E, editor. The Frontal Lobes Revisited. New York, NY: IRBN Press; 1987, pp. 41–72. 5. Sanides F. Comparative architectonics of the neocortex of mammals and their evolutionary interpretation. Annals N Y Acad Sci. 1969;167(1):404–23.

12. Rosvold HE. The prefrontal cortex and caudate nucleus: a system for effecting correction in response mechanisms. In Rupp C, editor. Mind as a Tissue; Proceedings. New York, NY: Hoeber Medical Division; 1968, pp. 21–38. 13. Divac I. Neostriatum and functions of prefrontal cortex. Acta Neurobiol Exp (Wars.) 1972;32(2): 461–77. 14. Johnson TN, Rosvold HE, Mishkin M. Projections from behaviorally-defined sectors of the prefrontal cortex to the basal ganglia, septum, and diencephalon of the monkey. Exp Neurol. 1968;21(1):20–34. 15. Groenewegen HJ, Berendse HW, Wolters JG, Lohman AH. The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization. Prog Brain Res. 1990;85:95–116;discussion 116–18. 16. Parent A. Extrinsic connections of the basal ganglia. Trends Neurosci. 1990;13(7):254–8. 17. Lichter DG, Cummings J. Introduction and overview. In Lichter DG, Cummings JL, editors. Frontalsubcortical Circuits in Psychiatric and Neurological Disorders. New York, NY: Guilford Press; 2001, pp. 1–43. 18. Selemon LD, Goldman-Rakic PS. Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J Neurosci. 1985;5(3):776–94.

6. Sanides F. Functional architecture of motor and sensory cortices in primates in the light of a new concept of neocortex evolution. In Noback CR, Montagna W, editors. The Primate Brain. New York, NY: Meredith Corp.; 1970, pp. 137–209.

19. Parent A, Bouchard C, Smith Y. The striatopallidal and striatonigral projections: two distinct fiber systems in primate. Brain Res. 1984;303(2):385–90.

7. Yeterian EH, Pandya DN. Prefrontostriatal connections in relation to cortical architectonic organization in rhesus monkeys. J Comp Neurol. 1991;312(1):43–67.

20. Smith Y, Hazrati LN, Parent A. Efferent projections of the subthalamic nucleus in the squirrel monkey as studied by the PHA-L anterograde tracing method. J Comp Neurol. 1990;294(2):306–23.

8. Yeterian EH, Van Hoesen GW. Cortico-striate projections in the rhesus monkey: the organization of certain cortico-caudate connections. Brain Res. 1978;139(1):43–63.

21. Ilinsky IA, Jouandet ML, Goldman-Rakic PS. Organization of the nigrothalamocortical system in the rhesus monkey. J Comp Neurol. 1985;236(3):315–30.

9. Selemon LD, Goldman-Rakic PS. Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior. J Neurosci. 1988;8(11): 4049–68. 10. Rosvold HE, Szwarcbart MK. Neural structures involved in delayed response performance. In Warren JM, Akert K, , editors. The Frontal Granular Cortex and Behavior. New York, NY: McGraw-Hill; 1964, pp. 1–15.

76

11. Divac I, Rosvold HE, Szwarcbart MK. Behavioral effects of selective ablation of the caudate nucleus. J Comp Physiol Psychol. 1967;63(2):184–90.

22. Kim R, Nakano K, Jayaraman A, Carpenter MB. Projections of the globus pallidus and adjacent structures: an autoradiographic study in the monkey. J Comp Neurol. 1976;169(3):263–90. 23. McFarland NR, Haber SN. Thalamic relay nuclei of the basal ganglia form both reciprocal and nonreciprocal cortical connections, linking multiple frontal cortical areas. J Neurosci. 2002;22(18):8117–32. 24. Kievit J, Kuypers HG. Organization of the thalamo-cortical connexions to the frontal lobe in the rhesus monkey. Exp Brain Res. 1977;29(3–4):299–322.


25. Giguere M, Goldman-Rakic PS. Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J Comp Neurol. 1988;277(2):195–213.

38. Kopell BH, Greenberg BD. Anatomy and physiology of the basal ganglia: implications for DBS in psychiatry. Neurosci Biobehav Rev. 2008;32(3):408–22.

26. Mega M, Cummings J. The cingulate and cingulate syndromes. In Trimble MR, Cummings JL, editors. Contemporary Behavioral Neurology. Boston, MA: Butterworth-Heinemann; 1997, pp. 189–214.

39. Haber SN, Lynd E, Klein C, Groenewegen HJ. Topographic organization of the ventral striatal efferent projections in the rhesus monkey: an anterograde tracing study. J Comp Neurol. 1990; 293(2):282–98.

27. Ongur D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000;10(3): 206–19.

40. Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E. The orbital and medial prefrontal circuit through the primate basal ganglia. J Neurosci. 1995;15(7 Pt 1): 4851–67.

28. Johnson TN, Rosvold HE. Topographic projections on the globus pallidus and the substantia nigra of selectively placed lesions in the precommissural caudate nucleus and putamen in the monkey. Exp Neurol. 1971;33(3):584–96.

41. Groenewegen HJ, Trimble M. The ventral striatum as an interface between the limbic and motor systems. CNS Spectr. 2007;12(12):887–92.

29. Middleton F, Strick PL. Revised neuroanatomy of frontal-subcortical circuits. In Lichter DG, Cummings JL, editors. Frontal-subcortical Circuits in Psychiatric and Neurological Disorders. New York, NY: Guilford Press; 2001, pp. 44–58. 30. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118(Pt 1):279–306. 31. Barbas H, Pandya DN. Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey. J Comp Neurol. 1989;286(3):353–75. 32. Morecraft RJ, Geula C, Mesulam MM. Architecture of connectivity within a cingulo-fronto-parietal neurocognitive network for directed attention. Arch Neurol. 1993;50(3):279–84. 33. Schmahmann JD, Pandya DN. Fiber Pathways of the Brain. Oxford: Oxford University Press; 2006. 34. Goldman-Rakic PS, Porrino LJ. The primate mediodorsal (MD) nucleus and its projection to the frontal lobe. J Comp Neurol. 1985;242(4): 535–60. 35. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000;4(6):215–22. 36. Kunishio K, Haber SN. Primate cingulostriatal projection: limbic striatal versus sensorimotor striatal input. J Comp Neurol. 1994;350(3):337–56. 37. Heimer L. The olfactory cortex and the ventral triatum. In Livingston KE, Hornykiewicz O, editors. Limbic Mechanisms: The Continuing Evolution of the Limbic System Concept. Proceedings of the Limbic System Symposium held at the University of Toronto, ON, Canada, November 5–6, 1976, as a satellite to the sixth annual meeting of the Society of Neuroscience. New York, NY: Plenum Press; 1978.

42. Haber SN, Lynd-Balta E, Mitchell SJ. The organization of the descending ventral pallidal projections in the monkey. J Comp Neurol. 1993;329(1):111–28. 43. Ongur D, Ferry AT, Price JL. Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol. 2003;460(3):425–49. 44. Freedman LJ, Insel TR, Smith Y. Subcortical projections of area 25 (subgenual cortex) of the macaque monkey. J Comp Neurol. 2000;421(2):172–88. 45. Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res. 2002;53(2):647–54. 46. Paus T. Primate anterior cingulate cortex: where motor control, drive and cognition interface. Nat Rev Neurosci. 2001;2(6):417–24. 47. Gutman DA, Holtzheimer PE, Behrens TE, Johansen-Berg H, Mayberg HS. A tractography analysis of two deep brain stimulation white matter targets for depression. Biol Psychiatry 2009; 65(4):276–82. 48. Vogt BA, Finch DM, Olson CR. Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. Cereb Cortex 1992;2(6):435–43. 49. Drevets WC, Price JL, Simpson JR, Jr. et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997;386(6627):824–7. 50. Yang TT, Simmons AN, Matthews SC et al. Adolescent subgenual anterior cingulate activity is related to harm avoidance. Neuroreport 2009;20(1):19–23. 51. Mega MS, Cummings JL, Salloway S, Malloy P. The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci. 1997;9(3):315–30. 52. Haber SN. The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat. 2003; 26(4):317–30.

77


53. An X, Ongur D, Price J. Prefrontostriatal projections in relation to cortico-cortical networks in the macaque monkey. Soc Neurosci Abstr. 1997;23:901. 54. Vogt BA, Pandya DN. Cingulate cortex of the rhesus monkey: II. Cortical afferents. J Comp Neurol. 1987;262(2):271–89. 55. Morecraft RJ, Geula C, Mesulam MM. Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey. J Comp Neurol. 1992;323(3):341–58. 56. Pandya DN, Van Hoesen GW, Mesulam MM. Efferent connections of the cingulate gyrus in the rhesus monkey. Exp Brain Res. 1981;42(3–4):319–30. 57. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex. 2006;16(7):916–28. 58. Barbas H. Specialized elements of orbitofrontal cortex in primates. Ann N Y Acad Sci. 2007;1121: 10–32. 59. Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci. 1989;12(10):366–75. 60. Groenewegen HJ, Roeling TAP, Voorn P, Berendse HW. The parallel arrangement of basal ganglia-thalamocortical circuits: a neuronal substrate for the role of dopamine in motor and cognitive functions. In Wolters EC, Scheltens P, editors. Mental Dysfunction in Parkinson’s Disease. Amsterdam: Vrije Universiteit; 1993, pp. 3–18. 61. Graybiel AM. Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci. 1990;13(7):244–54. 62. Lavoie B, Parent A. Immunohistochemical study of the serotoninergic innervation of the basal ganglia in the squirrel monkey. J Comp Neurol. 1990;299(1):1–16. 63. Chesselet MF, Gonzales C, Levitt P. Heterogeneous distribution of the limbic system-associated membrane protein in the caudate nucleus and substantia nigra of the cat. Neuroscience 1991;40(3):725–33. 64. Gibb WR. Melanin, tyrosine hydroxylase, calbindin and substance P in the human midbrain and substantia nigra in relation to nigrostriatal projections and differential neuronal susceptibility in Parkinson’s disease. Brain Res. 1992;581(2):283–91. 65. Fotuhi M, Dawson TM, Sharp AH et al. Phosphoinositide second messenger system is enriched in striosomes: immunohistochemical demonstration of inositol 1,4,5-trisphosphate receptors and phospholipase C beta and gamma in primate basal ganglia. J Neurosci. 1993;13(8):3300–8. 66. Parent A, Pare D, Smith Y, Steriade M. Basal forebrain cholinergic and noncholinergic projections to the

78

thalamus and brainstem in cats and monkeys. J Comp Neurol. 1988;277(2):281–301. 67. McGeer PL, McGeer EG. Neurotransmitters and their receptors in the basal ganglia. Adv Neurol. 1993;60:93–101. 68. Daniel DG, Weinberger DR, Jones DW et al. The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia. J Neurosci. 1991;11(7):1907–17. 69. Sawaguchi T. Catecholamine sensitivities of neurons related to a visual reaction time task in the monkey prefrontal cortex. J Neurophysiol. 1987;58(5):1100–22. 70. Arnsten AF. Fundamentals of attention-deficit/ hyperactivity disorder: circuits and pathways. J Clin Psychiatry 2006;67 (Suppl. 8):7–12. 71. Hoyer D, Palacios JM, Mengod G. 5-HT receptor distribution in the human brain: autoradiographic studies. In Marsden CA, Heal DJ, editors. Central Serotonin Receptors and Psychotropic Drugs. London: Blackwell Scientific Publications; 1992, pp. 100–25. 72. Flaherty AW, Graybiel AM. Anatomy of the basal ganglia. In Marsden CD, Fahn S, editors. Movement Disorders. Boston: Butterworth-Heinemann Ltd.; 1994, pp. 3–27. 73. Mogenson GJ, Jones DL, Yim CY. From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol. 1980;14(2–3): 69–97. 74. Scheibel AB. The thalamus and neuropsychiatric illness. J Neuropsychiatry Clin Neurosci. 1997; 9(3):342–53. 75. Salloway S, Cummings J. Subcortical structures and neuropsychiatric illness. Neuroscientist 1996;2(1): 66–75. 76. Gerfen CR. The neostriatal mosaic: compartmentalization of corticostriatal input and striatonigral output systems. Nature 1984; 311(5985):461–4. 77. Cairns H, Oldfield R, Pennybacker JB, Whitteridge DC. Akinetic mutism with an epidermoid cyst at the third ventricle. Brain. 1941;64:275–90. 78. Auerbach S. Beitrag zur diagnostik der geschwülste des stirnhirns. J Neurol. 1902;22(3):312–32. 79. van Domburg PH, ten Donkelaar HJ, Notermans SL. Akinetic mutism with bithalamic infarction. Neurophysiological correlates. J Neurol Sci. 1996;139(1):58–65. 80. Bhatia KP, Marsden CD. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 1994;117 (Pt 4):859–76. 81. Engelborghs S, Marien P, Pickut BA, Verstraeten S, De Deyn PP. Loss of psychic self-activation after


paramedian bithalamic infarction. Stroke 2000; 31(7):1762–5. 82. Bogousslavsky J, Regli F, Delaloye B et al. Loss of psychic self-activation with bithalamic infarction. Neurobehavioural, CT, MRI and SPECT correlates. Acta Neurol Scand. 1991;83(5):309–16. 83. Ghika-Schmid F, Bogousslavsky J. The acute behavioral syndrome of anterior thalamic infarction: a prospective study of 12 cases. Ann Neurol. 2000; 48(2):220–7. 84. Damasio H, Damasio AR. Lesion Analysis in Neuropsychology. New York, NY: Oxford University Press; 1989. 85. Barris RW, Schuman HR. [Bilateral anterior cingulate gyrus lesions; syndrome of the anterior cingulate gyri.] Neurology 1953;3(1):44–52. 86. Koski L, Paus T. Functional connectivity of the anterior cingulate cortex within the human frontal lobe: a brain-mapping meta-analysis. Exp Brain Res. 2000;133(1):55–65. 87. Damasio AR, Vanhoesen GW. Structure and function of the supplementary motor area. Neurology 1980;30(4):359. 88. Laplane D, Degos JD. Motor neglect. J Neurol Neurosurg Psychiatry 1983;46(2):152–8. 89. von Giesen HJ, Schlaug G, Steinmetz H et al. Cerebral network underlying unilateral motor neglect: evidence from positron emission tomography. J Neurol Sci. 1994;125(1):29–38. 90. Jenkins IH, Jahanshahi M, Jueptner M, Passingham RE, Brooks DJ. Self-initiated versus externally triggered movements. II. The effect of movement predictability on regional cerebral blood flow. Brain 2000;123 (Pt 6):1216–28. 91. Stuss DT. Differentiation of states and causes of apathy. In Borod JC, editor. The Neuropsychology of Emotion. New York, NY: Oxford University Press; 2000, pp. 340–63.

97. Stuss DT, Gow CA, Hetherington CR. “No longer Gage”: frontal lobe dysfunction and emotional changes. J Consult Clin Psychol. 1992;60(3):349–59. 98. Chow TW, Cummings J. Frontal-subcortical circuits. In Miller BL, Cummings JL, editors. The Human Frontal Lobes: Functions and Disorders. 2nd edition. New York, NY: Guilford Press; 2007, pp. 25–73. 99. Lhermitte F, Pillon B, Serdaru M. Human autonomy and the frontal lobes. Part I: Imitation and utilization behavior: a neuropsychological study of 75 patients. Ann Neurol. 1986;19(4):326–34. 100. Laiacona M, De Santis A, Barbarotto R et al. Neuropsychological follow-up of patients operated for aneurysms of anterior communicating artery. Cortex 1989;25(2):261–73. 101. Vanderploeg RD, Haley JA. Pseudosociopathy with intact higher-order cognitive abilities in patients with orbitofrontal cortical damage. J Clin Exp Neuropsychol. 1990;12:54–5. 102. Meyers CA, Berman SA, Scheibel RS, Hayman A. Case report: acquired antisocial personality disorder associated with unilateral left orbital frontal lobe damage. J Psychiatry Neurosci. 1992;17(3):121–5. 103. Mendez MF, Adams NL, Lewandowski KS. Neurobehavioral changes associated with caudate lesions. Neurology 1989;39(3):349–54. 104. Vonsattel JP, Myers RH, Stevens TJ et al. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol. 1985;44(6):559–77. 105. Bakchine S, Lacomblez L, Benoit N et al. Manic-like state after bilateral orbitofrontal and right temporoparietal injury: efficacy of clonidine. Neurology 1989;39(6):777–81. 106. Bogousslavsky J, Ferrazzini M, Regli F et al. Manic delirium and frontal-like syndrome with paramedian infarction of the right thalamus. J Neurol Neurosurg Psychiatry 1988;51(1):116–19.

92. Nauta WJ. The problem of the frontal lobe: a reinterpretation. J Psychiatr Res. 1971;8(3):167–87.

107. Cummings JL, Mendez MF. Secondary mania with focal cerebrovascular lesions. Am J Psychiatry 1984;141(9):1084–7.

93. Eslinger PJ, Damasio AR. Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology 1985;35(12):1731–41.

108. Starkstein SE, Boston JD, Robinson RG. Mechanisms of mania after brain injury. 12 case reports and review of the literature. J Nerv Ment Dis. 1988;176(2):87–100.

94. Damasio AR. Descartes’ Error: Emotion, Reason, and the Human Brain. New York, NY: Putnam; 1994.

109. Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol. 1993;50(8):873–80.

95. Blumer D, Benson DF. Personality changes with frontal and temporal lobe lesions. In Benson DF, Blumer D, editors. Psychiatric Aspects of Neurological Disease. New York, NY: Grune & Stratton; 1975.

110. Milner B. Effects of different brain lesions on card sorting: the role of the frontal lobes. Arch Neurol. 1963;9(1):90–100.

96. Reitman F. Orbital cortex syndrome following leucotomy. Am J Psychiatry 1946;103(2):238–41.

111. Strub RL. Frontal lobe syndrome in a patient with bilateral globus pallidus lesions. Arch Neurol. 1989;46(9):1024–7.

79


112. Sandson TA, Daffner KR, Carvalho PA, Mesulam MM. Frontal lobe dysfunction following infarction of the left-sided medial thalamus. Arch Neurol. 1991;48(12): 1300–3. 113. Stuss DT, Guberman A, Nelson R, Larochelle S. The neuropsychology of paramedian thalamic infarction. Brain Cogn. 1988;8(3):348–78. 114. Albert ML, Feldman RG, Willis AL. The ‘subcortical dementia’ of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 1974;37(2):121–30. 115. Peinemann A, Schuller S, Pohl C et al. Executive dysfunction in early stages of Huntington’s disease is associated with striatal and insular atrophy: a neuropsychological and voxel-based morphometric study. J Neurol Sci. 2005;239(1):11–19. 116. Sawamoto N, Piccini P, Hotton G et al. Cognitive deficits and striato-frontal dopamine release in Parkinson’s disease. Brain 2008;131(Pt 5):1294–302. 117. Owen AM. Cognitive dysfunction in Parkinson’s disease: the role of frontostriatal circuitry. Neuroscientist 2004;10(6):525–37. 118. Rinne JO, Rummukainen J, Paljarvi L, Rinne UK. Dementia in Parkinson’s disease is related to neuronal loss in the medial substantia nigra. Ann Neurol. 1989;26(1):47–50. 119. Litvan I, Paulsen JS, Mega MS, Cummings JL. Neuropsychiatric assessment of patients with hyperkinetic and hypokinetic movement disorders. Arch Neurol. 1998;55(10):1313–19. 120. Cummings J (editor). Introduction. In Subcortical Dementia. New York, NY: Oxford University Press; 1990, pp. 3–16. 121. Tatemichi TK, Desmond DW, Prohovnik I et al. Confusion and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome? Neurology 1992;42(10):1966–79. 122. Kolb B. Studies on the caudate-putamen and the dorsomedial thalamic nucleus of the rat: implications for mammalian frontal-lobe functions. Physiol Behav. 1977;18(2):237–44.

80

evidence for cortico-striatal network dysfunction? J Psychopharmacol. 2000;14(1):37–9. 127. Robinson D, Wu H, Munne RA et al. Reduced caudate nucleus volume in obsessive-compulsive disorder. Arch Gen Psychiatry 1995;52(5):393–8. 128. Peterson B, Riddle MA, Cohen DJ et al. Reduced basal ganglia volumes in Tourette’s syndrome using three-dimensional reconstruction techniques from magnetic resonance images. Neurology 1993; 43(5):941–9. 129. Singer HS, Reiss AL, Brown JE et al. Volumetric MRI changes in basal ganglia of children with Tourette’s syndrome. Neurology 1993;43(5):950–6. 130. Baxter LR, Jr., Schwartz JM, Bergman KS et al. Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder. Arch Gen Psychiatry 1992;49(9):681–9. 131. Braun AR, Stoetter B, Randolph C et al. The functional neuroanatomy of Tourette’s syndrome: an FDG-PET study. I. Regional changes in cerebral glucose metabolism differentiating patients and controls. Neuropsychopharmacology 1993;9(4):277–91. 132. Jeffries KJ, Schooler C, Schoenbach C et al. The functional neuroanatomy of Tourette’s syndrome: an FDG PET study III: functional coupling of regional cerebral metabolic rates. Neuropsychopharmacology 2002;27(1):92–104. 133. Eidelberg D, Moeller JR, Antonini A et al. The metabolic anatomy of Tourette’s syndrome. Neurology 1997;48(4):927–34. 134. Gerard E, Peterson BS. Developmental processes and brain imaging studies in Tourette syndrome. J Psychosom Res. 2003;55(1):13–22. 135. Singer HS, Minzer K. Neurobiology of Tourette’s syndrome: concepts of neuroanatomic localization and neurochemical abnormalities. Brain Dev. 2003;25 (S1):S70–84.

123. Rapoport JL. Recent advances in obsessive-compulsive disorder. Neuropsychopharmacology 1991;5(1):1–10.

136. Peterson B, Leckman JF, Arnsten AF. Neuroanatomical circuitry. In Leckman JF, Cohen DJ, editors. Tourette’s Syndrome – Tics, Obsessions, Compulsions: Developmental Psychopathology and Clinical Care. New York, NY: John Wiley & Sons; 1998, pp. 230–60.

124. Cummings JL, Cunningham K. Obsessive-compulsive disorder in Huntington’s disease. Biol Psychiatry 1992;31(3):263–70.

137. Leckman JF, Knorr AM, Rasmusson AM, Cohen DJ. Basal ganglia research and Tourette’s syndromes. Trends Neurosci. 1991;14(3):94.

125. Swedo SE, Rapoport JL, Cheslow DL et al. High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s chorea. Am J Psychiatry 1989;146(2):246–9.

138. Leckman JF, Pauls DL, Peterson BS et al. Pathogenesis of Tourette syndrome. Clues from the clinical phenotype and natural history. Adv Neurol. 1992;58:15–24.

126. Dursun SM, Burke JG, Reveley MA. Antisaccade eye movement abnormalities in Tourette syndrome:

139. Leckman JF, Walker DE, Goodman WK, Pauls DL, Cohen DJ. “Just right” perceptions associated with


compulsive behavior in Tourette’s syndrome. Am J Psychiatry 1994;151(5):675–80. 140. Modell JG, Mountz JM, Curtis GC, Greden JF. Neurophysiologic dysfunction in basal ganglia/ limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 1989;1(1): 27–36. 141. Insel TR. Toward a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiatry 1992;49(9):739–44.

152. Canales JJ, Graybiel AM. A measure of striatal function predicts motor stereotypy. Nat Neurosci. 2000;3(4):377–83. 153. Wise RA. Catecholamine theories of reward: a critical review. Brain Res. 1978;152(2):215–47. 154. Barkley RA, Grodzinsky G, DuPaul GJ. Frontal lobe functions in attention deficit disorder with and without hyperactivity: a review and research report. J Abnorm Child Psychol. 1992;20(2):163–88. 155. Shue KL, Douglas VI. Attention deficit hyperactivity disorder and the frontal lobe syndrome. Brain Cogn. 1992;20(1):104–24.

142. Rauch SL. Neuroimaging and neurocircuitry models pertaining to the neurosurgical treatment of psychiatric disorders. Neurosurg Clin N Am. 2003;14(2):213–23, vii–viii.

156. Kemp SL, Kirk U. An investigation of frontal executive dysfunction in attention deficit disorder subgroups. Ann N Y Acad Sci. 1993;682:363–5.

143. Masterman DL, Cummings JL. Frontal-subcortical circuits: the anatomic basis of executive, social and motivated behaviors. J Psychopharmacol. 1997; 11(2):107–14.

157. Towbin KE, Riddle MA. Attention deficit hyperactivity disorder. In Kurlan R, editor. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders. New York, NY: M. Dekker; 1993, pp. 89–109.

144. Makki MI, Behen M, Bhatt A, Wilson B, Chugani HT. Microstructural abnormalities of striatum and thalamus in children with Tourette syndrome. Mov Disord. 2008;23(16):2349–56.

158. Bamford KA, Caine ED, Kido DK, Plassche WM, Shoulson I. Clinical-pathologic correlation in Huntington’s disease: a neuropsychological and computed tomography study. Neurology 1989; 39(6):796–801.

145. Moriarty J, Costa DC, Schmitz B et al. Brain perfusion abnormalities in Gilles de la Tourette’s syndrome. Br J Psychiatry 1995;167(2):249–54. 146. Wolf SS, Jones DW, Knable MB et al. Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding. Science 1996;273(5279): 1225–7. 147. Bohlhalter S, Goldfine A, Matteson S et al. Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study. Brain 2006;129(8):2029–37. 148. Mink JW. Neurobiology of basal ganglia and Tourette syndrome: basal ganglia circuits and thalamocortical outputs. Adv Neurol. 2006;99:89–98. 149. Braun AR, Randolph C, Stoetter B et al. The functional neuroanatomy of Tourette’s syndrome: an FDG-PET Study. II: Relationships between regional cerebral metabolism and associated behavioral and cognitive features of the illness. Neuropsychopharmacology 1995;13(2):151–68. 150. Albin RL, Koeppe RA, Bohnen NI et al. Increased ventral striatal monoaminergic innervation in Tourette syndrome. Neurology 2003;1(3):310–15. 151. Groenewegen HJ, van den Heuvel OA, Cath DC, Voorn P, Veltman DJ. Does an imbalance between the dorsal and ventral striatopallidal systems play a role in Tourette’s syndrome? A neuronal circuit approach. Brain Dev. 2003;25(S1):S3–S14.

159. Hynd GW, Hern KL, Novey ES et al. Attention deficit-hyperactivity disorder and asymmetry of the caudate nucleus. J Child Neurol. 1993;8(4):339–47. 160. Castellanos FX, Giedd JN, Eckburg P et al. Quantitative morphology of the caudate nucleus in attention deficit hyperactivity disorder. Am J Psychiatry 1994;151(12):1791–6. 161. Lou HC, Henriksen L, Bruhn P, Borner H, Nielsen JB. Striatal dysfunction in attention deficit and hyperkinetic disorder. Arch Neurol. 1989;46(1):48–52. 162. Vaidya CJ, Austin G, Kirkorian G et al. Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci USA 1998;95(24):14 494–9. 163. Casey BJ, Castellanos FX, Giedd JN et al. Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1997;36(3):374–83. 164. Dickstein SG, Bannon K, Castellanos FX, Milham MP. The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. J Child Psychol Psychiatry 2006;47(10):1051–62. 165. McClure SM, York MK, Montague PR. The neural substrates of reward processing in humans: the modern role of FMRI. Neuroscientist 2004;10(3): 260–8. 166. Zink CF, Pagnoni G, Martin-Skurski ME, Chappelow JC, Berns GS. Human striatal responses to monetary

81


reward depend on saliency. Neuron 2004;42(3): 509–17. 167. Kringelbach ML, Rolls ET. The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology. Prog Neurobiol. 2004;72(5):341–72. 168. Voeller KK. What can neurological models of attention, intention, and arousal tell us about attention-deficit hyperactivity disorder? J Neuropsychiatry Clin Neurosci. 1991;3(2): 209–16. 169. Sonuga-Barke EJ. Psychological heterogeneity in AD/HD – a dual pathway model of behaviour and cognition. Behav Brain Res. 2002;130(1–2): 29–36. 170. Sonuga-Barke EJ. The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev. 2003;27(7):593–604. 171. Brennan AR, Arnsten AF. Neuronal mechanisms underlying attention deficit hyperactivity disorder: the influence of arousal on prefrontal cortical function. Ann N Y Acad Sci. 2008;1129:236–45. 172. Li BM, Mao ZM, Wang M, Mei ZT. Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys. Neuropsychopharmacology 1999;21(5):601–10. 173. Mayberg HS, Starkstein SE, Peyser CE et al. Paralimbic frontal lobe hypometabolism in depression associated with Huntington’s disease. Neurology 1992;42(9): 1791–7. 174. Mayberg HS, Starkstein SE, Sadzot B et al. Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson’s disease. Ann Neurol. 1990;28(1):57–64. 175. Rogers D. Bradyphrenia in Parkinson’s disease. In Huber SJ, Cummings JL, editors. Parkinson’s Disease: Neurobehavioral Aspects. New York, NY: Oxford University Press; 1992, pp. 86–96. 176. Tremblay LK, Naranjo CA, Graham SJ et al. Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry 2005; 62(11):1228–36.

82

179. Praag HM, Korf J, Lakke J, Schut T. Dopamine metabolism in depressions, psychoses, and Parkinson’s disease: the problem of the specificity of biological variables in behaviour disorders. Psychol Med. 1975;5(2):138–46. 180. Goodwin FK, Murphy DL, Brodie HK, Bunney WE, Jr. L-DOPA, catecholamines, and behavior: a clinical and biochemical study in depressed patients. Biol Psychiatry 1970;2(4):341–66. 181. Rampello L, Nicoletti G, Raffaele R. Dopaminergic hypothesis for retarded depression: a symptom profile for predicting therapeutical responses. Acta Psychiatr Scand. 1991;84(6):552–4. 182. Marsh GG, Markham CH. Does levodopa alter depression and psychopathology in Parkinsonism patients? J Neurol Neurosurg Psychiatry 1973; 36(6):925–35. 183. Mayeux R, Stern Y, Williams JB et al. Clinical and biochemical features of depression in Parkinson’s disease. Am J Psychiatry 1986;143(6):756–9. 184. Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9(3):471–81. 185. Mayberg HS, Liotti M, Brannan SK et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999;156(5):675–82. 186. Anand A, Li Y, Wang Y, Gardner K, Lowe MJ. Reciprocal effects of antidepressant treatment on activity and connectivity of the mood regulating circuit: an FMRI study. J Neuropsychiatry Clin Neurosci. 2007;19(3):274–82. 187. Mayberg HS. Depression and frontal-subcortical circuits: focus on prefrontal-limbic interactions. In Lichter DG, Cummings JL, editors. Frontal-subcortical Circuits in Psychiatric and Neurological Disorders. New York, NY: Guilford Press; 2001, pp. 177–206. 188. Mayberg HS, Lozano AM, Voon V et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45(5):651–60. 189. Johansen-Berg H, Gutman DA, Behrens TE et al. Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression. Cereb Cortex 2008;18(6):1374–83.

177. Martinot M, Bragulat V, Artiges E et al. Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation. Am J Psychiatry 2001; 158(2):314–16.

190. Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008;13(8):663–81.

178. Meyer JH, McNeely HE, Sagrati S et al. Elevated putamen D(2) receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study. Am J Psychiatry 2006;163(9):1594–602.

191. Van Laere K, Nuttin B, Gabriels L et al. Metabolic imaging of anterior capsular stimulation in refractory obsessive-compulsive disorder: a key role for the subgenual anterior cingulate and ventral striatum. J Nucl Med. 2006;47(5):740–7.


192. Sackeim HA, Greenberg MS, Weiman AL et al. Hemispheric asymmetry in the expression of positive and negative emotions. Neurologic evidence. Arch Neurol. 1982;39(4):210–18. 193. Starkstein SE, Robinson RG, Price TR. Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain 1987;110 (Pt 4):1045–59. 194. Starkstein SE, Preziosi TJ, Bolduc PL, Robinson RG. Depression in Parkinson’s disease. J Nerv Ment Dis. 1990;178(1):27–31.

and cerebral cortex in schizophrenia. Arch Gen Psychiatry 1991;48(10):881–90. 207. Grebb JA, Weinberger DR, Wyatt RJ. Schizophrenia. In Asbury AK, McKahann GM, McDonald WI, editors. Diseases of the Nervous System: Clinical Neurobiology. 2nd edition. Philadelphia, PA: W.B. Saunders; 1992, pp. 839–48. 208. Goldman-Rakic PS, Selemon LD. Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull. 1997;23(3):437–58.

195. Jorge RE, Robinson RG, Starkstein SE et al. Secondary mania following traumatic brain injury. Am J Psychiatry 1993;150(6):916–21.

209. Bunney WE, Bunney BG. Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia. Brain Res Brain Res Rev. 2000; 31(2–3):138–46.

196. Newberg AR, Catapano LA, Zarate CA, Manji HK. Neurobiology of bipolar disorder. Expert Rev Neurother. 2008;8(1):93–110.

210. Gusnard DA, Raichle ME. Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci. 2001;2(10):685–94.

197. Arnsten AF. Ameliorating prefrontal cortical dysfunction in mental illness: inhibition of phosphotidyl inositol-protein kinase C signaling. Psychopharmacology (Berl.) 2009;202(1–3): 445–55.

211. Garrity AG, Pearlson GD, McKiernan K et al. Aberrant “default mode” functional connectivity in schizophrenia. Am J Psychiatry 2007;164(3): 450–7.

198. Manji HK, Lenox RH. Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol Psychiatry 1999;46(10):1328–51. 199. Strakowski SM, Delbello MP, Adler CM. The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry 2005;10(1):105–16. 200. DelBello MP, Adler CM, Strakowski SM. The neurophysiology of childhood and adolescent bipolar disorder. CNS Spectr. 2006;11(4):298–311.

212. Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 1991;48(11):996–1001. 213. Williamson P. Are anticorrelated networks in the brain relevant to schizophrenia? Schizophr Bull. 2007; 33(4):994–1003. 214. Everitt BJ, Wolf ME. Psychomotor stimulant addiction: a neural systems perspective. J Neurosci. 2002; 22(9):3312–20.

201. Adler CM, DelBello MP, Strakowski SM. Brain network dysfunction in bipolar disorder. CNS Spectr. 2006;11(4):312–20.

215. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci. 2005; 8(11):1481–9.

202. Caetano SC, Olvera RL, Glahn D et al. Fronto-limbic brain abnormalities in juvenile onset bipolar disorder. Biol Psychiatry 2005;58(7):525–31.

216. Volkow ND, Wang GJ, Telang F et al. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26(24):6583–8.

203. Haldane M, Frangou S. New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28(6):943–60.

217. Yin HH, Knowlton BJ. The role of the basal ganglia in habit formation. Nat Rev Neurosci. 2006;7(6):464–76.

204. Swerdlow NR, Koob GF. Toward a unified hypothesis of cortico-striato-pallido-thalamus function. Behav Brain Sci. 1990;13(1):172–177. 205. Braff DL, Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 1990;47(2):181–8. 206. Jernigan TL, Zisook S, Heaton RK et al. Magnetic resonance imaging abnormalities in lenticular nuclei

218. Belin D, Everitt BJ. Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 2008; 57(3):432–41. 219. Koob GF, Nestler EJ. The neurobiology of drug addiction. J Neuropsychiatry Clin Neurosci. 1997;9(3):482–97. 220. Gardner E. Brain reward mechanisms. In Lowinson JH, editor. Substance Abuse: A Comprehensive Textbook. 3rd edition. Baltimore, MD: Williams & Wilkins; 1997, pp. 51–85.

83


221. Ivanov IS, Schulz KP, Palmero RC, Newcorn JH. Neurobiology and evidence-based biological treatments for substance abuse disorders. CNS Spectr. 2006;11(11):864–77. 222. Weintraub D. Dopamine and impulse control disorders in Parkinson’s disease. Ann Neurol. 2008; 64(Suppl. 2):S93–100.

235. Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid Y. Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson’s disease. Brain Res. 1983;275(2):321–8.

223. Joyce JN, Gurevich EV. D3 receptors and the actions of neuroleptics in the ventral striatopallidal system of schizophrenics. Ann N Y Acad Sci. 1999;877:595–613.

236. Portin R, Rinne UK. Predictive factors for cognitive deterioration and dementia in Parkinson’s disease. Adv Neurol. 1987;45:413–16.

224. Murray AM, Ryoo HL, Gurevich E, Joyce JN. Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain. Proc Natl Acad Sci USA 1994;91(23): 11 271–5.

237. Marsh L, Biglan K, Gerstenhaber M, Williams JR. Atomoxetine for the treatment of executive dysfunction in Parkinson’s disease: a pilot open-label study. Mov Disord. 2009;24(2):277–82.

225. Chen J, Marmur R, Paredes W, Pulles A, Gardner EL. Systemic cocaine challenge after chronic cocaine treatment reveals sensitization of extracellular dopamine levels in nucleus accumbens but direct cocaine perfusion into nucleus accumbens does not: implications for the neural locus of cocaine sensitization. Life Sci. 1996;58(8):PL139–46. 226. Cilia R, Siri C, Marotta G et al. Functional abnormalities underlying pathological gambling in Parkinson disease. Arch Neurol. 2008;65(12):1604–11. 227. Blanco C, Moreyra P, Nunes EV, Saiz-Ruiz J, Ibanez A. Pathological gambling: addiction or compulsion? Semin Clin Neuropsychiatry 2001;6(3):167–76. 228. Potenza MN. Should addictive disorders include non-substance-related conditions? Addiction 2006;101(Suppl. 1):142–51. 229. Hollander E. Behavioral and substance addictions: A new proposed DSM-V category characterized by impulsive choice, reward sensitivity, and fronto-striatal circuit impairment. CNS Spectr. 2006;11(11):814. 230. Potenza MN. The neurobiology of pathological gambling and drug addiction: an overview and new findings. Philos R Soc B. 2008;363(1507):3181–9. 231. Smith KS, Berridge KC. Opioid limbic circuit for reward: interaction between hedonic hotspots of nucleus accumbens and ventral pallidum. J Neurosci. 2007;27(7):1594–605. 232. Lange KW, Robbins TW, Marsden CD et al. L-dopa withdrawal in Parkinson’s disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacology (Berl.) 1992; 107(2–3):394–404. 233. Cooper JA, Sagar HJ, Doherty SM et al. Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson’s disease. A follow-up study of untreated patients. Brain 1992;115(Pt 6):1701–25.

84

234. Taylor AE, Saint-Cyr JA, Lang AE. Frontal lobe dysfunction in Parkinson’s disease. The cortical focus of neostriatal outflow. Brain 1986;109(Pt 5):845–83.

238. Arnsten AF, Contant TA. Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task. Psychopharmacology (Berl.) 1992;108(1–2):159–69. 239. Goldman-Rakic PS, Lidow MS, Gallager DW. Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex. J. Neurosci. 1990;10(7): 2125–38. 240. Arnsten AF, Cai JX, Goldman-Rakic PS. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci. 1988;8(11):4287–98. 241. Arnsten AF, Goldman-Rakic PS. Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 1985;230(4731):1273–6. 242. Fields RB, Van Kammen DP, Peters JL et al. Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res. 1988;1(6):417–23. 243. Mair RG, McEntee WJ. Cognitive enhancement in Korsakoff’s psychosis by clonidine: a comparison with L-dopa and ephedrine. Psychopharmacology (Berl.) 1986;88(3):374–80. 244. Moffoot A, O’Carroll RE, Murray C et al. Clonidine infusion increases uptake of 99mTc-Exametazime in anterior cingulate cortex in Korsakoff’s psychosis. Psychol Med. 1994;24(1):53–61. 245. Sahakian BJ, Coull JJ, Hodges JR. Selective enhancement of executive function by idazoxan in a patient with dementia of the frontal lobe type. J Neurol Neurosurg Psychiatry 1994;57(1):120–1. 246. Denckla MB, Reader MJ. Education and psychosocial interdentions: executive dysfunction and its consequences. In Kurlan R, editor. Handbook of Tourette’s Syndrome and Related Tic and Behavioral


Disorders. New York, NY: M. Dekker; 1993, pp. 431–51. 247. Golden GS. Treatment of attention deficit hyperactivity disorder. In Kurlan R, editor. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders. New York, NY: M. Dekker; 1993, pp. 423–30. 248. Leckman JF, Hardin MT, Riddle MA et al. Clonidine treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 1991;48(4):324–8. 249. Tannock R, Schachar RJ, Carr RP, Chajczyk D, Logan GD. Effects of methylphenidate on inhibitory control in hyperactive children. J Abnorm Child Psychol. 1989;17(5):473–91. 250. Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1995;34(1):50–4. 251. Arnsten AF, Steere JC, Hunt RD. The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1996;53(5):448–55. 252. Ungerstedt U. Is interruption of the nigro-striatal dopamine system producing the “lateral hypothalamus syndrome”? Acta Physiol Scand. 1970;80(4): 35A–6A. 253. Ungerstedt U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl. 1971;367:95–122. 254. Marshall JF, Richardson JS, Teitelbaum P. Nigrostriatal bundle damage and the lateral hypothalamic syndrome. J Comp Physiol Psychol. 1974;87(5):808–30. 255. Ljungberg T, Ungerstedt U. Reinstatement of eating by dopamine agonists in aphagic dopamine denervated rats. Physiol Behav. 1976;16(3):277–83. 256. Marshall JF, Ungerstedt U. Apomorphine-induced restoration of drinking to thirst challenges in 6-hydroxydopamine-treated rats. Physiol Behav. 1976;17(5):817–22. 257. Marshall JF, Gotthelf T. Sensory inattention in rats with 6-hydroxydopamine-induced degeneration of ascending dopaminergic neurons: apomorphineinduced reversal of deficits. Exp Neurol. 1979;65(2):398–411. 258. Ross ED, Stewart RM. Akinetic mutism from hypothalamic damage: successful treatment with dopamine agonists. Neurology 1981;31(11):1435–9. 259. Nemeth G, Hegedus K, Molnar L. Akinetic mutism and locked-in syndrome: the functional-anatomical basis for their differentiation. Funct Neurol. 1986;1(2):128–39.

260. Alexander MP. Reversal of chronic akinetic mutism after mesencephalic infarction with dopaminergic agents. Neurology 1995;45(4):A330. 261. Spiegel DR, Casella DP, Callender DM, Dhadwal N. Treatment of akinetic mutism with intramuscular olanzapine: a case series. J Neuropsychiatry Clin Neurosci. 2008;20(1):93–5. 262. Parks RW, Crockett DJ, Manji HK, Ammann W. Assessment of bromocriptine intervention for the treatment of frontal lobe syndrome: a case study. J Neuropsychiatry Clin Neurosci. 1992;4(1):109–11. 263. Barrett K. Treating organic abulia with bromocriptine and lisuride: four case studies. J Neurol Neurosurg Psychiatry 1991;54(8):718–21. 264. Holmes VF, Fernandez F, Levy JK. Psychostimulant response in AIDS-related complex patients. J Clin Psychiatry 1989;50(1):5–8. 265. Czernecki V, Schupbach M, Yaici S et al. Apathy following subthalamic stimulation in Parkinson disease: a dopamine responsive symptom. Mov Disord. 2008;23(7):964–9. 266. Marin RS, Fogel BS, Hawkins J, Duffy J, Krupp B. Apathy: a treatable syndrome. J Neuropsychiatry Clin Neurosci. 1995;7(1):23–30. 267. Craig AH, Cummings JL, Fairbanks L et al. Cerebral blood flow correlates of apathy in Alzheimer disease. Arch Neurol. 1996;53(11):1116–20. 268. Kaufer DI, Cummings JL, Christine D. Effect of tacrine on behavioral symptoms in Alzheimer’s disease: an open-label study. J Geriatr Psychiatry Neurol. 1996;9(1):1–6. 269. Masanic CA, Bayley MT, VanReekum R, Simard M. Open-label study of donepezil in traumatic brain injury. Arch Phys Med Rehabil. 2001;82(7):896–901. 270. Morey CE, Cilo M, Berry J, Cusick C. The effect of Aricept in persons with persistent memory disorder following traumatic brain injury: a pilot study. Brain Inj. 2003;17(9):809–15. 271. Cummings J. Behavioral disorders associated with frontal lobe injury. In Cummings JL, editor. Clinical Neuropsychiatry. Orlando, FL: Grune & Stratton; 1985, pp. 57–67. 272. Lesch KP, Merschdorf U. Impulsivity, aggression, and serotonin: a molecular psychobiological perspective. Behav Sci Law 2000;18(5):581–604. 273. Brown GL, Linnoila MI. CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence. J Clin. Psychiatry 1990;51(Suppl.):31–41; discussion 2–3. 274. Coccaro EF. Central serotonin and impulsive aggression. Br J Psychiatry Suppl. 1989;8:52–62.

85


275. Stein DJ, Hollander E, Liebowitz MR. Neurobiology of impulsivity and the impulse control disorders. J Neuropsychiatry Clin Neurosci. 1993;5(1):9–17. 276. Dougherty DM, Moeller FG, Bjork JM, Marsh DM. Plasma L-tryptophan depletion and aggression. Adv Exp Med Biol. 1999;467:57–65. 277. Leo RJ, Kim KY. Clomipramine treatment of paraphilias in elderly demented patients. J Geriatr Psychiatry Neurol. 1995;8(2):123–4. 278. Hollander E, Wong CM. Body dysmorphic disorder, pathological gambling, and sexual compulsions. J Clin Psychiatry 1995;56(Suppl. 4):7–12; discussion 3. 279. Olivier B, Mos J. Serenics and aggression. Stress Medicine 1986;2(3):197–209.

291. Goodman WK, Price LH, Delgado PL et al. Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder. Comparison of fluvoxamine and desipramine. Arch Gen Psychiatry 1990;47(6):577–85. 292. Greybiel AM, Ragsdale CW. Biochemical anatomy of the striatum. In Emson PC, editor. Chemical Neuroanatomy. New York, NY: Raven Press; 1983, pp. 427–507. 293. Nieuwenhuys R. Chemoarchitecture of the Brain. Berlin: Springer-Verlag; 1985.

280. Pazos A, Palacios JM. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res. 1985;346(2):205–30.

294. McDougle CJ, Goodman WK, Price LH. Dopamine antagonists in tic-related and psychotic spectrum obsessive compulsive disorder. J Clin Psychiatry 1994;55(Suppl.):24–31.

281. Hjorth S, Carlsson A. Is pindolol a mixed agonist-antagonist at central serotonin (5-HT) receptors? Eur J Pharmacol. 1986;129(1–2):131–8.

295. Korsgaard S, Gerlach J, Christensson E. Behavioral aspects of serotonin-dopamine interaction in the monkey. Eur J Pharmacol. 1985;118(3):245–52.

282. Bel N, Romero L, Celada P et al. editors. Neurobiological basis for the potentiation of the antidepressant effect of 5-HT reuptake inhibitors by the 5-HT1A antagonist pindolol. In Monitoring Molecules in Neuroscience: Proceeding of the 6th International Conference of in vivo Methods; 1994. Bordeaux: University of Bordeaux.

296. Ballantine HT, Jr., Bouckoms AJ, Thomas EK, Giriunas IE. Treatment of psychiatric illness by stereotactic cingulotomy. Biol Psychiatry 1987;22(7):807–19.

283. Bunney WE, Garland-Bunney BL. Mechanisms of action of lithium in affective illness: basic and clinical implications. In: Meltzer HY, editor. Psychopharmacology: The Third Generation of Progress. New York, NY: Raven Press; 1987, pp. 553–65.

298. Robertson M, Doran M, Trimble M, Lees AJ. The treatment of Gilles de la Tourette syndrome by limbic leucotomy. J Neurol Neurosurg Psychiatry 1990; 53(8):691–4.

284. Snyder SH. Second messengers and affective illness. Focus on the phosphoinositide cycle. Pharmacopsychiatry 1992;25(1):25–8. 285. Jouvent R, Lecrubier Y, Puech AJ, Simon P, Widlocher D. Antimanic effect of clonidine. Am J Psychiatry 1980;137(10):1275–6. 286. Shen WW. Mania, clonidine, and dopamine. Am J Psychiatry 1986;143(1):127. 287. Arnsten AF, Goldman-Rakic PS. Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey. Brain Res. 1984;306(1–2):9–18. 288. Cummings JL. Organic psychoses. Delusional disorders and secondary mania. Psychiatr Clin North Am. 1986;9(2):293–311. 289. Jankovic J. Deprenyl in attention deficit associated with Tourette’s syndrome. Arch Neurol. 1993;50(3):286–8. 290. Zohar J, Insel TR. Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment,

86

and pathophysiology. Biol Psychiatry 1987;22(6):667–87.

297. Sawle GV, Lees AJ, Hymas NF, Brooks DJ, Frackowiak RS. The metabolic effects of limbic leucotomy in Gilles de la Tourette syndrome. J Neurol Neurosurg Psychiatry 1993;56(9):1016–19.

299. Kurlan R, Kersun J, Ballantine HT, Jr., Caine ED. Neurosurgical treatment of severe obsessive-compulsive disorder associated with Tourette’s syndrome. Mov Disord. 1990;5(2): 152–5. 300. Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry 1937;38(4):725–43. 301. Mesulam M. Patterns in behavioral neuoranatomy: association areas, the limbic system, and hemispheric specialization. In Mesulam MM, editor. Principles of Behavioral Neurology. Philadelphia. PA: F.A. Davis; 1985, pp. 1–70. 302. Bingley T, Leksell L, Meyerson BA, Rylander G. Long-term results of stereotactic anterior capsulotomy in chronic obsessive-compulsive neurosis. In Sweet WH, Obrador S, Mart´ın-Rodr´ıguez JG, editors. Neurosurgical Treatment in Psychiatry, Pain, and Epilepsy. Proceedings of the Fourth World Congress of Psychiatric Surgery, September 7–10, 1975, Madrid, Spain. Baltimore, MD: University Park Press; 1977, pp. 287–99.


303. Lujan JL, Chaturvedi A, McIntyre CC. Tracking the mechanisms of deep brain stimulation for neuropsychiatric disorders. Front Biosci. 2008; 13:5892–904. 304. Greenberg BD, Malone DA, Friehs GM et al. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 2006;31(11):2384–93. 305. Rauch SL, Dougherty DD, Malone D et al. A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. J Neurosurg. 2006;104(4):558–65. 306. Nuttin BJ, Gabriels LA, Cosyns PR et al. Long-term electrical capsular stimulation in patients with obsessive-compulsive disorder. Neurosurgery 2003;52(6):1263–72; discussion 72–4. 307. Ackermans L, Temel Y, Cath D et al. Deep brain stimulation in Tourette’s syndrome: two targets? Mov Disord. 2006;21(5):709–13. 308. Shahed J, Poysky J, Kenney C, Simpson R, Jankovic J. GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities. Neurology 2007;68(2):159–60.

312. Flaherty AW, Williams ZM, Amirnovin R et al. Deep brain stimulation of the anterior internal capsule for the treatment of Tourette syndrome: technical case report. Neurosurgery 2005;57(4 Suppl.):E403; discussion E. 313. Servello D, Porta M, Sassi M, Brambilla A, Robertson MM. Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment: the surgery and stimulation. J Neurol Neurosurg Psychiatry 2008;79(2):136–42. 314. Bajwa RJ, de Lotbiniere AJ, King RA et al. Deep brain stimulation in Tourette’s syndrome. Mov Disord. 2007;22(9):1346–50. 315. Maciunas RJ, Maddux BN, Riley DE et al. Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome. J Neurosurg. 2007;107(5):1004–14. 316. Visser-Vandewalle V. DBS in Tourette syndrome: rationale, current status and future prospects. Acta Neurochir Suppl. 2007;97(Pt 2):215–22. 317. Temel Y, Visser-Vandewalle V. Surgery in Tourette syndrome. Mov Disord. 2004;19(1):3–14.

309. Welter ML, Mallet L, Houeto JL et al. Internal pallidal and thalamic stimulation in patients with Tourette syndrome. Arch Neurol. 2008;65(7):952–7.

318. Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano AM. The subthalamic nucleus in the context of movement disorders. Brain 2004;127(Pt 1): 4–20.

310. Dehning S, Mehrkens JH, Muller N, Botzel K. Therapy-refractory Tourette syndrome: beneficial outcome with globus pallidus internus deep brain stimulation. Mov Disord. 2008;23(9):1300–2.

319. Hauptman JS, DeSalles AA, Espinoza R, Sedrak M, Ishida W. Potential surgical targets for deep brain stimulation in treatment-resistant depression. Neurosurg Focus 2008;25(1):E3.

311. Houeto JL, Karachi C, Mallet L et al. Tourette’s syndrome and deep brain stimulation. J Neurol Neurosurg Psychiatry 2005;76(7):992–5.

320. Stelten BM, Noblesse LH, Ackermans L, Temel Y, Visser-Vandewalle V. The neurosurgical treatment of addiction. Neurosurg Focus 2008;25(1):E5.

87

Section I


Chapter

Arousal

6

C. Alan Anderson, Christopher M. Filley, David B. Arciniegas, and James P. Kelly

Arousal refers to the physiological state of wakefulness and alertness. Whereas the term has been used interchangeably with consciousness, arousal in fact has a more specific meaning as a neural foundation of what is required to be conscious. Arousal denotes the level of consciousness [1], which, in combination with the content of consciousness (attention, language, memory, praxis, gnosis, visuospatial skills, and executive function) creates the capacity for awareness and behavior. The arousal system involves multiple distributed neural networks working in harmony to permit normal sleep–wake cycles, satisfy internal drive states, and respond to environmental demands. Diseases and injuries that affect these systems represent some of the most serious and devastating conditions encountered in clinical medicine. The assessment of arousal therefore is as crucial in patient care as the details of higher cognitive function. Arousal represents a fundamental requirement for consciousness, providing the wakefulness and alertness that enable all other cognitive operations. It makes no sense, for example, to describe a patient as aphasic because of failure to produce meaningful language while he or she is asleep or in deep coma. Disorders of arousal highlight this core function of the brain while challenging the clinician to address a host of medical, neurologic, ethical, and social issues.

Neuroanatomy and neurophysiology of arousal and awareness Disorders of arousal typically involve pathology of the brainstem, thalamus, or widespread areas of both cerebral hemispheres. This useful generalization structures the consideration of how arousal is organized in the

normal brain. It has been long recognized that the ascending reticular activating system in the brainstem forms the foundation of the arousal system [2]. From these early observations, the understanding of the arousal system has been significantly refined through expanded knowledge of its anatomy and physiology (Figures 6.1 and 6.2). Key features of the distributed neural networks supporting arousal are their multiplicity and redundancy. These characteristics permit fine-tuning of the organism’s response to its environment, as well as provide protection against failure of any single component [3]. A parallel series of distinct neural networks using dopamine, histamine, serotonin, acetylcholine, and norepinephrine as neurotransmitters originates in the brainstem or in the basal forebrain [4]. The arousal systems then converge in the thalamus, and from there support and modulate arousal through widespread projections throughout the cerebral cortex [3]. These distributed reticulocortical, reticulothalamic, and thalamocortical networks are the foundation of consciousness, and comprise a highly integrated anatomy that matches the level of arousal to the requirements of the organism [5]. While there is a general level of arousal maintained during waking states, these networks also serve to modulate specific arousal states related to motivational systems including hunger, thirst, pain, fear, and sexual behavior [6]. The brainstem nuclei for these ascending arousal systems receive afferent sensory input including somatosensory, auditory, vestibular, and gustatory information. Somatosensory signals related to pain or sexual signals are amplified as they reach arousal networks [3]. Other forms of sensory information modulating arousal, however, enter the system through alternative


88

Chapter 6: Arousal

Figure 6.1. Key components of the ascending arousal system. A major input to the relay and reticular nuclei of the thalamus originates from cholinergic (ACh) cell groups in the upper pons, the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT). These inputs facilitate thalamocortical transmission. A second pathway activates the cerebral cortex to facilitate the processing of inputs from the thalamus; this arises from neurons in the monoaminergic cell groups, including the tuberomammillary nucleus (TMN) containing histamine (His), ventral periaqueductal gray (vPAG) dopamine-containing cell groups (DA), the dorsal and median raphe nuclei containing serotonin (5-HT), and the noradrenergic locus coeruleus (LC) containing noradrenaline (NA). This pathway also receives contributions from peptidergic neurons in the lateral hypothalamus (LH) containing orexin (ORX) or melanin-concentrating hormone (MCH), and from basal forebrain (BF) neurons that contain gamma-aminobutyric acid (GABA) or ACh. Reproduced from Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437(7063): 1257–63, with permission from Nature Publishing Group.

pathways. Olfactory input, for example, enters the system via the basal forebrain, which is tightly connected to the amygdala and modulates arousal based on relevant odors and their associated emotional valence. The visual system also has unique connections with the arousal system and, given the importance of visual input in humans, it is not surprising that multiple pathways exist by which vision can influence arousal. Projections from visual cortex to the superior colliculus in the midbrain are relayed to thalamic nuclei including the reticular and medial cell groups as well as the pulvinar [3]. Through widespread cortical connections these thalamic cell groups modulate arousal based on salient visual stimuli. Higher cortical processing of

Figure 6.2. A schematic drawing to show the key projections of the ventrolateral preoptic nucleus (VLPO) to the main components of the ascending arousal system. It includes the monoaminergic cell groups such as the tuberomammillary nucleus (TMN), the A10 cell group, the raphe cell groups and the locus coeruleus (LC). It also innervates neurons in the lateral hypothalamus, including the perifornical (PeF) orexin (ORX) neurons, and interneurons in the cholinergic (ACh) cell groups, the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT). Additional abbreviations: 5-HT – serotonin; GABA – gamma-aminobutyric acid; gal – galanin; NA – noradrenaline; His – histamine. Reproduced from Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437(7063):1257–63, with permission from Nature Publishing Group.

visual input influences arousal in a top-down fashion through reciprocal connections back to the thalamus as well as to upper brainstem nuclei, thus tailoring an appropriate level of arousal based on the biological significance of visual information [3, 7]. The ascending arousal systems include cholinergic, noradrenergic, dopaminergic, glutamatergic, and histaminic nuclei [6]. The pendunculopontine and laterodorsal tegmental nuclei in the brainstem send cholinergic projections to the reticular nuclei of the thalamus, forming the reticulothalamic component of the ascending arousal system, and modulating cortical engagement and information processing. Glutamatergic projections from the thalamus are broadly distributed to the cerebral cortex, activating these areas in preparation for information processing. Dopaminergic projections originating in the ventral tegmental area of the midbrain project widely throughout the

89


cerebral cortex and serve a similar activating function. These connections are bidirectional, providing for feedback in the system, and their bilateral distribution provides additional safety through redundancy against the failure of any single component [6]. Brainstem projections from serotonergic nuclei in the median and dorsal raphe nuclei, histamine-producing neurons in the hypothalamus, noradrenergic nuclei in the locus coeruleus, and additional cholinergic projections originating in the ventral forebrain nuclei also participate in the modulation of cortical activation [6]. The combination of reticulothalamic and reticulocortical projections, as well as ascending tracts originating in the ventral forebrain, provide balance and feedback mechanisms that help modulate the activity of diencephalic and cortical targets, and match the overall level of arousal and awareness to the everchanging needs for self- and environmental awareness, and behavior [4, 8]. The brainstem and basal forebrain structures are so closely linked that some investigators consider the basal forebrain nuclei a rostral extension of the reticular activating system in the brainstem rather than a separate functional entity [9]. The intralaminar and midline thalamic nuclei form a critical relay of the arousal system, receiving ascending arousal fibers originating in the brainstem and in turn projecting diffusely throughout the cerebral cortex [7, 10]. In addition to the input from the brainstem reticular activating system, thalamic intralaminar nuclei receive fibers from the spinothalamic tract and cerebellum, and have reciprocal connections to medial prefrontal and anterior cingulate cortex [10]. These nuclei serve more than a simple relay function. The thalamic nuclei are anatomically and functionally distinct, receiving targeted input from specific brainstem nuclei and projecting to specific sites in the striatum and cerebral cortex, thus allowing the integration of sensory input and internal drive states [7]. As such, these nuclei serve as part of a thalamic matrix that underlies cortical synchronization in support of awareness and higher cognitive functions [11]. In addition to their role in arousal and other cognitive functions, these thalamic nuclei modulate basal ganglia function and participate in the transmission of nociceptive inputs to the cerebral cortex [10]. Thus, the thalamic nuclei are positioned to integrate internal drive states, cognitive function, somatic and external sensory information, and motor systems into the modulation of arousal.

90

Disturbances at any level of this system can affect arousal. A wide variety of pathological processes including vascular disease, the compressive effects of tumors or other mass lesions, and the direct mechanical effects of trauma can injure brainstem nuclei and their ascending fibers. For example, white matter tracts that interconnect cortical and subcortical structures are particularly vulnerable to traumatic brain injury (TBI) and anoxia. The midline and intralaminar nuclei of the thalamus are also affected in TBI [10]. Hypoxic– ischemic brain injury (HI–BI) can produce a wide range of lesions involving the rostral brainstem [12], the cerebral white matter (with special vulnerability in areas between the major cerebral artery territories and subcortical regions irrigated by the distal branches of deep and superficial penetrating vessels), and the cerebral cortex, producing laminar necrosis that is usually most severe in layers three, four, and five [13–15].

Disorders of arousal and awareness Brain death Brain death represents the most severe disturbance of arousal, with total and irreversible cessation of any brain function, including that associated with the brainstem. In most of the USA, with the exception of a few state governments that amended the Uniform Determination of Death Act [16] to address physician qualifications or religious considerations, an individual determined to meet the criteria for brain death is clinically and legally dead. Determining the presence of brain death is not just an academic exercise, since once the diagnosis of brain death is established, it is permissible to discontinue patient care [17]. Current criteria for brain death include the absence of responsiveness, including any motor response to painful stimulation, and the loss of all brainstem reflexes (including respiratory drive). The diagnosis must be made in the absence of confounding medical problems that could affect the evaluation, including centrally active medications and hypothermia [18]. Complicating the assessment, some patients meeting the criteria for brain death are noted to retain autonomic responses including sweating, blushing, and tachycardia, intact limb reflexes, and they may even have spontaneous limb movements. Diagnostic studies used to confirm the diagnosis of brain death include conventional angiography, transcranial Doppler ultrasonography, and radionuclide

Chapter 6: Arousal

brain scans used to establish the absence of cerebral blood flow. Electroencephalographic (EEG) monitoring, typically for at least 30 minutes, can be performed to demonstrate the absence of cerebral electrical activity. Similarly, the absence of somatosensory evoked potentials with stimulation of the median nerve is a confirmatory finding [18]. Once the diagnosis of brain death is established, issues surrounding termination of care, the potential suitability of the patient as an organ donor, and postmortem examination must be decided. The complexity of these considerations make the diagnosis and management of brain death a challenging problem for medical personnel, staff, families, and other parties with vested interests in the outcome (e.g., organ transplant teams). Moving beyond the complete cessation of brain function constituting brain death, the discussion leads to patients with severe impairments of arousal and awareness but with at least some residual brain function. Coma, the vegetative state, and the minimally conscious state are disorders of consciousness with disturbances in both arousal and awareness. All of these states imply major brain dysfunction and, unlike typical portrayals in motion pictures and television programs, most patients with cardiac arrest, severe TBI, or other severe insult to the brain remain comatose for some time following the insult and their resuscitation. As patients begin the slow process of recovery, they emerge from coma and progress through levels of improving arousal and awareness; the eventual outcome varies considerably and is largely dependent on age, medical comorbidities, and the mechanism of injury [19].

Coma Coma is the state of neurological unconsciousness exhibited by unarousable unawareness of the external environment that is due to extensive damage to or depressed function of both cerebral hemispheres, bilateral diencephalic structures, or the ascending reticular activating system [1]. This state can last for several weeks or a matter of seconds. The loss of consciousness seen with concussion is due to rapid and widespread neuronal depolarization across the hemispheres, which resolves quickly but can initiate a neurochemical cascade, which further impairs brain function [20].

Coma patients typically (but not invariably) have their eyes closed, are unresponsive to verbal or painful physical stimuli, and lack sleep–wake cycles; while there may be reflex motor activity or purposeless restless movements, they lack any goal-directed motor activity [1, 21]. This state represents the effects of structural injury, pharmacologic effects, or metabolic disturbances of the brain’s arousal mechanisms, resulting in an unconscious and unarousable clinical condition [22]. In addition to making the diagnosis and recommending treatment, establishing the prognosis for patients in coma is a frequent clinical question. Depending on the mechanism and severity of the insult that results in coma, some patients may progress to higher levels of consciousness very quickly, while others remain in coma for prolonged periods of time. The setting where clinicians are most accurate in making prognostic determinations is in the aftermath of hypoxic–ischemic events. For example, validated neurological examination and laboratory findings support early predictions, within the first five to seven days after HI–BI, of survival and neurological outcome following cardiac arrest in adults [17, 23]. Established clinical markers associated with death or unconsciousness at one month, or unconsciousness or severe disability at six months following the hypoxic–ischemic event, include the absence of corneal reflexes or the pupillary light response, an absent or extensor motor response to noxious stimulation 72 hours following cardiac arrest, and the presence of myoclonic status epilepticus. Validated laboratory data predicting poor outcome following hypoxic–ischemic events include a serum neuron-specific enolase level of greater than 33 mcg per liter and the absence of cortical somatosensory evoked potentials performed at least 72 hours following resuscitation [23]. Prognosis based on these clinical measures, however, may be influenced by treatments administered as part of the resuscitation following cardiac arrest. Cooling protocols may change the predictive value of diagnostic tests as well as extend the time period for potential recovery [24, 25]. Coma in other settings – including trauma, infections, poisonings, metabolic disturbances, and hemorrhagic or ischemic cerebral vascular injury – presents greater prognostic challenges, with more variability in both short-term and long-term recovery. For these conditions, the prognosis is largely determined by the patient’s response to specific treatments aimed

91


at addressing the underlying process. This additional variable limits the development and application of prognostic criteria similar to that available for anoxic ischemic injury for these causes of coma. Finally, regardless of the mechanism of injury, accurate diagnosis, management, and prognostication may be complicated by ongoing treatments including paralytics, sedation, mechanical ventilation, and hypothermia, as well as the confounding effects of comorbid injury and medical conditions.

Vegetative state Vegetative states (VS) are distinguished from coma by the presence of spontaneous eye opening and sleep– wake cycles. Patients in VS demonstrate no response to verbal, visual, or physical stimulation and no awareness of self or the environment [26]. Patients in VS have no purposeful activity, and demonstrate no effort (or ability) to communicate (e.g., express or comprehend language). Diagnostic criteria have been established for VS and include the absence of any awareness of self or environment, the absence of purposeful voluntary responses to external stimuli, the absence of language expression or comprehension, adequate autonomic function to survive with medical and nursing care, bowel and bladder incontinence, the presence of sleep–wake cycles, and variable preserved cranial nerve and spinal reflexes [26]. Laboratory findings among patients in VS include polymorphic delta or theta activity on electroencephalogram (EEG), and evidence of diffuse gray and white matter injury and global volume loss on structural neuroimaging [27]. Progression from coma to VS represents recovery of some or nearly all brainstem arousal mechanisms with continued failure of the distal target networks; the persistent dysfunction of rostral brain networks can occur because of thalamic injury, disruption of white matter tracts, and diffuse cortical injury, alone or in combination. Positron emission tomography (PET) measurements of cerebral blood flow in VS patients demonstrate that there is actually hypermetabolism in the ascending reticular activating system with impaired functional connectivity between the brainstem arousal system and higher cortical structures [28]. Pathologically, patients in VS demonstrate variable findings, including injury in the upper brainstem, the central thalamus, the subcortical white

92

matter (often diffuse axonal injury), and widespread cortical injury, depending on the individual patient and mechanism(s) of injury [29–31]. The degree of brain injury in VS patients is typically greater than that of other severely brain-injured patients who demonstrate any degree of conscious behavior [30]. As described above, the diagnostic criteria for VS are based on clinical observation, meaning the assessment of the patient for the absence of any form of awareness, spontaneous communication, or responsiveness to the environment. This evaluation requires careful serial examinations over a period of time, and the recognition of subtle clinical signs can be difficult. The diagnostic process is subject to error, and a significant number of patients are incorrectly diagnosed [32]. Specific bedside assessment tools have been developed to measure neurological function as patients emerge from coma, which aids in the diagnosis, prognosis, and understanding of an individual patient’s level of consciousness [33–35]. Of particular concern is misdiagnosis of VS among individuals who are conscious and aware of their surroundings – including those whose clinical conditions are most accurately regarded as a “locked-in syndrome” (LIS) [36]. A subset of individuals with LIS – in which consciousness and higher cognitive abilities are intact – superficially appear to be in VS simply as a result of lost capacity for a motor response [37–39]. Functional magnetic resonance imaging (fMRI) and PET studies assessing language, facial recognition, and other cognitive functions in patients with VS have demonstrated cortical regions of preserved activation in some subjects [37]. The prognosis for patients in VS is to a large degree dependent on the mechanism(s) of injury. Establishing a prognosis in patients in VS has crucial medical–legal implications. Important decisions regarding ongoing care, end-of-life decisions including termination of care, and withdrawal of nutritional support and hydration are commonly based on these prognostications [40]. Whereas the overall prognosis for patients with brain insult of this severity is poor, there are patients who emerge from VS and recover to varying degrees while others remain in VS indefinitely [1, 40]. This condition has been referred to variably as a persistent or a permanent VS (PVS); given that these terms are not interchangeable, it is important to be clear in our use of these terms. Criteria for considering a patient to be in PVS is controversial, with proposed criteria varying based on

Chapter 6: Arousal

the cause: 30 days is considered adequate for patients following cardiac arrest and 12 months is required after TBI [1, 40]. The recommendation of the Aspen Neurobehavior Conference Working Group was to limit the diagnosis to the indefinite term “vegetative state” and include the cause of the injury (i.e., anoxic versus metabolic versus TBI) and the length of time that the patient had been in VS. Whereas overall rates of recovery from VS are poor, the likelihood of recovery is better for younger patients and for those with TBI than for patients with HI–BI [41]. The longer the time interval after onset of VS, the less likely the patient will see any significant recovery. It is unlikely for patients with TBI to return to consciousness after 12 months, and following non-TBI it is unlikely to see a return to consciousness after three months. While there are patients with late recovery from VS, even years after the onset, these patients are typically severely impaired neurologically [41].

Minimally conscious state The minimally conscious state (MCS) differs from VS by virtue of the patient having minimal and inconsistent evidence for conscious behavior and some awareness of self and the environment [40, 42]. While MCS represents a spectrum of severely altered consciousness, patients with MCS demonstrate inconsistent purposeful behavior including following commands, responding to physical stimulation, manifesting appropriate emotional responses, and making efforts to initiate communication. When patients begin to interact with their environment and communicate consistently, even if still functionally severely impaired, they are considered to have made the transition from MCS to a higher level of consciousness. While VS is defined by the absence of any purposeful behaviors, efforts to communicate, and unresponsiveness to the environment, MCS is defined by the presence of these features, albeit at an inconsistent and minimal level. Making the diagnosis of MCS requires careful patient observation and examination as well as consideration of the confounding effect of specific cognitive deficits including aphasia and apraxia to try to determine the true level of awareness for self and environment. This process is critical because the prognostic implications of MCS are quite different from those of the VS.

Because MCS includes a broader spectrum of function as well as a wider range of injury producing the condition, overall the prognosis is usually better than for VS [43]. Patients in MCS show slightly higher levels of cerebral metabolism compared to patients in VS, and functional imaging studies assessing responsiveness to auditory and tactile stimuli demonstrate large-scale activation of cortical networks in some MCS patients, to a much greater extent than is typically seen with similar paradigms applied to patients in VS [19, 44]. This distinction in the level of consciousness between MCS and VS has important medical–legal ramifications for decisions about ongoing management as well as termination of care, including withdrawal of nutritional support and hydration. While the distinction between VS and MCS is clear in principle, if not always clinically, it is still difficult to determine when patients have emerged from MCS. Similarly, given the severity of the cognitive dysfunction, it is sometimes difficult to gauge clinical improvement within the spectrum of MCS. In an effort to clarify this issue, the Aspen Neurobehavior Conference Working Group defined emergence from MCS as the ability to consistently demonstrate functional interactive communication, the functional use of objects, or both [42]. It is not surprising that the most useful prognostic measures for recovery from MCS are the patient’s age, intact auditory evoked potentials, functional level when evaluated, the duration of the condition, and the rate of improvement shown by the patient up to that point [43, 45]. In contrast to VS, in which late recovery is rare, in a recent study of patients with MCS, a third (including both traumatic and non-traumatic etiologies) emerged from MCS [43]. However, it is important to note that despite their late improvement, they all remained severely or totally disabled. The recent advances in functional imaging of aspects of arousal and awareness demonstrate the limitations of our current clinical approach to the assessment and prognosis of patients with disorders of consciousness, and highlight the need for better ways of evaluating and treating these challenging patients [39]. In summary, much has been clarified recently about the fundamental differences in arousal and awareness that distinguish brain death, coma, VS, and MCS. Brain death is the complete failure of brain function, including all aspects of cortical and brainstem function. This condition implies the complete and irreversible loss of arousal and consciousness, as well as all

93


other neurological functions of the brain and brainstem. In coma, elementary centrally mediated functions are preserved with an absence of arousal and awareness. Vegetative state is defined by wakefulness without any awareness of self or the environment and the absence of any purposeful behaviors. With the return of minimal awareness and interaction with the environment, the patient is defined as being in MCS.

Principles of treatment in the disorders of consciousness Most of what is known about the disorders of consciousness considered in this chapter relates to etiology, diagnosis, and prognosis. Given the broad range of clinical disorders that can produce these disturbances of arousal and awareness, there is a vast literature addressing specific interventions (i.e., the management of metabolic disorders, interventions for ischemic stroke and intracranial hemorrhage, and cooling protocols after cardiac arrest). Specific therapies aimed at the fundamental disturbance of arousal and awareness, however, remain an understudied area in clinical medicine. Regardless of the mechanism of injury, it is important to identify and aggressively treat ongoing medical problems, provide adequate nutritional support and hydration, and limit as much as possible the use of medications that reduce arousal (e.g., anticonvulsants, antipsychotics, pain medications, and sedatives). Because the diagnosis of the specific disorders of consciousness described above depends on careful assessments, and improvement, while clinically relevant, may be subtle, it is important to have systematic serial examinations on which to base treatment decisions. A number of clinical scales for use in this setting are available. These include the Coma Recovery Scale-Revised [46], the Coma–Near Coma Scale [47], the Glasgow Coma Scale [48], and the Rancho Los Amigos Levels of Cognitive Functioning [49]. In our experience, the Coma Recovery Scale and the Coma–Near Coma Scale have proved particularly useful in the evaluation of treatment response and recovery. The available literature, much of it related to patients with TBI, offers some evidence to help guide pharmacologic interventions and specific rehabilitative strategies in patients with disorders of arousal and consciousness. General considerations include providing the best possible environment for their

94

ongoing care. Specific steps include optimizing light– dark cycles, protecting time for sleep at night and encouraging wakefulness throughout the day, and providing regularly scheduled meals (by whatever means necessary, including tube feedings) in order to entrain circadian rhythms, limit distractions and other sources of unwanted stimulation such as treating pain and minimizing painful procedures, and provide necessary stimuli to help facilitate interaction with others and the environment. For coma patients, a specific rehabilitative strategy is coma stimulation, in which structured sensory stimulation is administered for the purposes of improving sensory awareness and facilitating improvements in arousal and awareness. A time-limited trial of this therapy represents a specific intervention with limited risk for patients in coma, and can also be considered for those in VS and MCS. There is mounting evidence supporting the use of this therapy when provided by well-trained and competent therapists in the proper setting [50]. The evidence for pharmacologic interventions in disorders of consciousness is limited and it is important to note that at present there are no FDA-approved treatment options for these patients. All proposed treatment options are based on off-label uses of these medications. Amantadine has been used in the treatment of severe disturbances of arousal, with two double-blind, placebo-controlled studies suggesting that it may be beneficial [45, 51]. A variety of other medications have demonstrated benefit in small case series and individual case reports. These medications include modafinil [52], methylphenidate [53– 55], bromocriptine [56], pramipexole [57], levodopa [58], and zolpidem [58, 59]. These drugs represent additional off-label treatment options as second-line therapies in patients where amantadine was either not tolerated or ineffective. Deep brain stimulation (DBS), in common use for the treatment of a variety of movement disorders, may offer an alternative to pharmacologic therapy in selected patients in the future. Deep brain stimulation targeting specific nuclei in the thalamus in a patient in MCS following TBI led to improvement in arousal, interactions with the environment, and the ability to communicate [60]. Bilateral DBS leads were placed in the anterior intralaminar nuclei and the adjacent paralaminar regions of the thalamus. This patient was selected for the procedure because fMRI studies indicated that large-scale bihemispheric language

Chapter 6: Arousal

networks remained intact and responsive to activation despite the marked functional impairment. The premise behind the DBS procedure was that increasing activation of neocortical and basal ganglia neurons through stimulation of the thalamus would compensate for the loss of arousal modulation normally provided by these structures in the intact brain [31]. Whereas these studies suggest great potential for DBS in this severely impaired population (in whom there are limited therapeutic options), the available evidence and experience with the procedure limits its application to selected research subjects. Whether the risks and benefits of this procedure warrant broader application remains to be seen.

Conclusion Arousal is a central function of the brain and, as such, makes possible all the higher functions characterizing the human species and collectively known as consciousness. Disorders of arousal affect consciousness at its most fundamental level, and serve well to illustrate how the capacity for wakefulness and awareness is so critical for all conscious human behavior. For clinicians engaged in the care of these severely compromised patients, clinical management commonly involves not only complex neurologic issues but also difficult medical–legal, ethical, and social concerns. Although specific treatments for these disorders are limited, a range of rehabilitative, pharmacologic, and environmental strategies can improve outcomes. As neuroscientific advances continue, a more informed approach to the topic of arousal and its disorders can be anticipated.

References 1. Posner JB, Saper CB, Schiff ND, Plum F. Plum and Posner’s Diagnosis of Stupor and Coma. 4th edition. New York, NY: Oxford University Press; 2007. 2. Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1949;1(4): 455–73. 3. Pfaff D. Brain Arousal and Information Theory. Cambridge, MA: Harvard University Press; 2006. 4. Parvizi J, Damasio A. Consciousness and the brainstem. Cognition 2001;79(1–2):135–60. 5. Mesulam M. Attentional networks, confusional states, and neglect syndromes. In Mesulam MM, editor. Principles of Behavioral and Cognitive Neurology. 2nd

edition. Oxford: Oxford University Press; 2000, pp. 174–256. 6. Pfaff D, Ribeiro A, Matthews J, Kow LM. Concepts and mechanisms of generalized central nervous system arousal. Ann N Y Acad Sci. 2008;1129:11–25. 7. Steriade M, Glenn LL. Neocortical and caudate projections of intralaminar thalamic neurons and their synaptic excitation from midbrain reticular core. J Neurophysiology 1982;48(2):352–71. 8. Kinomura S, Larsson J, Gulyas B, Roland PE. Activation by attention of the human reticular formation and thalamic intralaminar nuclei. Science 1996;271(5248):512–15. 9. Gray TS. Functional and anatomical relationships among the amygdala, basal forebrain, ventral striatum, and cortex. An integrative discussion. Ann N Y Acad Sci. 1999;877:439–44. 10. Benarroch EE. The midline and intralaminar thalamic nuclei: anatomic and functional specificity and implications in neurologic disease. Neurology 2008;71(12):944–9. 11. Jones EG. The thalamic matrix and thalamocortical synchrony. Trends Neurosci. 2001;24(10):595–601. 12. Hopkins RO, Tate DF, Bigler ED. Anoxic versus traumatic brain injury: amount of tissue loss, not etiology, alters cognitive and emotional function. Neuropsychology 2005;19(2):233–42. 13. Arbelaez A, Castillo M, Mukherji SK. Diffusion-weighted MR imaging of global cerebral anoxia. AJNR: Am J Neuroradiol. 1999;20(6): 999–1007. 14. Chalela JA, Wolf RL, Maldjian JA, Kasner SE. MRI identification of early white matter injury in anoxic-ischemic encephalopathy. Neurology 2001;56(4):481–5. 15. Greer DM. Mechanisms of injury in hypoxic-ischemic encephalopathy: implications to therapy. Semin Neurol. 2006;26(4):373–9. 16.

Guidelines for the determination of death. Report of the medical consultants on the diagnosis of death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. J Am Med Assoc. 1981;246(19):2184–6.

17. Geocadin RG, Eleff SM. Cardiac arrest resuscitation: neurologic prognostication and brain death. Curr Opin Crit Care 2008;14(3):261–8. 18. Wijdicks EF. Determining brain death in adults. Neurology 1995;45(5):1003–11. 19. Laureys S, Perrin F, Schnakers C, Boly M, Majerus S. Residual cognitive function in comatose, vegetative and minimally conscious states. Curr Opin Neurol. 2005;18(6):726–33.

95


20. Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train. 2001;36(3):228–35. 21. Stevens RD, Bhardwaj A. Approach to the comatose patient. Crit Care Med. 2006;34(1):31–41. 22. Schiff ND, Plum F. The role of arousal and “gating” systems in the neurology of impaired consciousness. J Clin Neurophysiol. 2000;17(5):438–52. 23. Wijdicks EFM, Hijdra A, Young GB et al. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67(2):203–10.

35. Pape TL, Senno RG, Guernon A, Kelly JP. A measure of neurobehavioral functioning after coma. Part II: Clinical and scientific implementation. J Rehabil Res Dev. 2005;42(1):19–27. 36. Andrews K, Murphy L, Munday R, Littlewood C. Misdiagnosis of the vegetative state: retrospective study in a rehabilitation unit. Br Med J. 1996; 313(7048):13–16. 37. Owen AM, Coleman MR. Detecting awareness in the vegetative state. Annals N Y Acad Sci. 2008;1129: 130–8.

24. Al Thenayan E, Savard M, Sharpe M, Norton L, Young B. Predictors of poor neurologic outcome after induced mild hypothermia following cardiac arrest. Neurology 2008;71(19):1535–7.

38. Laureys S, Boly M, Schnakers C et al. Revelations from the unconscious: studying residual brain function in coma and related states. Bull Mem Acad R Med Belg. 2008;163(7–9):381–8; discussion 8–90.

25. Leithner C, Ploner CJ, Hasper D, Storm C. Does hypothermia influence the predictive value of bilateral absent N20 after cardiac arrest? Neurology 2010;74(12):965–9.

39. Monti MM, Vanhaudenhuyse A, Coleman MR et al. Willful modulation of brain activity in disorders of consciousness. N Engl J Med. 2010;362(7):579–89.

26. The Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state (1). N Engl J Med. 1994;330(21):1499–508. 27. American Academy of Neurology. Practice parameters: assessment and management of patients in the persistent vegetative state (summary statement). Neurology 1995;45(5):1015–18. 28. Silva S, Alacoque X, Fourcade O et al. Wakefulness and loss of awareness: brain and brainstem interaction in the vegetative state. Neurology 2010;74(4):313–20. 29. Adams JH, Graham DI, Jennett B. The neuropathology of the vegetative state after an acute brain insult. Brain 2000;123(Pt 7):1327–38. 30. Jennett B, Adams JH, Murray LS, Graham DI. Neuropathology in vegetative and severely disabled patients after head injury. Neurology 2001;56(4): 486–90. 31. Schiff ND, Fins JJ. Deep brain stimulation and cognition: moving from animal to patient. Curr Opin Neurol. 2007;20(6):638–42. 32. Schnakers C, Vanhaudenhuyse A, Giacino J et al. Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC Neurol. 2009;9:35. 33. Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil. 2004;85(12):2020–9. 34. Pape TL, Heinemann AW, Kelly JP, Hurder AG, Lundgren S. A measure of neurobehavioral functioning after coma. Part I: Theory, reliability, and

96

validity of Disorders of Consciousness Scale. J Rehabil Res Dev. 2005;42(1):1–17.

40. Giacino J, Whyte J. The vegetative and minimally conscious states: current knowledge and remaining questions. J Head Trauma Rehabil. 2005;20(1): 30–50. 41. Estraneo A, Moretta P, Loreto V et al. Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state. Neurology 2010;75(3):239–45. 42. Giacino JT, Ashwal S, Childs N et al. The minimally conscious state: definition and diagnostic criteria. Neurology 2002;58(3):349–53. 43. Luaute J, Maucort-Boulch D, Tell L et al. Long-term outcomes of chronic minimally conscious and vegetative states. Neurology 2010;75(3):246–52. 44. Schiff ND, Rodriguez-Moreno D, Kamal A et al. fMRI reveals large-scale network activation in minimally conscious patients. Neurology 2005;64(3):514–23. 45. Whyte J, Katz D, Long D et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: a multicenter study. Arch Phys Med Rehabil. 2005;86(3):453–62. 46. Kalmar K, Giacino JT. The JFK Coma Recovery Scale–Revised. Neuropsychology 2005;15(3–4): 454–60. 47. Rappaport M, Dougherty AM, Kelting DL. Evaluation of coma and vegetative states. Arch Phys Med Rehabil. 1992;73(7):628–34. 48. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2(7872):81–4. 49. Hagen C, Malkmus D, Durham P. Levels of Cognitive Functioning. Downey, CA: Ranchos Los Amigos Hospital; 1972.

Chapter 6: Arousal

50. Lombardi F, Taricco M, De Tanti A, Telaro E, Liberati A. Sensory stimulation for brain injured individuals in coma or vegetative state. Cochrane Database Syst Rev. 2002;2:CD001427. 51. Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil. 2002;17(4):300–13. 52. Rivera VM. Modafinil for the treatment of diminished responsiveness in a patient recovering from brain surgery. Brain Injury 2005;19(9):725–7. 53. Hornyak JE, Nelson VS, Hurvitz EA. The use of methylphenidate in paediatric traumatic brain injury. Pediatr Rehabil. 1997;1(1):15–17. 54. Plenger PM, Dixon CE, Castillo RM et al. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil. 1996;77(6): 536–40.

55. Worzniak M, Fetters MD, Comfort M. Methylphenidate in the treatment of coma. J Fam Pract. 1997;44(5):495–8. 56. Passler MA, Riggs RV. Positive outcomes in traumatic brain injury-vegetative state: patients treated with bromocriptine. Arch Phys Med Rehabil. 2001; 82(3):311–15. 57. Patrick PD, Buck ML, Conaway MR, Blackman JA. The use of dopamine enhancing medications with children in low response states following brain injury. Brain Injury 2003;17(6):497–506. 58. Clauss R, Nel W. Drug induced arousal from the permanent vegetative state. NeuroRehabilitation 2006;21(1):23–8. 59. Cohen SI, Duong TT. Increased arousal in a patient with anoxic brain injury after administration of zolpidem. Am J Phys Med Rehabil. 2008;87(3):229–31. 60. Schiff ND. Central thalamic deep-brain stimulation in the severely injured brain: rationale and proposed mechanisms of action. Annals N Y Acad Sci. 2009;1157:101–16.

97

Section I


Chapter

Sleep

7

Martin L. Reite

The core function of sleep in maintaining the integrity of brain and bodily function in animals is still under debate [1], but its absolute necessity in humans is unequivocal. Total sleep deprivation leads to death [2]. In humans, sleep restriction and insufficient sleep lead to decreased cognitive and psychomotor performance [3], impaired antibody production following immunizations [4], increased C-reactive protein [5], decreased leptin, and increased grehlin production with concomitant higher risk for insulin resistance and type 2 diabetes [6, 7]. Recognition of the personal and economic cost of disturbed sleep has contributed to the development of the specialty of sleep medicine and improved the definition of the many sleep pathologies. Four major brain systems, and two state switching mechanisms, underlie the appearance and control of sleep. The major systems are the arousal system, the non-rapid eye movement (REM) slow-wave sleep (SWS) system, the REM sleep system, and the circadian timing system. The switching mechanisms are bistable neurophysiological mechanisms, one of which controls the wake/SWS transition, the other controlling the REM-on vs. REMoff state. A basic knowledge of these systems and switching mechanisms provides an important background for assessment and treatment of most sleep disorders. In the parlance of sleep medicine, the sleep homeostatic systems are encompassed by the term Process S, and the circadian timing systems by the term Process C [8]. Most sleep pathologies can be conceptualized as representing disturbances in Process S, Process C, or both. Historically, an important event in sleep medicine was the encephalitis lethargica epidemic of 1917– 1918, which was associated with profound changes

in sleep behavior, including severe hypersomnia, and, less frequently, profound insomnia. The Austrian neuropsychiatrist and World War I pilot Constantin von Economo examined the brains of deceased patients and found that lesions in the regions now known to encompass the ascending reticular activating system (ARAS) led to profound sleepiness and even coma, whereas lesions in regions now known to encompass the sleep-promoting ventrolateral pre-optic (VLPO) region led to profound insomnia. The cause was never found, and explanations ranged from viral to, more recently, delayed destructive autoimmune responses following streptococcal infection. Since that time, much progress in the understanding of sleep has been made. In this chapter, the organization of human sleep and the brain mechanisms that regulate it are reviewed, and the manner in which disturbances in those mechanisms lead to specific sleep disorders is discussed. For convenience we will group the sleep pathologies into three broad categories: (1) the insomnias, (2) the hypersomnias, and (3) the parasomnias. While there is much overlap between syndromes, patients often present with complaints representing these three categories (e.g., “I can’t sleep,” “I sleep too much,” or “strange things happen while I sleep”).

Basic wake–sleep organization and mechanisms Wake-promoting systems The ARAS lies in the upper brainstem and sends projections rostrally through two major pathways, one to the thalamus-activating thalamic relay neurons


98

Chapter 7: Sleep

which gate transmission of information to the cortex, and a second more direct system that bypasses the thalamus and activates neurons in the hypothalamus, basal forebrain, and cerebral cortex. These pathways, when active, promote wakefulness. The first pathway originates largely in cholinergic cell groups active during wakefulness and REM sleep that are located in the pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei. Whereas downregulation of this system during sleep might be thought to prevent sensory information from reaching the cortex, clinical and laboratory evidence show otherwise. For example, neurons in the auditory cortex respond to auditory input during sleep [9], and complex parasomnia behavior including driving can occur during sleep, indicating that the brain can respond appropriately to sensory input while not conscious of it. Several additional regions in the upper brainstem, predominantly monoaminergic, are involved in promoting wakefulness, including histaminergic nuclei (important in maintaining vigilance, as discussed below), the tubero-mammillary region (modulated by orexin/hypocretin), and serotonergic influences (primarily from the raphe nuclei). The second branch of the ARAS originates primarily in monoaminergic neurons in the upper brainstem and caudal hypothalamus, including the noradrenergic locus coeruleus (LC). The ARAS thus depends on acetylcholine (ACh), monoamines, and some neuropeptide neurotransmitter systems for its function. Overactivation of the ARAS leads to complaints of insomnia, suggesting stress, anxiety, or the general state of hyperarousal thought to underlie primary insomnia. Agents that inhibit the ARAS promote decreased arousal or sleep. It has been hypothesized that disturbances in ARAS function may be related to sleep–wake control problems found in a number of neurological and mental disorders [10]. The neurophysiology of arousal is discussed in more detail in Chapter 6.

Sleep-promoting systems As noted above, von Economo described a small percentage of patients with encephalitis lethargica whose response was to develop profound insomnia, sleeping only a few hours each day. Autopsy studies demonstrated that these patients had lesions involving the basal ganglia and adjacent hypothalamus. Subsequent

animal studies identified sleep-promoting neural systems located primarily in hypothalamic and contiguous regions, and emphasizing neuronal activity in the median pre-optic nucleus (MnPN) and VLPO region of the hypothalamus, the activity of which promotes non-REM or SWS and inhibits wakefulness. VLPO and MnPN neurons are primarily active during sleep, and send inhibitory output to all major cell groups of the hypothalamus and brainstem that participate in arousal [11, 12]. These neuronal systems depend significantly on the inhibitory neurotransmitter gamma-amino butyric acid (GABA) and the inhibitory neuropeptide galanin. They appear to be activated by preceding wakefulness, and may be modulated by the build-up of adenosine associated with the wakeful state. Adenosine appears to be an important homeostatic sleep factor acting through the adenosine (Ado) A1 and A2 receptors, whose release is triggered by inducible nitric oxide synthesis in the basal forebrain secondary to prolonged wakefulness [13]. Thus the longer one has been awake, the more likely sleep will be triggered, and the adenosine antagonist caffeine tends to prolong wakefulness. The VLPO hypothalamic areas in humans is a sexually dimorphic region, with volume and cell number peaking about age 2–4 and declining thereafter. In males, decreases do not begin until later in adulthood; men between 45 and 60 years of age show a decrease in cell number of about 3% per year until age 60, after which further decreases are not noted. In females, cell numbers decrease until the teen years, then remain fairly stable until after age 50 when a gradual decrease begins, dramatically increasing after age 75. Between the ages of 75 and 85 years, cell number decreases in females at a rate of 4–8% per year, leading to cell numbers only 10–15% of the peak seen between ages 2 and 4 [14]. These findings imply increasing difficulty in initiating and maintaining sleep in both men and women beginning around age 50, stabilizing in men by 60, but continuing to worsen in women with increasing age. Paralleling these neuroanatomic changes, it is notable that insomnia is a complaint that increases with age, especially in women, leading Gaus and colleagues to suggest that “ . . . shrinkage of the VLPO with advancing age may explain sleep deficits in elderly humans” [15]. The genetic regulation of SWS is not yet well understood, but advances are being made that should illuminate this likely important area [16, 17].

99


Bi-stable wake/sleep switch The ARAS and VLPO systems are mutually inhibitory, and can therefore set up a self-reinforcing loop such that activity in one decreases activity in the other, similar to electrical circuits termed “flip-flop” switches [11]. Increasing activity in one side of the circuit can abruptly switch the circuit and cause abrupt sleep/wake transitions. This flip-flop switch may be modulated by orexin neurons, which when depleted, as in narcolepsy (see below), lead to instability of the switch. Diminished strength of either side of the switch can increase its instability, and thus elderly individuals who have lost some VLPO neurons may also exhibit more frequent wake/sleep transitions.

REM sleep REM sleep is controlled independently by brainstem oscillators whose activation leads to the multiple physiological accompaniments of the REM state, including low-voltage fast, awake-like electroencephalographic (EEG) patterns, skeletal muscle paralysis, rapid eye movements, temporary suspension of thermoregulation, and EEG sharp waves termed PGO spikes, sharp complexes arising in the pons and transmitted through the lateral geniculate to the occipital cortex (hence PGO). The REM state normally appears only during SWS, although evidence suggests the underlying neurophysiological oscillator may run continuously. In narcolepsy, the REM state can break into the waking state with varying degrees of loss of skeletal muscle tone, termed cataplexy; this disorder, often triggered by emotional arousal, can result in the person falling to the ground and entering a full-blown REM episode complete with dream-like mentation. Brainstem neuronal systems appear to account for the periodic generation of the REM state in all mammals, including humans. Cholinergic systems residing in the laterodorsal and pedunculopontine (LDT/PPT) nuclei projecting to the mesencephalic and pontine reticular formation (mPRF) appear to play a prominent role in activating REM sleep [18]. These systems largely reside in the pontine tegmentum, and may constitute a separate component of the ARAS. The frequencies of these independent oscillators appear to be a function of body size (the smaller the animal, the faster the oscillator). Cholinergic systems appear involved in activating REM states, and monoamines in suppressing them. Agents that increase Ach activity, such as the Ach inhibitor physostigmine, increase

100

REM sleep, and agents that increase monoamine activity, such as certain antidepressants (most notably the monoamine oxidase inhibitors) decrease REM sleep.

REM flip-flop switch It has recently been suggested that a type of neurophysiological “flip-flop” switch also exists for controlling transitions into and out of the REM state (the “REM-on/REM-off” switch), consisting of mutually inhibitory GABAergic neurons with independent pathways mediating EEG and atonia effects [19]. In the cat, the REM-on neurons are thought to be concentrated in the sublaterodorsal nucleus and modulated by glutamatergic neurons in the lateral and ventrolateral periaqueductal gray. This switch is thought to be subsidiary to the putative wake–sleep flip-flop switch, preventing transitions into REM during wakefulness, unless narcolepsy is present and leads to a weakened wake side of the wake–sleep switch due to loss of orexin neurons.

Dreaming The dream is the unusual mental content that often accompanies REM sleep. Thought by Freud to encompass significant symbolism, the explanation of Hobson and McCarley that the dream is random mental content accompanying an activated cortex generated by brainstem structures led to a fundamental re-thinking of dreaming [20]. Several lines of evidence support this idea. Selective activation of the amygdalae and other emotion-generating limbic regions occurs during REM sleep, along with deactivation of the dorsolateral prefrontal cortex. Several aminergic systems, including noradrenergic, serotonergic, and histaminergic, are essentially shut down in REM sleep, while dopaminergic systems remain active. With the recognition that dopamine antagonists are used in the treatment of psychosis, it has been suggested that the relative predominance of dopamine activity during REM sleep may account for the psychotic quality of a typical dream [21].

Sleep timing regulation – the circadian system The primary body “clock” regulating circadian rhythms is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and has an intrinsic

Chapter 7: Sleep

rhythmicity of about 24 hours. This clock is primarily synchronized by light exposure. A set of photoreceptors distinct from rods and cones contain a vitamin A-based photoreceptor called melanopsin and project via the retino-hypothalamic pathway to the SCN to provide light information to the brain. A number of factors that affect the role of light in modulating circadian rhythms have been described, including light intensity and duration (more photons equals more activation), previous light exposure (less previous light exposure increases the effect of light, and vice versa) [22], timing (there is a phase response curve), and frequency (short wavelength more effective than longer wavelengths) of light [23]. Output from the SCN includes efferent projections to contiguous hypothalamic regions, as well as a major sympathetic pathway from the SCN via the intermediolateral cell column of the spinal cord and superior cervical ganglion to the pineal gland, which regulates production of melatonin, the primary circadian hormone. Melatonin production is activated when light diminishes as day transitions to night. Measurement of blood or salivary melatonin can assist in deriving a metric termed dim-light melatonin onset (DLMO), a primary circadian timing signal. The circadian system is largely under genetic control [24]. A number of circadian clock genes have been identified (e.g., Per1, Per2, Per3, Cry1, Cry2) that are transcriptional regulators thought to underlie circadian rhythm generation at the cellular level, and may also have a role in sleep homeostasis [25]. Disturbances in the regulation of these genes is thought to underlie many sleep disturbances [17]. Disturbances in circadian regulation, as seen in jet lag or shift work, and the circadian rhythm sleep disorders (e.g., delayed and advanced sleep phase syndrome, and free-running rhythms in blind individuals) constitute an important component of sleep medicine. These disorders usually present clinically as insomnia, as discussed below.

Sleep morphology and architecture The original Rechtschaffen and Kales sleep stage terminology [26] has recently been supplanted by a new scoring system developed by the American Academy of Sleep Medicine [27], which is used in this chapter. The EEG, however, remains central to the characterization of sleep morphology and architecture (see Chapter 28). Non-REM sleep typically progresses from

wakefulness to stage N1 (loss of alpha rhythm, lower voltage theta with some sharp wave activity), to N2 (development of sleep spindles, K-complexes, increasing ⬍1 to ∼4 Hz delta activity), to N3 (greater than 20% delta activity with diminution of spindles and K-complexes). The term SWS has been variably and confusingly used to represent non-REM sleep, stage N3 sleep, or sometimes simply delta activity ⬍2Hz. Sleep spindles result from recurrent inhibitory circuits in the reticular thalamic nuclei leading to hyperpolarization of thalamocortical neurons [28]. Sleep spindles can be divided into subtypes based upon both frequency and topography. ∼12 Hz spindle activity is dominant over precentral and frontal areas, and ∼14 Hz spindles are dominant post-centrally [29, 30]. Fast spindles have been related to visuomotor learning [31]. K-complexes are large (high voltage), sharp wave complexes, often followed by spindle bursts that are maximally seen over high central and central parietal regions. They are thought to represent a type of EEG “evoked response” triggered by external or internal stimuli, and may have, as their source, deeper brain structures. Spectral-based measurement of sleep EEG activity in the 0.75 Hz to 4.5 Hz band has been termed slow wave activity (SWA) and has proven very useful in measuring sleep homeostatic pressure. Slow wave activity varies regionally over the brain as a function of experience preceding sleep, suggesting a local regulation of SWA in addition to that relating to circadian timing and duration of wakefulness prior to sleep [32]. Conceptually, the term “Process S” was coined by Borbely and Achermann [8] to refer to the homeostatic sleep drive. The strength of this homeostatic drive, sometimes termed “sleep pressure,” is measured by computing the amount of SWA in the sleep EEG following varying periods of wakefulness. Longer periods of wakefulness result in substantial increases in SWA during the first several sleep cycles of recovery sleep. Animal studies suggest that the adenosine receptor Ado A1 gene is involved in regulating the efficiency of the SWA response and associated recovery of central nervous system (CNS) function following sleep loss [33]. Other EEG patterns are often seen during sleep, but their significance is not well understood and they are usually neither formally scored nor commented upon in typical clinical sleep recordings. One

101


such pattern is the cyclic alternating pattern (CAP), which consists of spontaneous, periodic, somewhat stereotypical interruptions of background activity during non-REM sleep and thought to be a measure of sleep stability [34, 35]. It has been suggested that CAP EEG waveforms may be related to learning [36], parasomnias in children [37], and sleep disturbances in other disorders, including chronic fatigue [38], depression [39], and developmental disabilities [37]. The suggestion has been made that it may be more meaningful to examine the wake and sleep EEG based on the coalescence of complex oscillatory phenomena, a metric that might index neuronal interactions in corticothalamic systems with greater neurobiological and functional meaning than that obtained with most current sleep staging based on analytic methods [40].

Local sleep While earlier it was thought that sleep reflects a state encompassing the entire brain, emerging evidence suggests that this is not so. It is now thought that the specific brain regions most used during the preceding period of wakefulness require a greater intensity and/or duration of sleep during a subsequent sleep period, thus sleep, especially SWS, will be differentially distributed across brain regions in a use-dependent fashion [41]. Krueger and colleagues suggest that sleep may be a fundamental property of cortical networks, dependent upon prior activity in each, and such difference may be expressed at the level of the cortical column [42].

Sleep physiology As humans transition from wakefulness to sleep, characteristic physiological changes include decreases in muscle tone (as measured by electromyographic activity), respiratory rate, heart rate, and blood pressure. Body temperature also decreases, and this change is related not only to the decreased metabolic activity accompanying sleep but also to the central circadian temperature regulation system. Sleep also modulates hormonal secretion, with decreases in cortisol and thyrotropin and increases in prolactin and growth hormone production. REM sleep is accompanied by increased variability in the heart rate, respiratory rate, and blood pressure. Adverse cardiac events such as arrhythmias and infarctions seem to cluster in the early morning hours

102

when REM sleep is more prominent, possibly indicating an increased vulnerability of those with impaired cardiac perfusion to this physiological activation and variability. Body temperature regulation temporarily ceases during REM sleep, and for a short time humans become essentially poikilothermic animals. REM sleep has other unique physiological signatures including penile or clitoral tumescence and the characteristic sharp occipital EEG waves called PGO spikes. Most pronounced of all, perhaps, is the general paralysis of descending skeletal muscle (with the exception of the diaphragm) that accompanies REM sleep, which not only prevents the acting out of dreams but also increases the probability of apneas, hypopneas, and hypoventilation because of hypotonia of the accessory muscles of respiration (e.g., the intercostal muscles) and the upper airway dilator muscles. Prominent disturbances in the regulation of REM sleep physiology are also seen in narcolepsy and REM behavior disorder (see below).

Development of sleep across the lifespan Human sleep patterns change dramatically during development (see [43] for review). At birth, sleep consists of two types, each occurring in 50% of sleep time: active sleep, an immature form of REM sleep, and quiet sleep, a prelude to non-REM SWS. Active sleep rapidly decreases such that by 6 months of age it represents only 25% of total sleep, approaching adult REM values. The two major processes termed homeostatic and circadian (Process S and Process C, respectively) are not developed at birth. Process S in infants consists of quiet sleep with gradual maturation into adult EEG sleep patterns as the neocortex develops. Process C is not apparent at birth, but begins to appear at about 16 weeks when a 24-hour sleep–wake cycle begins to emerge with sleep being consolidated in the night and waking in the day. At birth, quiet and active sleep are interspersed, but by 3 months of age adult sleep cycle patterns emerge and REM (active) sleep comes to constitute a greater percentage of later sleep periods, with non-REM or SWS being more prominent in earlier cycles. REMs are present at birth in active sleep; the skeletal muscle inhibition of adult REM sleep begins to appear at 6 months. Total sleep time is about 16–18 hours/day at birth, diminishing to 14–15 hours at one year and to more adult values as maturation continues.

Chapter 7: Sleep

There is an increase in SWS sleep during adolescence, likely associated with the onset of programmed synaptic pruning associated with brain maturation during this period [44]. Recent experimental data demonstrate the close association of SWA during sleep supporting the synaptic plasticity (“pruning and tuning”) associated with learning and memory consolidation [45]. During the nocturnal sleep period, “sleep cycles” usually beginning with non-REM sleep and ending in a REM period, repeat with about a 90minute periodicity, to be repeated four to five times during a typical night. Most SWS sleep occurs during the first several sleep cycles; REM periods become longer as the night progresses. After a period of sleep deprivation, SWS is the first sleep epoch to recover. Sleep morphology is generally reasonably stable during adulthood (late adolescence to the mid-50s or 60s); however, changes are prominent in the elderly. The amplitude of SWS diminishes such that formal criteria for Stage N3 may not be met, leaving primarily stages N1 and N2. The loss of VLPO neurons (see above) and their support of Process S lead to sleep fragmentation with frequent awakenings, less restorative sleep, and resultant insomnia complaints in the elderly. With respect to Process C, aging is accompanied by a decrease in the amplitude of body temperature and other circadian rhythms as well as a decrease in the ability to synchronize the circadian system to changes such as those associated with jet lag [46]. Adults over the age of 65 have decreased sensitivity to the phasedelaying effects of bright light exposure [47]. The nocturnal production of melatonin also decreases with age, so after age 60 this may be related to difficulties with sleep onset [48]. These changes may relate to functional or structural alterations within the SCN itself [46]. Complicating such sleep loss in the elderly is the fact that those genetic mechanisms subserving recovery from sleep deprivation may also be impaired in older individuals. Animal studies have shown that the endoplasmic reticulum (ER) is a major component of a quality control system that removes abnormal or misfolded proteins accumulated during the stress of sleep deprivation. The adaptive response of the ER to coping with these abnormal proteins appears to be attenuated in older individuals, and thus they may be disproportionately impacted by sleep deprivation as a result of impaired abnormal protein recovery systems [49].

Sleep disorders Insomnias The domain of the insomnias is the largest in terms of sleep complaints, and benefits from thoughtful differential diagnosis, as the causation may be both multiple and obscure. The 2005 National Institutes of Health (NIH) State-of-the-Science Conference on the Manifestations and Management of Chronic Insomnia in Adults estimated that 30% of people in the general population experience symptoms consistent with insomnia. Often essentially written off in the past with the attitude that “no one dies from insomnia” this disorder has been recently shown to be associated with significant daytime functional decrements, emphasizing that it is a 24-hour disorder, not just a sleep disorder. Problems include sleepiness and fatigue, cognitive and psychomotor impairments, worsened anxiety and depression, increased risk for some medical disorders, activation of the hypothalamic– pituitary–adrenal axis, impairment in immune function, and impairment in global functioning and/or quality of life. For a recent review of functional impairments associated with insomnia see [50]. Our conceptualization of insomnia has undergone a dramatic shift during the past few years, from being an annoying but not particularly serious symptom to the recognition that (1) sleep loss has serious consequences; (2) chronic insomnia and its associated impaired sleep are highly comorbid with (or indeed may cause) many other medical and psychiatric disorders; and (3) chronic insomnia in some cases may represent a separate medical disorder of its own with an independent neurobiological basis. Our primary concern is not the transient and short-term insomnias, which are generally related to stress, short-term illness, jet lag, or shift work (although clearly medically significant in its own right), but the chronic insomnias that require a systematic differential diagnosis. The diagnosis of an insomnia complaint should include a systematic review of the following areas, some or all of which may be contributory: (1) medical disorders and their treatments; (2) psychiatric disorders and substance misuse; (3) circadian rhythm disorders; (4) movement disorders; and (5) the conditioned insomnia, sleep state misperception, primary insomnia group. A systematic review of each of these categories is likely to encompass the potential contributions to most

103


insomnia complaints. It is important not to stop with the first potential causation encountered, as more than one cause is the rule rather than the exception. A brief discussion of each area follows.

Medical disorders The insomnia complaints that are comorbid with medical disorders include both sleep disturbances caused by medical symptoms (e.g., breathing difficulties, heartburn from gastroesophageal reflux disease, nocturia, pain), but also those sleep disturbances caused by the pathophysiology underlying the medical condition. Major entries on this list include the dementias, rheumatological disorders, chronic fatigue syndrome (CFS), and fibromyalgia. Sleep complaints are very common in CFS, and can include insomnia, hypersomnia, non-restorative sleep, and sleeping at the wrong time of the 24-hour period (e.g., circadian rhythm abnormalities). Conventional polysomnogram (PSG) findings are generally non-specific and include decreased sleep efficiency, decreased SWS, increased sleep latency, and alpha-delta sleep EEG patterns. CFS-related disturbances in regulation of underlying sleep control mechanisms are supported by several studies. One recent study found an increase in cyclic alternating pattern in the PSG of CFS patients complaining of non-restorative sleep [38], and there is also evidence of decreased sleep drive (Process S) in CFS [51]. Sleep disturbances, usually insomnia and non-restorative sleep, are also common components of fibromyalgia, and are not entirely explained by the pain and depression associated with this syndrome [52]. Chronic pain is of special concern, as it has been demonstrated that sleep loss lowers the pain threshold, and self-reported restorative sleep is associated with the resolution of pain complaints [53]. Treatments of sleep complaints in these disorders has been challenging, although recently positive results have been found in fibromyalgia using sodium hydroxybutyrate, which enhances GABAergic activity and increases delta sleep. Dementias including Alzheimer’s disease (AD) are often associated with severe insomnia that is quite disruptive to patients and families, and may be one of the factors precipitating institutional care. Neuropathologic changes of AD in the sleep and circadian rhythm control centers of the hypothalamus and SCN may contribute to this problem. Sleep is also disturbed in dementia with Lewy bodies (DLB), which has been found in up to 20% of dementia cases referred to autopsy [54]. This disturbance often

104

takes the form of increased motor activity and suggests REM behavior disorder. Body temperature and activity circadian rhythms can also be altered in the dementing disorders as a result of characteristic brain lesions. Alzheimer’s disease has been associated with a phase delay in both body temperature and activity rhythms, whereas frontotemporal dementia appears to produce fragmented sleep with a phase advance of the activity rhythm, apparently uncoupled from the body temperature rhythm [55]. Degeneration of cholinergic neurons in the nucleus basalis of Meynert may contribute to rest–activity disturbances and the “sundowning” syndrome in AD patients [56]. Pharmacotherapy of AD may contribute as well to sleep complaints, as tacrine and donepezil are centrally acting cholinesterase inhibitors, and may cause insomnia.

Psychiatric disorders Sleep complaints are very frequently comorbid with psychiatric disorders. Most common is insomnia, although hypersomnia may accompany atypical depression. In the case of mood disorders, dysregulation of hypothalamic systems controlling mood likely overlaps with systems controlling sleep. The striking and rapid antidepressive response to sleep deprivation, possibly due to a reduction in brain glutamatergic systems involving the cingulate, demonstrates the close relationship between sleep and mood regulation systems [57, 58]. Schizophrenia has also been associated with a wide variety of sleep disorders, including both Process S and Process C dysregulation [17]. Sleep spindles have been found to be deficient in schizophrenia, possibly reflecting dysfunction of the thalamic reticular nucleus and thalamocortical mechanisms [59].

Circadian rhythm disorders The circadian rhythm disorders include a number of phenotypes. Patients usually present with an insomnia complaint, but in fact these disorders are caused by abnormal function of the circadian timing system. Most common is the delayed sleep phase syndrome (DSPS), with onset usually in adolescence or early adulthood, significant difficulty getting to sleep at a normal bedtime, and a tendency to sleep late in the morning. If these patients are required to arise early, they become sleep-deprived, and complain of insomnia. Advanced sleep phase syndrome (ASPS), more common in older persons, is associated with

Chapter 7: Sleep

early waking and early bedtime. Both DSPS and ASPS are strongly familial, and to date, at least ten abnormalities in the clock genes regulating circadian timing have been found in these disorders [17]. Lack of circadian entrainment (free-running rhythms) is found in 50% of blind individuals, although light can be utilized as a zeitgeber in cortical-blind individuals with intact retinas and retino-hypothalamic tracts. Appropriately timed melatonin administration may re-entrain many blind free-runners [60]. Circadian components of chronic insomnia complaints should be independently identified and treated, primarily with proper sleep hygiene, light therapy, appropriately timed melatonin, or possibly the melatonin receptor MT1 and MT2 agonist ramelteon. Typical hypnotic agents are usually not particularly helpful.

Movement disorders Restless leg syndrome (RLS) and periodic limb movements of sleep (PLMS) are usually considered sleep disorders, but are perhaps more appropriately thought of as movement disorders that interfere with sleep. Restless leg syndrome is associated with both disordered brain iron homeostasis and altered CNS dopaminergic systems, with genetic influences considered likely [61]. Restless leg syndrome can also be secondary to a wide variety of other illnesses including renal failure, iron deficiency, neuropathy, pregnancy, multiple sclerosis, and other illnesses [62]. Periodic limb movements of sleep is closely associated with RLS, but occurs widely in the general population without sleep complaints, and may imply enhanced spinal cord excitability [63]. Periodic limb movements of sleep may be aggravated by a number of antidepressant agents, a point to be kept in mind during its evaluation.

Conditioned insomnia, sleep state misperception, and primary insomnia Insomnia complaints that remain after evaluation and treatment of the causes outlined above suggest a group including conditioned insomnia, sleep state misperception syndrome (SSMS), and primary insomnia. These disorders are grouped together under the term “psychophysiological insomnia” in the latest International Classification of Sleep Disorders [64]. Conditioned insomnia is precisely as it sounds – susceptible individuals are conditioned to arouse in their normal sleep environment, whereas they may

sleep normally in a sleep laboratory. Sleep state misperception syndrome is sometimes termed “paradoxical insomnia,” since patients are unaware they have been sleeping. Some evidence suggests an increase in fast activity in the sleep EEG of SSMS patients [65, 66] might account for a preservation of some level of awareness of mentation during sleep in these patients. Primary insomnia includes those subjects with insomnia complaints at least 30 days in duration, not explained by any other etiology, and associated with significant impairment of daytime function. Evidence supporting the notion that primary insomnia represents a state of physiological hyperarousal comes from a number of studies in such patients that include elevated metabolic activity [67], increased fast EEG activity during sleep [65, 68, 69], and auditory evoked potential findings supportive of impaired inhibitory mechanisms during sleep [70]. Additional evidence includes increased evening cortisol levels [71], elevations in inflammatory markers [72], and increases in waking whole-brain glucose metabolism [73]. Coortoos et al. have suggested that primary insomnia might best be considered a state of hyperarousal affecting both sleep and daytime function throughout the entire 24-hour period and not just during sleep [74].

Treatment considerations for the insomnias Assuming comorbid conditions have been optimally treated, and Process C components appropriately addressed, two options remain for treatment of continuing insomnia: behavioral, primarily cognitive behavioral therapy (CBT), and pharmacologic. Cognitive behavioral therapy has been reported as significantly effective for many forms of insomnia, including primary insomnia, and should be considered wherever possible [75–78]. Pharmacologic treatments have improved greatly over the years, with safe and effective medications now available. A decision should be made as to whether pharmacologic efforts will be directed at up-regulating the VLPO GABAergic sleep control systems, down-regulating the ARAS, or both. Unfortunately, adequate information is not yet available to enable this decision without some trial and error. GABAergic supplementation can be provided by benzodiazepine (BZ) hypnotics (triazolam, temazepam, estazolam, flurazepam, and quazepam) and newer non-BZ omega-1 agonists (zolpidem, zolpidem ER, zaliplon, and eszopiclone). With both BZ

105


and non-BZ hypnotics, the half-life is a major consideration in choosing specific agents. Benzodiazepine hypnotic agents are appropriate in patients who also have anxiety; for primary insomnia, the newer non-BZ agents have a better risk–benefit profile. Other GABAergic agents have been shown to influence sleep, but are not yet approved for use as hypnotics. Sodium oxybate, approved for narcolepsy, increases SWS. Tiagabine, a GABA reuptake inhibitor that increases synaptic GABA through selective inhibition of the GAT-1 GABA transporter, and is approved for epilepsy, has been shown to increase SWS in a dose-dependent fashion in primary insomnia [79]. Gaboxadol is a selective extrasynaptic GABAa agonist, possibly working at the thalamic level, that has been shown to improve sleep in a phase-advance model of insomnia [80], but has many adverse side effects. Alternative strategies include down-regulation of the ARAS. Sedative antidepressants have been used at low doses likely for their antihistaminic and antiserotonergic properties, but have not formally been studied as hypnotics and are used off-label. Promising drugs are histamine H1 antagonists such as lowdose (3–6 mg) doxepin, which improves sleep in primary insomnia, but has few anticholinergic or antinoradrenergic side effects at this dose [81]. Atypical antipsychotic agents are used off-label at low doses likely for the H1 and 5HT2a antagonism, but are probably not drugs of first choice. Several 5HT2a antagonists, which may actually increase SWS, are in clinical trials, including epilvanserin, volinanserin, and pruvanserin [82]. Orexin antagonists are also in development as possible hypnotic agents [83], based upon the yet unsubstantiated premise that since underactivity of the orexin systems leads to hypersomnia with state instability, overactivity of orexin systems may lead to insomnia. A good general rule is to consider GABAergic hypnotics, and CBT, as first-line approaches for most insomnias, and switching to and/or adding additional ARAS active sedative hypnotic agents is recommended only if the initial therapeutic response is inadequate. It may be necessary to use more than one agent, addressing different mechanisms (e.g., GABA up-regulation as well as ARAS down-regulation) in difficult cases. Using the lowest dose possible for the shortest time possible is standard practice, but considering the adverse consequences of sleep loss,

106

effective treatment should not be withheld when necessary.

Hypersomnias Excessive daytime sleepiness (EDS) is the primary symptom of the hypersomnias. It is important to distinguish true EDS from fatigue, which can present with EDS, although those complaining of fatigue will often not demonstrate short sleep latency on the Multiple Sleep Latency Test (MSLT). Any disorder (or lifestyle) that interferes with adequate sleep, or results in fragmented sleep, may present with an EDS complaint, but most germane to this chapter are the hypersomnia disorders that are thought to result from primary CNS dysfunction, which include narcolepsy, primary hypersomnia, and the periodic hypersomnias (e.g., Kleine–Levin syndrome). A number of neurological disorders may have EDS as an associated complaint, including Parkinson’s disease (PD) [84], and various infectious diseases, possibly related to cytokine production [85]. The most common cause of EDS (aside from not getting enough sleep at night – encountered surprisingly often) is a sleep-related breathing disorder, primarily obstructive sleep apnea (OSA). The hypersomnia of OSA is not considered to be of central origin, but rather secondary to the physiological disturbances associated with repeated respiratory obstructions. Decreased cerebrospinal fluid (CSF) histamine levels, a likely marker of central hypersomnia (see below), is not seen in OSA [86]. Evidence of altered cognition or affective regulation associated with the breathing disorder may indicate CNS involvement, but is more likely secondary to the OSA syndrome.

Narcolepsy Narcolepsy is a rare (worldwide prevalence estimated at 0.02% with some racial and national variation) but well-known cause of EDS. The primary characteristics of narcolepsy are EDS with uncontrollable sleep attacks, and evidence of abnormal REM sleeprelated phenomena such as cataplexy, sleep paralysis, and hypnagogic hallucinations (the so-called narcoleptic tetrad). There are thought to be two forms of narcolepsy, which have been termed idiopathic narcolepsy and symptomatic narcolepsy [87]. The more common form, idiopathic narcolepsy, has been linked

Chapter 7: Sleep

to an orexin/hypocretin deficiency from neuronal loss in the hypothalamus, possibly autoimmune in origin. Narcolepsy is closely associated with the HLA system, supporting a possible autoimmune basis. The main predisposing allele is DQB1∗ 0602, which is found in 95% of patients who have narcolepsy with cataplexy across all ethnic groups. However, this allele is neither necessary nor sufficient for developing narcolepsy [16]. Genetic variants of narcolepsy with cataplexy also exist with normal CSF hypocretin levels [88, 89]. Narcolepsy usually appears in late adolescence or early adulthood in previously healthy individuals. Early symptoms often begin with EDS, and irresistible sleep attacks may occur in school or other inappropriate places. Within several years episodes of cataplexy may appear, with loss of skeletal muscle tone in response to anger or emotional excitement. Patients may collapse in a chair or fall to the ground during a cataplectic episode, and if undisturbed a full-blown REM sleep episode may ensue. Loss of orexin/hypocretin neurons in the hypothalamus may result in instability of the sleep/wake and REM-on/REM-off bi-stable switches, thought to be modulated by the orexins, such that stable wakefulness cannot be maintained, and REM onset may not be restricted to non-REM sleep periods. Symptomatic narcolepsy is rare and may accompany or be seemingly caused by a large number of other disturbances of brain function [87]. The nocturnal sleep in most narcoleptic patients is often significantly disrupted. Patients are prone to frequent nocturnal spontaneous arousals as well as a greater incidence of PLMS and sleep apnea. The sleep disruption may be related to impaired function of the sleep/wake and REM-off/REM-on neurophysiological switches as a result of loss of the orexin/hypocretin controlling system. Narcolepsy is diagnosed by history and a PSG followed by MSLT. The MSLT will show decreased mean sleep latency (⬍5 minutes) and requires two sleep-onset REM periods for diagnosis. Narcolepsy without cataplexy will not have symptoms of REM breakthrough, but will have similar PSG/MSLT findings [90]. Histamine, a major contributor to vigilance, has been shown to be deficient in the CSF in narcolepsy, and may be related to the EDS. The histaminergic system is modulated by orexin/hypocretin, and loss of neurons may result in decreased histamine and resultant EDS [86]. However, decreased CSF histamine has

also been found in narcolepsy without hypocretin deficiency, thus decreased histamine may also be an index of central hypersomnia independent of hypocretins [89]. There is at this time no cure for narcolepsy. However, in most cases the symptoms can be adequately managed with alerting and, if necessary, wakepromoting agents [91].

Primary hypersomnia Idiopathic hypersomnia (IH) is a syndrome of persistent daytime somnolence. Patients with this disorder note an increasingly irresistible need to sleep during the day that leads to prolonged naps. These naps are lengthy, often 60 minutes or longer, and not very refreshing. When these patients are not sleeping, they are drowsy and have difficulty concentrating. This excessive sleepiness occurs after sufficient or even increased amounts of nocturnal sleep. Two forms of IH have been described, IH with a long sleep time and IH without a long sleep time. In the former, patients have documented EDS in spite of sleep durations greater than 10 hours, whereas in the latter, patients have excessive sleepiness documented after a preceding night’s sleep duration of 6–10 hours. Patients with either form of IH frequently have complaints of “sleep drunkenness” on awakening. Idiopathic hypersomnia can usually be differentiated from narcolepsy by the absence of cataplexy, hypnagogic hallucinations, and sleep paralysis. A PSG and MSLT are usually necessary to differentiate this disorder from other causes of EDS. Patients with IH will usually demonstrate short mean sleep latency on the MSLT, but not sleep-onset REM periods as commonly seen in narcolepsy. They also do not have the HLA genetic markers of narcolepsy or decreased CSF orexin/hypocretin levels, but they may have low CSF histamine levels [86]. The etiology remains obscure.

Periodic hypersomnias Kleine–Levin syndrome is an uncommon periodic hypersomnia disorder that is most common in males and often begins in the teenage years. Typically, the patient has one or more episodes yearly that are characterized by periods of excessive sleepiness often lasting for weeks. During these hypersomnolent periods the patient can be aroused from sleep, but when awake,

107


he or she is confused and agitated and has a loss of sexual inhibitions [92]. While in this state, patients can have insatiable appetites, especially when presented with food. The patient has minimal recollection of the hypersomnolent period after the episode clears, and appears to function normally between attacks. Usually, this disorder spontaneously remits by age 40. The etiology of Kleine–Levin syndrome is unknown, but disorders of several brain regions, including the thalamus, brainstem, frontal lobes, and hypothalamus, have been suggested [93]. Infections, trauma, and autoimmune conditions have also been proposed as etiologies [94]. Electroencephalograms performed during the wakeful portions of a hypersomnolent episode have shown mild intermittent slowing of brain-wave activity. Nocturnal sleep has been reported to lack Stage III and Stage IV (N3) sleep. Also, shortened REM latency has been reported, and even occasional sleep-onset REM periods [95]. Although the results of CSF analysis are usually normal in these patients, one study reported that levels of 5-hydroxyindoleacetic acid are elevated [96], and CSF hypocretin levels appear normal in asymptomatic patients but were reported as low in one patient while symptomatic [97]. The periodic nature of the somnolence, along with the abnormal behavior, confusion, and compulsive eating, differentiate Kleine–Levin syndrome from other common causes of excessive somnolence. The clinician should consider other psychiatric disorders (especially bipolar disorder and schizophrenia), drug-induced states, and metabolic and inflammatory disorders in the differential diagnosis. Because Kleine–Levin syndrome is self-limited, many patients are not treated. Stimulant medication has been useful to treat the somnolence but can worsen the behavioral problems. Lithium has had some success in prophylaxis of the hypersomnolent episodes [98]. Menstruation-associated hypersomnia is an uncommon condition occurring in women who become periodically hypersomnolent around the time of their menses. They may awaken only for bathroom visits and often act uncharacteristically (e.g., exhibiting withdrawal, apathy, and irritability). After menstruation, these women resume their regular behavior and daytime alertness. The etiology is not known, but hypothalamic dysfunction is hypothesized.

108

Parasomnias The third major category of sleep disorders is the parasomnias, or the strange things that happen during the night. These events range from the mundane (e.g., bruxism (tooth grinding)) or sleeptalking, to the spectacular (e.g., the rare but well-publicized homicidal incidents occurring during a somnambulistic state). They clearly represent interesting and sometimes clinically significant yet peculiar interactions of brain function and behavior. Parasomnias are often grouped into two major categories: (1) primary sleep parasomnias which include both non-REM (e.g., bruxism, night terrors, somnambulism (sleepwalking)) and REM sleep-related parasomnias (e.g., nightmares, REM behavior disorder), and (2) secondary parasomnias which represent disorders of function of other organ systems that manifest themselves during sleep. The former category is emphasized in this chapter, as its underlying disordered sleep mechanisms are beginning to be understood.

Non-REM sleep parasomnias The most common non-REM parasomnias – night terrors, confusional arousals, and somnambulism – are usually grouped together as “disorders of arousal” (which should not be confused with the disorders of consciousness discussed in Chapter 6) since they are thought to reflect partial but not complete activation of arousal systems such that complex motor behaviors can occur without conscious awareness or intent [99]. These parasomnias occur mainly in Stage N3 sleep and thus cluster during the first several hours of sleep. Night terrors usually begin with a cry at the onset of a period of intense agitation including motor behavior (even jumping out of bed) and evidence of physiological arousal including sweating, tachycardia, increased blood pressure, and dilated pupils. These disorders of arousal are more common in the immature CNS. Night terrors begin in early childhood, and somnambulism later in childhood, with most of both resolving by adulthood, although it is estimated that up to 5% of normal adults may still experience occasional parasomnias. Recall for such events is usually lacking, and they are not accompanied by typical complex dream imagery. Sleepwalking is highly hereditary; if both parents sleepwalk, there is a 60% chance that any child of the couple will sleepwalk [100]. If only one parent sleepwalks, the risk is still 45%.

Chapter 7: Sleep

Grillner suggested the term “central pattern generators” (CPG) for ensembles of neurons located in the mesencephalon, pons, and spinal cord, that subserve complex behavioral patterns, both motoric and emotional, when activated [101]. Tassinari and colleagues have suggested that such CPG neuronal systems, normally under the control of neocortical inhibition, may be released with suppression of neocortical inhibition, such as during sleep parasomnias and epileptic seizures [102]. Such a mechanism may help explain phenomena such as bruxism, sleep terrors and somnambulism, although the more complex parasomnias, i.e., those involving driving a car, are clearly also associated with modulation of motor activity by concurrent sensory input, even in the absence of consciousness. Treatment of most disorders of arousal remains in the domain of protecting the patient from injury, alerting others if possible, and avoiding factors known to increase frequency (e.g., sleep deprivation, sedatives such as alcohol). Anticipatory awakenings have been effectively used in children [103]. Considerable recent interest has been shown in the “night eating syndrome” first reported by Stunkard over half a century ago [104]. Two types are described: the night eating syndrome (NES), characterized by evening hyperphagia, nocturnal eating, and morning anorexia, and sleep-related eating disorder (SRED), characterized by recurrent episodes of eating after arousal from nighttime sleep with or without amnesia [105]. Night eating syndrome is thought to represent an abnormality in the circadian rhythm of meal timing with preservation of normal timing of sleep onset, rather than a true parasomnia, and has been reported to respond to sertraline [106]. Sleep-related eating disorder often accompanies other parasomnias, has been associated with use of zolpidem as well as other sedative hypnotic agents, and has been reported to respond to topiramate [105].

REM sleep parasomnias Nightmares are the most common REM sleep parasomnia, but REM behavior disorder is the most serious. Nightmares are frightening dreams usually accompanied by intense fear and anxiety. They are most common in children, and tend to decrease in frequency with age. They are seen in about 5–8% of the general adult population, and are more common in women. Some recent evidence has suggested that persons with low serum lipid levels (total cholesterol,

LDL, and triglycerides) may be especially susceptible to nightmares [107]. Severe cases may qualify for a diagnosis of nightmare disorder, and nightmares are common accompaniments of the post-traumatic stress disorder (PTSD) syndrome. Pharmacologic management has not been systematically evaluated, although recent evidence suggests prazosin [108], and possibly topiramate [109], to be effective in some cases. A manualized CBT program for chronic nightmares has recently been described with positive long-term results [110]. Imagery rehearsal therapy has also been described as successful in treatment of PTSD-induced nightmares [111, 112]. Of more concern is REM behavior disorder (RBD), representing an impairment of the descending skeletal muscle inhibition normally accompanying REM sleep such that affected individuals may sit up or jump out of bed and engage in vigorous physical activity during REM sleep as though they are acting out their dreams. Such motor activity may result in injury to themselves or others. REM behavior disorder is most commonly encountered in older men. A careful history will help in differential diagnosis to distinguish RBD from seizure disorders or non-REM disorders of arousal, as dream content synonymous with the unusual behavior can usually be elicited. Polysomnogram evidence of increased motor activity during REM sleep is required for definitive diagnosis, however. Boeve and colleagues have recently proposed a pathophysiology of RBD as indicative of an impairment in the operation of the putative flip-flop switch involved in REM sleep control [113]. REM behavior disorder has been associated with a variety of neurological disorders (e.g., autoimmune, neoplastic, vascular, infectious), often following the onset of the other disorder to suggest a pathophysiological commonality. Of concern is the evidence that RBD can frequently be a harbinger of a subsequent neurodegenerative disorder, most often PD or DLB, with an estimated risk of developing one of these disorders of 40% at 10 years [114]. Neurological evaluation and close follow-up may be warranted in these cases.

Secondary parasomnias There are a number of additional so-called “secondary parasomnias” that will not be considered here, including phenomena such as vascular headaches,

109


“exploding head syndrome,” “hypnic headache syndrome,” and several cardiopulmonary and gastrointestinal parasomnias that interested readers can find described in more comprehensive textbooks.

Conclusion This chapter provided a review of the basic neurophysiological mechanisms of wake/sleep systems, and discussed the relationships between disorders in the functioning of these complex systems and sleep pathologies observed in clinical medicine. If disorders of sleep are approached from the standpoint of the basic system disturbances that may be contributing to the phenomenology at issue, more rational treatment programs may be developed that can improve on approaching the problems from the standpoint of symptom alleviation alone.

References 1. Cirelli C, Tononi G. Is sleep essential? PLoS Biol. 2008;6(8):e216. 2. Rechtschaffen A, Bergmann BM. Sleep deprivation in the rat: an update of the 1989 paper. Sleep 2002; 25(1):18–24.

12. Szymusiak R, McGinty D. Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci. 2008;1129: 275–86. 13. Stenberg D. Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci. 2007;64(10):1187–204. 14. Hofman MA, Swaab DF. The sexually dimorphic nucleus of the preoptic area in the human brain: a comparative morphometric study. J Anat. 1989; 164:55–72. 15. Gaus SE, Strecker RE, Tate BA, Parker RA, Saper CB. Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species. Neuroscience 2002;115(1):285–94. 16. Hamet P, Tremblay J. Genetics of the sleep-wake cycle and its disorders. Metabolism 2006;55(10 Suppl 2): S7–12. 17. Wulff K, Porcheret K, Cussans E, Foster RG. Sleep and circadian rhythm disturbances: multiple genes and multiple phenotypes. Curr Opin Genet Dev. 2009;19(3):237–46. 18. McCarley RW. Mechanisms and models of REM sleep control. Arch Ital Biol. 2004;142(4):429–67.

3. Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature 1997;388(6639):235.

19. Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for control of REM sleep. Nature 2006;441(7093):589–94.

4. Lange T, Perras B, Fehm HL, Born J. Sleep enhances the human antibody response to hepatitis A vaccination. Psychosom Med. 2003;65(5):831–5.

20. Hobson JA, McCarley RW. The brain as a dream state generator: an activation-synthesis hypothesis of the dream process. Am J Psychiatry 1977;134(12):1335–48.

5. Meier-Ewert HK, Ridker PM, Rifai N et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol. 2004;43(4):678–83.

21. Hobson A. A model for madness? Nature 2004; 430(6995):21.

6. Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141(11):846–50. 7. Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol. 2005; 99(5):2008–19. 8. Borbely AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms 1999; 14(6):557–68. 9. Issa EB, Wang X. Sensory responses during sleep in primate primary and secondary auditory cortex. J Neurosci. 2008;28(53):14,467–80. 10. Garcia-Rill E. Disorders of the reticular activating system. Med Hypotheses 1997;49(5):379–87.

110

11. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437(7063):1257–63.

22. Nelson DE, Takahashi JS. Integration and saturation within the circadian photic entrainment pathway of hamsters. Am J Physiol. 1999;277(5 Pt 2):R1351–61. 23. Lockley SW, Evans EE, Scheer FA et al. Short-wavelength sensitivity for the direct effects of light on alertness, vigilance, and the waking electroencephalogram in humans. Sleep 2006; 29(2):161–8. 24. Cirelli C. The genetic and molecular regulation of sleep: from fruit flies to humans. Nat Rev Neurosci. 2009;10(8):549–60. 25. Franken P, Dijk DJ. Circadian clock genes and sleep homeostasis. Eur J Neurosci. 2009;29(9):1820–9. 26. Rechtschaffen A, Kales A (editors). A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Bethesda, MD: U.S. National Institutes of Health, U. S. National Institute of Neurological Diseases and Blindness, Neurological Information Network; 1968.

Chapter 7: Sleep

27. Iber C. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Westchester, IL: American Academy of Sleep Medicine; 2007. 28. Steriade M, Amzica F. Sleep oscillations developing into seizures in corticothalamic systems. Epilepsia 2003;44 (Suppl. 12):9–20. 29. Urakami Y. Relationships between sleep spindles and activities of cerebral cortex as determined by simultaneous EEG and MEG recording. J Clin Neurophysiol. 2008;25(1):13–24. 30. Bodizs R, Kormendi J, Rigo P, Lazar AS. The individual adjustment method of sleep spindle analysis: methodological improvements and roots in the fingerprint paradigm. J Neurosci Methods 2009;178(1):205–13. 31. Tamaki M, Matsuoka T, Nittono H, Hori T. Activation of fast sleep spindles at the premotor cortex and parietal areas contributes to motor learning: a study using sLORETA. Clin Neurophysiol. 2009; 120(5):878–86. 32. Dijk DJ. Regulation and functional correlates of slow wave sleep. J Clin Sleep Med. 2009;5(2 Suppl): S6–15. 33. Bjorness TE, Kelly CL, Gao T, Poffenberger V, Greene RW. Control and function of the homeostatic sleep response by adenosine A1 receptors. J Neurosci. 2009;29(5):1267–76. 34. Terzano MG, Parrino L, Sherieri A et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med. 2001;2(6):537–53. 35. Terzano MG, Parrino L, Smerieri A. [Neurophysiological basis of insomnia: role of cyclic alternating patterns]. Rev Neurol. (Paris) 2001;157(11 Pt 2):S62–6.

40. Steriade M. Grouping of brain rhythms in corticothalamic systems. Neuroscience 2006; 137(4):1087–106. 41. Rector DM, Schei JL, Van Dongen HP, Belenky G, Krueger JM. Physiological markers of local sleep. Eur J Neurosci. 2009;29(9):1771–8. 42. Krueger JM, Rector DM, Roy S et al. Sleep as a fundamental property of neuronal assemblies. Nat Rev Neurosci. 2008;9(12):910–19. 43. Heraghty JL, Hilliard TN, Henderson AJ, Fleming PJ. The physiology of sleep in infants. Arch Dis Child. 2008;93(11):982–5. 44. Feinberg I, Higgins LM, Khaw WY, Campbell IG. The adolescent decline of NREM delta, an indicator of brain maturation, is linked to age and sex but not to pubertal stage. Am J Physiol Regul Integr Comp Physiol. 2006;291(6):R1724–9. 45. Huber R, Ghilardi MF, Massimini M, Tononi G. Local sleep and learning. Nature 2004;430(6995):78–81. 46. Weinert D. Age-dependent changes of the circadian system. Chronobiol Int. 2000;17(3):261–83. 47. Duffy JF, Zeitzer JM, Czeisler CA. Decreased sensitivity to phase-delaying effects of moderate intensity light in older subjects. Neurobiol Aging 2007;28(5):799–807. 48. Haimov I, Lavie P, Laudon M et al. Melatonin replacement therapy of elderly insomniacs. Sleep 1995;18(7):598–603. 49. Naidoo N, Ferber M, Master M, Zhu Y, Pack AI. Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J Neurosci. 2008;28(26):6539–48. 50. Krystal AD. Treating the health, quality of life, and functional impairments in insomnia. J Clin Sleep Med. 2007;3(1):63–72.

36. Ferri R, Huber R, Arico D et al. The slow-wave components of the cyclic alternating pattern (CAP) have a role in sleep-related learning processes. Neurosci Lett. 2008;432(3):228–31.

51. Armitage R, Landis C, Hoffmann R et al. The impact of a 4-hour sleep delay on slow wave activity in twins discordant for chronic fatigue syndrome. Sleep 2007;30(5):657–62.

37. Bruni O, Ferri R, Vittori E et al. Sleep architecture and NREM alterations in children and adolescents with Asperger syndrome. Sleep 2007;30(11):1577–85.

52. Belt NK, Kronholm E, Kauppi MJ. Sleep problems in fibromyalgia and rheumatoid arthritis compared with the general population. Clin Exp Rheumatol. 2009;27(1):35–41.

38. Guilleminault C, Poyares D, Rosa A et al. Chronic fatigue, unrefreshing sleep and nocturnal polysomnography. Sleep Med. 2006;7(6):513–20. 39. Lopes MC, Quera-Salva MA, Guilleminault C. Non-REM sleep instability in patients with major depressive disorder: subjective improvement and improvement of non-REM sleep instability with treatment (Agomelatine). Sleep Med. 2007;9(1): 33–41.

53. Davies KA, Macfarlane GJ, Nicholl BI et al. Restorative sleep predicts the resolution of chronic widespread pain: results from the EPIFUND study. Rheumatology (Oxford) 2008;47(12):1809–13. 54. McKeith IG. Clinical Lewy body syndromes. Ann N Y Acad Sci. 2000;920:1–8. 55. Harper DG, Stopa EG, McKee AC et al. Differential circadian rhythm disturbances in men with Alzheimer

111


disease and frontotemporal degeneration. Arch Gen Psychiatry 2001;58(4):353–60. 56. Klaffke S, Staedt J. Sundowning and circadian rhythm disorders in dementia. Acta Neurol Belg. 2006; 106(4):168–75. 57. Benedetti F, Calabrese G, Bernasconi A et al. Spectroscopic correlates of antidepressant response to sleep deprivation and light therapy: a 3.0 Tesla study of bipolar depression. Psychiatry Res. 2009;173(3): 238–42. 58. Wirz-Justice A, Benedetti F, Berger M et al. Chronotherapeutics (light and wake therapy) in affective disorders. Psychol Med. 2005;35(7):939–44. 59. Ferrarelli F, Huber R, Peterson MJ et al. Reduced sleep spindle activity in schizophrenia patients. Am J Psychiatry 2007;164(3):483–92. 60. Sack RL, Auckley D, Auger RR et al. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep 2007; 30(11):1484–501. 61. Winkelmann J, Polo O, Provini F et al. Genetics of restless legs syndrome (RLS): state-of-the-art and future directions. Mov Disord. 2007;22(Suppl. 18):S449–58. 62. Ondo WG. Restless legs syndrome. Neurol Clin. 2009;27(3):779–99, vii. 63. Bara-Jimenez W, Aksu M, Graham B, Sato S, Hallett M. Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex. Neurology 2000;54(8):1609–16. 64. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd edition. Westchester, IL: American Academy of Sleep Medicine; 2005. 65. Krystal AD, Edinger JD, Wohlgemuth WK, Marsh GR. NREM sleep EEG frequency spectral correlates of sleep complaints in primary insomnia subtypes. Sleep 2002;25(6):630–40. 66. Edinger JD, Krystal AD. Subtyping primary insomnia: is sleep state misperception a distinct clinical entity? Sleep Med Rev. 2003;7(3):203–14. 67. Bonnet MH, Arand DL. 24-hour metabolic rate in insomniacs and matched normal sleepers. Sleep 1995;18(7):581–8. 68. Perlis ML, Kehr EL, Smith MT et al. Temporal and stagewise distribution of high frequency EEG activity in patients with primary and secondary insomnia and in good sleeper controls. J Sleep Res. 2001;10(2):93–104.

112

69. Merica H, Blois R, Gaillard JM. Spectral characteristics of sleep EEG in chronic insomnia. Eur J Neurosci. 1998;10(5):1826–34. 70. Bastien CH, St-Jean G, Morin CM, Turcotte I, Carrier J. Chronic psychophysiological insomnia: hyperarousal and/or inhibition deficits? An ERPs investigation. Sleep 2008;31(6):887–98. 71. Vgontzas AN, Bixler EO, Lin HM et al. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab. 2001;86(8): 3787–94. 72. Vgontzas AN, Chrousos GP. Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. Endocrinol Metab Clin North Am. 2002;31(1):15–36. 73. Nofzinger EA, Buysse DJ, Germain A et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004;161(11):2126–8. 74. Cortoos A, Verstraeten E, Cluydts R. Neurophysiological aspects of primary insomnia: implications for its treatment. Sleep Med Rev. 2006;10(4):255–66. 75. Edinger JD, Means MK. Cognitive-behavioral therapy for primary insomnia. Clin Psychol Rev. 2005; 25(5):539–58. 76. Morin CM, Bootzin RR, Buysse DJ et al. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998–2004). Sleep 2006;29(11): 1398–414. 77. Rybarczyk B, Stepanski E, Fogg L et al. A placebocontrolled test of cognitive-behavioral therapy for comorbid insomnia in older adults. J Consult Clin Psychol. 2005;73(6):1164–74. 78. Sivertsen B, Nordhus IH. Management of insomnia in older adults. Br J Psychiatry 2007;190:285–6. 79. Walsh JK, Perlis M, Rosenthal M et al. Tiagabine increases slow-wave sleep in a dose-dependent fashion without affecting traditional efficacy measures in adults with primary insomnia. J Clin Sleep Med. 2006;2(1):35–41. 80. Walsh JK, Deacon S, Dijk DJ, Lundahl J. The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia. Sleep 2007;30(5):593–602. 81. Goforth HW. Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009;10(10):1649–55. 82. Estivill E, Leger D, Soubrane C. A randomized double-blind placebo-controlled 12-week trial of

Chapter 7: Sleep

eplivanserin with long-term open extension in insomniac patients with sleep maintenance difficulties: results from the double-blind treatment period. Sleep 2009;32:A41-A. 83. Dingemanse J, Dorffner G, Goran H et al. Proof-of-concept study in primary insomnia patients with ACT-078573, a dual orexin receptor antagonist. Sleep Biol Rhythms 2007;5(Suppl 1; Late breaking abstracts):A194. 84. Monderer R, Thorpy M. Sleep disorders and daytime sleepiness in Parkinson’s disease. Curr Neurol Neurosci Rep. 2009;9(2):173–80. 85. Kapsimalis F, Basta M, Varouchakis G et al. Cytokines and pathological sleep. Sleep Med. 2008;9(6):603–14. 86. Kanbayashi T, Kodama T, Kondo H et al. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 2009;32(2):181–7. 87. Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev. 2005;9(4):269–310. 88. Khatami R, Maret S, Werth E et al. Monozygotic twins concordant for narcolepsy-cataplexy without any detectable abnormality in the hypocretin (orexin) pathway. Lancet 2004;363(9416):1199–200. 89. Nishino S, Okuro M, Kotorii N et al. Hypocretin/orexin and narcolepsy: new basic and clinical insights. Acta Physiol. (Oxford) 2010; 198(3):209–22. 90. Black JE, Brooks SN, Nishino S. Conditions of primary excessive daytime sleepiness. Neurol Clin. 2005;23(4): 1025–44. 91. Mignot E, Nishino S. Emerging therapies in narcolepsy-cataplexy. Sleep 2005;28(6):754–63. 92. Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Kleine-Levin syndrome: a systematic review of 186 cases in the literature. Brain 2005;128(Pt 12):2763–76. 93. Huang YS, Guilleminault C, Kao PF, Liu FY. SPECT findings in the Kleine–Levin syndrome. Sleep 2005;28(8):955–60. 94. Dauvilliers Y, Mayer G, Lecendreux M et al. Kleine–Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses. Neurology 2002;59(11):1739–45. 95. Huang YS, Lin YH, Guilleminault C. Polysomnography in Kleine–Levin syndrome. Neurology 2008;70(10):795–801. 96. Koerber RK, Torkelson R, Haven G et al. Increased cerebrospinal fluid 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in Kleine–Levin syndrome. Neurology 1984;34(12):1597–600.

97. Dauvilliers Y, Baumann CR, Carlander B et al. CSF hypocretin-1 levels in narcolepsy, Kleine–Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry 2003;74(12):1667–73. 98. Poppe M, Friebel D, Reuner U et al. The Kleine–Levin syndrome – effects of treatment with lithium. Neuropediatrics 2003;34(3):113–19. 99. Broughton RJ. Sleep disorders: disorders of arousal? Enuresis, somnambulism, and nightmares occur in confusional states of arousal, not in “dreaming sleep”. Science 1968;159(819):1070–8. 100. Mahowald MW, Schenck CH. Non-rapid eye movement sleep parasomnias. Neurol Clin. 2005;23(4):1077–106, vii. 101. Grillner S. The motor infrastructure: from ion channels to neuronal networks. Nat Rev Neurosci. 2003;4(7):573–86. 102. Tassinari CA, Rubboli G, Gardella E et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci. 2005; 26(Suppl. 3):s225–32. 103. Mason TB, 2nd, Pack AI. Pediatric parasomnias. Sleep 2007;30(2):141–51. 104. Stunkard AJ, Grace WJ, Wolff HG. The night eating syndrome; a pattern of food intake among certain obese patients. Am J Med. 1955;19(1):78–86. 105. Howell MJ, Schenck CH, Crow SJ. A review of nighttime eating disorders. Sleep Med Rev. 2009; 13(1):23–34. 106. O’Reardon JP, Stunkard AJ, Allison KC. Clinical trial of sertraline in the treatment of night eating syndrome. Int J Eat Disord. 2004;35(1):16–26. 107. Agargun MY, Gulec M, Cilli AS et al. Nightmares and serum cholesterol level: a preliminary report. Can J Psychiatry 2005;50(6):361–4. 108. Dierks MR, Jordan JK, Sheehan AH. Prazosin treatment of nightmares related to posttraumatic stress disorder. Ann Pharmacother. 2007;41(6): 1013–17. 109. Aalbersberg CF, Mulder JM. [Topiramate for the treatment of post traumatic stress disorder. A case study]. Tijdschr Psychiatr. 2006;48(6):487–91. 110. Davis JL, Wright DC. Randomized clinical trial for treatment of chronic nightmares in trauma-exposed adults. J Trauma Stress 2007;20(2):123–33. 111. Krakow B, Hollifield M, Johnston L et al. Imagery rehearsal therapy for chronic nightmares in sexual assault survivors with posttraumatic stress disorder: a randomized controlled trial. J Am Med Assoc 2001;286(5):537–45.

113


112. Moore BA, Krakow B. Imagery rehearsal therapy for acute posttraumatic nightmares among combat soldiers in Iraq. Am J Psychiatry 2007;164(4): 683–4. 113. Boeve BF, Silber MH, Saper CB et al. Pathophysiology of REM sleep behaviour disorder and relevance to

114

neurodegenerative disease. Brain 2007;130(Pt 11):2770–88. 114. Postuma RB, Gagnon JF, Vendette M et al. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 2009;72(15):1296–300.

Section I


Chapter

Attention

8

Joshua Cosman and Matthew Rizzo

The ability to effectively deal with the overwhelming amount of information present in the environment at any given time requires humans to focus on some things and ignore others. For example, imagine attempting to read a book in a crowded public place. This requires the reader to focus on the words on the page and ignore the sounds of conversations going on in the background, allowing an effective focus on the task at hand. The process by which people can both select relevant and suppress irrelevant environmental information refers to a number of processes collectively referred to as “attention.” From an information-processing standpoint, attention can be conceptualized as operating not as a single, monolithic process, but rather a group of more fragmented, domain-specific processes. For instance, in the example above, attention is required to select or suppress information across more than one sensory modality. In addition, attention can select information based on its location in space, its identity, or its relevance to current goals. For this reason, research in the cognitive and brain sciences has typically focused on specific subcomponents of attentional processing. One broad distinction that has been made in the study of attention has been between the control of attention (i.e., how attention selects stimuli) and the subsequent effects of attention (i.e., what is the fate of stimuli once attended to). Within the domain of control, attentional selection can occur as the result of cognitive (top-down) or stimulus-driven (bottom-up) processes. In turn, these selection processes can bias the way in which information provided by the environment is interpreted. Since the majority of research on attention has focused on the visual system, the discussion of attention in this chapter will center primarily on the control of different aspects of visual attention.

However, many of the principles discussed below hold true for the selection of information across other sensory domains. This chapter will outline relevant behavioral measures related to the control of attention, and functional theories of attention based on such measures. The major focus will be on the control of visual attention in both normal and neurologically impaired individuals, mapping functional theories of attention onto what is known about the cerebral structures subserving this process.

Control of attention One of the most important issues in attention research concerns how attention is controlled. At a basic level, attention can be considered a sensory gatekeeper, allowing humans to select and act upon only the subset of sensory information that is most relevant to carrying out specific goals. A familiar example illustrates this point. When conversing with a friend in a noisy room, one is able to carry on a normal conversation despite the milieu of irrelevant sensory information – in other words, to selectively attend to the conversation. However, if another friend shouts one’s name from across the room, attention is captured in a nearly automatic manner, putting on hold the conversation in which one was engaged. This scenario highlights two ways in which attention can be controlled. On one hand, you are able to voluntarily attend to a conversation with your friend – an example in which you exercise “goal-directed,” or top-down, control of attention. However, this voluntary focus of attention can be overridden if a sufficiently important stimulus (in this case, the shouting of your name by another friend) is detected in the environment – a case of “stimulus-driven,” or bottom-up,


115


(A)

(B)

Ti m Reaction time (milliseconds)

Reaction time (milliseconds)

e Valid

Invalid

Cue validity

Valid

Invalid

Cue validity

Figure 8.1. The order of events in Posner’s spatial cueing paradigm. Observers are asked to detect the appearance of a target that has been validly or invalidly pre-cued. (A) Peripheral pre-cue that automatically summons spatial attention to the cued region, and typical results. (B) Central, symbolic pre-cue that can be used to voluntarily shift spatial attention to the cued region, and typical results. Note that in both cases, subjects respond more quickly to targets that have been validly cued. However, central pre-cues typically elicit a slower response to the target, reflecting the voluntary nature of the attentional orienting produced by such cues.

factors controlling the allocation of attention. This distinction between the bottom-up and top-down control of attention has served as an important concept informing the study of attention in both cognitive psychology and neuroscience. The following section will outline the concepts of bottom-up and top-down control of attention, their interaction, and their consequences for subsequent sensory processing.

Bottom-up vs. top-down selection: evidence from spatial cueing and visual search Two experimental paradigms have contributed the most to the understanding of the control of visual attention: visual search and spatial cueing. In a spatial cueing paradigm, a stimulus or instruction precedes the presentation of a target stimulus. This stimulus or instruction is referred to as a “cue,” and this cue typically either predicts or does not predict the location of a subsequently presented target stimulus. One widely used spatial cueing task is that developed by Posner [1]. In Posner’s cueing task, depicted in Figure 8.1, each trial begins with a cue intended to orient an observer’s

116

attention to one of several possible locations. The cue can take the form of either a peripherally presented “flicker” appearing in a location where a subsequent target may appear, or may appear as a centrally presented symbol such as an arrow, or a directionally related word (“left”). After a delay, a target is presented and observers indicate that they detect the target (e.g., by pressing a button as soon as the target appears) or they discriminate among several targets (e.g., reporting if the target is a “T” or an “L”). On “valid” trials, the cue correctly predicts the target’s location; on “invalid” trials, the cue is misleading. Observers typically respond to valid trials fastest and invalid trials slowest, representing a “validity effect” of the cue. Each of the cues mentioned above are designed to direct attention to locations in space, but each does so through different mechanisms. Specifically, peripherally presented cues tap bottom-up attentional control processes, whereas centrally presented cues recruit top-down processes. This distinction allows for the examination of bottom-up and top-down influences on attention independently of one another, and data from these types of cueing tasks have provided useful information regarding differences between these two types of attentional control: (1) Observers typically cannot ignore peripheral cues, and these cues attract attention to the cued location more or less automatically. However, observers can ignore central cues when instructed, demonstrating that central cues do not direct attention in a stimulus-driven manner and are instead under voluntary control. (2) Peripheral cues operate more quickly than central cues, with reaction time differences between validly and invalidly cued trials emerging sooner with peripheral cues. This phenomenon reflects greater processing time required to use central cues, indicating that these cues require voluntary and effortful cognitive control. (3) Peripheral cues have the capacity to interrupt attentional orienting produced by a central cue, but central cues exert little effect on orienting from peripheral cues. This observation indicates that peripheral cues attract attention more or less automatically, in a stimulus-driven manner. (4) Studies that use central cues tend to present more valid than invalid trials, in an effort to encourage observers to attend to locations predicted by the cue. For example when using central cues, 75% of

Chapter 8: Attention

(C)

(D) Reaction time (milliseconds)

(B)


(A)

0

4 8 12 Set size (# of items)

0

4 8 12 Set size (# of items)

Figure 8.2. (A, B) Visual search displays and (C, D) typical results from a visual search task. Panel C shows an efficient search for a target that differs from distracters on a single feature dimension, such as color (A). D shows an inefficient search for a target that differs from distracters on two feature dimensions (B).

trials may include a valid cue, with only 25% of cues being invalid. By contrast, peripheral cues attract attention to a location regardless of validity, even if valid trials are less frequent than invalid (e.g., 25% valid, 75% invalid). Again, peripheral cues are shown to summon attention in an automatic manner. The other paradigm that has provided insight into the control of visual attention is the visual search task (Figure 8.2). Visual search refers to the act of looking for a visual target among distracters – similar to the process encountered when trying to “find Waldo” in the popular book series. In a typical visual search task, the number of distracters, or “set size,” is varied across trials, and reaction time (RT) to detect a target item is measured as a function of the set size. An “efficient” visual search results in shallow search slopes (i.e., set size has little influence on an efficient search), and “inefficient” searches result in steep search slopes (i.e., set size affects the time taken to detect a target). These differences in search functions can be conceptualized as representing the differential recruitment of bottom-up, stimulus-driven attention mechanisms and top-down, goal-directed attention mechanisms. In the case of an efficient search, the target is typically perceptually distinct from the distracter items. An example of an efficient search would be a case

where observers are asked to search for a red bar among green distracters (Figure 8.2A). In this case, attention would be attracted more or less automatically to the target based on bottom-up factors – in this example, the bar’s distinctive color. Since the target is defined on the basis of a distinct perceptual attribute, this type of search would remain efficient regardless of the number of distracters present in the array, resulting in the characteristic shallow slope seen during efficient search. By contrast, in the case of an inefficient search, the target is typically less perceptually distinct from the distracter items. For instance, if an observer were asked to search for a target based on a conjunction of multiple features (i.e., a red vertical bar among red horizontal and green vertical distracters, Figure 8.2B), the observer would be forced to carry out a more effortful search, requiring a greater amount of cognitive control. In this case, bottom-up information is not sufficient to define a target, and observers are required to adopt a strategy in which each item in the display is treated as a possible target, with each item or a subset of items being examined until the target is identified.

Functional models of attentional control An early explanation for the differential efficiency during visual search was based on serial and parallel processing models, with efficient searches being classified as “parallel” and inefficient searches “serial.” This conceptualization of search being either serial or parallel is the core of Treisman and Gelade’s [2] feature integration theory of visual search. In their original model [2], these investigators proposed that during an efficient search, all items in the array are processed preattentively in parallel – all incoming visual sensory information is processed simultaneously, and the target is detected in a more or less automatic manner, “popping out” based on its bottom-up salience. This “parallel search” would lead to the shallow search slopes described during efficient search, since all items in the display could be processed simultaneously regardless of the number of distracters present. Conversely, a search in which bottom-up information alone is not sufficient to identify the target requires subjects to perform a more effortful “serial search.” It was hypothesized that during inefficient searches, observers are forced to direct attention to each item in the display, with attention to each item being required to “bind” the two features and identify the stimulus [3].

117


“Feature maps” Vertical

Orientation

Horizontal “Saliency map”

Black

Top-down information Color

White

“Search for black vertical bar”

Consequently, set size would have a large impact on target detection RTs, as increasing the number of serially searched items theoretically increases RTs with each distracter item added to the array. Although this feature integration model of visual search provides a straightforward account of search slope differences between efficient and inefficient searches, it does not fully account for some findings in the visual search literature. Specifically, it has been shown that some “serial” looking processes can arise from parallel processing mechanisms. For instance, RT patterns that resemble those seen in serial search can be produced by limited capacity parallel search mechanisms. To illustrate this point, imagine that multiple items in a display can be processed in parallel. However, due to capacity limitations not all items in the display can be processed at once. Since not all items in the display can be searched through in parallel, searching through many items (large set size) in a display takes longer than searching through only a few items (small set size), producing RT slopes that resemble those seen in “serial” searches. In addition, searches that would be deemed “serial” by feature integration theory can be surprisingly efficient, resulting in RT slopes that resemble parallel searches [4]. Therefore, search is typically discussed with respect to its efficiency, where efficient search leads to shallow search functions (slopes ⬍10 ms/item) and inefficient search leads to steeper search functions (slopes ⬎20 ms/item), rather than in terms of serial or conjunction search.

118

Figure 8.3. An illustration of the visually guided search model of attentional allocation during visual search. In this model of attentional control, observers organize bottom-up information from the environment into “feature maps” that code for the identity and location of features in visual space. This information regarding stimulus features present in a scene is combined with top-down information based on the goals of the observer to create a “saliency map.” The saliency map then provides information on which areas of space are most likely to contain a particular stimulus in the environment, preferentially directing attention to these areas over others. This model allows the interaction of bottom-up and top-down information to bias the control of attention toward relevant visual stimuli.

To account for results that appeared to be inconsistent with feature integration theory, Wolfe [4, 5] proposed a two-stage “guided search” model of attentional control (Figure 8.3). As with feature integration theory, the initial stage of processing is carried out preattentively and in parallel across the entire visual field. From this processing, independent parallel representations of items in the search array are created based on basic visual features such as color, shape, or orientation. These representations are termed “feature maps,” and code for all of the features that are present in a given visual scene. Importantly, these maps also code for the location that the different features occupy. For example, if a subject were asked to search for a red bar among green distracters, all items in the display would be preattentively processed in parallel. From this processing, a feature map for “color” would be generated that included representations for items that were both red and green (since both types of items are present in the display). In addition to this color information, the location at which this information was detected would be represented in the map, providing the observer with a spatial map of features present in the scene. In contrast to feature integration theory, in the second stage of processing the bottom-up information represented in the feature map is combined with topdown information based on the goals of the observer. This combination, in turn, serves to bias attention toward particular elements of a visual scene [6]. In the case of the simple feature search described above, topdown information regarding target identity (i.e., the


target is red) is combined with bottom-up information regarding the location of red items in the display. This produces an “activation map” or “saliency map” that is used to direct the limited capacity resources of attention to a location or locations that are most likely to contain the target item. The guided search model is important for three reasons. First, it clears up the serial vs. parallel issues that are not easily explained by feature integration theory, providing a more plausible explanation of the control of attention during search. Second, the underlying mechanisms of the model are made explicit and can be studied empirically. Third, and most importantly, the model is transparent at a neural level: although it is based on behavioral research and computer simulation, it maps well onto what is known about the structural organization of brain regions involved in attentional control (to be discussed in detail later). This point illustrates an important principle in neuroscientific research, which is that functional accounts of cognition should correspond with what is known about the anatomy of cognitive functions and vice versa. The following section will focus on the major forms of attention, and how functional accounts of these constructs map on to neuropsychological and neuroanatomical data.

Major types of attention Having considered how attention is controlled, it is now important to turn to the types of information that attention can select. In this section, four different classes of selection will be considered: (1) spatial attention, in which stimuli are selected based on their position in space; (2) object-based attention, in which stimuli are selected based on their identity; (3) attentional selection in visual working memory, in which attention selects items that will be remembered; and (4) executive attention, in which attention is involved in choosing which task or behavior an observer will perform.

Spatial attention Attention can be selectively directed toward different regions in space, a concept traditionally referred to as “spatial attention.” Spatial attention selects stimuli based on their location in space, allowing stimuli at a particular location to receive further processing. One of the first and most widely used paradigms

in the study of spatial attention is the spatial cueing task mentioned in the previous section. Recall that when observers are directed to a specific location in space, subsequent stimuli appearing in this location are detected or discriminated better than those appearing in other locations. This phenomenon suggests that once attention selects a location, stimuli appearing in that location receive processing benefits over other stimuli. One way that spatial attention may exert an influence on stimulus processing at particular locations is by prioritizing these locations, so that stimuli located within a particular region are processed before those in other regions. In a standard spatial cueing task, the pre-cue draws attention to a particular location, putting stimuli falling within that region first in line for further processing. This sequence would result in the response time patterns seen in spatial cueing trials, with validly cued targets being detected or discriminated more quickly than those at invalidly cued locations based on the priority settings established by the cues. Another way that spatial attention may exert an influence on stimulus processing at particular locations is by enhancing the perceptual representation of stimuli at those locations. Since there is a great deal of noise in the visual system, effective selection of incoming stimuli requires a mechanism that increases the signal-to-noise ratio in favor of relevant sensory information. At a neural level, this perceptual enhancement may be achieved through increased firing amplitude of neurons coding for stimuli at the selected location. In other words, attention acts as a sensory gain control that effectively “turns up” the neural representation of stimuli in an attended location versus those in unattended locations, causing these attended stimuli to stand out [7]. For example, spatial attention has been shown to change the appearance of items, actually making them more perceptible. Carrasco and colleagues [8] showed that directing attention to a location in a display effectively increased contrast for the item falling within the attended region, thus leading to increased performance on a visual discrimination task. From this observation it was concluded that attention intensified the sensory representation of the attended item, producing a stronger sensory impression of the stimulus. In this way, spatial attention can actually alter the phenomenological perception of objects occupying a particular location.

119


Figure 8.4. Diagram indicating the region of the brain in which damage most commonly results in symptoms of visual neglect, the temporoparietal junction.

It has also been demonstrated that spatial attention can influence what information is allowed into visual working memory. If the appearance of multiple visual objects must be retained in working memory during a delay period, entry into visual working memory is necessary for these items to be remembered following the delay. If the location of one of the visual objects is cued either before or directly following its presentation, it is more easily remembered than other, uncued items [9]. Thus it appears that by directing attention to the location of one of the objects in a display, working memory is better able to encode the objects for later recall. These effects of spatial attention are contingent on the ability of the attention system to effectively orient to particular locations in space. This process has been shown to be deficient in patients with focal cerebral damage, and these patients have enabled the study of spatial attention defects. More recently, these investigations have been complemented by functional imaging studies, shedding further light on the neural mechanisms responsible for the control of spatial attention.

The parietal lobes, spatial attention, and neglect One of the most extensively studied cortical regions contributing to spatial attention processes is the posterior parietal lobe. Unilateral damage to the human parietal lobe, especially in the vicinity of the temporoparietal junction (or TPJ, see Figure 8.4), results in a profoundly disabling syndrome referred to as neglect or hemineglect [10, 11]. Because neglect

120

most often follows right parietal damage, clinical symptoms are most evident for the left side of extrapersonal space or the left side of the patient (i.e., left hemineglect). Neglect has been known to occur following focal lesions to areas other than the parietal lobes, such as the frontal lobes, but most studies of attention in patient populations have focused on damage to parietal lobe structures. Within the parietal lobe, there has been debate over what regions are most crucial to the control of attention. A number of studies have implicated damage to the TPJ in neglect, but others have associated symptoms of neglect with damage to the superior parietal lobe (SPL). Friedrich and colleagues [11] directly compared the effects of focal damage to either the TPJ or the SPL, and showed that patients with damage to the TPJ were more likely to display symptoms characteristic of neglect, supporting a central role of the TPJ in the control of spatial attention. Patients with neglect typically fail to attend to stimuli falling within the region of space contralateral to the lesion (the contralesional side of space). In many cases, individuals with neglect will fail to read words on the left side of the page, eat food on the left side of the plate, or shave the left side of the face. Importantly, this failure to attend to stimuli in the hemifield opposite to the lesion is not the result of visual sensory deficits such as scotoma or hemianopia. Patients with sensory disturbances alone are aware of their defects, and therefore will orient to a contralesional hemifield stimulus in order to compensate for their impairment. However, patients with hemineglect are generally unaware of their deficit, and if confronted with a defect on the impaired side (such as a hemiparesis) may even deny it, a phenomenon known as anosognosia. Insights into the nature of the attentional impairments seen in neglect have come from studies using the attention paradigms discussed above. Posner and colleagues [12] were among the first to study patients with right parietal lobe damage using the guidance of an explicit cognitive theory of attention. Using a spatial cueing task, they found asymmetries in attentional orienting in patients with right parietal lobe damage, who were slower to detect invalidly cued targets presented in the contralesional field. In other words, patients with right parietal damage were slower to detect targets appearing in the left hemifield following an invalid cue in the right hemifield than they were to detect targets


Target in right hemifield

Neglect subjects Normal subjects



Target in left hemifield

Valid Invalid Cue validity

Valid Invalid Cue validity

Figure 8.5. Hypothetical data depicting a typical “disengage” pattern of results on a spatial cueing task. Compared with normal subjects, patients with parietal lobe damage show slightly slower overall reaction times to targets. Importantly, these patients show a disproportionate slowing in their reaction time to invalidly cued targets following cues presented in their intact hemifield (note the disproportionate cost of invalid cues when the subsequent target appeared in the damaged hemifield). These results have been taken as evidence for a role of the parietal lobe in the disengagement of attention.

appearing in their right hemifield following an invalid cue in the left hemifield field (Figure 8.5). However, these patients were nearly as fast to detect validly cued targets in their contralateral hemifield as they were to detect targets in their ipsilesional hemifield, suggesting a disproportionate cost for reorienting attention following invalid cues in the ipsilesional hemifield. Based on this response asymmetry, Posner and colleagues [12] suggested that the parietal lobes allow disengagement of attention and that right parietal lesions cause a “disengage deficit,” that hinders disengagement from the ipsilesional visual field. Thus, when a cue appears in the ipsilesional field and a target follows in the contralesional field, a right parietal lobe patient would have difficulties detecting the target. This interpretation would predict that patients with damage to both the left and right parietal lobes would be equally likely to show symptoms of neglect. However, as discussed above, this is not the case, and severe or lasting neglect typically results only from damage to the right parietal lobe. Therefore, alternative theories of the deficits present in neglect have emphasized competitive interactions between left and right parietal regions and how this competition affects the control of attention. For example, Cohen and colleagues [13] presented a neural network model as an alternative explanation of the disengage deficit (Figure 8.6). In their model [13], neural representations of each visual hemifield compete with each other for attentional selection. If the representation of the left field is damaged, it competes less effectively with the representation of

the right field. As a consequence, when attention is directed to the right (good) field, a target appearing in the left (damaged) field is at a competitive disadvantage. Thus, detecting an invalidly cued target appearing in the left field would be difficult. In contrast, when attention is directed to the disordered left field, a target appearing in the intact right field could compete effectively for attention, allowing this target to be detected relatively quickly. Under this account, no mention of “attentional disengaging” is required. Patients’ behavior appears as though there is a disengagement of attention, but the mechanism underlying the patients’ behavior is based on competition between damaged and intact representations of space, not on an “attentional disengager.” Effects of right parietal damage on visual search are consistent with results from spatial cueing paradigms. Eglin and colleagues [14] asked patients with parietal damage to perform a conjunction search (e.g., color and shape, see Figure 8.2B) across a number of set sizes. The patients were much slower to detect target items when the distracters appeared in the ipsilesional field compared with when they appeared in the contralesional field. In the context of Cohen and colleagues’ model, the presence of ipsilesional distracters may have prevented the contralesional representation of the target from competing effectively for attention. Taken together, these data suggest that the attention deficits seen following parietal lobe damage are the result of impaired processing of bottom-up inputs to the attention system. This interpretation does not necessarily mean that neglect is an elemental sensory

121


Response unit

Attention units (left hemispace)

Perception units (left hemispace)

Attention units (right hemispace)

Inhibitory connections responsible for competition

Perception units (right hemispace)

Figure 8.6. An illustration based on the neural network that simulates the “disengage deficit” seen in patients with damage to the parietal lobe by performing a simulated version of Posner’s spatial cueing task. The perception units provide parallel input to both attention units and a response unit. Spatial cues and targets are presented as input to the model by “turning on” one of the perception units. This activation propagates through the network and activates the attention and response units. Thus, if a target is then presented to the right perception unit – an invalidly cued target – the model takes a long time to respond because the right pool of attention units has been inhibited. This model shows a disengage-like pattern of results because damage to one of the attentional pools impairs these units’ ability to compete with the intact pool of attentional units. If the right pool of attention units is damaged (e.g., in parietal damage) a spatial cue on the left (which activates the left pool of attention units) is able to inhibit the right pool of attention units more than if the model was undamaged.

deficit, but rather that it may involve an inability of the attention system to effectively use bottom-up sensory information in the allocation of attention. Recall Wolfe’s guided search model, where bottom-up and top-down inputs are combined to create a salience map of the visual environment. If the attention system is less able to use bottom-up information from contralesional space, salient items in that portion of the visual environment would be less able to compete for attentional selection. As a result, these items would not be readily detected and it would take the observer with neglect longer to respond to them, resulting in the types of search and detection deficits outlined above. Therefore, rather than conceptualizing the posterior parietal lobe as an “attentional disengager,” it may be more accurate to think of this region as being responsible for detecting salient aspects of the environment, allowing the attention system to reorient toward them.

Frontal lobe influences on spatial attention Although neglect has typically been studied in patients with parietal lobe damage, neglect can also occur in patients with damage to areas of the frontal lobes. Specifically, damage to the regions of the dorsolateral prefrontal cortex (DLPFC) has been implicated in neglect [15, 16]. Husain and colleagues [17] performed a lesion overlap analysis on lesion information

122

from patients with focal frontal lobe damage who showed symptoms of neglect. The region of greatest overlap in this analysis was located in a specific area of the DLPFC, the frontal eye field (FEF). This region has been implicated in both overt attentional orienting (attention requiring eye movements) and covert orienting (attentional orienting that does not require eye movements). Many studies of damage to the FEF have focused on the ability of patients with lesions to this region to overtly direct attention in space. Typically, directing the eyes to a region of space is preceded by directing covert spatial attention to the target region [18], and lesions to the FEF seem to disrupt particular types of eye movements. In a study by Henik and colleagues [19], performance on a spatial cueing task was compared between a group of patients with damage to the FEF and a group of patients with frontal lobe damage that did not include the FEF. In one portion of the experiment, patients performed a “saccade task” in which they were instructed to make eye movements to a peripheral location, indicated by either a central cue (an arrow) or a peripheral cue (a brief peripherally located flicker). In another portion of the experiment, patients performed a detection task in which they were told to respond to a target by pressing a particular key, without making saccades. As in the first task, subjects were presented with either a central arrow cue


or a peripheral flicker cue, which in this task was followed by the presentation of a target, which observers responded to with a button press. In both tasks, half of the cues (central and peripheral) were valid and half were neutral; there were no invalid cues. It was shown that FEF lesions disrupted eye movements to peripheral locations, but not all eye movements were disrupted equally [19]. The FEF patients were slower to make eye movements into the contralesional field than into the ipsilesional field following central cues. Conversely, following peripheral cues, the patients with frontal damage that included the FEF made faster eye movements into the contralesional field than into the ipsilesional field. However, frontal lobe patients with an intact FEF made eye movements into the contra- and ipsilesional field approximately equally following both central and peripheral cues. The results from the FEF patients indicate that overt, voluntary orienting to central cues is impaired in this group, as these patients are only slowed in directing eye movements to the contralesional field following the symbolic arrow cue. Thus the FEF appears to play a role in the voluntary, or top-down, orienting of attention. Further evidence implicating the frontal lobes in the voluntary orienting of attention comes from a study by Vecera and Rizzo [20]. In this study patient E.V.R., a well-known patient with bilateral frontal lobe damage, performed two spatial cueing tasks. In both tasks, E.V.R. was instructed to press a key as quickly as possible in response to the detection of a target appearing on either the left or right side of the screen. In one task, peripheral cues were used to direct attention to the location of the target, on either the left or right side of the display. In the other task, central word cues (left, right) were used to direct attention to the target location. It was shown that E.V.R. could use peripheral cues, as evidenced by quicker reaction times to validly vs. invalidly cued target locations. However, performance in the central cue task did not reflect any reaction time differences between validly and invalidly cued trials, indicating that E.V.R. could not use the directional information provided by the central cue. These results suggest that regions of the frontal lobes are critical for voluntary, top-down attentional control, with the FEFs being particularly important.

Functional imaging of spatial attention As already mentioned, top-down or “goal-directed” attentional processes are those that rely on an

observer’s knowledge about the environment to guide attention. This knowledge can include previously learned information (e.g., looking for a friend’s face in a crowd) or can be based on a particular goal state (e.g., searching for an empty chair in a crowded auditorium). Conversely, bottom-up, “stimulus-driven” attentional processes rely on the properties of the stimuli present in a scene and attract attention on the basis of some unique visual quality rather than any cognitive factors. Whereas the patient studies discussed above provided early insights into brain regions involved in the control of attention, a number of recent functional imaging investigations have attempted to more precisely elucidate the mechanisms involved in both stimulus-driven and goal-directed attentional orienting. In an early event-related functional magnetic resonance imaging (fMRI) study by Hopfinger and colleagues [21], hemodynamic responses of observers were recorded while they performed a cueing task that used a central cue. In this study, observers were presented with a central arrow cue that always indicated the location of the target to-be-discriminated. By using a predictive central cue, it was possible to isolate the activation of brain structures involved in voluntary allocation of attention in space. Analyses of hemodynamic responses to these stimuli revealed that a number of discrete regions of parietal and frontal cortex were differentially active during attentional orienting and response. Specifically, regions in superior frontal and parietal cortex showed increased activity in response to the presentation of the central cue. This increased activity was greatest for the FEF and intraparietal sulcus (IPs), suggesting that these regions were linked in controlling the voluntary orienting of attention to locations indicated by the cue. In contrast to the more dorsal activation in response to the top-down information provided by cue, ventral regions of the prefrontal and parietal cortex showed greater activation in response to the presentation of the target. In particular, the inferior frontal gyrus (IFG) and inferior parietal lobule (IPL) showed greater activity during target presentation, indicating that these regions may be involved in the selective processing of stimuli and subsequent response processes rather than attentional orienting in general. Further evidence for a dorsal-ventral distinction between structures supporting voluntary attentional orienting and stimulus detection comes from a study in which the neural activity in response to

123


peripheral and central cues was directly compared. Kincade and colleagues [22] used a spatial cueing task in which observers monitored a display for a target letter appearing on either the left or right side of the display, responding to the identity of the letter once presented. Before target presentation, a spatial cue was presented that could be either valid or invalid with respect to the subsequent target presentation. Critically, across blocks of trials the cue could be peripheral, central, or neutral (no cue), allowing for a comparison between cues that relied on voluntary and stimulus-driven shifts of attention. When central cues were used to direct attention, there was significantly higher activation in bilateral areas of the FEF and IPs than in conditions where either peripheral or neutral cues were presented, consistent with previously discussed findings. Moreover, these same dorsal regions showed greater activation in response to peripheral cues as well, suggesting that this dorsal frontoparietal network mediates both stimulus-driven (bottomup) and goal-directed (top-down) allocation of attention.

Object-based attention To this point, our discussion has focused on the control of attention in space. However, attention also may be directed toward objects. In particular situations, object selection can take place regardless of where the object appears, suggesting that object-based and space-based attention are dissociable processes. When studying object-based attention, it is important to use designs that rule out selection by spatial attention, since by necessity objects occupy locations in space. For this reason, most studies of object-based attention have used experimental designs that eliminate or hold constant the spatial separation between objects. Although a number of object-based attention paradigms have been employed in the attention literature, this discussion will be limited to two of the most widely used tasks. In the “object attribute” task developed by Duncan [23], observers view a stimulus which includes two overlapping objects: a box and a line (Figure 8.7). Each object has two features: the box can be tall or short, and has a gap on either the left or the right side; the line can be either dashed or dotted, and can be tilted either to the left or the right. A box/line stimulus is presented briefly (∼100 ms) and followed by a masking stimulus that disrupts perception. Observers are asked to report two of the

124

Figure 8.7. An illustration of stimuli used to study object-based attention. Participants report features from the same object (e.g., box height and side of gap) or from different objects (e.g., box height and line tilt).

four features mentioned above, and the features can come from the same object (e.g., box height and side of gap) or from different objects (e.g., box height and type of line). Observers are typically more accurate when reporting two features from the same objects than when reporting two features from different objects. A second paradigm developed for studies of objectbased attention uses an adaptation of the spatial cueing method already discussed. In a task developed by Egly and colleagues [24], observers view two rectangles, and the end of one of the rectangles is cued with a brief flash (i.e., a peripheral cue), followed by a target item (Figure 8.8). On most trials, the cue is valid and the target appears in the same location as the cue. Critically, on some trials the target appears at an uncued location, either within the same object that was cued or in another, uncued object. Even when uncued targets appear at the same distance from the cued region of the rectangle, observers are faster to respond to targets appearing in the uncued end of the cued rectangle than at any location in the uncued rectangle. This seems to suggest that attention automatically spreads across an entire object, conferring the benefits of attention to any region located within an attended object. Results from these studies suggest that space- and object-based attention can be dissociated from one another at the behavioral level. A number of patient and functional imaging studies seem to support this dissociation, although it appears that portions of the same attention system responsible for carrying out space-based attention are recruited during objectbased attention. The next section reviews relevant data from patient populations and functional imaging studies regarding the neural mechanisms of object-based selection.


e m Ti or

Invalid same object Invalid diff. object


Valid

or

Figure 8.8. An illustration of the object cueing paradigm and typical results. Following a pre-cue, a target appears at either the cued location (left), at an un-cued location in the same (cued) object (center), or at an un-cued location in the other (un-cued) object (right). Response times are faster to targets that appear in the cued object (Invalid Same) than in the un-cued object (Invalid Different [Diff.]), even though these two locations are the same spatial distance from the cued region.

Valid

Invalid same Invalid diff. Cue validity

Object-based attention in neglect As discussed above, patients with neglect due to parietal lobe damage often fail to attend to stimuli falling within the region of space contralateral to the lesion, neglecting to read words on the left side of the page or eat food on the left side of the plate. In addition to deficits in spatial attention, patients with neglect may also show deficits in object-based attention. Although it is possible that some object-based attention deficits in neglect patients arise as a secondary effect of their spatial attention deficits, a number of studies have shown that these deficits can be dissociated in these patients. An early study of object-based attention in parietal patients was carried out by Egly and colleagues [24], as a portion of the study described above. In their study, patients were placed into two groups based on the laterality of their parietal lobe lesion; one group consisted of patients with damage to the left parietal lobe, and the other group had damage to the right parietal lobe. With the use of a cued detection task identical to that described above (see Figure 8.8), objectbased attention effects were measured between the two groups. Results showed that the two groups exhibited different types of attentional impairment in the task. Both groups showed evidence of impaired disengagement following invalid cues, which would be expected

based on the site of their lesions. However, the two groups differed in their object-based results. Patients with damage to the right parietal lobe showed a typical object effect, responding faster to invalid targets appearing in the cued object than those appearing in the uncued object. In contrast, patients with damage to the left parietal lobe showed a larger object effect in their contralesional field than in their ipsilesional field, indicating that they had trouble shifting attention between objects when the objects fell within their contralesional field. The authors suggested that the performance differences between patients with damage to left and right parietal lobes was due to differential recruitment of left and right parietal lobes during object-based attentional selection. Specifically, it was hypothesized that the right parietal lobe may be more involved in spatial attention processes (since damage here results in space- but not object-based attention effects), whereas the left parietal lobe may be more involved in object-based attention processes.

Functional imaging of object-based attention The neural mechanisms underlying object-based attention effects have received a great deal of study using functional imaging in recent years. In many of these studies, locations of to-be-attended items are held constant, as described above, allowing the control

125


processes responsible for attention to objects to be isolated from those involved in attention to spatial locations. In a functional imaging study reported by Serences and colleagues [25], observers viewed a continuous stream of superimposed houses and faces, presented in the same location at the center of the display. Observers were asked to selectively attend to either the house stream or the face stream, monitoring the streams for one of four possible targets (two houses, two faces). One of the face or house targets signaled that attention should remain on the current stream of objects (the “hold” condition), and the other target signaled that attention should be shifted to the other object stream (the “shift” condition). By comparing activations in the hold and shift conditions, it was possible to isolate regions involved in object-based shifts of attention. It was shown that relative to the hold condition, there was increased activity in bilateral regions of the superior parietal lobule (SPL) during trials that required a shift of attention between object streams. The authors concluded that this response reflected a transient signal that indicated an object-based shift of attention. Further support for the involvement of the SPL in object-based shifts of attention comes from another study using an object-based cueing task similar to that in Figure 8.8 [26]. Observers viewed two rectangles oriented perpendicular to each other, with a color patch located in both ends of each rectangle, and were initially instructed to attend to a single color patch. The color patches changed in color synchronously every 250 ms, and observers were asked to monitor the stream for one of three particular target colors. One color indicated that observers should hold attention on the current patch, another indicated that they should shift attention to the color patch at the other end of the same object, and another indicated that they should shift attention to the color patch at the same end of the other object. Overall, activation in bilateral SPL regions was greater for shift trials versus hold trials, consistent with the results of Serences and colleagues [25]. In addition, activation in the left SPL showed object-based modulation; in trials that required within object shifts, left SPL activations were increased relative to trials requiring betweenobject shifts. These data indicate that regions of the left SPL may be specifically involved in object-based shifts of attention, a finding consistent with that reported

126

in Egly and colleagues’ [24] study of object-based attention in a patient with left parietal lobe damage. Taken together, these results show that some parietal regions involved in spatial attention processes may also be responsible for mediating object-based attention. Additionally, there appears to be a bias toward regions in the left SPL in mediating the control of attention to objects.

Attention and visual working memory Both spatial and object attention involve selection of perceptual characteristics that do not persist beyond the duration of the attentional operation. Visual working memory provides a mechanism for the storage of three to four objects in a more durable form over a longer period of time [9]. Recent research suggests that attention is vital for allowing information to enter into visual working memory, gating incoming sensory information, and keeping the working memory system from becoming overloaded. Evidence for this function of attention – as a gatekeeper for working memory – comes from studies of an event referred to as the “attentional blink.” In a typical attentional blink task, observers are presented with a rapid serial visual presentation (RSVP) of stimuli in which they are asked to detect two targets from the stream, responding at the end of the stream [27]. Figure 8.9 depicts a typical attentional blink task. In this example, observers are asked to identify two letters within a stream of numbers, with letter one being target one (T1) and letter two being target two (T2). There is a window of time following the detection of target one where observers fail to detect the presentation of a second target (see Figure 8.9A). However, if T2 is presented a sufficient time after T1, observers typically have little problem detecting the target (see Figure 8.9B). The period of time following the presentation of T1 where subjects are unable to detect T2 is referred to as the attentional blink because, as in an eyeblink, there is a brief period during which targets cannot be detected. Typical results from an attentional blink task are shown in Figure 8.9C. Note that the recognition of T2 depends upon the occurrence of T1. If no T1 target appears, observers are accurate at reporting T2, and there is no attentional blink. These results suggest that the attentional blink arises from an inability to store T2 in visual working


(A)

(B) +

+ F

e m Ti

T1

T1

A A

T C

C

F

X

T2

X

T

Percent reported

(C)

T2

Figure 8.9. Attentional blink paradigm and typical results from this paradigm. In this example, subjects are asked to monitor the stream of letters and respond to two targets – the letters A and X. (A) shows a rapid serial visual presentation (RSVP) stream of letters and numbers, with T1 and T2 separated by a single item. (B) shows the same RSVP task, but T1 and T2 are separated by a greater number of intervening letters. (C) shows a typical attentional blink result: After identifying the first target digit (T1), observers fail to correctly identify the second target digit (T2) when it appears shortly after T1, as in (A). However, if T2 is presented sufficiently long after T1, as in (B), observers can correctly identify both targets.

T1

80 70 60 50

T2

40 30 1

2

3

4

5

Number of items presented between T1 and T2

memory. This incapacity is due to the fact that attending to T1 delays the allocation of attention to the second target for a short period of time. Therefore, if the second target is presented soon after the first, it cannot be immediately processed and decays before being stored in working memory. However, as the time between T1 and T2 increases, processing of T1 is more likely to be completed by the time T2 appears, allowing attention resources to be allocated to T2 and resulting in detection of the second target. The attentional blink paradigm has been used in patient populations to shed light on the neural structures responsible for the type of memory-based attention outlined above. For example, Husain and colleagues [17] showed that an increased attentional blink can accompany visual neglect. Eight subjects with a mean age of 64 years were studied one month (on average) after a right hemisphere stroke affecting IPL, ventral frontal cortex (VFC), or the basal ganglia. All had clinically defined visual neglect and performed an attentional blink task similar to that in Figure 8.9. It was shown that the neglect patients could not identify the second target

in the visual stream until 1.4 s had elapsed after the identification of the first target, an attentional blink that was nearly twice that of non-brain-damaged subjects (540 ms). Based on these results, the authors concluded that visual neglect is a disorder that affects the patient’s ability to direct attention in time as well as space. Furthermore, this study implicated the same cortical regions involved in attention in space and attention to objects in higher-level memory-based attention. However, Rizzo and colleagues [28] provided further details in 13 subjects with chronic focal brain lesions on MRI and nine control subjects without neurological impairments performing an RSVP task that used letters as targets. The results showed that an abnormal attentional blink could occur with lesions in either hemisphere and persist for years. The abnormality affected both length and magnitude of the attentional blink; did not require a lesion in the parietal lobe, frontal lobe, or basal ganglia; occurred independently of spatial neglect, and persisted after spatial neglect resolved. The authors concluded that an increased attentional blink has no special status

127


in neglect, and that the neural mechanisms of spatial attention that are disrupted in the visual hemineglect syndrome differ from the neural mechanisms that underlie the attentional blink. Elucidation of the neural structures responsible for the type of temporal selection seen during the attentional blink is an active area of research, with a number of recent functional imaging studies providing insights into the neural correlates of memory-based attentional control [29].

Executive attention and task selection The last form of attentional selection to be discussed is the selection of one task from among many possible ones, which also implicates the coordination of multiple tasks [30, 31]. In all of the paradigms discussed above, observers perform the same attention task throughout, yet in real life, humans often perform different tasks concurrently or in series, such as rehearsing a phone number that was looked up, dialing the phone number, and conversing with the person just called. In general, executive functions control the focus of attention [32] and the executive system permits the awareness of marked changes in an object or a scene. The failure of executive control over attention has important real-world implications for noticing changes in the environment, particularly when information load is high. For example, automobile drivers navigating through complex driving environments with high traffic and visual clutter would be required to use the executive system to recognize and cope with changes in the driving environment [33, 34]. Driver errors occur when attention is focused away from a critical roadway event in which vehicles, traffic signals, and signs are seen but not acted upon, or are missed altogether [35]. Sometimes eye gaze is captured by irrelevant distracters [36] that may prevent a driver from seeing a critical event [37], such as an incurring vehicle or a child chasing a ball. Drivers with cerebral lesions disrupting the executive system are liable to be “looking but not seeing” despite low information load [38, 39]. Considering the multiple tasks involved in a complex task such as driving, executive control is needed to switch the focus of attention between various critical tasks such as tracking the road terrain, monitoring the changing locations of neighboring vehicles,

128

reading signs, maps, traffic signals, and dashboard displays, and checking the mirrors. This requires switching attention between disparate spatial locations, local and global object details, and different visual tasks. Drivers must also switch attention between modalities when they drive while conversing with other vehicle occupants, listening to the radio, using a mobile phone, and interacting with in-vehicle devices [40]. These attentional abilities can fail in drivers with visual processing impairments caused by cerebral lesions or fatigue [32, 41].

Neural systems involved in the control of attention Before the advent of functional imaging techniques, research on patients with focal brain damage provided a great deal of evidence for brain regions involved in the control of attention. From this work, a number of cortical areas involved in attentive processing were revealed, allowing an early classification of the neural systems involved in the control of attention [12, 42]. These theories paved the way for functional imaging studies that attempted to classify the large-scale operations of attention systems involved in the performance of specific attention-demanding tasks. To this point, the account has focused on distinct regions of the brain that play a role in the control of attention. This section will center on the relationships between these various regions, describing how specific brain areas directly interact to form large-scale neural systems responsible for the control of attention. A useful organizing concept is Corbetta and Shulman’s [43] model of selective attention, which was developed by synthesizing large amounts of data from patient and functional imaging studies, as well as information from early models of attentional selection. Based on this information, Corbetta and colleagues have developed a theoretical framework for the neural mechanisms of attentional selection. In their model, two separate attentional systems are posited that rely on differential frontoparietal connectivity, each system being involved in a different aspect of attentional control. The bilateral dorsal frontoparietal system is hypothesized to be involved in the overall control of attention, and consists of the IPs-FEF network shown to be responsible for the voluntary orienting of attention in response to relevant top-down information. This system is complemented by a right-lateralized


IPs/SPL

FEF

VFC (IFg/MFg)

TPJ (IPL/STG) Top-down control L FEF

R FEF

Novelty R VFC

L VFC

Circuit breaker

Stimulusresponse selection L TPJ

R IPs

L IPs

R TPJ

Behavioral valence Visual areas Stimulus-driven control

Figure 8.10. Illustration of a neuroanatomic model of attentional control. Top: diagram indicating brain regions involved in the control of attention. Bottom: Schematic of the mechanisms of a model of attentional control [43]. The dorsal network (IPs-FEF), indicated by the black arrows, is involved in the top-down, or “goal-directed,” control of attention. The ventral network (TPJ-VFC), indicated by the gray arrows, is involved in bottom-up, or “stimulus-driven,” control of attention. The dorsal system is also modulated by bottom-up information, with the TPJ communicating with the IPs and acting as a “circuit breaker” allowing salient bottom-up information to interrupt voluntary, top-down orienting, in turn reorienting attention to salient aspects of the environment. Abbreviations: IPs: intraparietal sulcus; SPL: superior parietal lobule; FEF: frontal eye field; TPJ: temporoparietal junction; IPL: inferior parietal lobule; STG: superior temporal gyrus; VFC: ventral frontal cortex; IFg: inferior frontal gyrus: MFg: middle frontal gyrus; L: left; R: right. Adapted from Corbetta M, Shulman GL. Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci. 2002;3(3):201–15, with permission from Macmillan Publishers Ltd. This figure is presented in color in the color plate section.

ventral-frontoparietal system that includes regions of VFC and the TPJ. The ventral-frontoparietal system is involved in the detection of salient or novel bottomup information, especially with regard to behaviorally relevant stimuli, and can act as a circuit breaker for the dorsal system. Specifically, it is hypothesized that the right TPJ is involved in detecting task-relevant or salient stimuli outside of the focus of processing, and through interactions with the IPs in the dorsal system can cause attention to re-orient in response to these stimuli (Figure 8.10). To illustrate this model, consider another familiar example. Imagine searching the night sky for a particular constellation. In an example such as this, one

uses previously learned information such as the constellation’s location or the way that it typically appears to guide one’s search. At a neural level, this process would rely on structures in the dorsal-frontoparietal circuit. Now imagine that, suddenly, a shooting star appears in the corner of one’s eye, capturing attention. This event would be detected by structures in the ventral-frontoparietal circuit, and a signal would be sent to the IPs to re-orient attention toward the shooting star. By this account, the dorsal attention system is responsible for the overall control of attention, but the ventral-frontoparietal system acts as an environmental sensor that picks up on relevant bottom-up information.

129


An appealing feature of this neural model of attentional control is that it maps well onto Wolfe’s guided search model of attentional control during visual search [4, 5]. Recall that according to guided search theory, salient bottom-up information from the visual field is represented by category-specific feature maps, with separate maps for features such as color and orientation. In addition, these maps include not only information about physical features present in the visual field, but also for the locations of these features, marking possible areas of interest for the allocation of attention. This information is combined with topdown information regarding current goals or previous knowledge, forming an overall salience map of the entire visual scene. This salience map is then used to guide attention to regions of a scene most likely to include stimuli of interest. In the context of Corbetta and Shulman’s model, the ventral frontoparietal system may act as a saliency detector that, through reciprocal connections with visual and association cortices, uses bottom-up information to alert the dorsal system to salient aspects of the environment. This arrangement would allow the ventral system to direct attention in a stimulusdriven manner to highly salient stimuli in the visual field through its interactions with the dorsal system. Based on the functional imaging findings discussed above, Kincade and colleagues [22] hypothesized that the dorsal frontoparietal system is an ideal candidate for the saliency map described in guided search theory. Through interactions with the ventral system, this map receives bottom-up information from the environment. In addition, its involvement in goal-directed attentional control indicates that it directly uses topdown information to direct attention. Therefore, in the context of guided search components, the dorsal system (especially the FEF) appears to be a candidate region responsible for overall saliency coding, representing a possible neural correlate of the saliency map [44].

Dorsal and ventral attention systems and neglect As we have already described in detail, damage to regions of the parietal lobe, particularly on the right, results in profound neglect of contralesional space. How does Corbetta and Shulman’s model of attention map onto the deficits seen in patients with neglect?

130

Mesulam [45] has hypothesized that the deficits seen in neglect result from damage to regions that control the deployment of attention in response to top-down signals, which in the context of Corbetta and Shulman’s model would imply that neglect arises following damage to the FEF or IPs, or the dorsal attention system. However, data previously discussed show that neglect is most often the result of damage to the TPJ [11], a component of the ventral attention system. Therefore, Corbetta and Shulman have suggested that neglect more likely reflects damage to the ventral TPJVFC system, an assertion based on the following findings from neglect studies: (1) Neglect most often arises following damage to regions of the TPJ, which is part of the ventral attention circuit [11, 46]. (2) Neglect is more frequent, severe, and lasting following right parietal lesions. Recall that the functions of the ventral TPJ-VFC system are right lateralized, whereas the functions of the dorsal system are bilateral. The stronger association of neglect with right parietal damage is consistent with ventral-system damage. (3) Neglect patients show impaired inability to effectively use bottom-up information in the control of attention, as evidenced by the “disengage” deficits described above – a function attributed to the ventral system. However, they retain the ability to effectively use top-down information to guide attention, indicating an intact dorsal attention system [47]. Although this model fits many of the data regarding the deficits seen during neglect, one point of divergence from the literature should be noted. In this model the ventral frontoparietal system is hypothesized to be right lateralized, with no homologous function attributed to the TPJ-VFC system in the left hemisphere. Therefore, damage to this system would predict bilateral deficits in attentional orienting to salient bottom-up sensory information by the dorsal IPs-FEF system. However, this is not typically the case: there is a disproportionate deficit in directing attention to stimuli appearing in contralesional space, with a relative sparing of the ability to orient to stimuli in the ipsilesional field. It is possible that damage to the right TPJ or underlying white matter could impair communication between the ventral saliency detector and dorsal


orienting system, resulting in a functional inactivation of the right dorsal IPs-FEF system. This would lead to the same types of “disengage” deficits described above, with the intact left dorsal attention system more effectively competing for attentional resources. Although Corbetta and Shulman’s model is tentative, it provides an intuitive framework for understanding the allocation of attention in response to bottom-up and topdown information. Importantly, this model maps well onto a widely accepted functional theory of attention, and is supported by a large amount of converging evidence from patient and functional imaging studies.

Conclusion Attention is required for focusing on relevant information in the environment, simultaneously suppressing irrelevant information. By restricting what stimuli are and are not processed, attention acts as a gating system that allows us to function efficiently in a highly complex, ever-changing environment. Although the term attention has traditionally been considered to represent a single, monolithic process, it is clear that attention can and does operate across a number of different functionally defined levels. Whereas it is evident from the above discussion that many forms of attention have been defined, further research is needed to better understand both the functional and anatomic mechanisms involved in the control of these processes. Using behavioral techniques provided by cognitive psychology, the processes of attention can be studied rigorously across these multiple domains. By using well-defined behavioral measures in conjunction with neuropsychological and neurophysiological techniques, it is also possible to study the multiple components of attention at a structural level, providing further insights into how the brain carries out attentive processing. This chapter has provided evidence for a number of cerebral sites that appear to be involved in the overall control of attention. Understanding how these sites interact and how they relate to functional theories of attentional control will greatly increase our understanding of normal and disordered attentional control processes.

References 1. Posner MI. Orienting of attention. Q J Exp Psychol. 1980;32(1):3–25.

2. Treisman AM, Gelade G. A feature-integration theory of attention. Cogn Psychol. 1980;12(1):97–136. 3. Treisman A. The binding problem. Curr Opin Neurobiol. 1996;6(2):171–8. 4. Wolfe JM, Cave KR, Franzel SL. Guided search: an alternative to the feature integration model for visual search. J Exp Psychol Hum Percept Perform. 1989; 15(3):419–33. 5. Wolfe JM. Guided Search 2.0 – a revised model of Visual-Search. Psychon B Rev. 1994;1(2):202–38. 6. Desimone R, Duncan J. Neural mechanisms of selective visual attention. Annu Rev Neurosci. 1995;18:193–222. 7. Hillyard SA, Vogel EK, Luck SJ. Sensory gain control (amplification) as a mechanism of selective attention: electrophysiological and neuroimaging evidence. Philos Trans R Soc Lond B Biol Sci. 1998;353(1373): 1257–70. 8. Carrasco M, Penpeci-Talgar C, Eckstein M. Spatial covert attention increases contrast sensitivity across the CSF: support for signal enhancement. Vision Res. 2000;40(10–12):1203–15. 9. Vogel EK, Woodman GF, Luck SJ. Storage of features, conjunctions and objects in visual working memory. J Exp Psychol Hum Percept Perform. 2001;27(1):92–114. 10. Bisiach E, Vallar G. Hemineglect in humans. In Boller F, Grafman J, editors. Handbook of Neuropsychology. Amsterdam: Elsevier; 1988. 11. Friedrich FJ, Egly R, Rafal RD, Beck D. Spatial attention deficits in humans: a comparison of superior parietal and temporal-parietal junction lesions. Neuropsychology 1998;12(2):193–207. 12. Posner MI, Walker JA, Friedrich FJ, Rafal RD. Effects of parietal injury on covert orienting of attention. J Neurosci. 1984;4(7):1863–74. 13. Cohen JD, Romero RD, Servanschreiber D, Farah MJ. Mechanisms of spatial attention – the relation of macrostructure to microstructure in parietal neglect. J Cogn Neurosci. 1994;6(4):377–87. 14. Eglin M, Robertson LC, Knight RT. Visual search performance in the neglect syndrome. J Cogn Neurosci. 1989;1(4):372–85. 15. Heilman KM, Valenstein E. Frontal lobe neglect in man. Neurology 1972;22(6):660–4. 16. Heilman KM, Valenstein E, Watson RT. Localization of neglect. In Kertesz A, editor. Localization in Neuropsychology. New York, NY: Academic Press; 1983, pp. 471–92. 17. Husain M, Shapiro K, Martin J, Kennard C. Abnormal temporal dynamics of visual attention in spatial neglect patients. Nature 1997;385(6612):154–6.

131


18. Colby CL, Goldberg ME. Space and attention in parietal cortex. Annu Rev Neurosci. 1999;22:319–49. 19. Henik A, Rafal R, Rhodes D. Endogenously generated and visually guided saccades after lesions of the human frontal eye fields. J Cogn Neurosci. 1994;6(4):400–11. 20. Vecera SP, Rizzo M. Attention: normal and disordered processes. In Rizzo M, Eslinger PJ, editors. Principles and Practice of Behavioral Neurology and Neuropsychology. Philadelphia, PA: W.B. Saunders; 2004, pp. 223–45. 21. Hopfinger JB, Buonocore MH, Mangun GR. The neural mechanisms of top-down attentional control. Nat Neurosci. 2000;3(3):284–91. 22. Kincade JM, Abrams RA, Astafiev SV, Shulman GL, Corbetta M. An event-related functional magnetic resonance imaging study of voluntary and stimulus-driven orienting of attention. J Neurosci. 2005;25(18):4593–604. 23. Duncan J. Selective attention and the organization of visual information. J Exp Psychol Gen. 1984; 113(4):501–17. 24. Egly R, Driver J, Rafal RD. Shifting visual attention between objects and locations: evidence from normal and parietal lesion subjects. J Exp Psychol Gen. 1994;123(2):161–77. 25. Serences JT, Schwarzbach J, Courtney SM, Golay X, Yantis S. Control of object-based attention in human cortex. Cereb Cortex 2004;14(12):1346–57. 26. Shomstein S, Behrmann M. Cortical systems mediating visual attention to both objects and spatial locations. Proc Natl Acad Sci USA 2006;103(30):11,387–92. 27. Raymond JE, Shapiro KL, Arnell KM. Temporary suppression of visual processing in an RSVP task: an attentional blink? J Exp Psychol Hum Percept Perform. 1992;18(3):849–60. 28. Rizzo M, Akutsu H, Dawson J. Increased attentional blink after focal cerebral lesions. Neurology 2001;57(5):795–800. 29. Hommel B, Kessler K, Schmitz F et al. How the brain blinks: towards a neurocognitive model of the attentional blink. Psychol Res. 2006;70(6): 425–35. 30. Allport DA, Styles EA, Hsieh ST. Shifting intentional set: Exploring the dynamic control of tasks. In Umiltà C, Moscovitch M, editors. Attention and Performance XV: Conscious and Nonconscious Information Processing. Cambridge, MA: MIT Press; 1994, pp. 396–419. 31. Rogers RD, Monsell S. Costs of a predictable switch between simple cognitive tasks. J Exp Psychol Gen. 1995;124(2):207–31.

132

32. Vecera SP, Rizzo M. Spatial attention: normal processes and their breakdown. Neurol Clin. 2003;21(3):575–607. 33. Caird JK, Edwards CJ, Creaser J. The effect of time constraints on older and younger driver decisions to turn at intersections using a modifed change blindness paradigm. 1st International Driving Symposium on Human Factors in Driver Assessment, Training and Vehicle Design; Aspen, CO: University of Iowa; 2001. 34. Batchelder S, Rizzo M, Vanderleest R, Vecera SP. Traffic scene related change blindness in older drivers. In Rizzo M, Lee JD, McGehee D, editors. Proceedings of Driving Assessment 2003: 2nd International Driving Symposium on Human Factors in Driver Assessment, Training and Vehicle Design, Park City, UT, July 21–24, 2003; Iowa City, IA: University of Iowa; 2003, pp. 177–81. 35. Treat JR. A Study of Pre-crash Factors Involved in Traffic Accidents. Ann Arbor, MI: University of Michigan; 1980. 36. Theeuwes J. Exogenous and endogenous control of attention: the effect of visual onsets and offsets. Percept Psychophys. 1991;49(1):83–90. 37. O’Regan JK, Rensink RA, Clark JJ. Change-blindness as a result of ‘mudsplashes’. Nature 1999;398(6722): 34. 38. Rizzo M, Reinach S, McGehee D, Dawson J. Simulated car crashes and crash predictors in drivers with Alzheimer disease. Arch Neurol. 1997;54(5):545–51. 39. Rizzo M, McGehee DV, Dawson JD, Anderson SN. Simulated car crashes at intersections in drivers with Alzheimer disease. Alzheimer Dis Assoc Disord. 2001;15(1):10–20. 40. Kantowitz BH. Using microworlds to design intelligent interfaces that minimize driver distraction. 1st International Driving Symposium on Human Factors in Driver Assessment, Training and Vehicle Design; Aspen, CO: University of Iowa; 2001, pp. 42–57. 41. Rizzo M. Safe and unsafe driving. In Rizzo M, Eslinger PJ, editors. Principles and Practice of Behavioral Neurology and Neuropsychology. Philadelphia, PA: W.B. Saunders; 2004, pp. 197–222. 42. Mesulam MM. A cortical network for directed attention and unilateral neglect. Ann Neurol. 1981;10(4):309–25. 43. Corbetta M, Shulman GL. Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci. 2002;3(3):201–15. 44. Schall JD, Thompson KG. Neural selection and control of visually guided eye movements. Annu Rev Neurosci. 1999;22:241–59.


45. Mesulam MM. Spatial attention and neglect: parietal, frontal and cingulate contributions to the mental representation and attentional targeting of salient extrapersonal events. Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1325–46. 46. Heilman KM, Watson RT, Valenstein E. Neglect I: Clinical and anatomic issues. In Feinberg TE, Farah

MJ, editors. Patient-based Approaches to Cognitive Neuroscience. Cambridge, MA: MIT Press; 2000. 47. Losier BJ, Klein RM. A review of the evidence for a disengage deficit following parietal lobe damage. Neurosci Biobehav Rev. 2001;25(1): 1–13.

133

Section I


Chapter

Motivation

9

Brian D. Power and Sergio E. Starkstein

The English term “motivation” was first recorded in 1873, and is defined as “the (conscious or unconscious) stimulus for action towards a desired goal” [1]. In neurobiological terms, motivation refers to the behaviorally relevant process that helps to regulate the organism’s internal (e.g., thirst, loneliness) and external environment (e.g., proximity to water, proximity to people) [2]. Motivation implies activation of the organism by external or internal stimuli resulting in goal-directed behaviors (e.g., drinking, companionship) [3]. A scheme for the motivated behavior is considered to involve the following steps: (a) formulating a goal and an intention to act; (b) response selection; (c) programming; and (d) initiation that precedes the execution of an action [4]. Cognitive operations of motivated behavior consist of the following necessary components: (1) attention and conscious awareness; (2) choice and control; and (3) intentionality. Disorders of motivation in humans have been reported since the nineteenth century [5]. Loss of motivation constitutes the core symptom of apathy, a syndrome frequently found among patients with acute or chronic neurological conditions such as stroke, traumatic brain injury, and dementia. This chapter will discuss the neurobiological basis of motivation. We will first review the most important findings obtained from animal research (mostly in rodents and non-human primates) and also discuss the putative mechanism of motivation in humans. We will then discuss conceptual issues that underlie the study of motivation in humans, and finish with a brief discussion of disorders of motivation.

Neurobiological basis of motivation The mechanism of motivated behavior is based on neural structures that attach salience (i.e., allocate importance) and valence (i.e., allocate positive or negative value) to a given stimulus, and activate and direct an appropriate behavior in response to that stimulus [6]. Goal-oriented behavior is thought to mostly depend on the neural connectivity of three relevant brain regions – the amygdala, nucleus accumbens, and the prefrontal cortex – with the neurotransmitter dopamine exerting an important influence on the activity of this neural circuitry [6]. This section will address the proposed role of each of these neural networks in motivation; before doing so, consideration will be given to some of the general concepts of the organization of these networks. First, it is important to note that motivation or intentional behavior does not depend on a single brain structure. Stimulation of a localized brain region may elicit a variety of motivated behaviors, which is partially related to contextual cues, individual predisposition, and exposure to previous events [7]. For instance, Berridge [8] demonstrated that motivated behavior evoked by brain stimulation may be changed gradually by manipulating the animal’s experiences during the stimulation process [7]. Second, with regard to the hierarchy of structures involved in motivation, the forebrain is considered to mediate the “higher” motivational functions and to interact with “lower” centers in the brainstem that mediates core functions, such as locomotion, autonomic changes, and emotional responses [9]. Given the complexity of re-entrant loops in forebrain limbic


134

Chapter 9: Motivation

Figure 9.1. Schema showing the mesolimbic and mesocortical DA systems.

wiring [10], Berridge [8] suggested that the relationship is likely to be more complex than the connections explained by a hierarchical system (e.g., from cortical centers to subcortical effectors), and proposed a heterarchical organization (i.e., non-hierarchical) to accommodate those circuits involved in motivated behavior.

Dopaminergic systems in the mechanism of motivation Dopaminergic systems in the brain have been implicated in numerous neurological and psychiatric disorders, from Parkinson’s disease to schizophrenia. Dopamine (DA) is considered to play a central role in the mechanism of motivation and regulation of effort-related processes, despite the fact that significant discussion is presently underway on the hypotheses related to DA function in this domain [2]. Below we shall discuss the structure and function of dopaminergic systems and how they relate to the neural circuitry of motivation.

Brainstem reticular formation and monoaminergic systems The brainstem in humans is a small structure that lies between the spinal cord and diencephalic structures (including the thalamus, where all sensory modalities,

with the exception of olfaction, feature a synaptic connection between the periphery and the cerebral cortex). The brainstem could be considered as a more sophisticated spinal cord, for it contains somatic and visceral sensory and motor fibers, as well as the nuclei of the cranial nerves that primarily subserve the head and neck. However, surrounding the major tracts and nuclei of the brainstem are the cells of the reticular formation that make more extensive connections, and which confer on the brainstem a functional importance that far outweighs its small size. Within the reticular formation are three major monoaminergic systems – the noradrenergic, serotonergic, and dopaminergic systems – whose efferent axons have widespread connections with most parts of the neuraxis. Although the serotonergic system is the most extensive monoaminergic system in the brainstem, the dopaminergic neurons are by far more numerous than noradrenergic neurons. Further, dopaminergic cells are highly organized topographically, and, on the basis of their efferent projections, are classified into two main systems, as illustrated in Figure 9.1. The mesostriatal system consists of dopaminergic cell bodies located in the retrorubal nucleus, substantia nigra, and ventral tegmental area (VTA), which project to striatal and related structures, including the caudate, putamen, subthalamic nucleus, and nucleus accumbens.

135


The mesolimbocortical system consists of dopaminergic cell bodies in the VTA, which project to limbic and cortical areas such as the habenula, amygdala, locus coeruleus, cingulate cortex, and piriform and entorhinal cortices. Dopaminergic neurons are also found in other parts of the central nervous system, such as the zona incerta, hypothalamus, the olfactory bulb, the retina, and pre-optic areas. It is postulated that dopaminergic neurons in the VTA are activated in response to a motivationally relevant event [11]. The dopaminergic system is therefore thought to have an enhancing or energizing effect on goal-oriented behavior by affecting the target structures innervated by the mesolimbic, mesocortical, and mesostriatal pathways, thereby placing the behavioral responses in a state of preparedness [12]. Further, it is thought that the release of DA at these sites facilitates cellular changes that establish learned associations with the event, thereby reinforcing the behavioral response should the event re-occur [13].

Experimental work in animals implicating dopaminergic systems in motivation The classical studies linking DA to motivation were based on stereotaxic injections of neurotoxin into the afferent projections of the mesolimbic and mesocortical pathways, which produced severe aphagia and adipsia [14]. Since the time of these studies, numerous means (e.g., pharmacologic, electrophysiological) have been used to study the effects of altering DA systems on motivated behaviors, such as hunger, thirst, and sex; some data remain inconclusive, while the interpretation of other results is the focus of much debate (see [15], [2], and [16] for review). Pharmacologic studies suggest a role for DA in motivation. Pharmacologic enhancement of DA release in the ventral striatum has been shown to increase the control by the animal over behavior exerted by conditioned reinforcing stimuli previously paired in a Pavlovian fashion with appetite reinforcement [17]. Other pharmacologic studies that implicate DA in motivation include infusion of DA into the nucleus accumbens altering animal approach behaviors [18], blockade of DA receptors by neuroleptics impairing intracranial self-stimulation by the animal [19], and observations of DA increases occurring during goal-directed behaviors for cocaine and natural reinforcers [20]. It should be noted, however, that there

136

is no clear evidence that antagonism of DA receptors blocks drug-induced euphoria [21]. Brain dialysis studies of DA in the nucleus accumbens and prefrontal cortex (i.e., sampling DA efflux over minutes) showed an increase in DA efflux in both of these structures before contact with food [22] or sexual reward stimuli [23]. Electrophysiological studies also suggest a role for DA in motivation. Neurons in the VTA projecting to the nucleus accumbens fire selectively in response to the presentation of reward cues [24]. Animals are shown to emit very high rates of responding for intracranial self-stimulation of the VTA [25], eliciting DA release in the nucleus accumbens [26], and self stimulation is suppressed by the injection of DA antagonist drugs [27]. Using a combination of electrochemistry, electrophysiology, and iontophoresis, Cheer and colleagues [28] demonstrated changes in firing and increased DA release in the nucleus accumbens shell, occurring for cues signaling award availability, and this was functionally linked to DA receptor activation. Further data supporting the role of DA in motivation are the findings that the ventral subiculum powerfully increases DA neuronal activity and elevates DA in terminal regions of the nucleus accumbens, prefrontal cortex, and amygdala, possibly via its connections with the prefrontal cortex [29].

Nucleus accumbens The nucleus accumbens (originally named, for its physical location in the brain, the nucleus accumbens septi, meaning the nucleus leaning against the septum), together with adjacent parts of the caudate and putamen, constitutes a striatal subdivision termed the ventral striatum. Whereas the dorsal striatum is considered to be involved in motor processes, the ventral striatum is considered to be involved in affective and goal-related behavior [15]. The nucleus accumbens may be regarded as a striatal nucleus with predominantly limbic connections, and hence a critical structure linking motor and motivational processes [2]. The nucleus accumbens seems to mediate the primary motivational characteristics of feeding and reproductive behavior as well as reward-motivated behaviors [30]. The nucleus accumbens contains two functionally distinct sectors, designated the shell and core [31]. The shell is connected to the hypothalamus and the VTA,


and plays an important role in unconditioned motivated behavior [32]. For instance, rises of dopamine in the accumbal shell has been found to precede goal-directed behavior [33]. On the other hand, the core is connected with the anterior cingulate and the orbitofrontal cortex, and may mediate the expression of learned behaviors in response to stimuli predicting motivationally relevant events [31]. Depletion of DA in the nucleus accumbens can interfere with instrumental behaviors in some conditions, including feeding [2], sexual behavior [34], and maternal behavior [35]. Further evidence from animal experimentation implicating the nucleus accumbens in motivation includes electrophysiological recordings of neurons that were shown to react to novel and previously reinforced stimuli, and the fact that DA release increases more robustly in the nucleus accumbens during reward anticipation than during reward consumption [36]. Neurons in the nucleus accumbens show response to impending rewards that are altered in DA receptor knock-out mice [37], and by VTA inactivation [38]. Further, DA efferents from the VTA to the nucleus accumbens become active with a motivationally relevant event [39]. Lesions of the nucleus accumbens have been shown to impair the ability of the animal to increase the rate of food-reinforced instrumental responding to a conditioned stimulus previously paired with food [36]. Taken together, these findings suggest that the nucleus accumbens plays a pivotal role in the motivation circuits, such as mediating the primary motivational characteristics of feeding and reproductive behavior as well as reward-motivated behaviors.

Prefrontal cortex Another critical region in the neural circuit of motivation is the prefrontal cortex, mainly the anterior cingulate and the orbitofrontal cortices [6]. To better understand the role of the prefrontal cortex in motivation, one must first consider some of the wiring paradigms that have been defined, the socalled frontal-subcortical circuits. Frontal-subcortical circuits are thought to form the main network by which motor activity and behavior in humans are mediated, and help explain the similarity of behavioral changes in frontal cortical and subcortical disorders [40].

Anterior cingulate

Cortex

Gyrus rectus/ medial orbital gyrus

Striatum

Nucleus accumbens

Globus pallidus substantia nigra

Globus pallidus/ substantia nigra

Ventral pallidum

Ventral anterior

Thalamus nucleus

Mediodorsal

Ventral striatum

Figure 9.2. Schema showing frontal-subcortical loops related to motivation.

There are five well-defined frontal-subcortical circuits named according to their function or site of origin in the cortex: the motor circuit, the oculomotor circuit, the dorsolateral prefrontal circuit, the lateral and medial orbitofrontal circuit, and the anterior cingulate circuit (see Chapter 5). The circuits share many features in common. For instance, they originate in the prefrontal cortex, project to the striatum (caudate, putamen, and ventral striatum); connect to the globus pallidus and substantia nigra, project to the thalamus, and are finally closed via projections back to the frontal cortex. There are also open-loop connections of each of these circuits, which are thought to integrate information from functionally related sites. Within each of these circuits there are both direct and indirect pathways, which can modulate input to the thalamus, the function of which is thought to modulate overall circuit activities in response to different inputs [40]. Limbic system connections involve both the anterior cingulate and medial orbitofrontal cortex (Figure 9.2). The anterior cingulate circuit originates in the anterior cingulate cortex and projects to the ventral striatum (ventromedial caudate, ventral putamen, nucleus accumbens, and olfactory tubercle). Efferents from this limbic part of the striatum go to the rostromedial globus pallidus interna, ventral pallidum, and rostrodorsal substantia nigra. The ventral pallidum in turn projects to the ventral anterior nucleus of the thalamus, and from the thalamus, neurons project back to the anterior cingulate cortex, thus closing the loop. The open connections

137


of the anterior cingulate circuit include inputs from the perirhinal area and hippocampus, and outputs to the substantia nigra, lateral hypothalamus, and subthalamic nucleus. The medial orbitofrontal circuit originates in the gyrus rectus and the medial orbital gyrus, and projects to the nucleus accumbens, ventral pallidum, and the mediodorsal thalamic nucleus in a closed loop fashion; open connections include the ventral striatum and amygdala. This prefrontal cortical region has a primary role in goal-directed behavior and affective processing [41]. More specifically, the prefrontal cortex may regulate the motivational salience of stimuli and determine the type of behavioral response [42]. Furthermore, the nucleus accumbens and the prefrontal cortex have reciprocal connections by which the prefrontal cortex may engage the nucleus accumbens to process motivationally salient stimuli [43]. Ventura and coworkers [44] demonstrated that norepinephrine projections from the prefrontal cortex modulate DA levels in the nucleus accumbens, which, in conjunction with the DA mesolimbic system, may play an important role in attaching motivational attribution to award- and aversion-related stimuli.

Amygdala The amygdala (derived from the Greek word for “almond” and named for its size and shape) is a collection of nuclei originally considered to be part of the basal ganglia, as in the temporal lobe it is adjacent to striatal structures (the tail of the caudate is continuous with the amygdala, which in turn is continuous with the putamen). Although the amygdala does have some connectivity with the striatum, its pattern of connectivity is more typical of limbic structures, and the amygdala forms one of the central components of the so-called lateral limbic system. The amygdala is situated below the uncus, at the anterior end of the hippocampus, and at the inferior horn of the lateral ventricle. It receives its main afferents from the inferior visual temporal cortex, the superior temporal auditory cortex, the cortex of the temporal pole (involved in the regulation of behavior), as well as from taste and auditory cortical centers. The main efferents of the amygdala are to the hypothalamus, autonomic centers of the medulla oblongata, the nucleus accumbens in the ventral striatum, and areas of the temporal insular and orbitofrontal cortices. The amygdala is

138

thus positioned to receive polymodal information from sensory regions and influence motor, autonomic, and endocrine systems. These connections allow the amygdala to influence drive-related behaviors and the subjective feelings that accompany them. Experimental data obtained from animal models support the role of the amygdala in motivation, with lesions of the central nucleus impairing the acquisition of learned orienting response to visual conditioned stimuli paired with food [45], and impairing the ability of a cue previously paired with food to increase the rate of food-reinforced instrumental responding [46]. Further, inactivation of the basolateral amygdala abolishes the increase in nucleus accumbens DA resulting from presentation of a stimulus previously associated with a reward [47]. The amygdala is thus considered a relevant region in the mechanism of goal-oriented behavior [6], and is traditionally considered to be primarily involved in fear-motivated behavior. The amygdala may mediate those processes that associate motivationally relevant events with otherwise neutral stimuli, which later become predictors of that specific event (i.e., the conditioned stimuli) [48]. The role of the amygdala in motivated behaviors may be inferred by the behavioral manifestations of the Klüver–Bucy syndrome produced by bilateral lesions of the amygdala, which usually results in tameness and lack of emotional responsivity.

The physiology of motivation Jahanshahi and Frith [4] proposed a “willed action route,” through which “goals and plans lead to formulation of intentions, which result in initiation of appropriate actions . . . and production of a response.” The dorsolateral prefrontal cortex, the anterior cingulate, and the supplementary motor area were suggested as the key cortical components of this route, with the thalamus and basal ganglia as its main subcortical components. Using functional magnetic resonance imaging (fMRI), Epstein and co-workers [12] found that depressed patients had less activation of ventral striatal regions compared with healthy individuals, and there was a significant correlation between patients’ failure to show brain activation to positive stimuli and loss of interest and motivation. The authors speculated


that the relatively low ventral activation in depressed patients may be related to deficits translating motivational information into behavior. Habib [49] proposed that a subset of the basal ganglia may subserve motivational functions in humans through previously described frontal-subcortical loops underlying motor acts, emotional expression, and cognitive activity. The main circuit considered to be involved in human motivation consists of projections from the anterior cingulate to the ventral striatum, the ventral globus pallidus, the dorsomedial thalamus, and back to the anterior cingulate. This striato-pallidal circuit is considered “an interface between motivation and action” [50], as well as the site of “conversion of motivational processes into behavioural output” [51]. Habib suggested that the crucial role of the “limbic striatopallidum” depends on relevant inputs from the amygdala (involved in “emotional labelling” of sensory stimuli) and the hippocampus (involved with comparing new information with biographical data). In turn, output from the striato-pallidum projects to sections of the basal ganglia involved in initiating and organizing motor behavior. Habib [49] explained loss of spontaneous action and poverty of thinking (which he labeled “athymormia”) as due to cortico-subcortical lesions disconnecting the anterior striatum from cortical afferents. The main connection runs from the anterior cingulate to the nucleus accumbens, and lesions of these structures may result in loss of initiative and spontaneous action, decreased interest and drive, and emotional blunting [52]. Bilateral lesions of the thalamus may also result in loss of motivation, but this is usually accompanied by cognitive deficits [49]. Laplane and Dubois used the term “loss of psychic auto-activation” [53] to refer to a deficit in spontaneous activation of mental processing, observed in behavioral, cognitive or affective domains, which can be totally reversed by external stimulation that activates normal patterns of response. Brown and Pluck [54] stressed that loss of motivation in humans does not result from lesions in any single structure, given that motivated behavior results from complex cortico-subcortical networks. They suggested that the auto-activation deficit usually results from damage to pathways linking the ventral striatum to the anterior cingulate, caudate nucleus, and the orbitofrontal cortex.

Limitations of current models of the neurobiology of motivation The fronto-subcortical circuit proposed to mediate motivation is not fully segregated, and connections between different circuits are the rule. Complex reentrant loops connect the nucleus accumbens, ventral pallidum, hypothalamus, amygdala, septum, hippocampus, VTA, cingulate and prefrontal cortex, with other forebrain limbic structures [8]. From a conceptual standpoint, it is important to consider how internal and external triggers “motivate” behavior. This interaction may not be problematic for basic or instinctive behaviors (e.g., feeding and sexual behaviors), although these behaviors are better considered reflex or automatic rather than motivated. More difficult is to conceptualize how complex goals and projects may engage a “motivation system,” given that goals, plans, and projects are all psychological concepts while behavior is instantiated by complex neural networks. Another concern is that motivation circuits should be in close functional association with systems mediating mood and arousal, given the well-known impact of mood and anxiety disorders upon motivated behavior. However, little is yet known about this association.

Loss of motivation Diminished motivation is a common finding of the aging process and neurodegenerative brain conditions. In 1991, Robert Marin [55] reported a series of patients with stroke, Parkinson’s disease, or Alzheimer’s disease who had comorbid loss of motivation in the absence of depression. He proposed apathy as an independent syndrome characterized by (1) deficits in goal-directed behaviors [55] as manifested by lack of effort, initiative, and productivity, (2) reduced goaldirected cognition, as manifested by decreased interests, lack of plans and goals, and lack of concern about one’s own health or functional status, and (3) reduced emotional concomitants of goal-directed behaviors, as manifested by flat affect, emotional indifference, and restricted emotional responses to important life events [55]. Starkstein organized these symptoms into a set of diagnostic criteria, which were validated for use in Alzheimer’s disease and stroke [56] (Box 9.1). Similarly, van Reekum and co-workers divided apathy into emotional, cognitive, and behavioral domains [57].

139


Box 9.1 Diagnostic criteria for apathy. Adapted from Starkstein SE, Leentjens AF. The nosological position of apathy in clinical practice. J Neurol Neurosurg Psychiatry 2008;79(10):1088–92, with permission from BMJ Publishing Group Ltd. A. Lack of motivation relative to the patient’s previous level of functioning or the standards of his or her age and culture, as indicated either by subjective account or observation by others. B. Presence for at least four weeks, during most of the day, of at least one symptom belonging to each of the following three domains: Diminished goal-directed behavior 1. Lack of effort or energy to perform everyday activities. 2. Dependency on prompts from others to structure everyday activities. Diminished goal-directed cognition 1. Lack of interest in learning new things, or in new experiences. 2. Lack of concern about one’s personal problems. Diminished concomitants of goal-directed behavior 1. Unchanging or flat affect 2. Lack of emotional responsivity to positive or negative events. A. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. B. The symptoms are not due to diminished level of consciousness or the direct physiological effects of a substance.

Diagnosis of loss of motivation One of the main limitations to the diagnosis of apathy is that structured clinical interviews and valid diagnostic criteria have only recently been developed. Thus, most assessments of apathy in clinical samples use scales to measure the severity of this condition. The Apathy Evaluation Scale was developed by Marin and co-workers [58], and consists of three sections, rated by an informant, the examiner, and the patient. The Apathy Scale developed by Starkstein and co-workers [59] is an examiner-rated scale based on Marin’s instrument. Robert and co-workers developed

140

the Apathy Inventory [60], which is structured similar to the Neuropsychiatric Inventory [61] and has been used to rate apathy in Parkinson’s disease. Strauss and Sperry developed the Dementia Apathy Interview and Rating [62] to assess apathy among individuals with cognitive decline. To our knowledge, the Structured Clinical Interview for Apathy [63] is the only standardized assessment for this condition. This instrument is assessed with the patient and an appropriate informant, but information from other sources, such as patients’ medical records or information from other medical providers, is also considered. This instrument has been validated for use in dementia, but it is currently used in Parkinson’s disease and stroke as well. Finally, diagnosis of apathy may be carried out using the diagnostic criteria proposed by Marin and modified by Starkstein and Leentjens [64] (Box 9.1). This set of criteria has been already validated for use in dementia.

Conclusion Motivation is a complex construct that is expressed in a wide variety of behaviors, ranging from instinctive behavior in mammals (e.g., feeding, fight or flight reactions), to complex human behaviors. The neuroanatomy of motivation is being increasingly clarified. Critical regions for motivation include the amygdala, nucleus accumbens, and prefrontal cortex, and the neurotransmitter dopamine plays an important role. Loss of motivation is a cardinal symptom of depression, but is also a conspicuous finding in many acute and chronic neuropsychiatric disorders such as traumatic brain injury, stroke, dementia, and Parkinson’s disease. The diagnosis of apathy is still fraught with methodological limitations, but valid and reliable structured interviews and diagnostic criteria are now being developed. A better knowledge of the brain mechanisms of motivation coupled with adequate diagnostic instruments will enhance the search for better treatments for this condition.

References 1. Berrios GE, Gili M. Abulia and impulsiveness revisited: a conceptual history. Acta Psychiatr Scand. 1995;92(3):161–7. 2. Salamone JD, Correa M, Farrar A, Mingote SM. Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacology (Berl.) 2007;191(3):461–82.


3. Salamone JD. Functions of mesolimbic dopamine: changing concepts and shifting paradigms. Psychopharmacology (Berl.) 2007;191(3):389. 4. Jahanshahi M, Frith CD. Willed action and its impairments. Cognitive Neuropsych. 1998;15(6–8):483–533. 5. Berrios GE. The History of Mental Symptoms: Descriptive Psychopathology since the Nineteenth Century. Cambridge: Cambridge University Press; 1996. 6. Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 2005;162(8):1403–13. 7. Valenstein ES, Cox VC, Kakolewski JW. Reexamination of the role of the hypothalamus in motivation. Psychol Rev. 1970;77(1):16–31. 8. Berridge KC. Motivation concepts in behavioral neuroscience. Physiol Behav. 2004;81(2):179–209. 9. Gallistel CR. The Organization of Action: A New Synthesis. Hillsdale, NJ: Lawrence Erlbaum Associates; distributed by Halsted Press; 1980. 10. Heimer L, Alheid GF, de Olmos JS et al. The accumbens: beyond the core-shell dichotomy. J Neuropsychiatry Clin Neurosci. 1997;9(3):354–81. 11. McClure SM, Daw ND, Montague PR. A computational substrate for incentive salience. Trends Neurosci. 2003;26(8):423–8. 12. Epstein J, Pan H, Kocsis JH et al. Lack of ventral striatal response to positive stimuli in depressed versus normal subjects. Am J Psychiatry 2006;163(10):1784–90. 13. Keitz M, Martin-Soelch C, Leenders KL. Reward processing in the brain: a prerequisite for movement preparation? Neural Plast. 2003;10(1–2):121–8. 14. Ungerstedt U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl. 1971;367:95–122. 15. Robbins TW, Everitt BJ. A role for mesencephalic dopamine in activation: commentary on Berridge (2006). Psychopharmacology (Berl.) 2007;191(3): 433–7. 16. Phillips AG, Vacca G, Ahn S. A top-down perspective on dopamine, motivation and memory. Pharmacol Biochem Behav. 2008;90(2):236–49. 17. Taylor JR, Robbins TW. 6-Hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine. Psychopharmacology (Berl.) 1986;90(3):390–7. 18. Ikemoto S, Panksepp J. Dissociations between appetitive and consummatory responses by

pharmacological manipulations of reward-relevant brain regions. Behav Neurosci. 1996;110(2):331–45. 19. Wise RA. Addictive drugs and brain stimulation reward. Annu Rev Neurosci. 1996;19:319–40. 20. Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM. Subsecond dopamine release promotes cocaine seeking. Nature 2003;422(6932):614–18. 21. Wachtel SR, Ortengren A, de Wit H. The effects of acute haloperidol or risperidone on subjective responses to methamphetamine in healthy volunteers. Drug Alcohol Depend. 2002;68(1):23–33. 22. Ahn S, Phillips AG. Dopaminergic correlates of sensory-specific satiety in the medial prefrontal cortex and nucleus accumbens of the rat. J Neurosci. 1999;19(19):RC29. 23. Fiorino DF, Coury A, Phillips AG. Dynamic changes in nucleus accumbens dopamine efflux during the Coolidge effect in male rats. J Neurosci. 1997;17(12):4849–55. 24. Schultz W, Tremblay L, Hollerman JR. Reward processing in primate orbitofrontal cortex and basal ganglia. Cereb Cortex 2000;10(3):272–84. 25. Crow TJ. A map of the rat mesencephalon for electrical self-stimulation. Brain Res. 1972;36(2):265–73. 26. Fiorino DF, Coury A, Fibiger HC, Phillips AG. Electrical stimulation of reward sites in the ventral tegmental area increases dopamine transmission in the nucleus accumbens of the rat. Behav Brain Res. 1993;55(2):131–41. 27. Mogenson GJ, Takigawa M, Robertson A, Wu M. Self-stimulation of the nucleus accumbens and ventral tegmental area of Tsai attenuated by microinjections of spiroperidol into the nucleus accumbens. Brain Res. 1979;171(2):247–59. 28. Cheer JF, Heien ML, Garris PA, Carelli RM, Wightman RM. Simultaneous dopamine and single-unit recordings reveal accumbens GABAergic responses: implications for intracranial self-stimulation. Proc Natl Acad Sci USA 2005;102(52):19,150–5. 29. Floresco SB, Todd CL, Grace AA. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci. 2001;21(13):4915–22. 30. Kluver H, Bucy PC. Preliminary analysis of functions of the temporal lobes in monkeys. 1939. J Neuropsychiatry Clin Neurosci. 1997;9(4):606–20. 31. Kelley AE. Ventral striatal control of appetitive motivation: role in ingestive behavior and reward-related learning. Neurosci Biobehav Rev. 2004;27(8):765–76. 32. Pecina S, Smith KS, Berridge KC. Hedonic hot spots in the brain. Neuroscientist 2006;12(6):500–11.

141


33. Cheer JF, Aragona BJ, Heien ML et al. Coordinated accumbal dopamine release and neural activity drive goal-directed behavior. Neuron 2007;54(2): 237–44.

46. Cardinal RN, Parkinson JA, Hall J, Everitt BJ. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev. 2002;26(3):321–52.

34. Hull EM, Weber MS, Eaton RC et al. Dopamine receptors in the ventral tegmental area affect motor, but not motivational or reflexive, components of copulation in male rats. Brain Res. 1991;554(1–2): 72–6.

47. Louilot A, Besson C. Specificity of amygdalostriatal interactions in the involvement of mesencephalic dopaminergic neurons in affective perception. Neuroscience 2000;96(1):73–82.

35. Pereira M, Uriarte N, Agrati D, Zuluaga MJ, Ferreira A. Motivational aspects of maternal anxiolysis in lactating rats. Psychopharmacology (Berl.) 2005;180(2):241–8. 36. Berridge KC, Robinson TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev. 1998;28(3):309–69.

48. Everitt BJ, Cardinal RN, Parkinson JA, Robbins TW. Appetitive behavior: impact of amygdala-dependent mechanisms of emotional learning. Ann N Y Acad Sci. 2003;985:233–50. 49. Habib M. Athymhormia and disorders of motivation in basal ganglia disease. J Neuropsychiatry Clin Neurosci. 2004;16(4):509–24. 50. Mogenson GJ, Jones DL, Yim CY. From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol. 1980;14(2–3): 69–97.

37. Tran AH, Tamura R, Uwano T et al. Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place. Proc Natl Acad Sci USA 2005;102(6):2117–22.

51. Apicella P, Ljungberg T, Scarnati E, Schultz W. Responses to reward in monkey dorsal and ventral striatum. Experimental Brain Res. 1991;85(3):491–500.

38. Yun IA, Wakabayashi KT, Fields HL, Nicola SM. The ventral tegmental area is required for the behavioral and nucleus accumbens neuronal firing responses to incentive cues. J Neurosci. 2004;24(12):2923–33.

52. Stuss DT, Benson DF. Emotional concomitants of psychosurgery. In Satz P, Heilman KM, editors. Neuropsychology of Human Emotion. New York, NY: Guilford Press; 1983, pp. 111–40.

39. Schultz W. Predictive reward signal of dopamine neurons. J Neurophysiol. 1998;80(1):1–27.

53. Laplane D, Dubois B. Auto-activation deficit: a basal ganglia related syndrome. Mov Disord. 2001; 16(5):810–14.

40. Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res. 2002;53(2):647–54. 41. Bechara A, Tranel D, Damasio H. Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions. Brain 2000;123 (Pt 11):2189–202. 42. Bush G, Vogt BA, Holmes J et al. Dorsal anterior cingulate cortex: a role in reward-based decision making. Proc Natl Acad Sci USA 2002;99(1): 523–8. 43. Ventura R, Cabib S, Alcaro A, Orsini C, Puglisi-Allegra S. Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release. J Neurosci. 2003;23(5):1879–85. 44. Ventura R, Morrone C, Puglisi-Allegra S. Prefrontal/accumbal catecholamine system determines motivational salience attribution to both reward- and aversion-related stimuli. Proc Natl Acad Sci USA 2007;104(12):5181–6. 45. Gallagher M, Graham PW, Holland PC. The amygdala central nucleus and appetitive Pavlovian conditioning: lesions impair one class of conditioned behavior. J Neurosci. 1990;10(6):1906–11.

142

54. Brown RG, Pluck G. Negative symptoms: the ‘pathology’ of motivation and goal-directed behaviour. Trends Neurosci. 2000;23(9):412–17. 55. Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci. 1991;3(3):243–54. 56. Starkstein SE. Apathy and withdrawal. Int Psychogeriatr. 2000;12(S1):135–7. 57. van Reekum R, Stuss DT, Ostrander L. Apathy: why care? J Neuropsychiatry Clin Neurosci. 2005;17(1): 7–19. 58. Marin RS, Butters MA, Mulsant BH, Pollock BG, Reynolds CF, 3rd. Apathy and executive function in depressed elderly. J Geriatr Psychiatry Neurol. 2003; 16(2):112–16. 59. Starkstein SE, Mayberg HS, Preziosi TJ et al. Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 1992;4(2):134–9. 60. Robert PH, Clairet S, Benoit M et al. The apathy inventory: assessment of apathy and awareness in Alzheimer’s disease, Parkinson’s disease and mild cognitive impairment. Int J Geriatr Psychiatry 2002; 17(12):1099–105.


61. Cummings JL, Mega M, Gray K et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44(12):2308–14.

63. Starkstein SE, Ingram L, Garau ML, Mizrahi R. On the overlap between apathy and depression in dementia. J Neurol Neurosurg Psychiatry 2005;76(8): 1070–4.

62. Strauss ME, Sperry SD. An informant-based assessment of apathy in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol. 2002;15(3):176–83.

64. Starkstein SE, Leentjens AF. The nosological position of apathy in clinical practice. J Neurol Neurosurg Psychiatry 2008;79(10):1088–92.

143

Section I


Chapter

Perception and recognition

10

Benzi M. Kluger and Gila Z. Reckess

The wind was flapping a temple flag. Two monks were arguing about it. One said the flag was moving; the other said the wind was moving. Arguing back and forth they could come to no agreement. The Sixth Patriarch said, “It is neither the wind nor the flag that is moving. It is your mind that is moving.” The two monks were struck with awe. Zen Koan

In this chapter we will discuss the processes by which we come to know the environment, namely sensation, perception, and recognition. Although seemingly effortless, these computational tasks are remarkably complex. For instance, we can recognize the face of a friend in the midst of a crowd or distinguish their voice despite significant background noise. While we typically take these abilities for granted, there are many symptoms and syndromes in Behavioral Neurology & Neuropsychiatry (BN&NP) in which specific aspects of perception or recognition are disrupted. The study of perceptual processes is historically one of the oldest fields of inquiry within psychology and neuroscience, and thus is one of the most highly developed. A comprehensive overview of what is currently known about perception would not be feasible within the confines of a single chapter. Therefore, we have endeavored to provide a concise, broad overview of the functional anatomy underlying perception and recognition within each of the five primary perceptual systems. To facilitate discussion of each system, we will first begin with an overview of shared terminology and general organizational principles, followed by an introduction to classes of perceptual disorders. Clinical cases have provided valuable insight into normal and pathologic mechanisms subserving

each sensory system. Conversely, understanding the structural architecture of sensory systems and behavioral correlates of normal and abnormal connectivity is essential for localizing anatomic and behavioral abnormalities. Therefore, for each sensory system we will first review the general functional neuroanatomy, followed by an overview of related syndromes that readers may encounter in the literature or clinic.

Defining perception and recognition Rather than engaging in a philosophical or semantic debate about the definitions of perception and recognition, we define these processes on the basis of their relatively concrete neuroanatomic and neuropsychological elements. The first of these is sensation, which involves transduction of external stimuli to neural signals and transmission of this information to the central nervous system (CNS). Basic sensory information includes stimulus timing (onset and offset), magnitude, location, and basic qualitative information related to the sensory modality. Perception builds upon basic sensation by extracting more complex attributes from sensory elements. For example, visual perception includes the ability to detect motion, differentiate colors, and distinguish basic forms. Primary sensation, however, is not a necessary precondition for perception, as demonstrated by internally generated perceptual phenomena such as hallucinations or imagery. Recognition involves identification of a sensory stimulus via access to and integration of stored representations of previously encountered stimuli. Recognition may be seen as a form of memory, and clearly involves learning and access to prior knowledge [1].


144

Chapter 10: Perception and recognition

Moreover, the role of learning in perception requires a certain degree of plasticity within these systems, which may allow for improved rehabilitation strategies [2]. We purposefully avoid conscious awareness as a criterion for our definitions of perception and recognition given that stimuli do not have to be consciously perceived in order to influence behavior or other neurophysiologic outcomes. Perceptual priming, for example, is a well-established phenomenon in which behavior is influenced by stimuli that are not consciously perceived [3]. Many aspects of perception and recognition are not passive, however, and require active allocation of attention and coordination of perceptual and motor systems. For example, the ability to recognize complex objects such as faces requires elaborate visual scanning to identify both global and local features [4]. In contrast, autistic individuals have a disorganized scanning pattern and spend less time fixating on critical facial areas such as the eyes [5].

Organizational principles All of our sensory and perceptual systems share certain organizational principles. Knowledge of these principles is helpful in understanding both the basic neuroscience of these systems, as well as understanding pathological syndromes. Sensation begins with the transduction of energy (in the case of hearing and vision), pressure (in the case of touch) or the detection of molecules (in the case of chemosensation – i.e., taste and smell) to neural signals by specialized receptor neurons. These receptor neurons then transmit sensory information to the CNS. This information is quantitatively coded in that stimuli of larger magnitudes typically induce higher firing rates (also known as frequency coding). It is also qualitatively coded based on the location of the receptor type that originated the signal (also known as location coding). This is true across modalities as well as within modalities. For example, sensory pathways mediating light touch remain distinct from those mediating vibration from peripheral neurons all the way through the primary sensory cortex. At the earliest stages of perception, sensory input is refined through center-surround inhibition. For example, if a beam of light hits the retina, stimulated cells will also inhibit neighboring cells. This mechanism allows for detection of edges (in vision and touch), fine-tuning of sensory input, and progressive refinement of accuracy. Neurons at progressively

higher levels of the CNS are tuned to detect more complex features, typically through combining input from multiple lower level neurons. For instance, while retinal neurons may detect light in a particular area, their projections in primary visual cortex are tuned to detect lines in a particular orientation anywhere on the retina. Sensory input is typically transmitted via a combination of serial and parallel circuitry. Most sensory systems project to the contralateral thalamus en route to primary cortical sensory areas. Mesulam [6] proposed a schema for dividing cortical areas into primary sensory cortex, unimodal cortex, and transmodal cortex (including heteromodal, limbic, and paralimbic cortices). In this model, the primary sensory cortices are the entry point of sensory information into cortical circuits and initiate modality specific perceptual processing. Information then travels in parallel to multiple unimodal association specialized to accomplish a particular perceptual or recognition task. Transmodal processing areas receive input from multiple sensory modalities to accomplish higher-order recognition, emotional or behavioral goals. In this chapter we will focus primarily on primary sensory and unimodal cortex. Examples of transmodal cortex include Wernicke’s area, the entorhinal-hippocampal complex, and posterior parietal cortices. Although traditional texts suggest that information flow is unidirectional in sensory systems, progressing from sensory neurons through polymodal association areas, more recent evidence demonstrates that there are multiple layers of both top-down and bottom-up reciprocal communication between primary sensory and unimodal areas [7]. Similarly, top-down influences from the prefrontal cortex have been demonstrated to modify many aspects of perception and recognition [8]. In addition to specialized cortical modules dedicated to certain perceptual or sensory functions, there are extensive connections between these modules. As we will discuss below, perceptual dysfunction may occur without damage to modules but from their disconnection from either afferent sensory input or efferent output to higher-order stores of verbal and nonverbal information [9, 10]. More recent research suggests that certain forms of information processing depend not only on the basic architecture of intermodal circuitry, but also on its temporal properties. For example, lesions that disrupt the timing of reciprocal communication between cortical areas, or cortical

145


and subcortical areas, may be sufficient to disturb normal perception and recognition. These clinical observations are consistent with basic research on the binding problem, which asks how functionally and structurally modular perceptual systems become integrated [11, 12].

Disorders of perception and recognition Acquired brain damage and developmental abnormalities may affect each level of processing discussed above, including primary sensation, cortically mediated perception, or higher-order aspects of perception or recognition. A useful distinction can be made between negative syndromes, those in which there is a failure to correctly perceive some element of the environment, and positive syndromes, those in which a patient perceives stimuli or stimulus features in the absence of associated external sensory input. Although relatively rare, the agnosias are among the more extensively studied negative perceptual syndromes and have provided invaluable insight into the functional neuroanatomy of perception and recognition. Agnosias are characterized by profound impairment in perceiving, identifying, and/or recognizing stimuli in the context of relatively unimpaired language, attention, and primary sensation. Therefore, an important part of making this diagnosis is to exclude other more general causes of perceptual disturbances. Additionally, agnosias are most commonly modality specific, which allows one to demonstrate that higherorder cortical processes are intact. For instance, a patient with a tactile agnosia may be unable to recognize a key placed in their hand but can recognize the sound of jangling keys or a picture of a key. Lissauer [13] drew a distinction between apperceptive agnosias, in which patients are limited by perceptual disturbances, and associative agnosias, in which patients are unable to attach appropriate concepts or meaning to perceptual objects. These syndromes are often difficult to distinguish, but can be differentiated if one tests the perceptual abilities necessary for recognition. For example, patients with visual associative agnosia can copy drawings of objects but cannot identify, name, or categorize objects; those with apperceptive agnosia are often unable to even copy simple object drawings, or do so in a manner that disregards the natural groupings of parts of objects. Lissauer’s initial model continues to form the basis of theories on

146

agnosia. However, it is now clear that this dichotomous distinction is an oversimplification. For example, there is now considerable evidence of perceptual deficits in patients with associative agnosia as well [14]. A further categorization of agnosias is integrative agnosias, characterized by a recognition deficit attributed to the inability to incorporate the parts of an object into a global percept. A classic example is simultanagnosia (as seen in Balint’s syndrome), in which patients with bilateral lesions of the occipitoparietal cortices are able to identify individual objects but are unable to recognize a larger scene. For example, when shown a picture of a picnic they may report seeing a blanket, a sandwich, or ants. There is some controversy about a final class of agnosia, termed category-specific agnosias, such as selective recognition impairment for living versus non-living things. Determining the characteristics of objects affected by category-specific agnosias remains elusive, as patients with agnosia for “living things” often have difficulties with musical instruments but not body parts [15]. Positive symptoms may be classified as either illusions, which are misinterpretations of existing stimuli, or hallucinations, which are perceptions that arise independently of external stimuli. Some authors further distinguish between hallucinations and pseudohallucinations, the latter of which are associated with preserved insight into the hallucination’s disconnection from objective reality; however, pseudohallucinations is not a universally accepted term. Hallucinations may be divided into release hallucinations, which are believed to arise from the release of perceptual areas from inhibitory input, and hyperexcitable or irritative hallucinations, which arise from excessive stimulation. Based on recent, sophisticated physiological models, Behrendt and Young [16] proposed that hallucinations are due to aberrant thalamocortical communications, leading to under-constrained perceptual processing. Release hallucinations may arise from destructive lesions at any level of the CNS, ranging from environmental sensory deprivation and peripheral nerve lesions to higher-cortical transmodal areas. Irritative hallucinations classically arise in the setting of ictal phenomena in epilepsy. Similar principles may apply to the balance of excitatory and inhibitory neurotransmitters impinging on perceptual areas in the setting of psychiatric disorders and pharmacologically induced hallucinations [17]. From a clinical standpoint, ictal hallucinations are characterized by their


brevity (seconds to a few minutes), stereotypic nature, and frequent association with other alterations in consciousness or post-ictal confusion; in contrast, release hallucinations are of longer duration, more variable with regard to their content, and may be associated with other fixed perceptual deficits. Although we will not discuss the physiology of perception in dreams, there appears to be a strong relationship between alterations in sleep and arousal systems and hallucinations. In peduncular hallucinosis, patients with strokes in the midbrain develop hallucinations (predominantly visual) in association with disturbances of arousal [18]. Similarly, hallucinations may be associated with primary sleep disorders (including narcolepsy) [19], secondary sleep disorders as in the setting of Parkinson’s disease (PD) [20], and even in normal individuals who are sleep-deprived [21].

Vision The paramount importance and inherent complexity of visual perception is evident in the sheer magnitude of cortical representation of this sensory system. More than one quarter of the cerebral cortex is involved in vision and vision-related processes, and more than 30 cortical areas with vision-related function had been identified by 1991 [22], only some of which will be highlighted in this section. Multiple systems of nomenclature are often used in reference to subregions within the visual cortex. Brodmann’s area (BA) 17, located along the banks of the calcarine fissure, is the primary visual cortex. It is also referred to as striate cortex due to the visibly pale striation of myelinated axons within the fourth of its six principal cortical layers. Consequently, visual association areas (BA18 and 19), which do not contain myelinated striations, are collectively referred to as extrastriate cortex. Additionally, subdivisions within human visual cortex are often referenced based on functional mapping studies in macaque monkeys, although the functional and structural correspondence of these areas may not be conserved across species [23]. Based on functional mapping, BA17 is equivalent to V1, BA18 includes V2 and V3, and BA19 includes V3a, V4, and V5.

The primary visual pathway The central, or primary, visual pathway refers to the series of connections through which input is relayed

from the retina to the visual cortex. Stimulus-initiated, or veridical, visual perception begins when light passes through the cornea, iris, and lens and is detected by photoreceptors (rods and cones) in the outermost layer of the retina. Visual input is inverted and reversed by the lens as it is projected onto the retina. Therefore, cells in the lower left portion of each retina process light from the upper-right portion of visual space. There is considerable overlap between the visual fields of each eye, which enables binocular vision and facilitates depth perception. Axons of retinal ganglion cells exit the retina via the optic disk and form the optic nerve (though technically not a “nerve” since the retina is actually part of the CNS). Axons from the medial half of each retina, or nasal hemiretina, decussate at the optic chiasm and project to the opposite cerebral hemisphere; axons from the temporal hemiretina (lateral to the fovea) do not cross. As a result, each cerebral hemisphere receives visual input from both eyes, with each hemisphere exclusively processing information from the opposite visual field. Posterior to the optic chiasm, retinal ganglion fibers are referred to as the optic tract. The majority of these fibers terminate in the lateral geniculate nucleus (LGN) of the thalamus as part of the central visual pathway. Although traditionally viewed as a simple relay station, the LGN may itself have a more active role in perception [24]. In fact, retinal input only accounts for 10–20% of input to the LGN [25]. Optic tract fibers also project to at least nine other targets [26] that contribute to functions, such as regulation of circadian rhythms (the hypothalamus), pupillary reflexes (Edinger–Westphal nucleus of midbrain) and oculomotor functions (superior colliculus). Extra-geniculate visual pathways have also been implicated in some visual functions, including collicular contribution to visually guided action [27] and visual motion detection functions in the pulvinar [28]. Within the geniculostriate pathway, axons of postsynaptic neurons in the LGN form the optic radiations, which arc around the lateral ventricles. The inferior radiations (also known as Meyer’s loop) transmit input from the superior visual field through the temporal lobe while the superior radiations transmit information from the inferior visual field through the parietal lobe. As its name implies, the geniculostriate pathway terminates in striate cortex (area V1), typically considered to be the final point along the central visual

147


pathway. Visual input from LGN to V1 maintains general topographic integrity such that input from the upper-right visual field is transmitted to the leftinferior portion of V1. Note, however, that the relative dimensions of this retinotopic map are not preserved. A disproportionately large portion (25–50%) of V1 is devoted to the very small amount of visual input processed by the fovea. V1 relays visual input to extrastriate visual areas for further processing. Additionally, evidence suggests that V1 also projects to subcortical regions, including the superior colliculus and feedback fibers to the LGN [29].

Functional specialization within the visual system In 1890, Lissauer proposed that there are three perceptual processes – color, motion, and form – that are differentially affected by brain damage and that therefore are functionally and neuroanatomically distinct (see [30] for review). These three functional distinctions correspond to input from at least three parallel pathways, beginning with distinct classes of retinal ganglion cells [31]. M ganglion cells are relatively large and respond to gross visual features, including luminance contrast, temporal frequency, and movement. P cells comprise the vast majority (approximately 80%) of ganglion cells and are most sensitive to finer visual details, including spatial frequency and stimulus orientation. Additionally, there appear to be two subdivisions within the P cell pathway, one of which transmits color input, whereas the other contributes to form/shape perception. Although some cross-projections have been identified, the M and P pathways remain largely segregated throughout the visual system, including formation of synapses within different layers of the LGN (e.g., magnocellular and parvocellular layers) and projection to different portions of primary and association cortices [32]. M and P pathways also serve as bases for the distinct ventral (“what”) and dorsal (“where”) visual streams originally proposed by Ungerleider and Mishkin [33]. V1 and V2 are the largest visual cortical subregions and contribute to early processing for both dorsal and ventral visual systems, although evidence suggests that each is also involved in higherorder functions [34]. The ventral visual stream processes object properties such as color and shape and is closely associated with the two P pathways [35].

148

Within extrastriate cortex, the ventral system includes V4, located in the lingual and fusiform gyri, and adjacent area V8, both of which are highly sensitive to chromatic input and serve as the main loci for color perception [36]. The fusiform gyrus, located anterior to V8, is also part of the ventral visual stream and contributes to object and form perception. Movement and spatially relevant visual features relayed via the M pathway predominantly contribute to the dorsal visual system [35]. Motion perception in the extrastriate cortex is largely attributed to areas V5 (motion-sensitive middle temporal cortex in humans, designated hMT+) [37] and V3, followed by projection through the medial superior temporal area (MST, or V5a). The dorsal stream projects through the parietal cortex, bridging between the visual and sensorimotor cortices. Although colloquially referred to as the “where” pathway due to its role in spatial perception [33, 38], the complex and nuanced functions of the parietal portion of the dorsal visual stream continue to be a matter of debate. Milner and Goodale [39] emphasized the system’s contribution to visually guided action and contrasted this with the ventral visual stream’s more perceptually based function. Jeannerod [40] characterized the dorsal stream as “pragmatic” and proposed that the parietal portion serves multiple visually related functions [41]. The authors argue that these functional distinctions correspond to differentiable contributions of superior and inferior parietal lobules, such that the superior lobule contributes to non-lateralized visuomotor processing whereas the inferior lobule subserves visuospatial perception (right hemisphere) and goal-directed action (left hemisphere). Rizzolatti and Matelli [42] also suggest that the dorsal visual stream is comprised of two functionally independent subsystems: the dorsodorsal and ventro-dorsal streams both contribute to coordination of action but only the ventrodorsal stream plays a pivotal role in visuospatial perception. At the level of recognition, both dorsal and ventral visual streams project to the medial temporal lobe, where visual information is translated into stored representations for future access. However, even at this point, spatial and object input appear to remain largely segregated in primates, such that dorsal visual input projects to the parahippocampal cortex whereas ventral visual input primarily projects to the perirhinal cortex [43].


Disorders of visual perception and recognition Visual field cuts (anopsias) may result from lesions at any point within the central visual pathway, and, based on the serial trajectory, visual field defects often facilitate localization of CNS lesions. Lesions to the optic nerve result in monocular visual loss; damage affecting the optic chiasm classically results in bitemporal hemianopia; and lesions posterior to the optic chiasm result in loss of vision in the contralateral visual field (contralateral homonymous hemianopia). Unilateral lesions within superior or inferior V1 or V2 result in contralateral homonymous quadrantanopia [44]. Cortically mediated vision loss is not functionally identical to vision loss from peripheral visual pathway lesions. Severe bilateral damage to V1 results in cortical blindness. This syndrome often presents as Anton’s syndrome, which, unlike direct retinal damage, is accompanied by anosognosia and confabulation of visual experiences [45]. Patients with visual cortical lesions may also present with blindsight, a curious combination of impaired conscious visual perception despite residual implicit visual abilities, including localization of visual stimuli. Recall that a minority of retinal ganglion cells do not synapse within the LGN, and instead project to other structures including the hypothalamus, superior colliculus, and pretectal areas. Functions subserved by these additional pathways are not necessarily disrupted by damage at the level of V1. In a recent review [46], Weiskrantz provides compelling evidence that blindsight cannot be simply explained as degraded vision. Rather, it is most likely that residual vision-related functions are attributable to unaffected cortical and subcortical brain regions with vision-related functionality, including collicular input to the dorsal visual stream [27]. In contrast to lesions of V1 and V2, extrastriatal damage may result in apperceptive agnosias that predominantly affect perception of one aspect of visual input. Patients with akinetopsia consequent to damage in V5 demonstrate selectively impaired motion perception relative to intact color and form perception [47, 48]. In contrast, lesions to V4 typically result in selective impairment of color perception, called central achromatopsia. Since V4 is located within the inferior visual cortex, central achromatopsia is characteristically accompanied by visual field defects restricted to the superior visual field. Both color and motion perception can also be impaired consequent to lesions

elsewhere in the brain. For example, achromatopsia may result from central visual pathway damage [49], and motion perception may be impaired in patients with cerebellar, midbrain, or vestibular lesions [48]. Another category of visual deficit is simultanagnosia, which refers to impaired perception or recognition of a stimulus or group of stimuli despite comparatively unimpaired processing of subcomponents of the stimulus or array. Although features of simultanagnosia can be associated with ventral damage [14], it most commonly occurs in the context of bilateral occipitoparietal (dorsal) lesions. Simultanagnosia is a hallmark feature of Balint’s syndrome, which is additionally characterized by optic ataxia (impaired visually guided reaching) and oculomotor apraxia (impaired voluntary saccadic movement to visual targets). Ventral visual stream lesions may result in associative visual object agnosias characterized by impaired object identification, categorization and naming, despite relatively unimpaired visual object perception. Prosopagnosia was originally considered to be an example of a category-specific associative agnosia for faces and resulting from damage to the fusiform face area in the medial occipitotemporal gyrus, analogous to inferotemporal cortex (area IT) in non-human primates [50]. Deficits no longer appear to be constrained to face perception/recognition, and may include other aspects of configural processing and non-face exemplars [51]. Multiple variants of prosopagnosia also have been identified, including both apperceptive and associative forms [50]. Additionally, other brain regions appear to contribute to facial perception and recognition, including the left inferior occipital gyrus (i.e., “occipital face area”) and the right posterior superior temporal sulcus [52]. Recent evidence also suggests that category-specific representations within the ventral visual pathway may not be vision-specific, but rather represent object forms based on multi modal input [53]. All of the above are examples of negative symptoms, or deficits, resulting from damage to stimulusinduced (veridical) sensory-perceptual systems. In contrast, non-veridical, or positive, perceptual abnormalities are not directly triggered by external stimulation of the retina. Visual hallucinations are less common in psychosis than their auditory counterparts, but they are prominent features in numerous other disorders ranging from neurodegenerative dementias to migraines and epilepsy [54, 55]. Simple, or

149


elementary, hallucinations typically arise from pathology within the occipital lobe or central visual pathway and are characterized by nondescript (e.g., phosphenes) and/or simple geometric visual experiences. Visual auras with migraines and ictal visual phenomena in occipital lobe epilepsy typically present as elementary visual hallucinations, although evidence suggests they can be clinically differentiated based, for example, on the tendency for visual seizures to be shorter in duration, more frequent, and characterized by circular, colored patterns [56]. Complex, or formed, hallucinations include perception of complete objects, animals, or people. The nature of complex hallucinations strongly implicates aberrant neuronal activity within visual association cortex, particularly within the temporal lobe. For example, Bien and colleagues [57] found that complex hallucinations occurred in temporal lobe epilepsy patients but not in patients with occipital lobe seizure onset. Complex hallucinations can also occur in the context of lesions to early visual pathways (e.g., retina and optic nerve), as is the case of the Charles Bonnet syndrome [58]. Finally, neurodegenerative disorders may also lead to visual symptoms. Posterior cortical atrophy (PCA) is a progressive neurodegenerative disease characterized by prominent visual deficits that affect higherorder visual functions over time, eventually leading to deficits including Balint’s syndrome, Gerstmann’s syndrome, and/or visual object agnosia [59]. This clinical profile has been identified most often as a variant of Alzheimer’s disease (AD), and a visual variant of AD associated with asymmetric cortical degeneration has been proposed [54]; however PCA also develops as a result of other neurological diseases, including progressive subcortical gliosis [60]. Consistent with the role of subcortical regions in visual processing, neurodegenerative disorders with subcortical pathology may also result in positive or negative visual abnormalities. For example, up to 60% of patients with PD experience positive visual abnormalities including complex hallucinations [61].

Audition Auditory pathways are activated when sound waves are transmitted to the cochlea through the temporal bone and the tympanic membrane and ossicles of the inner ear. The cochlea is a fluid-filled structure shaped like a snail’s shell. Separating the cochlea into two chambers

150

is the basilar membrane, which is a specialized structure designed to mechanically capture sound on the basis of pitch and loudness. This is accomplished by the physical characteristics of the basal membrane, which vary from a broad flexible quality at its base to a narrower more rigid quality at the apex. Sound is transduced to neural signals in the organ of Corti, which lies along the basilar membrane. The organ of Corti contains hair cells that have mechanically gated ion channels activated when their region of the basilar membrane is moved by a sound wave (see [62] for additional details). Thus there is an inherent spatial organization to pitch even at the level of the cochlea, and this tonotopic organization is maintained even at the level of the primary auditory cortex. Hair cells transmit information to neurons of the cochlear (i.e., spiral) ganglion, which, in turn, reaches the CNS as the eighth cranial nerve and terminates in the cochlear nucleus at the pontomedullary junction. From here information is transmitted to the superior olivary complex in the ventral pons (via the trapezoid body), the nucleus of the lateral lemniscus in the superior pons, and the inferior colliculus (via the lateral lemniscus). The superior olivary complex is notably important in sound localization. The inferior colliculus is important in some multisensory processing, including the startle reflex, and may also be important in auditory vigilance [63]. From the inferior colliculus, information passes to the medial geniculate nucleus (MGN) of the thalamus and then to the primary auditory cortex (also known as A1 or Brodmann’s areas 41 and 42) located in the superior temporal gyrus or Heschl’s gyrus. The primary auditory cortex is organized tonotopically, with low frequencies located anterolateral to higher frequencies and with segregated but bilateral representation of sound from both ears. Two other tonotopic maps exist in the temporal cortex adjacent to A1, namely areas R (rostrolateral to A1), which receives direct input from the MGN, and CM (centromedial), which is dependent on A1 for auditory and tonal information [64]. Similar to visual processing, there is increasing evidence in primates and humans of distinct “what” and “where” pathways of higher unimodal cortices that lie adjacent to primary auditory cortex (often referred to as belt and parabelt regions as they form a belt around A1). The “where” auditory system is primarily involved in sound localization, although it may play some role in other auditory tasks including language,


and is located posteriorally to primary auditory areas [65]. The “what” auditory system is involved primarily in sound discrimination, including speech. Functional imaging studies and lesion studies in humans suggest that the “what” pathway proceeds anterolaterally from A1, with higher-order discrimination of speech being processed in the left superior temporal gyrus (STG), and higher-order pitch discrimination in both speech and music being processed in the right STG. Results from both functional imaging and lesion studies suggest that posterior portions of the middle temporal gyrus, particularly on the right, are involved in the recognition of environmental sounds [66].

Disorders of auditory perception and recognition As with the visual system, negative perceptual symptoms involving hearing may affect primary sensory processes, secondary perceptual abilities, or recognition. Hearing loss or deafness may occur on the basis of either peripheral or central lesions. Because of the extensive crossing of tracts in the brainstem, most cases of unilateral deafness reflect peripheral causes or brainstem lesions at the level of the cochlear nucleus. However, subtle signs of decreased auditory discrimination can be detected contralateral to temporal lobe lesions [67]. Cases of cortical deafness typically involve bilateral damage to the temporal cortex and frequently extend beyond A1. In fact, the majority of cases of bilateral lesions to auditory cortices have auditory agnosias rather than true cortical deafness as demonstrated by intact hearing abilities [68]. Analogous to blindsight, two patients have been reported to demonstrate “deaf-hearing” through either acoustic startle responses [69] or the ability to determine tone onset and offset when specifically directed to do so [70]. In one patient, these abilities appeared to be mediated by residual temporal cortex and prefrontal cortex when studied using functional imaging [70]. Cortical auditory disorder or auditory agnosia refers to a non-specific loss of the ability to discriminate both speech and environmental auditory stimuli. As noted above, this is a more frequent outcome from bilateral damage to auditory cortices. Pure word deafness (PWD) or auditory verbal agnosia is a rare disorder that refers to the specific loss of the ability to discriminate auditory speech in the face of otherwise intact language and ability to recognize non-speech

sounds. Lesions typically involve bilateral temporal cortex, although isolated left STG lesions [71] suggest that this area may have a unique contribution to speech analysis. Similarly, isolated left subcortical lesions have been described, which presumably interrupted auditory input to Wernicke’s area [72]. Auditory sound or auditory object agnosia refers to a deficit in the ability to recognize environmental sounds in the face of intact speech recognition. Pure auditory object agnosia has been reported most frequently with right temporal lesions, although bilateral and left-sided lesions have also been reported [73]. Phonagnosia refers to the loss of the ability to recognize or discriminate voices, similar to prosopagnosia for faces. Van Lancker and colleagues [74] have distinguished between an inability to discriminate between unfamiliar voices, associated with lesions of the STG, and the ability to recognize familiar voices, which occurs with lesions of the right inferior parietal lobe. Receptive amusia refers to impairments in the ability to recognize or appreciate music. Music appreciation is a complex function that depends on the subject’s level of musical expertise and the precise aspects of music that are assessed. In general, research suggests that global aspects of music (such as melody) are mediated through the right hemisphere, while more local aspects (such as rhythm) are related to the left hemisphere. However, lesion analyses only partially support this division (showing a disruption of rhythm with left hemisphere lesions) and there are increasing data to suggest that music perception relies on crosshemispheric networks [75]. While basic science studies support the notion of auditory “what” and “where” systems, deficits of sound localization in humans do not reliably localize to these “where” pathways [76]. The complexity of the auditory agnosias is further displayed by observations that, in addition to cortical lesions, subcortical [77], thalamic [78], and brainstem lesions [79] may also be responsible. Positive auditory symptomatology includes palinacusis, tinnitus, and auditory hallucinations. Palinacusis refers to an auditory illusion in which an external sound is perseverated internally, typically for seconds but occasionally as long as hours. It is most frequently associated with temporal lobe seizures and may be an aura, ictal event, or post-ictal event [80]. Tinnitus, which is experienced most commonly as ringing in the ears, may be associated with peripheral lesions or damage to the ear. However, increasing evidence suggests

151


that most chronic tinnitus results from neuroplastic changes within primary and secondary auditory pathways; these models of chronic tinnitus are analogous to those proposed as explanations for chronic central pain [81]. Chronic tinnitus is frequently difficult to treat and may have severe neuropsychiatric sequelae including impaired attention, depression, and an increased risk for suicide. Recent studies have suggested the repetitive transcranial magnetic stimulation to the primary auditory cortex may have some potential for treating this condition [82]. Whereas auditory hallucinations are one of the classic symptoms of schizophrenia, they may also be seen in many other psychiatric disorders as well as with lesions of the peripheral and central auditory pathways. Similar to the Charles Bonnet syndrome in vision, hearing loss from any cause may result in auditory release hallucinations [17]. With regard to central etiologies, Lampl and colleagues [83] reviewed over 600 stroke cases and found four patients with acute auditory hallucinations following right temporal lobe infarcts. This phenomenon may be due to release of the left temporal lobe, which may be more strongly associated with auditory hallucinations in schizophrenia [84], and which may be the site of auditory hallucinations associated with negative affect in epilepsy [85]. As for musical hallucinations, these may be seen in psychiatric disease, hearing loss, epilepsy and focal brain lesions of either hemisphere, mostly involving the temporal lobes [86].

Somatosensation Although “touch” is considered colloquially to be one of the five main senses, it is just one element of a group of sensations processed by somesthesis (also referred to as somatic sensation or somatosensation). Somesthesis is unique in that it incorporates mechanical, thermal, and chemical sensory transduction, and receptors are distributed throughout the body rather than within one discrete organ/location. Tactile (or haptic) sensation is one of three primary cutaneous senses, along with temperature (thermoreception) and pain (nociception). Another prominent somatic sense is proprioception, which includes perception of static limb and body position, and perception of limb movement (kinesthesia). Dorsal root ganglion neurons serve as the primary sensory receptor for each modality, although there is a range of receptor subtypes. For example,

152

mechanoreceptors mediate proprioception and fine touch via large, myelinated fibers whereas nociceptors transmit pain via small myelinated or unmyelinated fibers. Regarding serial connectivity, most somesthesis is accomplished via a three-neuron system: primary afferent fibers from skin, muscles, joints, and internal organs relay sensory input to second-order neurons, which then synapse within the contralateral thalamus. Post-synaptic, tertiary neurons project to four cytoarchitecturally differentiable regions within the primary somatosensory cortex (S-I), including BA 1, 2, 3a, and 3b. In addition to internal cross-projections, S-I projects to the secondary somatosensory cortex (S-II). Central somatosensory pathways also include parallel circuitry. Input with high spatial and temporal resolution, including proprioception and some aspects of tactile sensation (e.g., discriminative (fine) touch and vibration), is relayed via the dorsal column-medial lemniscal pathway; crude touch, pain, temperature, and visceroreception are transmitted via the anterolateral pathways, which include the spinothalamic tract. Both pathways terminate in the ventral posterior lateral (VPL) nucleus, and the spinothalamic tract also projects to medial and intralaminar thalamic nuclei. Tactile sensation is relayed by multiple pathways and this redundancy ensures that selective damage to one pathway does not result in complete loss of haptic sensation. Somatosensory input from the face is transmitted from the trigeminal nerve (cranial nerve V) and ascends to the ventral posterior medial (VPM) nuclei of the thalamus via the ventral trigeminal thalamic tract (VTTT). Segregation by submodality and by input location appears to be conserved throughout the ascending pathways and within primary somatosensory cortex (S-I). Each of the four subdivisions of S-I (BA 1, 2, 3a, and 3b) contains a full somatotopic representation of input (homunculus), with proportional allocation of cortical and subcortical maps based on density of input receptors. Areas 1 and 3b process cutaneous input, whereas proprioceptive information is processed in areas 2 and 3a [87]. Both S-I and S-II project to the posterior parietal and insular cortices, which are both involved in higher-order and multimodal sensory processing. Dijkerman and Haan [88] recently proposed that the posterior parietal and posterior insular cortices receive projections from the anterior parietal cortex via two


somatosensory processing streams, similar to the differentiation between dorsal and ventral visual streams. In this model, the stream projecting to posterior insular cortex is akin to the ventral visual stream and primarily contributes to object perception and recognition. In contrast, the role of the posterior parietal cortex in somesthesis is closely related to its role in visual perception, including spatial and actionoriented functions. In addition to direct pathways to somatosensory cortex, there are also indirect pathways through which spinal afferents project to areas other than primary somatosensory cortex, some of which also have somesthetic functions. For example, proprioceptive input to the cerebellum relayed via the spinocerebellar tracts was traditionally thought to subserve motor planning and/or reflexive action, but recent evidence suggests that it may also contribute to tactile perception and non-motor sensory support functions [89]. Visual cortical regions have also been implicated in tactile perception in healthy individuals, including haptic shape discrimination [90] and gating orientation discrimination [91, 92]. Evidence for occipital involvement in tactile perception is even more compelling in early blind individuals, including recent evidence for somatotopic representation of tactile finger sensations in early blind Braille readers [93].

Disorders of somatosensory perception and recognition Sensory loss may arise from damage at any point within the somatosensory system. Since afferents decussate within the spinal cord or brainstem and synapse within the contralateral thalamus, lesions within or above the level of the thalamus result in contralateral deficits. Cortical sensory loss is classically associated with “cortical sensory deficits,” namely agraphesthesia (impaired recognition of numbers or letters traced on the palm or fingers) and astereognosis (impaired spatiotemporal discrimination, typically evaluated via recognition and discrimination of objects placed in the hand). These deficits are frequently associated with stroke but may also present in the context of neurodegenerative disorders, most notably corticobasal degeneration [94]. Bauer and Demery [49] suggest that astereognosis is primarily a deficit in perception and may be differentiated from associative forms of tactile agnosia in which marked object recognition deficits occur in

the absence of notable somatosensory impairment. Agraphesthesia and astereognosis may also be found consequent to damage elsewhere in the dorsal columnlemniscal system, including damage restricted to the dorsal columns. Somatosensation is critically important for normal motor function, and thus lesions affecting somatosensory systems are often associated with motor deficits as well. Positive somatic symptoms, called paresthesias, also may develop consequent to lesions at any level within the somatosensory systems. The Dejerine– Roussy syndrome is characterized by contralateral pain associated with unilateral thalamic lesions. Tactile, or haptic, hallucinations are physical sensations in the absence of cutaneous input. Formications are one subtype of tactile hallucinations, and are characterized by the sensation of insects or snakes crawling along the skin. In the general population, one study found that haptic hallucinations were the most frequent form of hypnagogic (while falling asleep) and hypnopompic (while waking up) hallucinations, and the prevalence of daytime haptic hallucinations was 2.6% [95]. Haptic hallucinations may also occur in the context of neurological or neuropsychiatric dysfunction, including substance withdrawal and lesions affecting the thalamus or parietal cortex. Phantom limb sensations are present in the vast majority of amputees, a subset of whom also experience pain in the amputated or deafferented body part. The precise etiology of these phantom phenomena is not known, but clinical and animal studies suggest possible contributory roles throughout the somatosensory pathway, including injured nerve endings, abnormal activity within the dorsal root ganglia, and both spinal and supraspinal CNS mechanisms. Additionally, research suggests that the S-I undergoes neuroplastic changes after amputation or deafferentation of a limb, and phantom sensations at least in part reflect invasion of cortical regions previously dedicated to perceptual processes for the amputated limb (for a review, see [96]). The proximity and overlap of higher-order somatosensory processing with the dorsal visual stream may have clinical implications as well. In addition to its role in somesthesis, the posterior parietal cortex is involved in spatial perception and visuomotor integration (see Vision section above), and evidence suggests that it contributes to attention orientation [97]. Hemineglect consequent to posterior parietal lesions may therefore present with tactile

153


symptoms, including tactile extinction (impaired tactile perception during simultaneous, bilateral stimulation). Finally, clinical symptoms may arise from deficient integration of somatosensory modalities and/or coordination with motor execution. For example, movement disorders primarily characterized by motor impairment may present with features of somatic abnormalities as well. Aberrant somatosensory evoked potentials have been demonstrated in patients with Parkinson’s disease (PD) or Huntington’s disease, and patients with dystonia often present with sensory symptoms in addition to their primary motor impairment [98].

Chemosensation: olfaction and gustation Olfaction begins with specialized neurons in the olfactory epithelium of the nose. These neurons are unique in that they have a relatively short lifespan (30–60 days) and are continuously being replaced by basal cells in the olfactory epithelium. Olfactory neurons project cilia into the nasal cavity. On the surface of these cilia are specialized odor receptors that detect specific molecular configurations and cause depolarization through a second messenger system. Each olfactory neuron expresses one of approximately 350 unique odorant receptor genes [99]. Unlike other sensory modalities, these neurons do not have a relay in the thalamus, but proceed to an area directly above the olfactory epithelium on the ventral surface of the prefrontal cortex known as the olfactory bulb. Some authors, however, have argued that the olfactory bulb serves many functions similar to those of the thalamus, including inhibitory modulation and oscillatory communication with higher olfactory cortical areas [100]. From the olfactory bulb, information is transmitted to several structures including the primary olfactory cortex (the piriform and peri-amygdaloid cortex), the amygdala, the olfactory tubercle, and the anterior entorhinal cortex. From these structures there are direct projections to the orbitofrontal cortex (OFC) olfactory area, as well as indirect projections that pass through the mediodorsal nucleus of the thalamus. Similar to other sensory systems, the olfactory system has several higher-order functions including odor discrimination and odor localization [101]. In

154

humans, odor discrimination appears to rely mainly on the piriform cortex and OFC. At least one functional imaging study suggests that in humans there may be hemispheric asymmetry such that the right OFC is more strongly associated with higher-order odor discrimination [102]. With regard to localization of odors, functional imaging studies in humans suggest a role for the piriform cortex (left greater than right) and in the posterior superior temporal gyrus near areas previously identified in the dorsal visual stream [103]. The strong connections and proximity of olfactory cortex to limbic and paralimbic areas seem to facilitate the ability of olfactory stimuli to trigger both autobiographical memories and emotional reactions [104]. Taste is a complex sensation that incorporates stimuli not only from primary taste receptors (taste buds), but also from olfaction and somatosensory information including the presence of capsaicin (found in spicy hot foods such as chili peppers), and the temperature and consistency of ingested food or liquids. Basic taste begins with taste cells, which are located primarily within taste buds on the tongue but also the pharynx and upper esophagus. Microvilli from taste cells interact with chemicals in foods and liquids either through specific receptors and second messenger systems (e.g., sweet) or ion channels (e.g., salt) that then lead to depolarization of the taste cell [105]. These interactions result in the five primary tastes of humans: sweet, salt, bitter, sour, and umami (derived from the combined Japanese words umai (delicious) and mi (taste), and translated into English as “savory,” this taste is related to glutamate in many high-protein foods such as meat). The facial, glossopharyngeal, and vagal nerves carry taste information to the rostral portion of the nucleus tractus solitarius (NTS). Somatosensory information from the trigeminal nerve also converges on the NTS. From the NTS information travels to the ventroposterior medial parvicellular (VPMpc) portion of the thalamus and from the VPMpc to the primary taste cortex, which lies just anterior to the face areas of the post-central gyrus as well as the anterior insula. Unlike other primary sensory modalities, there is evidence of polymodal integration (e.g., olfaction and taste) in the anterior insula. From the primary taste cortex, information is transmitted to the amygdala, hypothalamus, and the secondary taste cortex located in the caudolateral OFC. Pathways exist from all of these secondary taste areas


to the NTS, and are able to modulate brainstem taste function [106].

Disorders of olfactory and gustatory perception and recognition Although disorders of olfaction are rarely brought to medical attention, they may affect nutritional status through their interaction with taste and are often associated with neuropsychiatric diseases. Anosmia refers to the loss of smell and is most frequently associated with diseases of the nasal cavity. Hyposmia refers to an incomplete deficit in olfaction. The term olfactory agnosia is rarely used as most researchers test only for odor discrimination ability, rather than other primary aspects of smell such as stimulus onset/offset or intensity. Anosmia or hyposmia is frequently seen following traumatic brain injury as a result of shearing injury of the olfactory nerve at the cribriform plate, as well as possible secondary injuries to other nasal structures or the olfactory cortex in the basal forebrain. Deficits in olfactory discrimination are seen following lesions of the temporal lobe, particularly the uncinate region. Jones-Gotman and colleagues [107] reported that olfactory dysfunction is common in patients who have had temporal lobe resection for intractable epilepsy. Consistent with the functional imaging literature, lesions of the right OFC have also been associated with central anosmia [108]. Olfactory deficits may also be seen in other neuropsychiatric disorders that affect the medial temporal lobe and olfactory bulbs including AD and mild cognitive impairment [109], PD [110], and schizophrenia [111]. The easy accessibility of neural tissue and neural stem cells within the olfactory epithelium has spurred efforts to use nasal biopsies as a means of diagnosing neuropsychiatric conditions with pathological specimens including Creutzfeldt–Jakob disease [112], AD [113], and PD [114]. Olfactory testing is also being studied as a means of determining preclinical risk for AD, which involves mediotemporal olfactory cortex as an early event, and PD, which affects the olfactory bulbs [109, 114]. Olfactory hallucinations are typically unpleasant and have been described with temporal lobe epilepsy (uncinate fits), AD, parkinsonism, schizophrenia, post-traumatic stress disorder, and depression [115]. Ageusia and hypogeusia refer to lack and loss of taste respectively. In addition to changes in

olfactory function, these syndromes may be associated with peripheral lesions, brainstem lesions interrupting ascending pathways from the NTS [116], and occasionally from medications (notably phenytoin and chemotherapy). Gustatory agnosia has rarely been reported with one case demonstrating bilateral anterior medial temporal lobe lesions [117]. Gustatory hallucinations have been noted in schizophrenia, temporal lobe lesions, and temporal lobe epilepsy [17].

Crossmodal integration Humans typically do not experience the world in terms of individual sensory modalities, but rather as a seamlessly integrated whole based on information from multiple sensory sources. Crossmodal integration may change perception within a sensory modality through information from a separate modality, as may be seen through the influence of visual information on our sense of taste or smell [118]. Alternatively, crossmodal integration may be necessary to accomplish a truly multisensory task such as sound localization or lip reading. Crossmodal integration depends on the communication between unimodal and transmodal sensory areas, particularly the OFC, hippocampal-entorhinal complex, and posterior parietal lobe. Although patients with lesions in these areas do not typically present with deficits in crossmodal integration, these deficits may be demonstrated through neuropsychological testing [119]. Many conditions in BN&NP, including AD [120] and schizophrenia [121], demonstrate crossmodal integration deficits when clinical examinations sensitive to such impairments are performed. Synesthesia refers to a phenomenon in which a stimulus presented in one sensory modality automatically invokes a distinct perception in a secondary sensory modality. This condition is most commonly seen in otherwise normal (and often artistic) individuals, although a case of “feeling sounds” has been reported following a thalamic stroke [122]. The most common type of synesthesia involves the linking of graphemic forms (often numbers) with the experience of particular colors. Other types of synesthesia may involve crossmodal perception, as in seeing the color of certain auditory tones. Experiments in individuals with synesthesia have demonstrated that synesthesia occurs at relatively early perceptual processing stages and is

155


not dependent on conscious associations. Synesthesia is proposed to arise from abnormal connectivity between either unimodal perceptual areas or within transmodal cortex (see [123] for an excellent review).

Self-perception and recognition A final topic of importance to BN&NP is the unique human ability to recognize self-generated actions, sounds, images, and touch as distinct from environmental stimuli from other sources. This ability involves the generation of a feed-forward or efferent copy of our motor actions to be sent to transmodal sensory areas to tag the ensuing stimuli as self-generated. Research from both lesion and functional imaging studies in humans implicates a predominantly right cerebral network for feelings of agency for actions, particularly the inferior parietal lobule and anterior cingulate cortex [124], and a predominantly left cerebral network for the perception of agency regarding inner voice, particularly the left inferior frontal lobe [125]. Disturbances in these networks have been hypothesized to underlie several neuropsychiatric symptoms, particularly hallucinations and delusions of control [126]. Support for this hypothesis comes from functional imaging studies demonstrating disruptions within these networks in individuals with hallucinations and passivity experiences, as well as the surprising ability of these individuals to tickle themselves [127].

Conclusion The study of perceptual processes is among the oldest fields of inquiry in neurology and also one of the most highly developed. In this chapter, a concise, broad overview of the functional neuroanatomy underlying perception and recognition within each of the five primary perceptual systems was provided. Perception and recognition were defined in terms of their neuroanatomic and neuropsychological elements. The organizational principles common to all human sensory and perceptual processes were reviewed, and the general types of perception and recognition disorders were presented. Specific discussion of the neuroanatomy and neuropsychology of vision, audition, somatosensation, and chemosensation (i.e., olfaction and gustation) was offered, and specific types of perception and recognition disturbances for each sensory modality were presented. Finally, the importance of crossmodal integration as well as self-perception and recognition were discussed. Throughout this review,

156

understanding the structural architecture of sensory systems and behavioral correlates of normal and abnormal connectivity was emphasized and identified as prerequisite knowledge for clinical examination and lesions localization of persons with disorders of perception and recognition.

References 1. Rugg MD, Yonelinas AP. Human recognition memory: a cognitive neuroscience perspective. Trends Cogn Sci. 2003;7(7):313–19. 2. Anderson SW. Neuropsychologic rehabilitation for visuoperceptual impairments. Neurologic Clinics 2003;21(3):729–40. 3. Murphy ST, Zajonc RB. Affect, cognition, and awareness: affective priming with optimal and suboptimal stimulus exposures. J Pers Soc Psychol. 1993;64(5):723–39. 4. Heisz JJ, Shore DI. More efficient scanning for familiar faces. J Vis. 2008;8(1):9.1–10. 5. Pelphrey KA, Sasson NJ, Reznick JS et al. Visual scanning of faces in autism. J Autism Dev Disord. 2002;32(4):249–61. 6. Mesulam MM. From sensation to cognition. Brain 1998;121(Pt 6):1013–52. 7. Pascual-Leone A, Walsh V. Fast backprojections from the motion to the primary visual area necessary for visual awareness. Science 2001;292(5516): 510–12. 8. Bar M, Kassam KS, Ghuman AS et al. Top-down facilitation of visual recognition. Proc Natl Acad Sci USA 2006;103(2):449–54. 9. Geschwind N. Disconnexion syndromes in animals and man. I. Brain 1965;88(2):237–94. 10. Geschwind N. Disconnexion syndromes in animals and man. II. Brain 1965;88(3):585–644. 11. Buzsáki G. Rhythms of the Brain. Oxford: Oxford University Press; 2006. 12. Tsodyks M, Gilbert C. Neural networks and perceptual learning. Nature 2004;431(7010):775–81. 13. Shallice T, Jackson M. Lissauer on agnosia. Cogn Neuropsych. 1988;5(2):153–6. 14. Bauer RM. The agnosias. In Snyder PJ, Nussbaum PD, Robins DL, editors. Clinical Neuropsychology: A Pocket Handbook for Assessment. 2nd edition. Washington, DC: American Psychological Association; 2006, pp. 508–33. 15. Barbarotto R, Capitani E, Laiacona M. Living musical instruments and inanimate body parts? Neuropsychologia 2001;39(4):406–14.


16. Behrendt RP, Young C. Hallucinations in schizophrenia, sensory impairment, and brain disease: a unifying model. Behav Brain Sci. 2004;27(6):771–87; discussion 787–830.

32. Nealey TA, Maunsell JH. Magnocellular and parvocellular contributions to the responses of neurons in macaque striate cortex. J Neurosci. 1994; 14(4):2069–79.

17. Brasic JR. Hallucinations. Percept Mot Skills 1998; 86(3 Pt 1):851–77.

33. Ungerleider L, Mishkin M. Two cortical visual systems. In Ingle D, Goodale MA, Mansfield RJW, editors. Analysis of Visual Behavior. Cambridge, MA: MIT Press; 1982.

18. Benke T. Peduncular hallucinosis: a syndrome of impaired reality monitoring. J Neurol. 2006;253(12): 1561–71. 19. Black JE, Brooks SN, Nishino S. Conditions of primary excessive daytime sleepiness. Neurol Clin. 2005;23(4): 1025–44. 20. Kulisevsky J, Roldan E. Hallucinations and sleep disturbances in Parkinson’s disease. Neurology 2004;63(8 Suppl. 3):S28–30. 21. Babkoff H, Sing HC, Thorne DR, Genser SG, Hegge FW. Perceptual distortions and hallucinations reported during the course of sleep deprivation. Percept Mot Skills 1989;68(3 Pt 1):787–98. 22. Felleman DJ, Van Essen DC. Distributed hierarchical processing in the primate cerebral cortex. Cereb Cortex 1991;1(1):1–47. 23. Eysenck MW, Keane MT. Basic processes in visual perception. In Eysenck MW, Keane MT, editors. Cognitive Psychology: A Student’s Handbook. 5th edition. Hove: Psychology Press; 2005, pp. 33–67. 24. Wunderlich K, Schneider KA, Kastner S. Neural correlates of binocular rivalry in the human lateral geniculate nucleus. Nat Neurosci. 2005;8(11): 1595–602. 25. Wurtz RH, Kandel ER. Central visual pathways. In Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science. 4th edition. New York, NY: McGraw-Hill; 2000, pp. 523–47. 26. Zillmer EA, Spiers MV. Sensory-perceptual and motor systems. In Zillmer E, Spiers M, Culbertson WC, editors. Principles of Neuropsychology. Belmont, CA: Wadsworth Pub. Co.; 2001. 27. Ro T. Unconscious vision in action. Neuropsychologia 2008;46(1):379–83. 28. Casanova C, Merabet L, Desautels A, Minville K. Higher-order motion processing in the pulvinar. Prog Brain Res. 2001;134:71–82. 29. Sillito AM, Jones HE. Corticothalamic interactions in the transfer of visual information. Philos Trans R Soc Lond B Biol Sci. 2002;357(1428):1739–52. 30. Riddoch MJ, Humphreys GW. Visual agnosia. Neurol Clin. 2003;21(2):501–20. 31. Livingstone M, Hubel D. Segregation of form, color, movement, and depth: anatomy, physiology, and perception. Science 1988;240(4853):740–9.

34. Super H. Cognitive processing in the primary visual cortex: from perception to memory. Rev Neurosci. 2002;13(4):287–98. 35. Wurtz RH, Kandel ER. Perception of motion, depth, and form. In Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science. 4th edition. New York, NY: McGraw-Hill; 2000, pp. 548–71. 36. Stoerig P. The neuroanatomy of phenomenal vision: a psychological perspective. Ann N Y Acad Sci. 2001; 929:176–94. 37. Grill-Spector K, Malach R. The human visual cortex. Annu Rev Neurosci. 2004;27:649–77. 38. Mishkin M, Ungerleider LG, Macko KA. Object vision and spatial vision: two cortical pathways. Trends Neurosci. 1983;6:414–17. 39. Milner AD, Goodale MA. The Visual Brain in Action. Oxford: Oxford University Press; 1995. 40. Jeannerod M. The Cognitive Neuroscience of Action. Oxford: Blackwell Publishing; 1997. 41. Jeannerod M, Jacob P. Visual cognition: a new look at the two-visual systems model. Neuropsychologia 2005;43(2):301–12. 42. Rizzolatti G, Matelli M. Two different streams form the dorsal visual system: anatomy and functions. Exp Brain Res. 2003;153(2):146–57. 43. Burwell RD. The parahippocampal region: corticocortical connectivity. Ann N Y Acad Sci. 2000; 911:25–42. 44. Horton JC, Hoyt WF. Quadrantic visual field defects. A hallmark of lesions in extrastriate (V2/V3) cortex. Brain 1991;114(Pt 4):1703–18. 45. Bresch D. Beyond Wernicke’s: a lexicon of eponyms in psychiatry. J Neuropsychiatry Clin Neurosci. 2002; 14(2):155–60. 46. Weiskrantz L. Is blindsight just degraded normal vision? Exp Brain Res. 2009;192(3):413–16. 47. Zeki S. Cerebral akinetopsia (visual motion blindness). A review. Brain 1991;114(Pt 2):811–24. 48. Nawrot M. Disorders of motion and depth. Neurol Clin. 2003;21(3):609–29. 49. Bauer RM, Demery JA. Agnosia. In Heilman KM, Valenstein E, editors. Clinical Neuropsychology.

157


4th edition. Oxford: Oxford University Press; 2003, pp. 236–95. 50. Barton JJ. Disorders of face perception and recognition. Neurol Clin. 2003;21(2):521–48. 51. Gauthier I, Behrmann M, Tarr MJ. Can face recognition really be dissociated from object recognition? J Cogn Neurosci. 1999;11(4):349–70. 52. Sorger B, Goebel R, Schiltz C, Rossion B. Understanding the functional neuroanatomy of acquired prosopagnosia. Neuroimage 2007;35(2): 836–52. 53. Pietrini P, Furey ML, Ricciardi E et al. Beyond sensory images: object-based representation in the human ventral pathway. Proc Natl Acad Sci USA 2004;101(15): 5658–63. 54. Caselli RJ. Visual syndromes as the presenting feature of degenerative brain disease. Semin Neurol. 2000; 20(1):139–44. 55. Norton JW, Corbett JJ. Visual perceptual abnormalities: hallucinations and illusions. Semin Neurol. 2000;20(1):111–21. 56. Panayiotopoulos CP. Visual phenomena and headache in occipital epilepsy: a review, a systematic study and differentiation from migraine. Epileptic Disord. 1999;1(4):205–16. 57. Bien CG, Benninger FO, Urbach H, et al. Localizing value of epileptic visual auras. Brain 2000;123(Pt 2): 244–53. 58. Plesnicar BK, Zalar B, Bocic MB. The Charles Bonnet syndrome: a case report. Wien Klin Wochenschr. 2004;116(Suppl. 2):75–7. 59. Kirshner HS, Lavin PJ. Posterior cortical atrophy: a brief review. Curr Neurol Neurosci Rep. 2006;6(6): 477–80. 60. Caine D. Posterior cortical atrophy: a review of the literature. Neurocase 2004;10(5):382–5.

158

65. Scott SK, Blank CC, Rosen S, Wise RJ. Identification of a pathway for intelligible speech in the left temporal lobe. Brain 2000;123(Pt 12):2400–6. 66. Lewis JW, Wightman FL, Brefczynski JA et al. Human brain regions involved in recognizing environmental sounds. Cereb Cortex 2004;14(9):1008–21. 67. Duane D. A neurologic perspective of central auditory dysfunction. In Keith RW, editor. Central Auditory Dysfunction. New York, NY: Grune & Stratton; 1977, p. 1. 68. Kaga K, Shindo M, Tanaka Y. Central auditory information processing in patients with bilateral auditory cortex lesions. Acta Otolaryngol Suppl. 1997; 532:77–82. 69. Garde MM, Cowey A. “Deaf hearing”: unacknowledged detection of auditory stimuli in a patient with cerebral deafness. Cortex 2000;36(1): 71–80. 70. Engelien A, Huber W, Silbersweig D et al. The neural correlates of ‘deaf-hearing’ in man: conscious sensory awareness enabled by attentional modulation. Brain 2000;123(Pt 3):532–45. 71. Stefanatos GA, Gershkoff A, Madigan S. On pure word deafness, temporal processing, and the left hemisphere. J Int Neuropsychol Soc. 2005;11(4): 456–70; discussion 5. 72. Hayashi K, Hayashi R. Pure word deafness due to left subcortical lesion: neurophysiological studies of two patients. Clin Neurophysiol. 2007;118(4):863–8. 73. Clarke S, Bellmann A, Meuli RA, Assal G, Steck AJ. Auditory agnosia and auditory spatial deficits following left hemispheric lesions: evidence for distinct processing pathways. Neuropsychologia 2000; 38(6):797–807. 74. Van Lancker DR, Kreiman J, Cummings J. Voice perception deficits: neuroanatomical correlates of phonagnosia. J Clin Exp Neuropsychol. 1989;11(5): 665–74.

61. Diederich NJ, Goetz CG, Stebbins GT. Repeated visual hallucinations in Parkinson’s disease as disturbed external/internal perceptions: focused review and a new integrative model. Mov Disord. 2005;20(2): 130–40.

75. Schuppert M, Munte TF, Wieringa BM, Altenmuller E. Receptive amusia: evidence for cross-hemispheric neural networks underlying music processing strategies. Brain 2000;123(Pt 3):546–59.

62. Hudspeth AJ. Hearing. In Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science. 4th edition. New York, NY: McGraw-Hill; 2000, pp. 590–613.

76. Adriani M, Maeder P, Meuli R et al. Sound recognition and localization in man: specialized cortical networks and effects of acute circumscribed lesions. Exp Brain Res. 2003;153(4):591–604.

63. Li L, Yue Q. Auditory gating processes and binaural inhibition in the inferior colliculus. Hear Res. 2002;168(1–2):98–109.

77. Tanaka Y, Nakano I, Obayashi T. Environmental sound recognition after unilateral subcortical lesions. Cortex 2002;38(1):69–76.

64. Rauschecker JP, Tian B. Mechanisms and streams for processing of “what” and “where” in auditory cortex. Proc Natl Acad Sci USA 2000;97(22): 11,800–6.

78. Biedermann F, Bungert P, Dorrscheidt GJ, von Cramon DY, Rubsamen R. Central auditory impairment in unilateral diencephalic and


telencephalic lesions. Audiol Neurootol. 2008;13(2): 123–44. 79. Johkura K, Matsumoto S, Hasegawa O, Kuroiwa Y. Defective auditory recognition after small hemorrhage in the inferior colliculi. J Neurol Sci. 1998;161(1):91–6. 80. Di Dio AS, Fields MC, Rowan AJ. Palinacousis – auditory perseveration: two cases and a review of the literature. Epilepsia 2007;48(9):1801–6.

95. Ohayon MM. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res. 2000;97(2–3):153–64. 96. Flor H, Nikolajsen L, Staehelin Jensen T. Phantom limb pain: a case of maladaptive CNS plasticity? Nat Rev Neurosci. 2006;7(11):873–81.

81. Saunders JC. The role of central nervous system plasticity in tinnitus. J Commun Disord. 2007;40(4): 313–34.

97. Verfaellie M, Heilman KM. Neglect syndromes. In Snyder PJ, Nussbaum PD, Robins DL, editors. Clinical Neuropsychology: A Pocket Handbook for Assessment. 2nd edition. Washington, DC: American Psychological Association; 2006, pp. 489–507.

82. Langguth B, Hajak G, Kleinjung T et al. Repetitive transcranial magnetic stimulation and chronic tinnitus. Acta Otolaryngol Suppl. 2006;(556):102–5.

98. Abbruzzese G, Berardelli A. Sensorimotor integration in movement disorders. Mov Disord. 2003;18(3): 231–40.

83. Lampl Y, Lorberboym M, Gilad R, Boaz M, Sadeh M. Auditory hallucinations in acute stroke. Behav Neurol. 2005;16(4):211–16.

99. Mombaerts P. The human repertoire of odorant receptor genes and pseudogenes. Annu Rev Genomics Hum Genet. 2001;2:493–510.

84. Bogerts B. The temporolimbic system theory of positive schizophrenic symptoms. Schizophr Bull. 1997;23(3):423–35.

100. Kay LM, Sherman SM. An argument for an olfactory thalamus. Trends Neurosci. 2007;30(2): 47–53.

85. Florindo I, Bisulli F, Pittau F et al. Lateralizing value of the auditory aura in partial seizures. Epilepsia 2006; 47(Suppl. 5):68–72.

101. Wilson DA, Kadohisa M, Fletcher ML. Cortical contributions to olfaction: plasticity and perception. Semin Cell Dev Biol. 2006;17(4):462–70.

86. Evers S, Ellger T. The clinical spectrum of musical hallucinations. J Neurol Sci. 2004;227(1):55–65.

102. Zatorre RJ, Jones-Gotman M, Evans AC, Meyer E. Functional localization and lateralization of human olfactory cortex. Nature 1992;360(6402): 339–40.

87. Gardner EP, Kandel ER. Touch. In Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science. 4th edition. New York, NY: McGraw-Hill; 2000, pp. 451–71. 88. Dijkerman HC, de Haan EH. Somatosensory processes subserving perception and action. Behav Brain Sci. 2007;30(2):189–201; discussion 201–39. 89. Parsons LM. Integrating cognitive psychology, neurology and neuroimaging. Acta Psychol. (Amsterdam) 2001;107(1–3):155–81. 90. Peltier S, Stilla R, Mariola E et al. Activity and effective connectivity of parietal and occipital cortical regions during haptic shape perception. Neuropsychologia 2007;45(3):476–83. 91. Sathian K, Zangaladze A, Hoffman JM, Grafton ST. Feeling with the mind’s eye. Neuroreport 1997;8(18): 3877–81. 92. Zangaladze A, Epstein CM, Grafton ST, Sathian K. Involvement of visual cortex in tactile discrimination of orientation. Nature 1999;401(6753):587–90. 93. Ptito M, Schneider FC, Paulson OB, Kupers R. Alterations of the visual pathways in congenital blindness. Exp Brain Res. 2008;187(1):41–9. 94. Mahapatra RK, Edwards MJ, Schott JM, Bhatia KP. Corticobasal degeneration. Lancet Neurol. 2004;3(12):736–43.

103. Porter J, Anand T, Johnson B, Khan RM, Sobel N. Brain mechanisms for extracting spatial information from smell. Neuron 2005;47(4):581–92. 104. Willander J, Larsson M. Olfaction and emotion: the case of autobiographical memory. Mem Cognit. 2007;35(7):1659–63. 105. Buck LB. Smell and taste: the chemical senses. In Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science. 4th edition. New York, NY: McGraw-Hill; 2000, pp. 548–71. 106. Simon SA, de Araujo IE, Gutierrez R, Nicolelis MA. The neural mechanisms of gustation: a distributed processing code. Nat Rev Neurosci. 2006;7(11): 890–901. 107. Jones-Gotman M, Zatorre RJ, Cendes F et al. Contribution of medial versus lateral temporal-lobe structures to human odour identification. Brain 1997;120(Pt 10):1845–56. 108. Ishimaru T, Miwa T, Nomura M, Iwato M, Furukawa M. Reversible hyposmia caused by intracranial tumour. J Laryngol Otol. 1999;113(8):750–3. 109. Wilson RS, Schneider JA, Arnold SE et al. Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry 2007; 64(7):802–8.

159


110. Ponsen MM, Stoffers D, Booij J et al. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol. 2004;56(2):173–81. 111. Kopala L, Clark C. Implications of olfactory agnosia for understanding sex differences in schizophrenia. Schizophr Bull. 1990;16(2):255–61. 112. Tabaton M, Monaco S, Cordone MP et al. Prion deposition in olfactory biopsy of sporadic Creutzfeldt–Jakob disease. Ann Neurol. 2004;55(2): 294–6. 113. Attems J, Jellinger KA. Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol. 2006;25(6):265–71. 114. Hawkes C, Shah M, Findley L. Olfactory function in essential tremor: a deficit unrelated to disease duration or severity. Neurology 2003;61(6):871–2; author reply 872. 115. Carter JL. Visual, somatosensory, olfactory, and gustatory hallucinations. Psychiatr Clin North Am. 1992;15(2):347–58. 116. Lee BC, Hwang SH, Rison R, Chang GY. Central pathway of taste: clinical and MRI study. Eur Neurol. 1998;39(4):200–3. 117. Small DM, Bernasconi N, Bernasconi A, Sziklas V, Jones-Gotman M. Gustatory agnosia. Neurology 2005;64(2):311–17. 118. Gottfried JA, Dolan RJ. The nose smells what the eye sees: crossmodal visual facilitation of human olfactory perception. Neuron 2003;39(2):375–86.

160

119. Valenza N, Murray MM, Ptak R, Vuilleumier P. The space of senses: impaired crossmodal interactions in a patient with Balint syndrome after bilateral parietal damage. Neuropsychologia 2004;42(13):1737–48. 120. Delbeuck X, Collette F, Van der Linden M. Is Alzheimer’s disease a disconnection syndrome? Evidence from a crossmodal audio-visual illusory experiment. Neuropsychologia 2007;45(14):3315–23. 121. de Gelder B, Vroomen J, Annen L, Masthof E, Hodiamont P. Audio-visual integration in schizophrenia. Schizophr Res. 2003;59(2–3):211–18. 122. Ro T, Farne A, Johnson RM et al. Feeling sounds after a thalamic lesion. Ann Neurol. 2007;62(5):433–41. 123. Ramachandran VS, Hubbard EM, Butcher PA. Synesthesia, cross-activation and the foundations of neuroepistemology. In Calvert G, Spence C, Stein BE, editors. The Handbook of Multisensory Processes. Cambridge, MA: MIT Press; 2004, pp. 867–83. 124. Farrer C, Franck N, Georgieff N et al. Modulating the experience of agency: a positron emission tomography study. Neuroimage 2003;18(2):324–33. 125. Morin A, Michaud J. Self-awareness and the left inferior frontal gyrus: inner speech use during self-related processing. Brain Res Bull. 2007;74(6): 387–96. 126. Frith C. The neural basis of hallucinations and delusions. C R Biol. 2005;328(2):169–75. 127. Blakemore SJ, Wolpert D, Frith C. Why can’t you tickle yourself? Neuroreport 2000;11(11):R11–16.

Section I


Chapter

Memory

11

Felipe DeBrigard, Kelly S. Giovanello, and Daniel I. Kaufer

Human memory consists of several functional systems that collectively support the acquisition, retention, and subsequent retrieval of information. Much of what is known about different memory processes has been gleaned from experiments in non-human primates and other mammals, which allow for direct manipulation of experimental conditions but provide limited information about the human condition. Complementing animal lesion experimental data are individual case studies in a few human subjects uniquely affected with specific lesions that isolate different memory systems. Data generated from these select individuals have widely influenced current theories of memory function by yielding inferences regarding component processes and anatomical substrates based on brain–behavioral correlation. More recently, high-resolution structural and functional imaging methods have greatly facilitated the investigation of structure–function relationships associated with different human memory functions. In particular, functional magnetic resonance imaging (fMRI) allows for assaying neural circuitry in real-time during the performance of various memory tasks. Memory systems are classified according to the temporal duration (short- vs. long-term memory) or the qualitative nature of the information being retained (Figure 11.1). Short-term memory (STM) generally refers to the retention of information over brief periods of time, on the order of seconds. Working memory (WM) is a form of STM that entails a temporary storage buffer for information that undergoes further processing; long-term memory (LTM) involves the acquisition and retention of information over longer intervals of time. Long-term memory can be further subdivided into declarative memory, which

Figure 11.1. A framework for understanding memory and its subtypes.

refers to the acquisition and retention of knowledge, and non-declarative memory, reflecting experienceinduced changes in performance. In a clinical context, the temporal aspects of learning and memory are parsed into immediate recall (processing and recitation over a period of seconds), recent memory (anterograde learning over a period of minutes), and remote memory (retrograde recall of previously learned information). These terms reflect stages of information processing (encoding, storage, retrieval) that form the basis of standard clinical tests of verbal episodic memory (e.g., word-list or paragraph recall). This chapter will review the clinical context and describe the functional–anatomic architecture of multiple memory systems including WM, declarative memory (i.e., semantic memory and episodic memory), and non-declarative memory (i.e., implicit


161


memory and procedural memory). The account will be based on neuropsychological and functional neuroimaging studies of normal individuals and clinical populations.

Clinical overview The anatomical substrates of memory include distributed networks of cortical and subcortical nuclei interconnected by white matter projection pathways. For example, the Papez circuit – comprising the entorhinal complex, hippocampal formation, fornix, mammillary bodies, and anterior/dorsomedial thalamus, and the cingulate gyrus – contributes to learning new information; lesions affecting any of these structures may interfere with this process, resulting in a learning or storage deficit [1]. Although susceptible to injury from a variety of insults, these structures are particularly susceptible to the effects of hypoxicischemic, hypoglycemic, or other metabolic injury (i.e., CA1 region of the hippocampus), increased glucose metabolism in the setting of thiamine deficiency (i.e., mammillary bodies and thalamus), trauma (i.e., hippocampus and fornix), and Alzheimer’s disease (AD) (i.e., entorhinal complex–hippocampal formation). By contrast, injury to frontal–subcortical systems is more often associated with difficulty retrieving recently learned information (producing a retrieval deficit). Accordingly, lesions associated with traumatic brain injury, cerebrovascular disease, multiple sclerosis, HIV/AIDS, and other conditions may have a deleterious effect on frontal-subcortical circuits and are common causes of impaired memory retrieval. Degenerative conditions such as Parkinson’s disease (PD) and Huntington’s disease (HD) that affect basal ganglia and cerebellar structures involved in perceptual-motor processing may cause impairments in WM and procedural memory [2]. From a therapeutic perspective, research on memory functions has focused on remediating “core” cognitive deficits (i.e., short-term episodic memory deficits) in the setting of AD, and WM deficits in the context of attention-deficit disorder (ADD) and schizophrenia. Memory impairment is the most common reason for seeking a cognitive evaluation, and this problem has multiple possible causes. In most cases, memory impairments are comorbid with other cognitive and neurobehavioral problems. Disorders such as herpes encephalitis, which has a predilection for limbic and paralimbic cortical regions, may cause an

162

amnestic syndrome associated with other neurobehavioral features, such as personality change and seizures. Alcohol amnestic disorder (also known as Korsakoff ’s syndrome or Korsakoff ’s psychosis), transient global amnesia (TGA), and amnestic mild cognitive impairment (MCI) are the most common causes of isolated impairment of declarative memory. Although well known to be associated with Korsakoff ’s syndrome, an amnestic syndrome in which a tendency to confabulate features prominently also may develop after rupture of an anterior cerebral artery aneurysm. Secondary memory impairments may develop as complications of electroconvulsive therapy (ECT), epileptic seizures (i.e., complex partial or generalized seizures), or severe alcohol intoxication (“alcoholic blackouts”). A variety of nutritional, metabolic, endocrine, and toxic conditions may impair memory function directly or indirectly via compromise in attentional systems, as with an acute confusional state or delirium.

Multiple memory systems Memory is not a unitary function, but instead denotes a large and diverse set of psychological processes and neural systems involved in learning and retrieving information. These processes include, among others, WM, declarative (episodic, semantic) memory, and non-declarative (implicit, procedural) memory, each of which will be considered in the following sections of this chapter.

Working memory Working memory refers to the retention of information over brief intervals of time, typically on the order of seconds. It involves the temporary online storage and manipulation of information that can be used for immediate behavior, without being directly available to the senses. It is different from the notion of STM in that it is not merely a relaying stage prior to the storage of information in LTM. Rather, WM encompasses an array of cognitive processes. The amount of information WM can handle is both limited in time (approximately 20 seconds) and in capacity (approximately four to nine items), and is somewhat flexible. By actively rehearsing an informational item, one can keep information in WM for extended periods of time. Similarly, by grouping different items into meaningful chunks of information, WM capacity can increase substantially [3]. The limited capacity of WM allows cognitive scientists to study its nature using a dual-task

Chapter 11: Memory

methodology. This research strategy is based on the assumption that if two activities are conducted in tandem and neither is impaired, then the processes do not depend on the same system. However, if performance on one task decreases as a function of being carried out along with the other task, then both tasks depend upon the same mnemonic system. This methodology has been widely used by Alan Baddeley in shaping his WM model [4]. The model comprises four components: three material-specific slave systems and one central executive. One slave system is called the “phonological loop.” It mediates the temporal storage and rehearsal of phonemes and sounds. As such, it is essential for language production and comprehension, as well as for the temporary storage of numeric and other symbolic representations. Experimental studies have shown that rehearsal and retrieval of information processed by the phonological loop is sensitive to phono-articulatory characteristics. It has been suggested, for instance, that the phonological loop stores information in a phonetic format, as evidenced by the phonological similarity effect in which recall is poorer for sequences of phonologically similar items [5]. Similarly, it has been suggested that phonological rehearsal involves highlevel activation of speech-motor planning processes [6]. This claim finds support in the word length effect, which states that serial recall accuracy is correlated with length of phonological articulation – the longer and more complex the word, the longer it takes to rehearse. Neuroimaging and neuropsychological studies support dissociation between phonological storage and rehearsal [7–9]. On the one hand, patients with damage to the left supramarginal gyrus of the inferior parietal cortex exhibit poor repetition, produce phonemic paraphasias, and have reduced auditory verbal span, deficits indicative of an impaired phonological store [10, 11]. On the other hand, patients with damage to the left inferior frontal gyrus display output deficits characterized by diminished phrase length and poor articulation, findings indicative of impaired articulatory rehearsal [11, 12]. Importantly, functional neuroimaging studies have shown that storage and maintenance of information involves interactions between posterior buffer regions and anterior rehearsal mechanisms. For example, verbal WM appears to be mediated by the left posterior parietal cortex, which subserves the phonological store, as well as Broca’s area, the left premotor area,

and the left supplementary area, which are involved in articulatory rehearsal [13]. Another slave system is the visuospatial sketchpad, which stores and manipulates visual and spatial information. The visuospatial sketchpad is independent of the phonological loop, as it is associated with activity in the right – and not the left – cerebral hemisphere [14]. Additionally, it is selectively disrupted by concurrent activities that do not influence the phonological loop [15]. It is also thought to involve two different components: a visual store that preserves perceptual features of objects, and a spatial or sequential component that may serve a rehearsal function. Neuropsychological findings offer strong support for this dissociation. Patients with occipital and temporal damage exhibit impaired visual storage, but preserved spatial WM [16]. In contrast, patients with parietal deficits show impaired spatial storage, but preserved visual WM [17, 18]. Recent research has also revealed that eye-movements play a key role in the maintenance of spatial, but not object, representations in the visuospatial sketchpad [19]. The final slave system, the episodic buffer, is the most recent addition to the model [20]. The function of this buffer is to represent and integrate inputs from all subcomponents of WM, as well as LTM, in a multimodal neural code. As such, it is thought to process multidimensional information that will later be consolidated or reconsolidated in episodic memory. Moreover, the episodic buffer is thought to link semantic information from the visuospatial sketchpad and the phonological loop in order to integrate this information into complex episodic representations via modulation by the central executive. The observation that amnestic patients can produce coherent episodic narratives despite profound deficits in LTM supports the postulated role of the episodic buffer. Although the precise neural correlates of this episodic buffer remain unspecified, preliminary fMRI evidence suggests that the right frontal lobe may play a key role [21]. Each of the aforementioned slave systems depends on a central executive system. This system, which is also limited in capacity, plays a fundamental role in complex memory span tasks (e.g., random digit generation) and it is closely linked to attentional control. Indeed, Baddeley [22] suggested that the central executive may in fact correspond to Shallice’s [23] supervisory attentional system. It is thought to regulate the flow of information with WM, and the retrieval of material from more permanent LTM into WM.

163


In addition, the central executive permits attentional shifts between tasks as well as selective attention and inhibition. Neuropsychological evidence suggests that there are two main types of dysexecutive syndrome, each reflecting dysfunction in the central executive system. One type involves marked perseveration, indicating decreased ability to disengage and shift attention, whereas the other is characterized by excessive distractibility, which reflects impairments in attentional inhibition. It has been observed that individuals with AD and frontotemporal dementias are impaired when performing concurrent multiple tasks, indicating that the frontal and prefrontal cortices may be selectively involved in the functioning of the executive system [24]. Furthermore, neuroimaging studies indicate that executive control processes are mediated by the cingulate and dorsolateral prefrontal cortices [25, 26]. Finally, it is worth noting that despite the influence of Baddeley’s WM model, other models have been suggested. Of note is Nelson Cowan’s [27] model, which unlike Baddeley’s model, suggests that WM and LTM process the same types of memory representations. According to Cowan’s model, there are not different kinds of systems operating upon different kinds of WM representations, but rather a unique executive system activating and deactivating memory representations via attentional modulation. Further research is needed to assess the relative virtues of these different models.

Declarative memory Declarative memory encompasses the acquisition, long-term retention, and retrieval of events, facts, and concepts [28]. Such knowledge can be retrieved at will and used in a variety of contexts. Declarative memory can be subdivided depending on whether memories are concerned with personally relevant events (i.e., episodic memory) or impersonal information (i.e., semantic memory).

Episodic memory Episodic memory enables individuals to recollect conscious experiences from their personal past (e.g., remembering what one had for breakfast this morning). According to Tulving [29], episodic memories are characterized by a sense of subjective awareness of having experienced the remembered events in the past.

164

To tap into this particular feeling or “recollective experience,” Tulving developed the so-called remember/know paradigm. In this paradigm, participants are first presented with stimulus material and then asked to retrieve this information on a memory test. During recall, participants are asked whether they remember the studied event – that is, whether they can picture it in their minds with some detail – or, instead, if they only know that they have studied it (i.e., a sense of knowing something without being able to conjure up additional informational details). This widely implemented paradigm has produced robust results, suggesting two different mnemonic processes: recollection and familiarity. As later suggested by Tulving [30], the hallmark of recollection is a sense of autonoetic (self-awareness) consciousness accompanying the recollective experience; it pertains, therefore, to episodic memory. On the other hand, the absence of autonoetic consciousness during familiarity evidences a different sort of processing, this time related to semantic memory. Although the nature and exact relation between recollection and familiarity is a matter of debate [31] convergent evidence suggests that episodic memory is a distinct memory system. A pervasive deficit in episodic memory is dramatically exemplified in patients with anterograde amnesia, who are unable to acquire and retrieve any events or episodes from their personal life that occurred since the onset of their amnesia. This phenomenon was first documented in patient H.M., a man who, in 1953, underwent surgery for treatment of refractory seizures [32]. The surgery involved bilateral resection of the medial temporal region, which reportedly included removal of the amygdala, anterior two-thirds of the hippocampus, and hippocampal gyrus. Although the surgery was successful in substantially reducing H.M.’s seizures, the procedure produced a pervasive impairment of memory that was termed “global amnesia” [33]. From the time of his surgery at the age of 27 until his death in 2008, H.M. was unable to consciously learn and remember new episodic information. Patients with global amnesia also manifest retrograde amnesia (i.e., the loss of memory for experienced events that occurred prior to brain injury onset). Frequently, remote memories are better preserved than memories for events that occurred shortly before brain injury. This effect, which was described over a century ago by Théodule Ribot [34] and referred subsequently to as Ribot’s law, is only now coming to be understood,

Chapter 11: Memory

as cognitive neuroscientists investigate how the hippocampus and surrounding medial-temporal structures contribute to the enduring storage of episodic memories. Although there is general agreement that the hippocampus is critical for memory consolidation (i.e., the permanent laying down) of information, memory theorists disagree as to the role the hippocampus plays in the storage of consolidated memories. The traditional view suggests that the medial temporal lobes are not the ultimate repositories for new memories [35, 36]. Rather, storage of new memories requires interaction between medial-temporal and neocortical areas. The hippocampus receives input from distributed neocortical sites about an event to be remembered and forms a compressed representation that binds together the information from different sites that form a complete representation of that event. Partial reinstatement of the activation pattern associated with that event leads to a spreading of activation, whereby the initial pattern of neocortical activation is regenerated. Whenever a neocortical pattern is reinstated, the functional connections between constituent sites are reinforced. Over time, permanent cortico-cortical connections are established, allowing a memory to be retrieved without mediation from the limbic system. As a result, information that is not fully consolidated is vulnerable to partial or complete loss in the setting of hippocampal damage, whereas fully consolidated (i.e., older, representationally stable) memories are able still to be retrieved successfully. More recently, alternative views have been proposed in which the hippocampus plays a more permanent role in the retrieval of episodic memories. One such theory, known as the Multiple Trace Theory [37], suggests that recollection of episodic memories always depends on the hippocampus, and that every time one recollects an episodic memory, a new memory trace is created. Thus, episodic memories that are more frequently remembered have been coded in multiple traces, rendering them less vulnerable to damage. Other views suggest that the hippocampus is always required for recollection, but not for familiarity [38, 39], insofar as it permits the recombination of episodic components into a single memory event [40]. Finally, some views suggest that the hippocampus stores allocentric (i.e., non-self-centered) representations of spatial context, which allow humans and other mammals not only to navigate their immediate surroundings, but

also to mentally access the spatio-temporal content of their memories. Further research is needed to fully understand the specific role of the hippocampus and the medial temporal lobes in retrieval. Neuroimaging studies provide additional evidence for the role of the medial temporal lobes in episodic memory. Activation of the medial temporal region is observed during both initial registration of novel events and also during retrieval of recently acquired information [41, 42]. Medial temporal lobe activity is greater during the encoding of experiences that are later remembered versus those that are later forgotten [43, 44]. Episodic memory also depends on frontal lobe function. Although patients with frontal lobe lesions may demonstrate normal performance on tasks of recognition memory, prose recall, and some cued recall tasks, they typically show impairments on free recall, memory for temporal order, and source memory tasks [45]. These latter tasks depend on elaboration of information at encoding, as well as monitoring and decision processes at retrieval – strategic processes proposed to be mediated by frontal regions. On recognition tests, some patients with frontal lesions (primarily in the right hemisphere) make an unusually high number of errors in which items are designated as “old” when they in fact are “new” (i.e., false alarms) [46, 47]. Additionally, Levine and collaborators [48] reported the case of M.L., who after suffering closed head trauma, experienced a severe episodic retrograde amnesia: he was unable to remember any autobiographical experiences prior to the accident. Interestingly, M.L. did not experience anterograde amnesia, as he was still able to encode and further recall events occurring after the accident. M.L.’s pathology was restricted to the right ventral frontal lobe, including the uncinate fasciculus, while his hippocampus was intact. Taken together, these cases indicate that while the hippocampus is essential for encoding episodic information, the frontal lobes are essential for episodic recollection. Finally, the most recent conceptual development in our understanding of episodic memory is the relationship between remembering the past and imagining the future. When studying patient K.C. – an individual whose case offers the clearest known example of a dissociation between episodic memory and semantic memory [49] – researchers noted his inability to remember the past in concert with his inability to envision himself in the future. The capacity to think about

165


one’s future is related to the capacity to remember previous episodes from one’s life [50]; more specifically, these capacities share the same neural underpinnings [51–54] and are phenomenologically [55] and ontogenetically related [56].

Semantic memory Semantic knowledge encompasses a wide range of information, including facts about the world, the meanings of words and concepts, and the names attached to objects and people. Unlike episodic memories, semantic memories can be retrieved without associated information regarding the context in which they were acquired. By virtue of its diverse nature, not all forms of semantic knowledge share the same properties. Some forms of knowledge can be acquired after a single exposure (e.g., knowledge that Lisbon is the capital of Portugal), whereas other forms may be gradually acquired across multiple repetitions (e.g., understanding the concept “website”). Additionally, semantic information, when first encountered, may vary in the extent to which it is truly novel. For instance, semantic learning may involve establishing new associations between pre-existing representations in memory (e.g., learning that William Shakespeare wrote Romeo and Juliet) or acquiring a new label for information already represented in memory (e.g., foreign-language learning). Finally, a new label and a novel set of properties may be linked to each other (e.g., learning the meaning of the word “microbrew”). Neuropsychological studies of semantic memory have focused on brain lesions that selectively impair different stages of information processing (i.e., acquisition, storage, or retrieval) as well as the organization of knowledge. Evidence for the neural structures subserving the acquisition of new semantic knowledge has come primarily from studying patients with amnesia. Patients with extensive medial temporal lesions, such as amnesic H.M., are unable to acquire the meanings of words that entered the language after the onset of their amnesia [57, 58]. Some findings suggest that the integrity of structures surrounding the hippocampus (subhippocampal cortices) may be critical for new semantic learning. Vargha-Khadem and collaborators [59] reported three young amnestic individuals who sustained severe bilateral hippocampal atrophy as a result of anoxia. Importantly, their deficit appeared to be confined to episodic memory, as they were unable to remember or encode any specific events of their lives,

166

while their capacity to remember and learn new facts was preserved. Inspection of available neuroanatomic data revealed that in all three children, damage was limited to the hippocampus proper with sparing of subhippocampal cortices. These cases suggest that while the hippocampus is necessary for episodic memory, subhippocampal cortices may mediate semantic memory. Consistent with these findings, an adult patient with hippocampal and subhippocampal damage demonstrated profoundly impaired episodic and semantic learning, whereas another adult patient with only hippocampal damage had disproportionately preserved semantic learning [60]. Whereas subhippocampal cortices appear critical for acquiring new semantic information, these areas are not implicated in information storage. Studies of patients with semantic dementia or focal temporal lobe lesions suggest that semantic knowledge is stored/represented in the lateral temporal lobes in a distributed network of information [61, 62]. Memory retrieval requires interaction between retrieval cues and stored representations so as to trigger cortical storage sites to provide memory output. This retrieval process is thought to be mediated by inferolateral frontal and temporopolar regions, as patients with lesions in these areas, especially in the left hemisphere, have significant difficulty retrieving old semantic memories [63]. Neuroimaging studies also have shown activation in these areas when normal subjects make semantic judgments about objects or words [64]. Insight into the organization of semantic memory has come from investigating patients with circumscribed lesions who demonstrate category-specific knowledge deficits. An especially striking dissociation has been observed between knowledge of living and non-living things. Some patients have impaired knowledge of living things (e.g., animals and vegetables), but preserved knowledge of non-living things (e.g., tools and furniture), whereas other patients show the reverse pattern [65, 66]. One interpretation of category-specific deficits is that semantic memory is represented in the brain according to taxonomic categories. Another interpretation is that categories differ in their reliance on knowledge from different sensorimotor modalities, with living things known predominately by their visual attributes and non-living things by their function. Accordingly, category-specific knowledge deficits for living and non-living things may reflect impairments in the

Chapter 11: Memory

representation of visual and functional knowledge, respectively. Consistent with the neuropsychological literature, pioneering neuroimaging studies showed differential activations for category-specific stimuli. Using positron emission tomography (PET) scans, Martin and collaborators [67] found greater activation in left medial occipital cortex during naming pictures of animals relative to pictures of tools. In contrast, naming pictures of tools revealed greater activation in left premotor and middle temporal cortices. Additionally, several neuroimaging studies showed activation in left prefrontal cortices during semantic retrieval [68]. Perhaps the stronger piece of evidence supporting the observation that left-lateralized damage to the anterior temporal cortex affects semantic rather than episodic memory comes from patients suffering from semantic dementia. One of the best-documented cases of semantic dementia is patient A.M. [69]. Upon examination, A.M. showed severe difficulty remembering the names of things (anomia), even though his speech and prosody remained largely intact. Further testing revealed intact non-verbal episodic retrieval, evidenced by normal performance during tasks such as copying the Rey complex figure. More recently, Davies and collaborators [70], using post-mortem data from a group of seven individuals with semantic dementia cases, discovered that, relative to controls, semantic dementia was associated with anterior temporal atrophy, including parts of the perirhinal cortex, and preservation of adjacent areas in the temporal lobe. The extent to which other brain areas are implicated in semantic memory, as well as the nature of semantic representations in memory, remains an area of active scientific research.

Non-declarative memory Non-declarative memory refers to a variety of forms of memory in which learning is expressed as enhanced performance [71]. In this chapter, we focus on two forms of non-declarative memory: implicit memory and procedural memory.

Implicit memory Implicit memory describes a type of non-declarative memory in which previous experiences aid task performance without any requirement for conscious awareness of those previous experiences [72]. One well-studied form of implicit memory is repetition

priming (referred to as “priming” hereafter). A typical priming task is comprised of study and test phases. During the study phase, participants are exposed to a series of words, pictures, or objects. For example, they might see a word list that contains the word “turnip.” During the test phase, participants perform a seemingly unrelated task. For example, they might have to identify briefly flashed words or generate as many words as possible when cued with the semantic category “vegetable.” Priming is measured as the facilitation in task performance induced by recent exposure to task stimuli (e.g., enhanced accuracy in identifying or generating the word “turnip”), as compared with a baseline condition in which that word had not appeared on the prior study list. Studies in normal participants have identified two types of priming: perceptual priming, which requires analysis of the perceptual attributes of a stimulus (e.g., identification of perceptually degraded stimuli), and conceptual priming, which requires analysis of the meaning of a stimulus (e.g., category exemplar generation) [73]. Importantly, these two types of priming are differentially affected by experimental manipulations that vary the amount of overlap between study and test phases. A change in the perceptual format between study and test reduces perceptual priming, but has no impact on conceptual priming. Alternatively, enhanced conceptual priming occurs with elaborate processing of stimuli at study versus when only shallow processing occurs; this processing manipulation has no effect on perceptual priming. Neuropsychological investigations indicate that globally amnesic patients show intact performance on perceptual and conceptual priming tasks [74]. This finding suggests that the mnemonic operations involved in priming are not dependent on the medial temporal and diencephalic structures implicated in global amnesia. Like globally amnesic patients, AD patients have pathologic changes in limbic structures and show impairments on declarative memory tasks. Unlike amnesic patients, however, those with AD also have extensive neocortical pathology, particularly in frontal, temporal, and parietal association areas [75], and show impaired conceptual priming despite preserved perceptual priming [76, 77]. This pattern of impaired and preserved priming in AD suggests that conceptual priming processes may be localized to frontal, temporal, and parietal association areas that are compromised in AD. In contrast, perceptual priming processes may be localized to early

167


modality-specific cortices that are relatively spared in AD. Further neuropsychological evidence that perceptual priming is mediated by modality-specific cortices comes from patients with focal occipital lobe lesions who show impaired priming on visual perceptual tasks and preserved priming on conceptual tasks [78, 79]. Taken together, these findings lend strong support to the notion that perceptual and conceptual priming are mediated by separable neural substrates. Neuroimaging studies aimed at localizing priming processes are generally consistent with findings from clinical studies [80]. Visual perceptual priming is mediated by visual association areas, whereas conceptual priming is mediated by more anterior cortices (e.g., superior temporal and anterior frontal regions). Furthermore, these studies have demonstrated that the facilitation resulting from repeated processing of a stimulus is associated with decreased neural activation (also called response suppression) for repeated stimuli relative to new stimuli. Depending on the technique, the reduction in hemodynamic response can be measured as decreased regional cerebral blood flow (using PET) or as decreased blood oxygen-level dependent (BOLD) signal (using fMRI). Using event-related fMRI, Henson, Shallice and Dolan [81] presented a series of familiar faces and familiar symbols while subjects were instructed to search for a target. Simply viewing repeated faces or symbols was associated with decreased neural activation in the fusiform gyrus. Such decreases in neural activity have been interpreted to map onto the behavioral priming effect, as the facilitated, more efficient processing of previously perceived stimuli (see [82] for a thoughtful discussion of this issue). According to one model [83], such decreased activation reflects a neural tuning, or sharpening mechanism, in which only the neurons that respond best to the stimulus are recruited for reprocessing that stimulus at a later time (but see [82, 84] for important caveats with regard to this model). Neural priming is typically evident in areas of stimulus- or concept-specific processing, such as extrastriate cortex of the occipital lobe (for visually perceived stimuli), fusiform cortex (for object or face stimuli), primary auditory cortex in lateral temporal lobe (for aurally perceived stimuli), or inferior frontal gyrus (for priming of semantic information). More recently, Schacter and colleagues [85] reviewed numerous studies reporting reductions in cortical activity during priming. Their review

168

yielded several observations. First, prefrontal regions demonstrate sensitivity to both conceptual- and stimulus-decision mapping components of repetition priming. Robust correlations have been observed between the magnitude of behavioral priming and neural priming in this region, and trancranial magnetic stimulation (TMS) applied to the left prefrontal cortex (PFC) during semantic classification tasks disrupts subsequent behavioral priming. Second, regions in the lateral temporal cortex demonstrate sensitivity to conceptual components of repetition priming and, similar to prefrontal regions, respond amodally. Third, perceptual cortices demonstrate sensitivity to perceptual components of priming and tend not to be correlated with behavior during tasks that encourage conceptual or semantic priming. Neural priming in these regions demonstrates a gradient of stimulus specificity such that the degree of stimulus-specific priming decreases as one proceeds from early (posterior) to late (anterior) regions with the perceptual system, and there is a laterality effect (i.e., less specific in the left than right hemisphere) across later visual regions.

Procedural memory Procedural memory is involved in the acquisition of skills and habits, results from repeated practice, and is relatively impervious to the effects of decay or interference. Research studies investigating the acquisition of new perceptual-motor skills have employed simple tasks, such as mirror tracing or rotary pursuit. During mirror tracing, a participant uses a metal stylus to trace a geometric pattern seen in a mirror, while the geometric pattern and the individual’s hand are obscured from view by a board. Learning is measured by the reduction in time to complete tracing of the pattern, as well as the number of errors committed. During rotary pursuit, a participant is given a metal stylus that must be kept in contact with a revolving disk. Learning occurs as the individual becomes more proficient at matching his or her motor movement with the movement of the disk. Early studies of patient H.M. were among the first to establish that globally amnesic patients could acquire and retain new motor skills [33, 86]. Such findings are especially significant given that these patients are frequently unaware of having been previously exposed to the tasks. These results suggest that procedural memory is mediated by neural structures outside the medial temporal-diencephalic region.

Chapter 11: Memory

In contrast to amnesic patients, other neurological populations, such as PD and HD patients, have poor rotary pursuit learning [87]. Based on these data, it appears that the basal ganglia, which are compromised by these diseases, play a critical role in motor skill learning. However, basal ganglia lesions do not impair all motor skill tasks to the same extent; for example, Gabrieli and colleagues observed that HD patients demonstrate normal mirror tracing despite impaired rotary pursuit learning [88]. In contrast, patients with cerebellar lesions show impaired mirror tracing [89]. These observations suggest that the basal ganglia and cerebellum both contribute to motor skill learning but do so differentially: the basal ganglia are critical for sequence learning whereas the cerebellum is involved in error correction [88]. The perceptual skill that has been studied most extensively in neurological patients is learning to read text that has been geometrically transformed (such as reading mirror-reversed words). Current interest in perceptual skill learning was driven by the classic study of Cohen and Squire [90] in which they examined the performance of amnesic patients on the mirror reading task. The results of the study showed that the amnesic patients were able to learn to read mirrorreversed text as well as age-matched control participants, despite having poor declarative memory for the practice episodes and stimuli. Subsequent studies have replicated these findings in other groups of amnesic patients [91, 92]. Evidence for the role of the basal ganglia in perceptual skill learning comes from patients with HD, who show a mild impairment in mirror reading, despite good declarative memory for the words read [91]. Studies of mirror reading in patients with PD have been mixed, however, with some studies reporting impaired learning [93–95] and other studies reporting intact learning [96, 97]. Perceptual learning studies in healthy adults have used psychophysical tasks such as contrast detection, orientation, and visual search [98, 99]. This research suggests that perceptual learning proceeds in two stages: an initial learning stage, characterized by unskilled and effortful performance, that reflects establishment of task-specific processing routines; and a subsequent stage, ultimately leading to skilled performance, reflecting modification of representations within the processing system [100]. Accordingly, functional imaging studies have demonstrated different neural contributions in the

early versus later stages of skill learning. For instance, a study of mirror-reversed reading in normal subjects demonstrated that skill acquisition was accompanied by decreasing activation in regions including both occipital and right superior parietal cortices during initial learning, and increasing activation in regions including the left inferior temporal cortex later on [101]. On the basis of these results, it was proposed that learning to read mirror-reversed text may reflect a transition from right hemisphere visuospatial processing of mirror-reversed stimuli to left hemisphere object recognition areas involved in establishing new representations of mirror-reversed letters [101, 102]. Interestingly, in a follow-up study, Poldrack and Gabrieli [103] found that the caudate was active during initial mirror-reading and showed a significant learning-related increase in activation, consistent with the reported impairment of HD and PD patients in learning the mirror-reading task. In an analogous manner, studies investigating the acquisition of new motor skills have revealed that prefrontal and cerebellar regions are primarily activated early in the course of learning [104, 105]. As task proficiency increases, this activation gives way to a slowly evolving, long-term, experience-dependent reorganization of primary motor cortex [106]. More recent studies have further delineated the roles of prefrontal, cerebellar, and motor cortices during motor skill learning, as well as the parameters under which new motor skill learning occurs. For example, using fMRI and a motor sequence task, Doyon and colleagues [107] found evidence for an experienceinduced shift from the cerebellar cortex to the dentate nucleus during early learning, and from cerebellarcortical to striatal-cortical networks with extended practice; these findings suggest that intrinsic modulation within the cerebellum, together with activation of motor-related cortical activations, serves to establish a procedurally acquired sequence of movements. More recently, Doyon and colleagues [108] investigated the contribution of sleep to consolidation of two motor skills: finger tapping sequence learning (FTSL) and visuomotor adaptation (VMA). They demonstrated that the consolidation processes involved in the FTSL task benefited from sleep (even a short nap) while the simple passage of time was as effective as sleep time for the consolidation of VMA to occur. Such findings point to important task differences in the study of motor skill learning. Finally, Rozanov, Keren and Karni [109] examined the specificity of memory

169


for a highly trained finger movement sequence. Their results demonstrated that the gains attained in the performance of a well-trained sequence of motor movements can be expressed only when the order of the movements is exactly as practiced. These results may have important implications for the transfer of new motor skills in patient populations, particularly in neurorehabilitation efforts directed at improving motor functions impaired by injury or disease.

Conclusion Multiple human memory systems subserve the retention of knowledge, skills, experience, and emotions over a time frame that spans seconds to decades. Neural pathways that encode information within these overlapping systems are being elucidated with structural and functional brain imaging techniques and sophisticated cognitive test paradigms. Such work is enriching our understanding of component memory processes and has great potential for informing clinical diagnostic and therapeutic efforts. Translating research advancements in the cognitive neuroscience of memory into practical clinical assessments and interventions will be greatly facilitated by increased collaboration among basic scientists, clinical investigators, and clinicians.

References 1. Arciniegas D, McAllister TW, Kaufer D. Cognitive impairment. In Coffey CE, McAllister TW, Silver JM, editors. Guide to Neuropsychiatric Therapeutics. Philadelphia, PA: Lippincott Williams & Wilkins; 2007, pp. 24–78. 2. Budson AE. Understanding memory dysfunction. Neurologist 2009;15(2):71–9. 3. Baddeley A, Vallar G, Wilson B. Sentence comprehension and phonological memory: some neuropsychological evidence. In Colheart M, editor. Attention and Performance XII. London: Lawrence Erlbaum Associates; 1987, pp. 509–29. 4. Baddeley A, Hitch GJ. Working memory. In Bower GA, editor. The Psychology of Learning and Motivation. New York, NY: Academic Press; 1975, pp. 47–89. 5. Surprenant AM, Neath I, LeCompte DC. Irrelevant speech, phonological similarity, and presentation modality. Memory 1999;7(4):405–20. 6. Bishop DVM, Robson J. Unimpaired short-term-memory and rhyme judgment in congenitally speechless individuals – implications for the notion of articulatory coding. Q J Exp Psychol–A. 1989;41(1):123–40.

170

7. Chein JM, Fiez JA. Dissociation of verbal working memory system components using a delayed serial recall task. Cereb Cortex 2001;11(11):1003–14. 8. Muller NG, Knight RT. The functional neuroanatomy of working memory: contributions of human brain lesion studies. Neuroscience 2006;139(1):51–8. 9. Vallar G, Papagno C. Neuropsychological impairments of verbal short-term memory. In Baddeley AD, Kopelman MD, Wilson BA, editors. The Handbook of Memory Disorders. 2nd edition. New York, NY: John Wiley and Sons; 2002, pp. 249–70. 10. Vallar G, Papagno C. Neuropsychological impairments of short-term memory. In Baddeley AD, Wilson BA, Watts FN, editors. Handbook of Memory Disorders. Chichester: John Wiley and Sons; 1995, pp. 135–65. 11. Murray LL, Ramage AE, Hopper A. Memory impairments in adults with neurogenic communication disorders. Semin Speech Lang. 2001; 22(2):127–36. 12. Shallice T, Warrington EK. The possible role of selective attention in acquired dyslexia. Neuropsychologia 1977;15(1):31–41. 13. Awh E, Jonides J, Smith EE et al. Dissociation of storage and rehearsal in verbal working memory: evidence from positron emission tomography. Psychol Sci. 1996;7(1):25–31. 14. Gathercole SE. Cognitive approaches to the development of short-term memory. Trends Cogn Sci. 1999;3(11):410–19. 15. Brooks LR. The suppression of visualization by reading. Q J Exp Psychol. 1967;19(4):289–99. 16. Hanley JR, Young AW, Pearson NA. Impairment of the visuo-spatial sketch pad. Q J Exp Psychol A. 1991;43(1): 101–25. 17. Della Sala S, Gray C, Baddeley A, Allamano N, Wilson L. Pattern span: a tool for unwelding visuo-spatial memory. Neuropsychologia 1999;37(10):1189–99. 18. Della Sala S, Logie R. Neuropsychological impairments of visual and spatial working memory. In Baddeley AD, Kopelman MD, Wilson BA, editors. The Handbook of Memory Disorders. 2nd edition. New York, NY: John Wiley and Sons; 2002, pp. 271–92. 19. Postle BR, Ferrarelli F, Hamidi M et al. Repetitive transcranial magnetic stimulation dissociates working memory manipulation from retention functions in the prefrontal, but not posterior parietal, cortex. J Cogn Neurosci. 2006;18(10):1712–22. 20. Baddeley A. The episodic buffer: a new component of working memory? Trends Cogn Sci. 2000;4(11): 417–23. 21. Prabhakaran V, Narayanan K, Zhao Z, Gabrieli JD. Integration of diverse information in working memory

Chapter 11: Memory

within the frontal lobe. Nature Neuroscience 2000; 3(1):85–90. 22. Baddeley AD. Working Memory. Oxford: Clarendon Press; 1986. 23. Shallice T. Specific impairments of planning. Philos Trans R Soc Lond B Biol Sci. 1982;298(1089):199–209. 24. Baddeley AD, Bressi S, Della Sala S, Logie R, Spinnler H. The decline of working memory in Alzheimer’s disease. A longitudinal study. Brain 1991;114(Pt 6): 2521–42. 25. Smith EE, Jonides J. Storage and executive processes in the frontal lobes. Science 1999;283(5408):1657–61. 26. Kaufer D. Frontal lobe anatomy: dorsolateral and cingulate cortex. In Miller BL, Cummings JL, editors. The Human Frontal Lobes: Functions and Disorders. 2nd edition. New York, NY: Guilford Press; 2007, pp. 44–58. 27. Cowan N. Attention and Memory: an Integrated Framework. New York, NY: Oxford University Press; 1995. 28. Squire LR. Declarative and nondeclarative memory: multiple brain systems supporting learning and memory. In Andersen P et al., editors. Memory Concepts – 1993: Basic and Clinical Aspects. Proceedings of the 7th Novo Nordisk Foundation Symposium “Memory Concepts-1993”, Copenhagen, Denmark, 28–30 June 1993. Amsterdam: Excerpta Medica; 1993, pp. 3–25. 29. Tulving E. Elements of Episodic Memory. Oxford: Clarendon Press; 1983. 30. Tulving E. Episodic memory: from mind to brain. Annu Rev Psychol. 2002;53:1–25.

37. Nadel L, Moscovitch M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol. 1997;7(2):217–27. 38. Aggleton JP, Brown MW. Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci. 1999;22(3):425–44; discussion 4:44–89. 39. Rugg MD, Yonelinas AP. Human recognition memory: a cognitive neuroscience perspective. Trends Cogn Sci. 2003;7(7):313–19. 40. Cohen NJ, Eichenbaum H. Memory, Amnesia, and the Hippocampal System. Cambridge, MA: MIT Press; 1993. 41. Gabrieli JD, Brewer JB, Desmond JE, Glover GH. Separate neural bases of two fundamental memory processes in the human medial temporal lobe. Science 199;276(5310):264–6. 42. Nyberg L, McIntosh AR, Houle S, Nilsson LG, Tulving E. Activation of medial temporal structures during episodic memory retrieval. Nature 1996;380(6576): 715–17. 43. Brewer JB, Zhao Z, Desmond JE, Glover GH, Gabrieli JD. Making memories: brain activity that predicts how well visual experience will be remembered. Science 1998;281(5380):1185–7. 44. Wagner AD, Schacter DL, Rotte M et al. Building memories: remembering and forgetting of verbal experiences as predicted by brain activity. Science 1998;281(5380):1188–91. 45. Shimamura AP. Memory and frontal lobe function. In Gazzaniga MS, Bizzi E, editors. The Cognitive Neurosciences. Cambridge, MA: MIT Press; 1995, pp. 803–13.

31. Yonelinas AP. The nature of recollection and familiarity: a review of 30 years of research. J Mem Lang. 2002;46(3):441–517.

46. Rapcsak SZ, Reminger SL, Glisky EL, Kaszniak AW, Comer JF. Neuropsychological mechanisms of false facial recognition following frontal lobe damage. Cogn Neuropsych. 1999;16(3–5):267–92.

32. Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 1957;20(1):11–21.

47. Schacter DL, Curran T, Galluccio L, Milberg WP, Bates JF. False recognition and the right frontal lobe: a case study. Neuropsychologia 1996;34(8):793–808.

33. Milner B, Corkin S, Teuber HL. Further analysis of the hippocampal amnesic syndrome: 14-year follow-up study of H.M. Neuropsychologia 1968;6(3):215–34.

48. Levine B, Black SE, Cabeza R et al. Episodic memory and the self in a case of isolated retrograde amnesia. Brain 1998;121(Pt 10):1951–73.

34. Ribot T. Les maladies de la mémoire. Paris: Libraire Germer Baillere; 1881.

49. Tulving E. Memory and consciousness. Can Psychol. 1985;26(1):1–12.

35. McClelland JL, McNaughton BL, O’Reilly RC. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol Rev. 1995;102(3):419–57.

50. Atance CM, O’Neill DK. The emergence of episodic future thinking in humans. Learn Motiv. 2005;36(2): 126–44.

36. Squire LR, Alvarez P. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol. 1995;5(2):169–77.

51. Addis DR, Wong AT, Schacter DL. Remembering the past and imagining the future: common and distinct neural substrates during event construction and elaboration. Neuropsychologia 2007;45(7):1363–77. 52. Klein S, Loftus J, Kihlstrom JF. Memory and temporal experience: the effects of episodic memory loss on an

171


amnesic patient’s ability to remember the past and imagine the future. Social Cogn. 2002;20(5):353–79. 53. Szpunar KK. Episodic future thought: an emerging concept. Perspect Psychol Sci. 2010;5(2):142–62. 54. Okuda J, Fujii T, Ohtake H et al. Differential involvement of regions of rostral prefrontal cortex (Brodmann area 10) in time- and event-based prospective memory. Int J Psychophysiol. 2007;64(3): 233–46. 55. D’Argembeau A, Van der Linden M. Phenomenal characteristics associated with projecting oneself back into the past and forward into the future: influence of valence and temporal distance. Conscious Cogn. 2004;13(4):844–58. 56. Suddendorf T. Episodic memory versus episodic foresight: Similarities and differences. WIREs Cogn Sci. 2010;1(1):99–107. 57. Gabrieli JD, Cohen NJ, Corkin S. The impaired learning of semantic knowledge following bilateral medial temporal-lobe resection. Brain Cogn. 1988; 7(2):157–77. 58. Verfaellie M, Croce P, Milberg WP. The role of episodic memory in semantic learning: an examination of vocabulary acquisition in a patient with amnesia due to encephalitis. Neurocase 1995;1(4):291–304. 59. Vargha-Khadem F, Gadian DG, Watkins KE et al. Differential effects of early hippocampal pathology on episodic and semantic memory. Science 1997; 277(5324):376–80. 60. Verfaellie M, Koseff P, Alexander MP. Acquisition of novel semantic information in amnesia: effects of lesion location. Neuropsychologia 2000;38(4): 484–92.

67. Martin A, Wiggs CL, Ungerleider LG, Haxby JV. Neural correlates of category-specific knowledge. Nature 1996;379(6566):649–52. 68. Nyberg L, Cabeza R, Tulving E. PET studies of encoding and retrieval: the HERA model. Psychon B Rev. 1996;3(2):135–48. 69. Hodges JR, Graham KS. A reversal of the temporal gradient for famous person knowledge in semantic dementia: implications for the neural organisation of long-term memory. Neuropsychologia 1998;36(8): 803–25. 70. Davies RR, Halliday GM, Xuereb JH, Kril JJ, Hodges JR. The neural basis of semantic memory: evidence from semantic dementia. Neurobiol Aging 2009; 30(12):2043–52. 71. Squire LR. Declarative and nondeclarative memory – multiple brain systems supporting learning and memory. J Cognitive Neurosci. 1992;4(3):232–43. 72. Schacter DL. Implicit memory: history and current status. J Exp Psychol. 1987;13:501–18. 73. Roediger III HL, McDermott KB. Implicit memory in normal human subjects. In Spinnler H, Boller F, editors. Handbook of Neuropsychology. Amsterdam: Elsevier; 1993, pp. 63–130. 74. Schacter DL, Chiu CY, Ochsner KN. Implicit memory: a selective review. Annu Rev Neurosci. 1993; 16:159–82. 75. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1991;1(1):103–16.

61. Alexander MP. Specific semantic memory loss after hypoxic-ischemic injury. Neurology 1997;48(1): 165–73.

76. Gabrieli JD, Keane MM, Stanger BZ et al. Dissociations among structural-perceptual, lexical-semantic, and event-fact memory systems in Alzheimer, amnesic, and normal subjects. Cortex 1994;30(1):75–103.

62. Kapur N, Ellison D, Parkin AJ et al. Bilateral temporal lobe pathology with sparing of medial temporal lobe structures: lesion profile and pattern of memory disorder. Neuropsychologia 1994;32(1):23–38.

77. Keane MM, Gabrieli JD, Fennema AC, Growdon JH, Corkin S. Evidence for a dissociation between perceptual and conceptual priming in Alzheimer’s disease. Behav Neurosci. 1991;105(2):326–42.

63. Kroll NE, Markowitsch HJ, Knight RT, von Cramon DY. Retrieval of old memories: the temporofrontal hypothesis. Brain 1997;120(Pt 8):1377–99.

78. Gabrieli JDE, Fleischman DA, Keane MM, Reminger SL, Morrell F. Double dissociation between memory-systems underlying explicit and implicit memory in the human brain. Psychol Sci. 1995;6(2): 76–82.

64. Kapur S, Craik FI, Tulving E et al. Neuroanatomical correlates of encoding in episodic memory: levels of processing effect. Proc Natl Acad Sci USA 1994;91(6): 2008–11. 65. Warrington EK, Shallice T. Category specific semantic impairments. Brain 1984;107(Pt 3):829–54.

79. Keane MM, Gabrieli JD, Mapstone HC, Johnson KA, Corkin S. Double dissociation of memory capacities after bilateral occipital-lobe or medial temporal-lobe lesions. Brain 1995;118(Pt 5):1129–48.

66. Warrington EK, McCarthy R. Category specific access dysphasia. Brain 1983;106(Pt 4):859–78.

80. Schacter DL, Buckner RL. Priming and the brain. Neuron 1998;20(2):185–95.

172

Chapter 11: Memory

81. Henson R, Shallice T, Dolan R. Neuroimaging evidence for dissociable forms of repetition priming. Science 2000;287(5456):1269–72.

95. Yamadori A, Yoshida T, Mori E, Yamashita H. Neurological basis of skill learning. Brain Res Cogn Brain Res. 1996;5(1–2):49–54.

82. Henson RN, Rugg MD. Neural response suppression, haemodynamic repetition effects, and behavioural priming. Neuropsychologia 2003;41(3):263–70.

96. Bondi MW, Kaszniak AW. Implicit and explicit memory in Alzheimer’s disease and Parkinson’s disease. J Clin Exp Neuropsychol. 1991;13(2):339–58.

83. Wiggs CL, Martin A. Aging and feature-specific priming of familiar and novel stimuli. Psychol Aging 1994;9(4):578–88.

97. Harrington DL, Haaland KY, Yeo RA, Marder E. Procedural memory in Parkinson’s disease: impaired motor but not visuoperceptual learning. J Clin Exp Neuropsychol. 1990;12(2):323–39.

84. Grill-Spector K, Henson R, Martin A. Repetition and the brain: neural models of stimulus-specific effects. Trends Cogn Sci. 2006;10(1):14–23. 85. Schacter DL, Dobbins IG, Schnyer DM. Specificity of priming: a cognitive neuroscience perspective. Nat Rev Neurosci. 2004;5(11):853–62. 86. Corkin S. Acquisition of motor skill after bilateral medial temporal-lobe excision. Neuropsychologia 1968;6(3):255–65. 87. Heindel WC, Salmon DP, Shults CW, Walicke PA, Butters N. Neuropsychological evidence for multiple implicit memory systems: a comparison of Alzheimer’s, Huntington’s, and Parkinson’s disease patients. J Neurosci. 1989;9(2):582–7. 88. Gabrieli JD, Stebbins GT, Singh J, Willingham DB, Goetz CG. Intact mirror-tracing and impaired rotary-pursuit skill learning in patients with Huntington’s disease: evidence for dissociable memory systems in skill learning. Neuropsychology 1997;11(2): 272–81.

98. Chun MM, Jiang Y. Contextual cueing: implicit learning and memory of visual context guides spatial attention. Cogn Psychol. 1998;36(1):28–71. 99. Karni A, Bertini G. Learning perceptual skills: behavioral probes into adult cortical plasticity. Curr Opin Neurobiol. 1997;7(4):530–5. 100. Karni A, Sagi D. The time course of learning a visual skill. Nature 1993;365(6443):250–2. 101. Poldrack RA, Desmond JE, Glover GH, Gabrieli JD. The neural basis of visual skill learning: an fMRI study of mirror reading. Cereb Cortex 1998;8(1):1–10. 102. Poldrack RA. Neural systems for perceptual skill learning. Behav Cogn Neurosci Rev. 2002;1(1):76–83. 103. Poldrack RA, Gabrieli JD. Characterizing the neural mechanisms of skill learning and repetition priming: evidence from mirror reading. Brain 2001;124(Pt 1): 67–82.

89. Sanes JN, Dimitrov B, Hallett M. Motor learning in patients with cerebellar dysfunction. Brain 1990; 113(Pt 1):103–20.

104. Friston KJ, Frith CD, Passingham RE, Liddle PF, Frackowiak RSJ. Motor practice and neurophysiological adaptation in the cerebellum – a positron tomography study. Proc R Soc Lond Series B. 1992;248(1323):223–8.

90. Cohen NJ, Squire LR. Preserved learning and retention of pattern-analyzing skill in amnesia: dissociation of knowing how and knowing that. Science 1980;210(4466):207–10.

105. Jenkins IH, Brooks DJ, Nixon PD, Frackowiak RS, Passingham RE. Motor sequence learning: a study with positron emission tomography. J Neurosci. 1994; 14(6):3775–90.

91. Martone M, Butters N, Payne M, Becker JT, Sax DS. Dissociations between skill learning and verbal recognition in amnesia and dementia. Arch Neurol. 1984;41(9):965–70.

106. Karni A, Meyer G, Jezzard P et al. Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature 1995;377(6545):155–8.

92. Schmidtke K, Handschu R, Vollmer H. Cognitive procedural learning in amnesia. Brain Cogn. 1996; 32(3):441–67.

107. Doyon J, Song AW, Karni A et al. Experiencedependent changes in cerebellar contributions to motor sequence learning. Proc Natl Acad Sci USA 2002;99(2):1017–22.

93. Koenig O, Thomas-Anterion C, Laurent B. Procedural learning in Parkinson’s disease: intact and impaired cognitive components. Neuropsychologia 1999;37(10): 1103–9.

108. Doyon J, Korman M, Morin A et al. Contribution of night and day sleep vs. simple passage of time to the consolidation of motor sequence and visuomotor adaptation learning. Exp Brain Res. 2009;195(1):15–26.

94. Roncacci S, Troisi E, Carlesimo GA, Nocentini U, Caltagirone C. Implicit memory in parkinsonian patients: evidence for deficient skill learning. Eur Neurol. 1996;36(3):154–9.

109. Rozanov S, Keren O, Karni A. The specificity of memory for a highly trained finger movement sequence: change the ending, change all. Brain Res. 2010;1331:80–7.

173

Section I


Chapter

Language

12

Mario F. Mendez

Language is the distinctive human facility for communication through symbols. The expression of language includes all symbolic communication, including speech, reading and writing, sign language, Braille, Morse code, and even musical notation. Language evolved during the last 2.5 million years from a primitive system of individual sounds with concrete referents to strings or sequences of symbols with abstract and generalizable meanings. The main processes of language are the decoding and encoding of sequences of symbols and associating them with concepts and meanings [1]. How is language organized in the brain? Our basic understanding of the neuroanatomy of language and the brain is based on a classical lesion model derived from the study of brain-injured patients in the nineteenth and early twentieth centuries. Clinicians identified the existence of dedicated language centers from the observation of different language impairments after brain lesions in these areas or their interconnecting fiber tracts. Today, we know that the elements of language are not as fixed as defined by the classical lesion model, and that the neuroanatomy of language is complex. Rapid advances in cognitive neuroscience indicate the existence of mental lexicons or dictionaries and processes for phonology, morphology, syntax, semantics, and other features, all interacting in a rapid, large-capacity system. In this neurocomputational system composed of rapid processing streams, there is simultaneous activation at multiple levels and top-down, as well as bottom-up, influences on language production and language comprehension. This chapter describes the neuroanatomy of language beginning with the foundation in the classical lesion model and concludes with an updated view of language-brain organization.

Figure 12.1. Brain of Paul Broca’s original patient M. Leborgne, commonly known as “Tan Tan.” Reproduced from Dronkers NF, Plaisant O, Iba-Zizen MT, Cabanis EA. Paul Broca’s historic cases: high resolution MR imaging of the brains of Leborgne and Lelong. Brain 2007;130(Pt 5):1432–41, with permission from Oxford University Press.

Classical lesion model of language and the brain Clinical aphasia or language impairments from brain lesions have been the window to localization of language in the brain. In 1861, Paul Broca inaugurated the modern study of language with a description of his patient “Tan Tan” who had lost the ability to speak from a focal brain injury in the inferior frontal region (see Figure 12.1) [2]. Later, Broca reported on the association of impaired verbal fluency with left inferior frontal damage in what came to be known as “Broca’s area” (see Figure 12.2). In 1874, Karl Wernicke described aphasia from loss of language comprehension consequent to left superior temporal injury. He then elaborated a group of specialized and interconnected


174

Chapter 12: Language

Figure 12.2. Lateral view of the left hemisphere indicating the perisylvian area. The illustration shows Broca’s area in the frontal operculum and Wernicke’s area in the superior temporal gyrus and the corresponding Brodmann’s areas. Reprinted with permission from Mark Dubin, PhD, Department of Molecular, Cellular & Developmental Biology, University of Colorado at Boulder (http://spot.colorado.edu/∼dubin/talks/brodmann/brodmann.html). This figure is presented in color in the color plate section.

language regions in the left perisylvian region. The early work of Broca, Wernicke, and others established the dominance of the left hemisphere for language and demonstrated an anterior-posterior dichotomy around the Sylvian fissure, with two hubs, Broca’s area (Brodmann’s area [BA] 44, 45) for language production in the inferior frontal region and Wernicke’s area (BA 22) for language comprehension in the superior temporal gyrus (Figure 12.2). Norman Geschwind subsequently described how disconnection of cortical centers, such as Broca’s and Wernicke’s, can produce distinct language and other syndromes [3, 4]. This localization concept is embodied in the classical lesion or “Wernicke–Geschwind” model of language and the corresponding aphasia syndromes [5] (Figure 12.3).

Each classic aphasic syndrome suggests a neuroanatomical association of a specific language function (Table 12.1). Broca’s aphasics are non-fluent and have difficulty encoding language, using grammar, and articulating words and sentences. This profile suggests that Broca’s area processes grammatical structure, including syntactic rules and grammatical morphemes, rather than elements of language that have content or specific meaning. It also suggests that a major role of Broca’s area is the articulation of language. Wernicke’s aphasics, on the other hand, are fluent but have difficulty decoding and understanding language. This suggests that Wernicke’s area selects and uses elements of language with concrete meaning, including content words. Conduction aphasia is a

175


Table 12.1. The aphasia syndromes and their characteristics.

Aphasia syndrome

Fluency

Auditory comprehension

Repetition

Naming

Reading comprehension

Writing

Broca’s

Abnormal

Relatively normal

Abnormal

Abnormal

Normal or abnormal

Abnormal

Wernicke’s

Normal, paraphasic

Abnormal

Abnormal

Abnormal

Abnormal

Abnormal

Global

Abnormal

Abnormal

Abnormal

Abnormal

Abnormal

Abnormal

Conduction

Normal, paraphasic

Relatively normal

Abnormal

Usually abnormal

Relatively normal

Abnormal

Transcortical motor

Abnormal

Relatively normal

Relatively normal

Abnormal

Relatively normal

Abnormal

Transcortical sensory

Normal, echolalic

Abnormal

Relatively normal

Abnormal

Abnormal

Abnormal

Mixed transcortical

Abnormal, echolalic

Abnormal

Relatively normal

Abnormal

Abnormal

Abnormal

Anomic

Normal

Relatively normal

Normal

Abnormal

Normal or abnormal

Normal or abnormal

Transcortical motor aphasia

Broca’s aphasia

Concepts

Motor patterns

Figure 12.3. Wernicke–Geschwind model. The diagram illustrates the organization of language and corresponding aphasia syndromes in the left hemisphere.

Transcortical sensory aphasia

Auditory images

Wernicke’s aphasia

Conduction aphasia

m

third perisylvian aphasia, and is due to the disconnection of Broca’s and Wernicke’s areas. This disorder features a prominent disturbance in repetition out of proportion to any other language disturbance. Most cases of conduction aphasia have neuropathology involving the anterior inferior parietal lobe, including the arcuate fasciculus and the supramarginal gyrus [6]. Additional syndromes localize outside of the perisylvian region in the Wernicke–Geschwind model [7]. Transcortical motor and transcortical sensory aphasias have relative preservation of the ability to repeat spoken language in the presence of language impairments otherwise consistent with Broca’s aphasia

176

a

or Wernicke’s aphasia, respectively. The neuropathologic lesion underlying transcortical motor aphasia is in the supplementary motor area of the left hemisphere or between that area and Broca’s area. The neuropathologic lesion underlying transcortical sensory aphasia is in the left angular gyrus in the parietal region or in the left posterior superior or middle temporal gyri. Subcortical aphasias can result from lesions in the left basal ganglia, the anterolateral nuclei of the thalamus, or white matter [8]. Language impairment from the basal ganglia may resemble transcortical motor aphasia, and language impairment from the thalamus may resemble transcortical sensory aphasia. With these “subcortical” aphasias, cortical involvement or


distal hypometabolism is probably necessary for permanent language changes [9, 10]. Alexias are characterized by the inability to read with or without accompanying agraphia, the inability to write. Alexia with agraphia can result from left angular gyrus lesions, and alexia without agraphia from lesions in the left visual occipital region combined with damage to the splenium of the corpus callosum. Finally, frontal lesions involving motor areas impair speech, or the motor aspects of verbal communication, and can produce dysarthria, apraxia of speech, reiterative speech disorders, and even mutism.

Problems with the classical lesion model The classical lesion model does not address a number of critical aspects of language organization and the brain. The model does not formally consider basic linguistic elements such as phonology (the sound pattern of language), morphology (the combination of language’s smallest meaningful units), syntax (the structure of sentences), semantics (the relationship of language to meaning), and pragmatics (intonation, gesture, and other aspects of discourse). In addition, the model does not consider the speed with which children acquire language and the related suggestion by Chomsky that there is a brain region or process that restricts the set of possible human grammars and thereby facilitates language acquisition [11]. Finally, the classical lesion model does not consider brain plasticity or the effects of age, sex, and handedness. The greatest challenge to the classical lesion model, however, comes from advances in neuroimaging and related methodologies. For a long time, information about how the brain processed language could only come from the study of the effects of neurological disease in humans. In the last few decades, many imaging technologies have expanded our understanding of language and the brain, and moved us beyond dependency on the lesion model. These include voxelbased morphometry, positron and single photon emission tomography, functional magnetic resonance imaging, special analyses of electroencephalograms, magnetoencephalography, and transcortical magnetic stimulation. These methodologies have dramatically expanded our understanding of the neuroanatomic relationships and functional connectivity of language organization in the brain [12, 13] (Figure 12.4). Using these methodologies, investigators have challenged the basic assumptions of the classical lesion

model. First, damage to more than Broca’s area is needed to cause Broca’s aphasia. Although Broca’s area does participate in syntactic processing and the execution of articulatory movements, lesions confined to Broca’s area may not result in language production deficits [14]. Lesions of the two sections of Broca’s area, the pars triangularis (BA 44) and the pars opercularis (BA 45), are not sufficient or necessary for Broca’s aphasia. In fact, a re-analysis of the preserved brains of Broca’s two original patients confirmed that their lesions extended well beyond BA 44 and 45, deep into the white matter, and involved the insula and the superior longitudinal fasciculus [2]. The anterior insula, which is implicated in the labored articulation and non-fluency, or apraxia of speech, is evident in Broca’s aphasia [15]. This suggests that the complete Broca’s aphasia syndrome is predicated on injury not only to Broca’s area but also to the white matter underlying Broca’s area and to the anterior insula. Second, Wernicke’s aphasia requires more than damage to Wernicke’s area alone. Although Wernicke’s area plays a role in word comprehension, isolated destruction of this area does not necessarily result in decreased auditory comprehension. Involvement of the underlying white matter and adjacent areas, such as the supramarginal and angular gyri in the inferior parietal region, is necessary for a complete disturbance of auditory verbal comprehension [16]. So, neither Broca’s area lesions nor Wernicke’s area lesions are necessary or sufficient for Broca’s aphasia and Wernicke’s aphasia, respectively, challenging the usefulness of the classical lesion model of aphasia.

Current views on language and the brain New data support some of the aspects of the classical lesion model of aphasia but dispute or modify others. There is continued support for a left hemispheric specialization for language in the perisylvian region. Recent studies, however, have modified the classic role of Broca’s area. Similarly, recent studies have also modified the classic role of Wernicke’s area. Additionally, more recent characterizations of uncommon language disorders add to our understanding of language and the brain. Finally, lesion re-analysis and functional neuroimaging point to a new organization based on a neurocomputational model of rapid processing streams in which language areas are embedded within complex and highly interconnected networks.

177


Figure 12.4. Examples of language mapping in the frontal lobe (A) and the combined temporal and parietal lobes (B). Yellow and green circles represent numbered electrocortical stimulation mapping (ESM) language sites and clean ESM sites, respectively. Red boxes represent expression fMR imaging activations. Blue boxes represent comprehension fMR imaging activations. The frontal lobe slices are shown with an ESM radius of 5 mm (determined to produce the highest sensitivity with the least cost to specificity) and temporoparietal lobe slices are shown with an ESM radius of 9 mm. A: For frontal lobe mapping, these brain slices demonstrate that red (expression) activations tend to overlap with, or are adjacent to, essential (yellow) ESM sites, but avoid non-essential (green) ESM sites. Blue activations in the frontal lobe also appear predictive. B: In most cases of temporoparietal lobe mapping, such as the one illustrated here, comprehension fMR imaging

178


Hemispheric specialization The perisylvian area of the language-dominant hemisphere most closely approximates a “language organ” in the human brain. Broca suggested an association between the dominant hand and the dominant hemisphere for language [17], and almost all right-handed persons are left hemisphere dominant for language. Among aphasics, left hemisphere lesions occur in 92% or more of all patients, nearly 100% if they are righthanded, but only about 63% if they are left-handed. Most non-right-handed (left-handed and ambidextrous) persons are also left hemisphere language dominant, although they usually have additional language representation in the right hemisphere. The greater bilaterality of language in most left-handers decreases the clinical value of the classic aphasia syndromes in these patients. Henri Hecaen distinguished familial left-handers with a decreased left hemisphere predominance of language and a greater likelihood of hemispheric symmetry for language compared with righthanders [18]. Neuroanatomic evidence for this organization is the relative absence of hemisphere asymmetry of the planum temporale, which contains Wernicke’s area, in familial left-handers. The planum temporale, an enlargement located on the posterior surface of the temporal lobe, is larger on the left in 65 of 100 post-mortem brains [19]. Most right-handers have a larger planum temporale in the left hemisphere compared with the right, and this asymmetry is evident at about 30 weeks of gestation. In contrast to the left hemisphere, the right hemisphere has a dominant role for emotional features, including determining the emotional prosodic aspects of communication and the emotional state of a speaker from tone of voice [20]. There is increased metabolic activity, cerebral blood flow, and neural activity in perisylvian areas of the left hemisphere when subjects are using

language [21]. In comparison, language is temporarily disrupted with sodium amytal injection into the left carotid artery or with electrical charges sent to certain areas of the left hemisphere [22]. Patients who have undergone a “split-brain” procedure with transection of the corpus callosum cannot name objects visible only in the left visual field or held in their left hand [23]. In addition, normal individuals perceive spoken words or phonemes better in the right ear than in the left [24].

Alternative role for Broca’s area Rather than a static seat of grammar or speech articulation, Broca’s area is part of a processing stream of lexical integration that forms sentences. It appears to be a node through which linguistic units are combined and broken down, selected and compared, and also through which integration of the syntactic, semantic, and phonological elements into sentences is accomplished prior to their expression. First, Broca’s area (BA 44, 45) engages other brain areas in which mental lexicon (or dictionary) is represented and facilitates selections of words of interest (lexical selection). Second, it assigns and constructs grammatical structures (“lemmas” or grammatical morphological aspect of words) so as to relate words to each other. This process occurs at the word level, with grammatical morphemes and function words, and at the sentence level with syntax [25]. The words require semantic integration into the context of preceding words in a sentence for the sequences of words to have meaning. Third, Broca’s area constructs a phonological output lexicon. Phonological encoding involves activating word sounds (phonemes, syllables) and monitoring and segmenting them. Through this phonological encoding, Broca’s area plays a role in speech perception, and phoneme, syllable, and word discrimination and identification [14]. Fourth, phonetic encoding precedes actual articulation. This information is

← Figure 12.4. (cont.) activations matched well with ESM language sites (yellow) in the temporoparietal lobes and did not overlap with clean ESM sites (green). Very little expression fMR imaging activations are seen in the temporoparietal lobe region and the reason why such tasks as verbal object naming and word generation do not accurately predict language sites in these regions. C: These maps were obtained in an individual case in which preoperative fMR imaging was the least effective at accurately predicting whether a given cortical area would be involved in language function. In this case, only two of the three essential ESM sites overlapped with fMR imaging activations, and only two of seven of the clean ESM sites completely avoided fMR imaging activations. Reproduced from Pouratian N, Bookheimer SY, Rex DE, Martin NA, Toga AW. Utility of preoperative functional magnetic resonance imaging for identifying language cortices in patients with vascular malformations. J Neurosurg. 2002;97(1):21–32, with permission of Journal of Neurosurgery Publishing Group. This figure is presented in color in the color plate section.

179


conveyed to motor areas including the anterior insula and supplementary motor area. The cortex just in front of the face part of the motor strip is involved in the control of movements of the mouth, jaw, tongue, palate, larynx and other articulators that are needed for speech, and the anterior insula functions to select and sequence phonemes. Finally, other dorsolateral and ventromedial frontal areas participate in short-term memory for language, retrieval and manipulation of semantic representations, and social elements of discourse such as topic initiation, turn-taking, and personal references. The alternative role of Broca’s area explains many problems seen among persons with Broca’s aphasia. These individuals do not use action words (verbs), function words, and inflections correctly, and they have difficulty connecting morphemes to build words [26]. When comprehension is dependent on understanding the syntactical information in a sentence, individuals with Broca’s aphasia demonstrate comprehension impairments and difficulty integrating words into the context of a sentence [14]. They also demonstrate difficulty discriminating or identifying phonemes or speech syllables and pronouncing new or unfamiliar words, reflecting problems with the phonological output lexicon [27].

Alternative role for Wernicke’s area Wernicke’s area is part of a processing stream that accesses and selects from the mental lexicon, which in turn, activates related concepts or semantics. First, prelexical acoustic or phonetic analysis takes place bilaterally in the left superior temporal gyrus [14]. This region partially segregates different vowel categories suggestive of initial stages of speech sound mapping [28]. These acoustic or phonetic percepts are mapped as a phonological input code in the left midsuperior temporal gyrus. In reading, letters and the orthographic input code are also integrated in the left superior temporal cortex [29]. Second, word recognition requires lexical access and selection from the phonological input lexicon or the best-fitting auditory word forms in the left superior temporal sulcus. The left ventral mid-superior temporal sulcus appears to discriminate speech sounds (words, pseudo-words, reversed speech) from non-speech sounds. Third, word recognition further requires activated word form representations that are subsequently combined with

180

grammatical features (lemma). Fourth, these lexicalphonological elements access a semantic network of contextual and background knowledge. The left midinferior temporal gyrus and anterior temporal pole store and retrieve these semantic word representations. Some individuals with lesions in Wernicke’s area have preserved phoneme discrimination and identification (phonological information) but impaired access to semantics, possibly from damage in the left posterior inferior temporal region (BA 37). Finally, there is a working memory capacity specific to sentence processing that is different for that tapped by span tasks. The alternative role of Wernicke’s area explains many of the language problems experienced by persons with Wernicke’s aphasia. These individuals perceive speech sounds normally but are unable to access the phonological input lexicon and/or auditory word forms. Consequently, they produce erroneous but well-articulated words, paraphasic errors, or neologisms rather than appropriate content words. In Wernicke’s aphasia, content words tend to be absent or replaced by general terms or associations based on context.

Contributions of other language disorders Clarification of several uncommon conditions has added to our understanding of language and the brain. Pure word deafness is a pre-language disturbance from bilateral or unilateral lesions undercutting Wernicke’s area and causing impaired comprehension of speech sounds but not of most non-speech sounds. This disorder suggests that there are different systems for speech and non-speech auditory perception [14]. Patients with pure word deafness have deficits at the level of extracting the acoustic cues to speech due to difficulty in perceiving rapid changes in complex pitch patterns. Pure word deafness further indicates that speech perception depends on the ability to perceive rapid temporal changes. Pure anomia or “word-selection” anomia is a disturbance from left inferior, posterior temporal (BA 37) lesions causing confrontation naming difficulty with intact word comprehension. This disorder suggests that this region is crucial for the retrieval of phonological word forms, and that these word forms are dissociable from semantic knowledge [14]. Progressive non-fluent aphasia results from left frontotemporal atrophy and presents with gradual


Figure 12.6. Diffusion tensor imaging pathways in conduction aphasia. Reproduced from Catani M, Jones DK, Ffytche DH. Perisylvian language networks of the human brain. Ann Neurol. 2005;57(1):8–16, with permission from John Wiley & Sons, Inc. This figure is presented in color in the color plate section.

input lexicon, and associated with posterior temporalinferior parietal dysfunction [34]. Figure 12.5. MRI (T2) images of a patient with semantic aphasia. There is bilateral anterior temporal atrophy disproportionately affecting the left temporal lobe.

progression of non-fluency, agrammatism, and articulation difficulty [30, 31]. Recent information indicates that much of the non-fluency may be apraxia of speech from extension of the atrophy to the underlying left anterior insular cortex [15]. Semantic dementia includes semantic aphasia and is associated with atrophy in the anterior, infero-lateral temporal lobe; in this dementia, the aphasia involves impaired understanding of word meaning, often disproportionately affecting specific word categories [32, 33] (Figure 12.5). This profile indicates that the semantic system is organized and coordinated from the anterior temporal poles. On reading, these patients also demonstrate “surface dyslexia,” or the inability to read irregularly spelled words but preserved ability to sound them out, emphasizing the dual route model of reading. Deep dyslexia is a reading disorder from large left hemisphere lesions resulting in residual reading for meaning only. Deep dyslexia, with its access to semantics but difficulty in single-word repetition, supports independent phonological input and output lexicons. Finally, investigators recently described a “logopenic” form of aphasia characterized by difficulty with a phonological store, possibly a part of the phonological

Neurocomputational model Language is organized in a complex and highly interconnected network engaged in successive integration of information. Linguistic functions result from distributed groups of connected neurons organized around two processing hubs, Broca’s area and Wernicke’s area, in the perisylvian region of the languagedominant hemisphere. These areas form a central axis of interconnected nodes enabling nearly simultaneous iterative computation of the “best fit” needed for a linguistic task, depending on top-down, as well as bottom-up, influences [35, 36]. An example of processing distributed between hubs rather than localized with specific centers is conduction aphasia: the clinical manifestations of this aphasia vary with the specific inter-hub pathway between Broca’s and Wernicke’s areas that is interrupted [37] (Figure 12.6). Some investigators suggest that, similar to the visual system, there are two main processing streams for language, a ventral stream and a dorsal stream [38]. A bilaterally organized ventral processing stream mediates speech signals for comprehension, and a left-sided dorsal processing stream mediates speech signals for articulation. Language also depends on the production and detection of precise time intervals. Both speech production and detection are unusually fast processes,

181


and precise timing is needed for both aspects of language. Quick temporal variants characterize language sounds, the processing of which appears to be essential to a correct perception of speech. Speech sounds can be continuously varied, but a subject only hears categories (categorical perception; i.e., no “in between” representations); this auditory “chunking” mechanism facilitates the speed at which such sounds are processed. Fast-changing temporal cues seem to elicit preponderant activation in the auditory system of the dominant hemisphere, and the superior temporal gyrus in that hemisphere is particularly sensitive to the rate of change over time in speech signals. A neuroanatomical correlate of this dominant-hemisphere temporal advantage in processing speed is the greater amount of white matter and myelination in the dominant vs. nondominant temporal lobe [39]. A further important factor for effective speech production is the rapid syntactic organization provided by the left inferior frontal region [40].

Conclusion Current information modifies the classical Wernicke– Geschwind model of language to incorporate the contributions of perisylvian processing hubs that participate in sequential, neurocomputational operations on language-related information. The human brain has the innate capacity to manipulate complex symbol systems such as language, and in childhood the structure of the brain allows for the rapid and efficient acquisition of language. The left perisylvian areas are predisposed for fast timing of strings of symbols organized on a syntactic scaffolding. Broca’s area and Wernicke’s area are critical hubs for rapid processing streams that integrate steps from the extraction of phonetic features to lexical-phonological representations to semantic representations and so on, eventually to articulation and motor speech. Recent and continuing advances in neuroimaging and related technologies offer great promise of clarifying further the structural and functional neuroanatomy of language.

References 1. Hauser MD, Chomsky N, Fitch WT. The faculty of language: what is it, who has it, and how did it evolve? Science 2002;298(5598):1569–712. 2. Dronkers NF, Plaisant O, Iba-Zizen MT, Cabanis EA. Paul Broca’s historic cases: high resolution MR

182

imaging of the brains of Leborgne and Lelong. Brain 2007;130(5):1432–41. 3. Geschwind N. Disconnexion syndromes in animals and man. I. Brain 1965;88(2):237–94. 4. Geschwind N. Disconnexion syndromes in animals and man. II. Brain 1965;88(3):585–644. 5. Benson DF, Ardila A. Aphasia: A Clinical Perspective. New York, NY: Oxford University Press; 1996. 6. Damasio H, Damasio AR. The anatomical basis of conduction aphasia. Brain 1980;103(2):337–50. 7. Berthier ML. Poststroke aphasia: epidemiology, pathophysiology and treatment. Drugs Aging 2005; 22(2):163–82. 8. Nadeau SE, Crosson B. Subcortical aphasia. Brain Lang. 1997;58(3):355–402; discussion 18–23. 9. Bhatia KP, Marsden CD. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 1994;117(Pt 4):859–76. 10. Hillis AE, Barker PB, Wityk RJ et al. Variability in subcortical aphasia is due to variable sites of cortical hypoperfusion. Brain Lang. 2004;89(3): 524–30. 11. Chomsky N. Language and Mind. Enl. edition. New York, NY: Harcourt Brace Jovanovich; 1972. 12. Pouratian N, Bookheimer SY, Rex DE, Martin NA, Toga AW. Utility of preoperative functional magnetic resonance imaging for identifying language cortices in patients with vascular malformations. J Neurosurg. 2002;97(1):21–32. 13. Lee A, Kannan V, Hillis AE. The contribution of neuroimaging to the study of language and aphasia. Neuropsychol Rev. 2006;16(4):171–83. 14. Martin RC. Language processing: functional organization and neuroanatomical basis. Annu Rev Psychol. 2003;54:55–89. 15. Peach RK. Acquired apraxia of speech: features, accounts, and treatment. Top Stroke Rehabil. 2004; 11(1):49–58. 16. Binder JR. Neuroanatomy of language processing studied with functional MRI. Clin Neurosci. 1997; 4(2):87–94. 17. Josse G, Tzourio-Mazoyer N. Hemispheric specialization for language. Brain Res Brain Res Rev. 2004;44(1):1–12. 18. Foundas AL, Leonard CM, Hanna-Pladdy B. Variability in the anatomy of the planum temporale and posterior ascending ramus: do right- and left handers differ? Brain Lang. 2002;83(3):403–24. 19. Geschwind N, Levitsky W. Human brain: left-right asymmetries in temporal speech region. Science 1968; 161(837):186–7.


20. Borod JC. Interhemispheric and intrahemispheric control of emotion: a focus on unilateral brain damage. J Consult Clin Psychol. 1992;60(3):339–48. 21. Cardebat D, Demonet JF, De Boissezon X et al. Behavioral and neurofunctional changes over time in healthy and aphasic subjects: a PET Language Activation Study. Stroke 2003;34(12):2900–6. 22. Wyllie E, Luders H, Murphy D et al. Intracarotid amobarbital (Wada) test for language dominance: correlation with results of cortical stimulation. Epilepsia 1990;31(2):156–61. 23. Gazzaniga MS. The role of language for conscious experience: observations from split-brain man. Prog Brain Res. 1980;54:689–96. 24. Manning WH, Louko LJ, DiSalvo VS. A right-ear effect for auditory feedback control of children’s newly acquired phonemes. J Speech Hear Res. 1978;21(3): 580–8. 25. Dapretto M, Bookheimer SY. Form and content: dissociating syntax and semantics in sentence comprehension. Neuron 1999;24(2):427–32. 26. Piras F, Marangolo P. Noun-verb naming in aphasia: a voxel-based lesion-symptom mapping study. Neuroreport 2007;18(14):1455–8. 27. Baldo JV, Schwartz S, Wilkins D, Dronkers NF. Role of frontal versus temporal cortex in verbal fluency as revealed by voxel-based lesion symptom mapping. J Int Neuropsychol Soc. 2006;12(6):896–900. 28. Obleser J, Boecker H, Drzezga A et al. Vowel sound extraction in anterior superior temporal cortex. Hum Brain Mapp. 2006;27(7):562–71. 29. van Atteveldt N, Formisano E, Goebel R, Blomert L. Integration of letters and speech sounds in the human brain. Neuron 2004;43(2):271–82. 30. Clark DG, Charuvastra A, Miller BL, Shapira JS, Mendez MF. Fluent versus nonfluent primary

progressive aphasia: a comparison of clinical and functional neuroimaging features. Brain Lang. 2005; 94(1):54–60. 31. Westbury C, Bub D. Primary progressive aphasia: a review of 112 cases. Brain Lang. 1997;60(3): 381–406. 32. Gorno-Tempini ML, Dronkers NF, Rankin KP et al. Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol. 2004;55(3): 335–46. 33. Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain 1992;115(Pt 6):1783–806. 34. Gorno-Tempini ML, Brambati SM, Ginex V et al. The logopenic/phonological variant of primary progressive aphasia. Neurology 2008;71(16):1227–34. 35. Hillis AE, Boatman D, Hart J, Gordon B. Making sense out of jargon: a neurolinguistic and computational account of jargon aphasia. Neurology 1999;53(8): 1813–24. 36. Mesulam M. Imaging connectivity in the human cerebral cortex: the next frontier? Ann Neurol. 2005; 57(1):5–7. 37. Catani M, Jones DK, ffytche DH. Perisylvian language networks of the human brain. Ann Neurol. 2005;57(1): 8–16. 38. Hickok G, Poeppel D. The cortical organization of speech processing. Nat Rev Neurosci. 2007;8(5): 393–402. 39. Zatorre RJ, Belin P, Penhune VB. Structure and function of auditory cortex: music and speech. Trends Cogn Sci. 2002;6(1):37–46. 40. Rodd JM, Longe OA, Randall B, Tyler LK. The functional organisation of the fronto-temporal language system: evidence from syntactic and semantic ambiguity. Neuropsychologia 2010;48(5):1324–35.

183

Section I


Chapter

Affective prosody

13

Elliott D. Ross

In humans, vocal–acoustic communication is a highly evolved behavior. Although lower animals have wellestablished systems of vocal–acoustic communication, humans possess a communication system of complexity and flexibility sufficient to qualify as language: this system encompasses the ability to store and cognitively modulate vast numbers of verbal-semantic representations, to produce intricate patterns of articulation, and to generate syntactical relationships with nearly infinite flexibility [1–9]. It has been assumed therefore, that human language is an evolutionary adaptation related to the marked expansion of prefrontal and temporoparietooccipital heteromodal neocortex [10– 17]. This gradual encephalization leads, in turn, to the corticalization and resultant cognitization [18–23] of communication systems that in lower animals are heavily represented in non-neocortical areas, including the basal ganglia, thalamus, limbic system, paralimbic mesocortex, brainstem, and cerebellum [24–34]. Based on the fundamental discoveries of Broca [35, 36], Wernicke [37], and Lichtheim [38] in the late 1800s that focal lesions in the left but not right hemisphere (in strongly right-handed individuals) may produce deficits in the verbal-linguistic aspects of language resulting in various aphasic syndromes [39], language is viewed as a dominant and highly lateralized function of the left hemisphere [9]. Because language is a distinguishing feature of humans, the right hemisphere has been relegated inappropriately to the role of the non-dominant or “minor” hemisphere [40]. Nevertheless, the very first functional imaging study of language [41], which was expected to show predominantly left-sided activation, showed instead that both hemispheres were activated in a relatively homologous pattern that included the posterior and

anterior opercular regions and the medial surfaces of the frontal lobes. In fact, all subsequent functional imaging research that has probed various aspects of language, including verbal-linguistic and paralinguistic functions has shown robust bilateral activations on initial data acquisition that, at minimum, involve the posterior perisylvian regions [9, 42–49]. Thus, modern functional imaging data overwhelmingly support the concept that human language is, in fact, a distributed process that actively engages both hemispheres [9]. This chapter considers the topic of affective prosody as an important aspect of language that appears to be lateralized to the right hemisphere.

Constituents of language and communication Human language is composed of various basic elements that are classified as being either linguistic or paralinguistic [2, 50]. The linguistic or propositional elements are characterized by words (vocabulary, lexicon) and syntactical relationships (grammar) that convey meaning based on word sequences. The basic acoustical features underlying word production (phonology) and comprehension (phonetics) are called segments, and these have distinctive acoustical signatures associated with various consonants, vowels, and syllables. It is these word-related constituents of language that are primarily disrupted by focal lefthemisphere injury that causes aphasic syndromes [9, 39]. In contrast, paralinguistic aspects of language are accessory to words, and include prosody and kinesics. The acoustical features underlying prosody include pitch, intonation (variation of pitch over time), melody, cadence, loudness, timbre (voice quality),


184

Chapter 13: Affective prosody

stress, and pauses. As will be described in subsequent sections of this chapter, there are various levels of prosodic communication that convey linguistic, affective (attitudinal and emotional), dialectical, and idiosyncratic information [50]. Kinesics refers to facial, limb, and body movements associated with language and communications [51]. Movements that are used for standard, well-defined communication (semiotics), such as the thumbs down sign for displeasure or the “V” for “victory” sign, are classified as pantomime whereas movements used to color, emphasize, and embellish communication are classified as gestures. Most spontaneous kinesic activity often blends gestures and pantomime into a single movement.

Prosody Monrad-Krohn [52] initiated the modern clinical study of prosody after caring for a native Norwegian woman during WWII who sustained a shrapnel wound to the left frontal area that precipitated acute Broca’s aphasia. The woman made an excellent recovery except that she acquired a foreign accent. The acquired accent caused her considerable emotional distress during the Nazi occupation of Norway because she was mistaken for being a German and, consequently, socially ostracized. Although her speech had preserved melody, as evidenced by her ability to sing, intone, and emote, she had inappropriate application of stresses and pauses to her speech giving it the patina of a foreign accent. Based on this patient and others, Monrad-Krohn [53] divided prosody into four major components: intrinsic (or linguistic), intellectual (or attitudinal), emotional, and inarticulate. Intrinsic (or linguistic) prosody enhances and clarifies the linguistic aspects of a language through judicious use of stress pauses and intonation without altering either words or word order. For example, raising the intonation at the end of a statement by a halfoctave transforms a statement into a question. Altering word stress and timing may clarify word meaning, i.e., “the Redcoats are coming” (British regulars) versus “the red-coats are coming” (red-colored coats) or changing the stress on certain words and altering the pausal structure of the sentence may clarify potentially ambiguous syntax, i.e., “The man . . . and woman dressed in black . . . came to visit” (only the woman was dressed in black) versus “The man and woman dressed in black . . . came to visit” (both were dressed in black) [54, 55].

Intellectual (or attitudinal) prosody imparts attitudinal information to discourse that may drastically alter meaning. For example, if the sentence “He is smart” is spoken with emphatic stress on “is,” then it becomes a resounding acknowledgment of the person’s ability. If, instead, the emphasis resides on “smart” with a terminal rise in intonation, then sarcasm is communicated. Emotional prosody infuses speech with primary types of emotions such as happiness, sadness, fear, and anger. In modern terminology, the term affective prosody refers to the combination of Monrad-Krohn’s intellectual and emotional prosody [50]. Inarticulate prosody is the use of certain paralinguistic non-verbal elements, such as grunts and sighs, to embellish discourse. In addition, there is also dialectical (or regional) prosody that belies a speaker’s origin and idiosyncratic prosody that gives rise to voice patterns and qualities that are unique to an individual. Both these subclassifications can be considered as part of intrinsic prosody. Monrad-Krohn [53] also described various clinical disorders of prosody caused by brain injury or disease. Dysprosody is a change in voice quality that may result in a foreign accent syndrome [56–58]. It is encountered primarily in patients with reasonably good recovery from non-fluent aphasias due to left hemisphere lesions that alter the patient’s dialectical and idiosyncratic aspects of prosody. Aprosody is the general lack of attitudinal and emotional prosody observed, for example, in patients with Parkinson’s disease as part of their bradykinesia, masked facies, and softly monotonous voice. Hyperprosody refers to the excessive use of prosody that occurs in acutely manic or psychotic patients, or in Broca’s or global aphasics who have very few words at their disposal but use them vehemently to convey their emotional states, an observation first made by Hughlings Jackson in the nineteenth century [59]. Although Monrad-Krohn did not attribute disorders of prosody specifically to focal right brain damage, he did predict that, in addition to aprosodic speech, disturbed prosodic comprehension should also be encountered after brain damage. Indeed, publications over the last three decades, discussed below, establish that focal lesions of the right hemisphere lead to fundamental disturbances in the production and/or comprehension of affective prosody. The resulting syndromes have been termed aprosodias, and research has shown that functional-anatomic correlations of

185


the aprosodias in the right hemisphere are similar to those of the aphasias in the left hemisphere [60– 62]. Lastly, the syndrome of phonagnosia has been described [63, 64] in which patients with lesions of the right parietal region lose the ability to identify familiar individuals by their voice characteristics alone, similar to the syndrome of prosopagnosia [65] (the inability to identify familiar individuals by facial features alone).

Kinesics Disturbances in pantomime, involving both production and comprehension, have been linked to left brain damage [66–72]. Goodglass and Kaplan [66] proposed that disorders of pantomime in aphasics with significant comprehension deficits may be related to their inability to comprehend symbols whereas disorders of pantomime in aphasics without significant comprehension deficits are associated with ideomotor apraxia. Although other investigators have not shown such tight correlation of a specific pantomimal disturbance with a specific linguistic disturbance [68, 69, 71, 72], disorders of pantomime are almost always associated with left hemisphere damage that usually results in aphasia, unless corpus callosum injury is the responsible lesion [73]. Gestural kinesics, however, is often preserved in aphasic patients [51, 59]. In 1979, Ross and Mesulam [74] reported two right-handed patients with ischemic infarctions of the right frontoparietal operculum who, in addition to affectively flat speech, had a general loss of spontaneous gestural activity that involved the non-paralyzed right face and limbs. Neither patient had disturbances in ideomotor praxis. Based on these patients, it was suggested that gestural as opposed to pantomimal behavior was a dominant and lateralized function of the right hemisphere. Subsequent studies lend further support to this hypothesis by showing that the right hemisphere is not only specialized for producing gestures but also for comprehending their meaning [75–86]. In summary, affective prosody, gestures, and other paralinguistic features of language impart vitality to human discourse that is essential for overall communication competency [54, 86–90]. These features are also important for enabling the experience of satisfactory psychosocial interactions, and for overall emotional well-being in both children and adults [91–95]. In fact, all the index cases that provided insights into

186

the potential role of the right hemisphere in dominantly modulating the affective aspects of communication, which in turn initiated contemporary programs of research, presented clinically because of psychosocial discord [96–98]. Although affective prosody is considered a paralinguistic or subservient feature of language, it is crucial to emphasize that if the affectiveprosodic message of a statement is at variance with its verbal-linguistic message, such as encountered in irony or sarcasm, adults and most children will overwhelmingly believe the affective-prosodic intent [55, 87, 90, 99, 100].

The role of the right hemisphere in language and communication The first clinician to suggest a lateralized role for the right hemisphere in communication was Hughlings Jackson in his 1879–1880 publication [59]. He observed that patients with dense aphasias were often still able to communicate intent through gestures and vocalizations using the few words available to them. Thus, he suggested that the emotional aspects of language and communication might be dominant functions of the right hemisphere. Clinicians, however, did not formally investigate his observations, until the 1970s when Heilman and colleagues [100–105] and Ross and colleagues [60–62, 74, 106] published a series of papers describing loss of the affective-prosodic aspects of language following focal brain damage. In 1975, Heilman and colleagues [101] tested 12 right-handed patients with temporoparietal lesions on their ability to comprehend affective prosody by presenting verbally neutral sentences with various emotional intonations. Six had left brain damage (LBD) and six had right brain damage (RBD). The patients with LBD had minimal aphasic deficits that did not interfere with testing. Patients with RBD scored near chance in their ability to detect emotions compared to controls and LBD patients. In a follow-up study [102], LBD and RBD patients with temporoparietal injuries were tested for their ability to repeat verbally neutral sentences with various emotional intonations. Once again, the RBD patients were severely impaired on the task compared with controls and LBD patients. In 1979, Ross and Mesulam [74] published a report describing two patients with computed tomography (CT)-verified ischemic lesions of the right frontoparietal operculum. Both of these patients had left hemiplegia. They displayed markedly flattened affect


Table 13.1. The aprosodias. Note: (∗ ) Indicates types of aprosodias with functional–anatomic correlations in the right hemisphere that are similar to the aphasias resulting from left hemisphere lesions that are predominantly cortical in location (9, 39, 60–62, 110–113, 138, 186). Agesic (aprosodia) (187) is similar to anomic aphasia (188).

Spontaneous Comprehension Repetition of affective of affective Type of aprosodia communication affective prosody prosody

Comprehension Lesion location in of gestures right hemisphere

Motor ∗

Poor

Poor

Good

Good

Frontoparietal operculum

Sensory ∗

Good

Poor

Poor

Poor

Temporoparietal operculum

Conduction

Good

Poor

Good

Good

(insufficient cases)

Global ∗

Poor

Poor

Poor

Poor

Perisylvian

Transcortical Motor ∗

Poor

Good

Good

Good

Medial frontal

Transcortical Sensory ∗ Good

Good

Poor

Poor

Temporal parasylvian

Mixed Transcortical

Poor

Good

Poor

Poor


Agesic

Good

Good

Good

Poor


because they could not project emotions into their speech or kinesic behaviors, yet retained the ability to comprehend affect in the speech of others. Both patients were right-handed and neither demonstrated aphasic or apraxic deficits. Based on these cases and those published by Heilman and colleagues [101, 102], it was hypothesized that the affective aspects of communication, as originally proposed by Hughlings Jackson [59], were dominant and lateralized functions of the right hemisphere, and that the functional–anatomic organization of affective prosody in the right hemisphere was similar to that of propositional language in the left hemisphere. An issue not resolved in the paper, however, was whether all prosodic aspects of language were impaired by RBD. Subsequent studies [93, 103, 107–109] have carefully examined this issue, and the composite data indicate that the linguistic features of prosody may be impaired by either LBD or RBD. Based on the hypothesized organization of affective prosody in the right hemisphere [74], Ross [60] studied ten patients with focal RBD due to stroke. The patients were tested within four weeks of their event, except for one patient tested at 10 months after stroke, and the lesions were localized by CT. The patients underwent a bedside assessment of their ability to modulate affective prosody and gestures in a manner similar to methods utilized for assessing propositional language. The patients were examined qualitatively for their ability to: (1) spontaneously project affect into their speech (affective prosody) and

display kinesic behaviors (gestures) during discourse; (2) repeat verbally neutral sentences with different emotional intonations, i.e., happiness, sadness, surprise, disinterest, and anger; (3) comprehend affective prosody auditorily; and (4) comprehend gestures visually. When analyzed for functional–anatomic relationships, all patients with opercular lesions bordering the right Sylvian fissure had some disorder of affective communication with loss of affective repetition. Transcortical syndromes were also observed in which patients retained the ability to repeat with affective variation but had flattened affect and/or loss of the ability to comprehend affective prosody and gestures. The specific combinations of affective-prosodic deficits following localized lesions in the right hemisphere appeared to be reasonably analogous to the functional–anatomic relationships of aphasic deficits observed after focal left brain damage. Thus, the syndromes associated with RBD were called “aprosodias,” and the same modifiers used for classifying the aphasias were adopted for descriptive purposes (Table 13.1). In a follow-up study, using blinded evaluations of affective communication in patients with ischemic infarctions localized by CT, Gorelick and Ross [61] corroborated the proposed aprosodia classifications and their functional–anatomic relationships in the right hemisphere. They also reported that the prevalence of aprosodic syndromes following RBD was equal to the prevalence of aphasic syndromes following LBD, underscoring that the aprosodias are common syndromes.

187


Using quantitative testing methods, including acoustical analysis of voice, and magnetic resonance imaging (MRI) to localize lesions in patients with ischemic infarctions, Ross and Monnot [62] confirmed robustly that RBD patients with loss of the ability to produce affective prosody in their spontaneous speech had, at minimum, lesions that involved the right posterior frontal operculum or homolog of Broca’s area, whereas RBD patients with loss of the ability to comprehend affective prosody had, at minimum, lesions that involved the right posterior temporal operculum or homolog of Wernicke’s area. These localizations have also been confirmed by other investigators [110– 113]. However, these functional–anatomic relationships only hold for acute brain damage for the time period immediately post-injury because of long-term recovery of function due to neural re-organization [9, 62]. Reports that have not confirmed these functional– anatomic relationships have either studied patients many months to years after brain injury or used patients with mixed etiologies of brain injury [62, 114–119]. In addition, patients with slowly progressive lesions such as brain tumors may not show expected aprosodic deficits, as noted by Lebrun and colleagues [120]; as the tumor gradually destroys cerebral tissue, the brain has time to re-organize itself and functional– anatomic relationships change accordingly [9, 62]. This phenomenon was first noted and conceptualized by Hughlings Jackson ([59] see pp. 343–5) as the “Momentum of Lesions” [121]. Similar to the aphasias, strictly subcortical lesions that involve right basal ganglia structures and thalamus have also been reported to cause aprosodias [9, 60–62, 117, 122–125]. There has also been a case report of crossed aprosodia, in which a strongly righthanded patient becomes aprosodic but not aphasic following a left hemisphere stroke, similar to cases of crossed aphasia, in which a strongly right-handed patient becomes aphasic following a right hemisphere stroke [126]. When functional imaging studies are performed probing the affective-prosodic aspects of language, bilateral activations are always observed that, at minimum, involve the posterior perisylvian regions, analogous to the results of functional imaging studies probing the semantic, phonetic, or phonologic aspects of language [9, 41–49]. However, if the stimuli are manipulated by incrementally reducing the articulatory– verbal content, asymmetries in the intensity of the

188

bilateral perisylvian activations occur with a relative shift to the right hemisphere [49, 127–129], supporting the concept that affective prosody is a lateralized and dominant function of the right hemisphere. Nevertheless, aprosodic deficits have been described following LBD [111, 119] bringing into question the concept that affective prosody is always a lateralized and dominant function of the right hemisphere [104].

Hemispheric lateralization of affective prosody The terms “dominant” and “lateralized” are used interchangeably in the literature even though they have different neurological implications regarding brain functions. If a unilateral lesion produces a behavioral deficit that affects both sides of space, then the function is considered dominant [9, 106], a criterion met easily by the various aphasic and aprosodic syndromes. If a behavioral function is also strongly lateralized, then it must be shown that the behavioral deficit does not occur following lesions of the opposite hemisphere, as exemplified by the aphasias. A behavioral function may be lateralized but not necessarily dominant, as exemplified by forebrain lesions that cause contralateral but not ipsilateral paralysis. Unlike the aphasias, the lateralization of affective prosody has been more difficult to resolve because various publications have documented affective-prosodic disturbances among patients with left hemisphere damage with and without aphasic deficits [106, 111, 119]. In patients with dense aphasias, the ability to comprehend affective prosody correlates positively with the severity of aphasic deficits [130, 131], suggesting that the presence of moderate to severe propositional language impairments may interfere with the ability of examiners to assess affective prosody [106]. However, patients with left hemisphere damage may develop affective-prosodic impairments that are not aphasic [106, 111, 118, 119]. Thus, some investigators call into question whether affective prosody is truly a lateralized dominant function of the right hemisphere [111, 119]. There is, however, another possible explanation for these findings [106]. If one assumes that affective prosody is a dominant and lateralized function of the right hemisphere and propositional language is a dominant and lateralized function of the left hemisphere, then considerable inter-hemispheric interaction must occur to ensure that the articulatory-verbal and affective-prosodic


elements of speech are temporally and behaviorally coherent [106, 122, 132, 133]. For example, if a speaker wishes to express anger, the right hemisphere must be apprised by the left hemisphere of what words will be articulated and their temporal pace, so that the right hemisphere can properly time the insertion of affective-prosodic information into the spoken sentence or phrase. Conversely, in order for the right hemisphere to insert attitudinal information such as sarcasm or irony into a sentence, certain syllables may need to be prolonged to obtain the correct temporal pace [87, 134–136]. Thus, left hemisphere damage could alter the inter-hemispheric coordination of language functions, causing an indirect disruption of affective prosody. This possibility was explored by Ross and colleagues [62, 106] in a series of patients with RBD and LBD due to ischemic infarction localized by MRI. The patients were tested within 6 weeks of their stroke using the Aprosodia Battery, in which the verbalarticulatory demands are reduced incrementally when assessing comprehension and production of affective prosody; that is, stimuli were presented with varying affects carried either by a fully articulated sentence (“I am going to the other movies”), a repeated monosyllabic utterance (“ba ba ba ba ba ba”), or an asyllabic utterance (“aaaaaaaaaah”). Among LBD patients, reducing the verbal articulatory demands caused a robust incremental improvement in their ability to comprehend and repeat affective prosody compared with controls, whereas the similar maneuver among RBD patients led to either no improvement or worsening of performance compared with controls. In addition, the affective prosodic deficits of LBD patients were not correlated to the presence, severity, or type of aphasic deficits or the cortical location of lesions [62, 106]. However, lesions involving the paracallosal white matter located below the supplementary motor area and cingulate gyrus best predicted loss of spontaneous affective prosody and affective prosodic repetition in LBD patients. In contrast, affective prosodic deficits were highly correlated with the cortical location of lesions among patients with RBD [62]. These findings suggested that the predominant mechanism underlying affective-prosodic deficits following LBD is loss of interhemispheric integration of the dominant and lateralized language functions represented in each hemisphere (the LBD/Callosal profile). In contrast, the predominant mechanism underlying affective prosodic deficits following RBD is loss

of the ability to directly modulate affective prosody (the RBD/Aprosodic profile), a finding supporting the hypothesis of Blonder and colleagues [104] and Bowers and colleagues [105] that RBD causes loss of affective-communicative representations as the theoretical basis for the aprosodias, similar to LBD causing loss of semantic-syntactic representations as the theoretical basis for the aphasias.

Bedside assessment of affective communication Although quantitative acoustical and neuropsychological test batteries are available for assessing affective prosody such as the Aprosodia Battery [62, 106] and the Florida Affective Battery [137, 138], clinicians can readily incorporate an examination of aprosodic deficits into their bedside neurological examination. This procedure is similar to the assessment commonly used for aphasic deficits [39, 50].

Spontaneous affective prosody and gesturing When interviewing patients, the examiner should observe whether or not they gesture or impart affect into their spontaneous conversation. Also, patients should be asked questions that are emotionally laden, such as those probing their reactions to the current illness or past emotional experiences. Attention should also be devoted to how well patients insert appropriate affective prosody and gestures into their discourse.

Repetition of affective prosody This process involves patients imitating the examiner immediately after being presented with an emotionally neutral sentence or a repeated monosyllable using different affects, such as happy, sad, angry, surprised, disinterested, or neutral. The key observation is how well patients insert the appropriate affective prosody and gestures into their imitation. In an attempt to imitate surprise (terminal rise in intonation of ∼2 octaves), some patients may slightly raise their voice at the end of the repetition (terminal rise in intonation of ∼1/2 octave). This is not a correct response because they are attempting to imitate surprise using linguistic prosody by converting the repetition from a statement into a question.

189


Comprehension of affective prosody After patients are presented with an emotionally neutral sentence or a repeated monosyllable using different vocal affects, such as happy, sad, angry, surprised, disinterested, or neutral, they are immediately asked to identify the affect verbally. If needed, multiple choices can be presented. Standing behind patients during this assessment avoids giving them visual clues to the intended affect.

Comprehension of gestures The examiner stands in front of patients and mimes a particular emotion using only gestural activity involving the face and limbs. As with affective-prosodic comprehension, patients are requested to verbally identify the mimed emotion. Again, if needed, multiple choices can be presented.

Affective prosody in other clinical settings Congenital or early childhood lesions involving the right hemisphere have been associated with aberrant psychosocial development, including excessive shyness, poor eye contact, and deficient modulation of affective prosody and gestures. These deficits have been conceptualized as right hemisphere learning disability [91–93], similar to dyslexia being considered a left hemisphere learning disability. Recent studies by Monnot and colleagues [139, 140] using the Aprosodia Battery have examined the effects of ethanol exposure and abuse on comprehension of affective prosody. A highly robust relationship with age of ethanol exposure was found (r = 0.88 and r2 = 0.78, explaining 78% of the data variance), such that the earlier the exposure to ethanol, the more devastating the deficit. Individuals who were exposed to ethanol in utero, even if they were not alcohol abusers themselves, had mean comprehension score of −5.0 standard deviations below controls, essentially performing at chance. Yet these individuals did not meet criteria for either fetal alcohol syndrome or fetal alcohol effects, and had no other cognitive or language deficits [139]. In contrast, patients whose exposure and ethanol abuse began as adults (⬎24 years of age) did not have impaired comprehension of affective prosody. From these data, it was postulated that early exposure to alcohol may cause a developmental disorder

190

that preferentially affects affective rather than propositional communication systems. Affective prosody has also been studied in normal elderly individuals. Comprehension appears to deteriorate with advancing age [141–144]. In patients with Alzheimer’s disease, affective prosodic comprehension is impaired well before the onset of anomicaphasic deficits, a finding thought to reflect an aging effect [145, 146]. Orbelo and colleagues [143, 144] used the Aprosodia Battery in normal elders and observed that the pattern of comprehension deficit fits the RBD/Aprosodic profile, but is less severe and not explainable by hearing loss. Thus the findings lend support to the hypothesis that cognitive aging is due primarily or, at least initially, to right hemisphere decline [147–149]. In addition, aging substantially impairs the comprehension of attitudinal prosody [143]. In this regard, a common occurrence in dementia clinics is that elderly patients and their spouses, whether cognitively impaired or not, often fail to appreciate jokes, sarcasm, double entendres, witticisms, or irony (unpublished observation). These individuals may react negatively to comments meant to put them at ease because they tend to interpret conversations literally. This clinical observation and the documented age-associated loss of the ability to comprehend attitudinal prosody [143] suggest that interaction with elderly patients should strive to employ literal communication whenever possible. One of the cardinal aspects of schizophrenia is flattening of affect [150–152], which includes loss of the ability to modulate affective prosody [153– 155]. Using the Aprosodia Battery, Ross and colleagues [156] examined 45 patients with medically stable schizophrenia to ascertain if the pattern of deficit suggested left, right, or mixed hemispheric dysfunction. The results showed that 84% of the patients had an aprosodic syndrome with 58% having significant deficits in comprehension. The pattern of deficits for both comprehension and repetition was statistically identical to the RBD/Aprosodic pattern, but not related statistically to other cardinal symptom clusters associated with schizophrenia. This suggests that loss of affective prosodic comprehension could be a core deficit contributing to the psychosocial impoverishment characteristic of the disease. Deficits in spontaneous affective prosody, however, were associated with avolition, apathy, and asociality. Most recently, Freeman and colleagues [157] used the comprehension portion of the Aprosodia Battery


to assess patients with well-documented chronic posttraumatic stress disorder (PTSD) [158]. This research was initiated because some of the symptoms of PTSD suggest right hemisphere dysfunction; that is, patients often have a restricted range of affect and family members often report difficulty in reading their emotions. In addition, an intriguing case report documented that nightmares and intrusive recollections of combat experience associated with PTSD, were ameliorated after a right frontal stroke [159], and there is preliminary evidence that low-frequency repetitive right transcranial magnetic stimulation, causing cortical inhibition, improves PTSD symptoms [160, 161]. Eleven patients with PTSD were evaluated [157]. Every patient had deficient comprehension of affective prosody compared with age-matched controls. As in schizophrenia [156], the performance was identical statistically to the RBD/Aprosodic profile found in patients with RBD. Ethanol was not found to contribute to the findings because, if ethanol abuse occurred, it began, with one exception, after age 23. The authors surmised that without evidence for RBD it was unlikely that an affective-prosodic comprehension deficit could be acquired as a result of PTSD. Rather, the individuals may have had a pre-existing developmental deficit in processing affective prosody, making them vulnerable to chronic PTSD when exposed to combat.

Affective prosody, gestures, and the neurology of emotions The aprosodias are disturbances in the modulation of graded emotional behaviors associated with language and communication that are organized predominantly, but not exclusively, in the neocortex [9, 62]. As such, the aprosodias represent disruptions of cognitive functions that can be manipulated for psychosocial purposes and ulterior motives as part of the social emotional system [162–164]. Other aspects of emotions, such as the experience of an emotion or the display of coarse, all or none, emotional behaviors, such as laughing, crying, and anger, may be unaffected by lesions causing aprosodias because they are organized predominantly by the limbic system and related descending pathways via the hypothalamus and brainstem [163–166]. Because of this neuroanatomic arrangement, paradoxical behaviors may occur during clinical interactions that may interfere with arriving at a correct diagnosis.

A dramatic example involves the challenge of diagnosing depression in patients with focal brain lesions [167]. For example, patients with motor types of aprosodia will exhibit a flat affect even when discussing highly emotional issues, such as depression or suicide [167, 168]. Consequently, clinicians may discount their verbal reports of emotional distress and not diagnose or treat their depression. Patients with RBD, in addition to being aprosodic, may have neglect and denial of illness causing them to verbally deny that they are depressed even though they have appropriate behavioral, vegetative, and neuroendocrine indicators of melancholic depression that will respond to antidepressant medications. Patients with motor or global aprosodia may be able to display appropriate emotional behaviors during very sad, happy, or angry situations even though they have an otherwise flat affect during normal discourse [60, 61]. However, if the emotional displays are excessive and inappropriate to the psychosocial situation, similar to patients with pathologic regulation of affect due to pseudobulbar palsy [163, 164, 169, 170], then the patient may have an underlying depression [167, 168]. The pathological regulation of affect responds very quickly to antidepressant medications, in contrast to other symptoms associated with depression, especially mood [168].

Other contributions of the right hemisphere to language and communication Although this chapter has focused on affective prosody and disorders of affective communication, the right hemisphere makes other contributions to language and communication that are not well appreciated by clinicians [9]. Some functions contribute to higherorder semantic-linguistic competency and include: (1) the comprehension of connotative, non-standard (third and fourth order) word meaning as opposed to denotative or standard word meaning; (2) comprehension of metaphor; (3) thematic comprehension, i.e., understanding communicative intent conveyed by paragraphs and chapters as opposed to words and sentences; and (4) comprehension of complex linguistic relationships [171–181]. In addition, the right hemisphere is involved in the comprehension of non-literal, idiomatic, types of expressions that are not semantically or literally feasible [182–184], e.g., “he is walking

191


on clouds,” and the modulation of semantically emotional words and curses [59, 76, 185].

Conclusion This chapter considered the topic of the right hemisphere’s contribution to language and communication, with special emphasis on affective prosody and gestures. The various levels of prosodic communication that convey linguistic, dialectical, and idiosyncratic information were also reviewed. Formal methods for assessing disturbances of affective prosody, and a brief description of the bedside assessment of affective prosody were provided in order to enhance the clinical skill set of BN&NP subspecialists. Finally, the clinical conditions in which disturbances of affective prosody occur commonly were reviewed, thereby illuminating the contexts in which it may be productive for clinicians to undertake assessment for aprosodic defects [91–93, 139–146, 156, 157, 167, 168].

Acknowledgments This work was supported, in part, by grants from the Merit Review Board, Medical Research Service, Department of Veterans Affairs, Washington, DC. I am indebted to Marilee Monnot, PhD, for suggestions to improve the manuscript.

References

7. Schoenemann PT. Syntax as an emergent characteristic of the evolution of semantic complexity. Minds Machines 1999;9(3):309–46. 8. Bass AH, Gilland EH, Baker R. Evolutionary origins for social vocalization in a vertebrate hindbrain-spinal compartment. Science 2008;321(5887):417–21. 9. Ross ED. Cerebral localization of functions and the neurology of language: fact versus fiction or is it something else? Neuroscientist 2010;16(3):222–43. 10. Geschwind N. The development of the brain and the evolution of language. In Stuart CIJM, editor. Monograph Series on Language and Linguistics. Washington, DC: Georgetown University Press; 1964, pp. 155–69. 11. Geschwind N. Disconnexion syndromes in animals and man. I. Brain 1965;88(2):237–94. 12. Geschwind N. Disconnexion syndromes in animals and man. II. Brain 1965;88(3):585–644. 13. Penfield W. Speech, perception and the uncommitted cortex. In Eccles JC, editor. Brain and Conscious Experience Study Week, September 28–October 4, 1964, of the Pontificia Academia Scientiarum [papers and discussions]. New York, NY: Springer-Verlag; 1966, pp. 217–37. 14. Passingham RE. Anatomical differences between the neocortex of man and other primates. Brain Behav Evol. 1973;7(5):337–59. 15. Killackey HP. Neocortical expansion: an attempt toward relating phylogeny and ontogeny. J Cogn Neurosci. 1990;2(1):1–17.

1. Thorpe WH. Animal vocalization and communication. In Millikan CH, Darley FL, editors. Brain Mechanisms Underlying Speech and Language; Proceedings. New York, NY: Grune and Stratton; 1967, pp. 2–12.

16. Killackey HP. Evolution of the human brain: a neuroanatomical perspective. In Gazzaniga MS, Bizzi E, editors. The Cognitive Neurosciences. Cambridge, MA: MIT Press; 1995, pp. 1243–53.

2. Fromkin V, Rodman R. An Introduction to Language. 2nd edition. New York, NY: Holt, Rinehart and Winston; 1978.

17. Mesulam MM. Large-scale neurocognitive networks and distributed processing for attention, language, and memory. Ann Neurol. 1990;28(5):597–613.

3. Wilson EO. Animal communication. In Wang WSY, editor. The Emergence of Language: Development and Evolution: Readings from Scientific American Magazine. New York, NY: W.H. Freeman; 1991, pp. 3–15.

18. Jackson JH. The Croonian Lectures on evolution and dissolution of the nervous system. Br Med J. 1884;1(1213, 1214, 1215):591–3, 660–3, 703–7.

4. Savage-Rumbaugh ES, Murphy J, Sevcik RA et al. Language comprehension in ape and child. Monogr Soc Res Child Dev. 1993;58(3–4):1–222. 5. Fisher SE, Marcus GF. The eloquent ape: genes, brains and the evolution of language. Nat Rev Genet. 2006; 7(1):9–20.

192

6. Stumpner A, von Helversen D. Evolution and function of auditory systems in insects. Naturwissenschaften 2001;88(4):159–70.

19. Jackson JH. Remarks on evolution and dissolution of the nervous system. In Tuke DH, Savage GH, editors. The Journal of Mental Science. London: Association of Medical Officers of Asylums and Hospitals for the Insane (London England), Medico-psychological Association of Great Britain and Ireland, Royal Medico-psychological Association, Longman, Green, Longman & Roberts; 1887, pp. 25–48.


20. Harlow HF. The neuro-physiological correlates of learning and intelligence. Psychol Bull. 1936;33(7): 479–525.

37. Eggert GH, Wernicke C. Wernicke’s Works on Aphasia: A Sourcebook and Review. The Hague: Mouton; 1977.

21. Jerison HJ. Animal intelligence as encephalization. Philos Trans R Soc Lond B Biol Sci. 1985;308(1135): 21–35.

38. Lichtheim L. On aphasia. In Bucknill JC, Crichton-Browne J, Ferrier D, Jackson JH, de Watteville A, editors. Brain: A Journal of Neurology. London: Macmillan & Co.; 1885, pp. 433–84.

22. Mesulam MM. From sensation to cognition. Brain 1998;121(Pt 6):1013–52. 23. Deacon TW. Evolutionary perspectives on language and brain plasticity. J Commun Disord. 2000;33(4): 273–90; quiz 90–1. 24. Schmahmann JD, Pandya DN. Disconnection syndromes of basal ganglia, thalamus, and cerebrocerebellar systems. Cortex 2008;44(8):1037–66. 25. Myers RE. Comparative neurology of vocalization and speech: proof of a dichotomy. Ann N Y Acad Sci. 1976;280:745–60. 26. Nottebohm F. Reassessing the mechanisms and origins of vocal learning in birds. Trends Neurosci. 1991;14(5): 206–11. 27. Jurgens U. The role of the periaqueductal grey in vocal behaviour. Behav Brain Res. 1994;62(2):107–17. 28. Jurgens U. Neural pathways underlying vocal control. Neurosci Biobehav Rev. 2002;26(2):235–58. 29. MacLean PD, Newman JD. Role of midline frontolimbic cortex in production of the isolation call of squirrel monkeys. Brain Res. 1988;450(1–2):111–23. 30. Davis PJ, Zhang SP, Winkworth A, Bandler R. Neural control of vocalization: respiratory and emotional influences. J Voice 1996;10(1):23–38. 31. Lieberman P. On the nature and evolution of the neural bases of human language. Am J Phys Anthropol. 2002;Suppl. 35:36–62. 32. Reiner A, Perkel DJ, Mello CV, Jarvis ED. Songbirds and the revised avian brain nomenclature. Ann N Y Acad Sci. 2004;1016:77–108. 33. Kittelberger JM, Land BR, Bass AH. Midbrain periaqueductal gray and vocal patterning in a teleost fish. J Neurophysiol. 2006;96(1):71–85. 34. Ackermann H, Mathiak K, Riecker A. The contribution of the cerebellum to speech production and speech perception: clinical and functional imaging data. Cerebellum 2007;6(3):202–13. 35. Broca P. Rermarques sue le siége de la faculté du langage articulé, suivies d’une observation d’aphémie. Bull Société Anatomique 1861;6:330–57, 98–407. 36. Berker EA, Berker AH, Smith A. Translation of Broca’s 1865 report: localization of speech in the third left frontal convolution. Arch Neurol. 1986;43(10): 1065–72.

39. Benson DF. Aphasia, Alexia, and Agraphia. New York, NY: Churchill Livingstone; 1979. 40. Benton AL. The ‘minor’ hemisphere. J Hist Med Allied Sci. 1972;27(1):5–14. 41. Larsen B, Skinhoj E, Lassen NA. Variations in regional cortical blood flow in the right and left hemispheres during automatic speech. Brain 1978;101(2): 193–209. 42. Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME. Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature 1988;331(6157):585–9. 43. Binder JR, Frost JA, Hammeke TA et al. Human brain language areas identified by functional magnetic resonance imaging. J Neurosci. 1997;17(1): 353–62. 44. Buchanan TW, Lutz K, Mirzazade S et al. Recognition of emotional prosody and verbal components of spoken language: an fMRI study. Brain Res Cogn Brain Res. 2000;9(3):227–38. 45. Wildgruber D, Pihan H, Ackermann H, Erb M, Grodd W. Dynamic brain activation during processing of emotional intonation: influence of acoustic parameters, emotional valence, and sex. Neuroimage 2002;15(4):856–69. 46. Demonet JF, Thierry G, Cardebat D. Renewal of the neurophysiology of language: functional neuroimaging. Physiol Rev. 2005;85(1):49–95. 47. Van Lancker Sidtis D. Does functional neuroimaging solve the questions of neurolinguistics? Brain Lang. 2006;98(3):276–90. 48. Sidtis JJ. Some problems for representations of brain organization based on activation in functional imaging. Brain Lang. 2007;102(2):130–40. 49. Mitchell RL, Ross ED. fMRI evidence for the effect of verbal complexity on lateralisation of the neural response associated with decoding prosodic emotion. Neuropsychologia 2008;46(12):2880–7. 50. Ross E. Affective prosody and the aprosodias. In Mesulam MM, editor. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 316–31. 51. Critchley M. The Language of Gesture. London: E. Arnold & Co.; 1939.

193


52. Monrad-Krohn GH. Dysprosody or altered melody of language. Brain 1947;70(Pt 4):405–15. 53. Monrad-Krohn GH. The third element of speech: prosody and its disorders. In Halpern L, editor. Problems in Dynamic Neurology. Jerusalem: Hebrew University Press; 1963, pp. 101–18.

69. Seron X, van der Kaa MA, Remitz A, van der Linden M. Pantomime interpretation and aphasia. Neuropsychologia 1979;17(6):661–8.

54. Crystal D. The English Tone of Voice: Essays in Intonation, Prosody and Paralanguage. London: Edward Arnold; 1975.

70. De Renzi E, Motti F, Nichelli P. Imitating gestures. A quantitative approach to ideomotor apraxia. Arch Neurol. 1980;37(1):6–10.

55. Van Lancker D, Canter GJ, Terbeek D. Disambiguation of ditropic sentences: acoustic and phonetic cues. J Speech Hear Res. 1981;24(3):330–5.

71. Feyereisen P, Seron X. Nonverbal communication and aphasia: a review. I. Comprehension. Brain Lang. 1982;16(2):191–212.

56. Aronson AE. Clinical Voice Disorders: An Interdisciplinary Approach. New York, NY: B.C. Decker; 1980.

72. Feyereisen P, Seron X. Nonverbal communication and aphasia: a review. II. Expression. Brain Lang. 1982; 16(2):213–36.

57. Berthier ML, Ruiz A, Massone MI, Starkstein SE, Leiguarda RC. Foreign accent syndrome – behavioral and anatomical findings in recovered and non-recovered patients. Aphasiology 1991;5(2):129–47.

73. Heilman KM, Watson RT. The disconnection apraxias. Cortex 2008;44(8):975–82.

58. Edwards RJ, Patel NK, Pople IK. Foreign accent following brain injury: syndrome or epiphenomenon? Eur Neurol. 2005;53(2):87–91. 59. Jackson JH. On affections of speech from diseases of the brain In Bucknill JC, Crichton-Browne J, Ferrier D, Jackson JH, De Watteville A, editors. Brain: A Journal of Neurology. London: Macmillan & Co; 1879–1880, pp. 304–30; 203–22; 323–56. 60. Ross ED. The aprosodias. Functional-anatomic organization of the affective components of language in the right hemisphere. Arch Neurol. 1981;38(9): 561–9.

74. Ross ED, Mesulam MM. Dominant language functions of the right hemisphere? Prosody and emotional gesturing. Arch Neurol. 1979;36(3):144–8. 75. Buck R, Duffy RJ. Nonverbal communication of affect in brain-damaged patients. Cortex 1980;16(3):351–62. 76. Cicone M, Wapner W, Gardner H. Sensitivity to emotional expressions and situations in organic patients. Cortex 1980;16(1):145–58. 77. DeKosky ST, Heilman KM, Bowers D, Valenstein E. Recognition and discrimination of emotional faces and pictures. Brain Lang. 1980;9(2):206–14. 78. Benowitz LI, Bear DM, Rosenthal R et al. Hemispheric specialization in nonverbal communication. Cortex 1983;19(1):5–11.

61. Gorelick PB, Ross ED. The aprosodias: further functional-anatomical evidence for the organisation of affective language in the right hemisphere. J Neurol Neurosurg Psychiatry 1987;50(5):553–60.

79. Borod JC, Koff E, Lorch MP, Nicholas M. Channels of emotional expression in patients with unilateral brain damage. Arch Neurol. 1985;42(4):345–8.

62. Ross ED, Monnot M. Neurology of affective prosody and its functional-anatomic organization in right hemisphere. Brain Lang. 2008;104(1):51–74.

80. Borod JC, Koff E, Perlman Lorch M, Nicholas M. The expression and perception of facial emotion in brain-damaged patients. Neuropsychologia 1986; 24(2):169–80.

63. Van Lancker DR, Cummings JL, Kreiman J, Dobkin BH. Phonagnosia: a dissociation between familiar and unfamiliar voices. Cortex 1988;24(2):195–209. 64. Van Lancker DR, Kreiman J, Cummings J. Voice perception deficits: neuroanatomical correlates of phonagnosia. J Clin Exp Neuropsychol. 1989;11(5): 665–74. 65. Meadows JC. The anatomical basis of prosopagnosia. J Neurol Neurosurg Psychiatry 1974;37(5):489–501.

194

68. Cicone M, Wapner W, Foldi N, Zurif E, Gardner H. The relation between gesture and language in aphasic communication. Brain Lang. 1979;8(3):324–49.

81. Borod JC, Koff E, Lorch MP, Nicholas M, Welkowitz J. Emotional and non-emotional facial behaviour in patients with unilateral brain damage. J Neurol Neurosurg Psychiatry 1988;51(6):826–32. 82. Mammucari A, Caltagirone C, Ekman P et al. Spontaneous facial expression of emotions in brain-damaged patients. Cortex 1988;24(4):521–33.

66. Goodglass H, Kaplan E. Disturbance of gesture and pantomime in aphasia. Brain 1963;86:703–20.

83. Blonder LX, Burns AF, Bowers D, Moore RW, Heilman KM. Right hemisphere facial expressivity during natural conversation. Brain Cogn. 1993; 21(1):44–56.

67. Gainotti G, Lemmo MS. Comprehension of symbolic gestures in aphasia. Brain Lang. 1976;3(3):451–60.

84. Borod JC, Bloom RL, Brickman AM, Nakhutina L, Curko EA. Emotional processing deficits in


individuals with unilateral brain damage. Appl Neuropsychol. 2002;9(1):23–36. 85. Charbonneau S, Scherzer BP, Aspirot D, Cohen H. Perception and production of facial and prosodic emotions by chronic CVA patients. Neuropsychologia 2003;41(5):605–13. 86. Blonder LX, Heilman KM, Ketterson T et al. Affective facial and lexical expression in aprosodic versus aphasic stroke patients. J Int Neuropsychol Soc. 2005; 11(6):677–85. 87. Bolinger DLM. Language, the Loaded Weapon: The Use and Abuse of Language Today. London: Longman; 1980. 88. Plutchik R. The nature of emotions: clinical implications. In Clynes M, Panksepp J, editors. Emotions and Psychopathology. New York, NY: Plenum Press; 1988. p. xiii. 89. Arndt H, Janney RW. Verbal, prosodic, and kinesic emotive contrasts in speech. J Pragmatics 1991; 15(6):521–49.

100. Bowers D, Coslett HB, Bauer RM, Speedie LJ, Heilman KM. Comprehension of emotional prosody following unilateral hemispheric lesions: processing defect versus distraction defect. Neuropsychologia 1987;25(2):317–28. 101. Heilman KM, Scholes R, Watson RT. Auditory affective agnosia. Disturbed comprehension of affective speech. J Neurol Neurosurg Psychiatry 1975;38(1):69–72. 102. Tucker DM, Watson RT, Heilman KM. Discrimination and evocation of affectively intoned speech in patients with right parietal disease. Neurology 1977;27(10): 947–50. 103. Heilman KM, Bowers D, Speedie L, Coslett HB. Comprehension of affective and nonaffective prosody. Neurology 1984;34(7):917–21. 104. Blonder LX, Bowers D, Heilman KM. The role of the right-hemisphere in emotional communication. Brain 1991;114:1115–27.

90. Mehrabian A. Nonverbal Communication. New Brunswick, NJ: Aldine Transaction; 2007.

105. Bowers D, Bauer RM, Heilman KM. The nonverbal affect lexicon: theoretical perspectives from neuropsychological studies of affect perception. Neuropsychology 1993;7(4):433–44.

91. Weintraub S, Mesulam MM. Developmental learning disabilities of the right hemisphere. Emotional, interpersonal, and cognitive components. Arch Neurol. 1983;40(8):463–8.

106. Ross ED, Thompson RD, Yenkosky J. Lateralization of affective prosody in brain and the callosal integration of hemispheric language functions. Brain Lang. 1997;56(1):27–54.

92. Voeller KK. Clinical neurologic aspects of the right-hemisphere deficit syndrome. J Child Neurol. 1995;10(Suppl. 1):S16–22.

107. Danly M, Shapiro B. Speech prosody in Broca’s aphasia. Brain Lang. 1982;16(2):171–90.

93. Trauner DA, Ballantyne A, Friedland S, Chase C. Disorders of affective and linguistic prosody in children after early unilateral brain damage. Ann Neurol. 1996;39(3):361–7. 94. Carton JS, Kessler EA, Pape CL. Nonverbal decoding skills and relationship well-being in adults. J Nonverbal Behav. 1999;23(1):91–100. 95. Wymer JH, Lindman LS, Booksh RL. A neuropsychological perspective of aprosody: features, function, assessment, and treatment. Appl Neuropsychol. 2002;9(1):37–47. 96. Ross ED. The divided self. Sciences 1982;22(2):8–12. 97. Ross E. Right hemisphere syndromes and the neurology of emotions. In Schachter SC, Devinsky O, editors. Behavioral Neurology and the Legacy of Norman Geschwind. Philadelphia, PA: Lippincott-Raven; 1997, pp. 183–4.

108. Danly M, Cooper WE, Shapiro B. Fundamental frequency, language processing, and linguistic structure in Wernicke’s aphasia. Brain Lang. 1983; 19(1):1–24. 109. Weintraub S, Mesulam MM, Kramer L. Disturbances in prosody. A right-hemisphere contribution to language. Arch Neurol. 1981;38(12):742–4. 110. Denes G, Caldognetto EM, Semenza C, Vagges K, Zettin M. Discrimination and identification of emotions in human voice by brain-damaged subjects. Acta Neurol Scand. 1984;69(3):154–62. 111. Cancelliere AE, Kertesz A. Lesion localization in acquired deficits of emotional expression and comprehension. Brain Cogn. 1990;13(2):133–47. 112. Darby DG. Sensory aprosodia: a clinical clue to lesions of the inferior division of the right middle cerebral artery? Neurology 1993;43(3 Pt 1):567–72.

98. Heilman KM. Matter of Mind: A Neurologist’s View of Brain–Behavior Relationships. Oxford: Oxford University Press; 2002.

113. Starkstein SE, Federoff JP, Price TR, Leiguarda RC, Robinson RG. Neuropsychological and neuroradiologic correlates of emotional prosody comprehension. Neurology 1994;44(3 Pt 1):515–22.

99. De Groot AW. Structural linguistics and syntactic laws. Word 1949;5:1–12.

114. Ehlers L, Dalby M. Appreciation of emotional expressions in the visual and auditory modality in

195


normal and brain-damaged patients. Acta Neurol Scand. 1987;76(4):251–6.

prosody, as revealed by functional magnetic resonance imaging. Neuropsychologia 2003;41(10):1410–21.

115. Bradvik B, Dravins C, Holtas S et al. Disturbances of speech prosody following right hemisphere infarcts. Acta Neurol Scand. 1991;84(2):114–26.

129. Wildgruber D, Riecker A, Hertrich I et al. Identification of emotional intonation evaluated by fMRI. Neuroimage 2005;24(4):1233–41.

116. Pell MD, Baum SR. The ability to perceive and comprehend intonation in linguistic and affective contexts by brain-damaged adults. Brain Lang. 1997;57(1):80–99.

130. Schlanger BB, Schlanger P, Gerstman LJ. The perception of emotionally toned sentences by right hemisphere-damaged and aphasic subjects. Brain Lang. 1976;3(3):396–403.

117. Breitenstein C, Daum I, Ackermann H. Emotional processing following cortical and subcortical brain damage: contribution of the fronto-striatal circuitry. Behav Neurol. 1998;11(1):29–42.

131. Seron X, Van der Kaa MA, Vanderlinden M, Remits A, Feyereisen P. Decoding paralinguistic signals: effect of semantic and prosodic cues on aphasics’ comprehension. J Commun Disord. 1982;15(3):223–31.

118. Wertz RT, Henschel CR, Auther LL, Ashford JR, Kirshner HS. Affective prosodic disturbance subsequent to right hemisphere stroke: a clinical application. J Neurolinguistics 1998;11(1–2):89–102.

132. Speedie LJ, Coslett HB, Heilman KM. Repetition of affective prosody in mixed transcortical aphasia. Arch Neurol. 1984;41(3):268–70.

119. Adolphs R, Damasio H, Tranel D. Neural systems for recognition of emotional prosody: a 3-D lesion study. Emotion 2002;2(1):23–51. 120. Lebrun Y, Lessinnes A, De Vresse L, Leleux C. Dysprosody and the non-dominant hemisphere. Lang Sci. 1985;7(1):41–52. 121. Riese W. Aphasia in brain tumors; its appearance in relation to the natural history of the lesion. Confin Neurol. 1949;9(1–2):64–79. 122. Ross ED, Harney JH, deLacoste-Utamsing C, Purdy PD. How the brain integrates affective and propositional language into a unified behavioral function. Hypothesis based on clinicoanatomic evidence. Arch Neurol. 1981;38(12):745–8. 123. Wolfe GI, Ross ED. Sensory aprosodia with left hemiparesis from subcortical infarction. Right hemisphere analogue of sensory-type aphasia with right hemiparesis? Arch Neurol. 1987;44(6):668–71. 124. Cohen MJ, Riccio CA, Flannery AM. Expressive aprosodia following stroke to the right basal ganglia: a case report. Neuropsychology 1994;8(2):242–5. 125. Van Lancker Sidtis D, Pachana N, Cummings JL, Sidtis JJ. Dysprosodic speech following basal ganglia insult: toward a conceptual framework for the study of the cerebral representation of prosody. Brain Lang. 2006;97(2):135–53. 126. Ross ED, Anderson B, Morgan-Fisher A. Crossed aprosodia in strongly dextral patients. Arch Neurol. 1989;46(2):206–9. 127. Meyer M, Alter K, Friederici AD, Lohmann G, von Cramon DY. FMRI reveals brain regions mediating slow prosodic modulations in spoken sentences. Hum Brain Mapp. 2002;17(2):73–88. 128. Mitchell RL, Elliott R, Barry M, Cruttenden A, Woodruff PW. The neural response to emotional

196

133. Klouda GV, Robin DA, Graff-Radford NR, Cooper WE. The role of callosal connections in speech prosody. Brain Lang. 1988;35(1):154–71. 134. Haverkate H. A speech act analysis of irony. J Pragmat. 1990;14(1):77–109. 135. Anolli L, Ciceri R, Infantino MG. Irony as a game of implicitness: acoustic profiles of ironic communication. J Psycholinguist Res. 2000;29(3): 275–311. 136. Rockwell P. Lower, slower, louder: vocal cues of sarcasm. J Psycholinguist Res. 2000;29(5):483–95. 137. Bowers D, Blonder LX, Heilman KM. Florida Affective Battery. Gainsville, FL: University of Florida, Center for Neuropsychological Studies, Cognitive Neuroscience Laboratory; 1999. Available from: http://www.neurology.ufl.edu/forms/fab manual.pdf. 138. Heilman KM, Leon SA, Rosenbek JC. Affective aprosodia from a medial frontal stroke. Brain Lang. 2004;89(3):411–16. 139. Monnot M, Nixon S, Lovallo W, Ross E. Altered emotional perception in alcoholics: deficits in affective prosody comprehension. Alcohol Clin Exp Res. 2001; 25(3):362–9. 140. Monnot M, Lovallo WR, Nixon SJ, Ross E. Neurological basis of deficits in affective prosody comprehension among alcoholics and fetal alcohol-exposed adults. J Neuropsychiatry Clin Neurosci. 2002;14(3):321–8. 141. Cohen ES, Brosgole L. Visual and auditory affect recognition in senile and normal elderly persons. Int J Neurosci. 1988;43(1–2):89–101. 142. Allen R, Brosgole L. Facial and auditory affect recognition in senile geriatrics, the normal elderly and young adults. Int J Neurosci. 1993;68(1–2):33–42. 143. Orbelo DM, Testa JA, Ross ED. Age-related impairments in comprehending affective prosody with


comparison to brain-damaged subjects. J Geriatr Psychiatry Neurol. 2003;16(1):44–52.

with chronic posttraumatic stress disorder. J Neuropsychiatry Clin Neurosci. 2009;21(1):52–8.

144. Orbelo DM, Grim MA, Talbott RE, Ross ED. Impaired comprehension of affective prosody in elderly subjects is not predicted by age-related hearing loss or age-related cognitive decline. J Geriatr Psychiatry Neurol. 2005;18(1):25–32.

158. Freeman T, Powell M, Kimbrell T. Measuring symptom exaggeration in veterans with chronic posttraumatic stress disorder. Psychiatry Res. 2008;158(3):374–80.

145. Roberts VJ, Ingram SM, Lamar M, Green RC. Prosody impairment and associated affective and behavioral disturbances in Alzheimer’s disease. Neurology 1996;47(6):1482–8. 146. Testa JA, Beatty WW, Gleason AC, Orbelo DM, Ross ED. Impaired affective prosody in AD: relationship to aphasic deficits and emotional behaviors. Neurology 2001;57(8):1474–81. 147. Botwink J. Intellectual abilities. In Birren JE, Schaie KW, editors. Handbook of the Psychology of Aging. New York, NY: Van Nostrand Reinhold; 1977. 148. Hochnadel G, Kaplan E. Neuropsychology of normal aging. In: Albert ML, editor. Clinical Neurology of Aging. New York, NY: Oxford University Press; 1984, pp. 231–44. 149. Prodan CI, Orbelo DM, Ross ED. Processing of facial blends of emotion: support for right hemisphere cognitive aging. Cortex 2007;43(2):196–206. 150. Abrams R, Taylor MA. A rating scale for emotional blunting. Am J Psychiatry 1978;135(2):226–9. 151. Andreasen NC. Affective flattening and the criteria for schizophrenia. Am J Psychiatry 1979;136(7):944–7. 152. Alpert M, Rosen A, Welkowitz J, Sobin C, Borod JC. Vocal acoustic correlates of flat affect in schizophrenia. Similarity to Parkinson’s disease and right hemisphere disease and contrast with depression. Br J Psychiatry Suppl. 1989;(4):51–6. 153. Fricchione G, Sedler MJ, Shukla S. Aprosodia in eight schizophrenic patients. Am J Psychiatry 1986;143(11): 1457–9. 154. Borod JC, Alpert M, Brozgold A et al. A preliminary comparison of flat affect schizophrenics and brain-damaged patients on measures of affective processing. J Commun Disord. 1989;22(2):93–104.

159. Freeman TW, Kimbrell T. A “cure” for chronic combat-related posttraumatic stress disorder secondary to a right frontal lobe infarct: a case report. J Neuropsychiatry Clin Neurosci. 2001;13(1): 106–9. 160. McCann UD, Kimbrell TA, Morgan CM et al. Repetitive transcranial magnetic stimulation for posttraumatic stress disorder. Arch Gen Psychiatry 1998;55(3):276–9. 161. Cohen H, Kaplan Z, Kotler M et al. Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study. Am J Psychiatry 2004;161(3):515–24. 162. Ross ED, Homan RW, Buck R. Differential hemispheric lateralization of primary and social emotions – implications for developing a comprehensive neurology for emotions, repression, and the subconscious. Neuropsychiatry Neuropsychol Behav Neurol. 1994;7(1):1–19. 163. Ross E. Cortical representation of the emotions. In Trimble MR, Cummings JL, editors. Contemporary Behavioral Neurology. Boston, MA: Butterworth-Heinemann; 1997, pp. 107–26. 164. Ross ED, Prodan CI, Monnot M. Human facial expressions are organized functionally across the upper-lower facial axis. Neuroscientist 2007;13(5): 433–46. 165. Ross ED. Hemispheric specialization for emotions, affective aspects of language and communication and the cognitive control of display behaviors in humans. Prog Brain Res. 1996;107:583–94. 166. Ross ED. Sensory-specific amnesia and hypoemotionality in humans and monkeys: gateway for developing a hodology of memory. Cortex 2008; 44(8):1010–22.

155. Murphy D, Cutting J. Prosodic comprehension and expression in schizophrenia. J Neurol Neurosurg Psychiatry 1990;53(9):727–30.

167. Ross ED, Rush AJ. Diagnosis and neuroanatomical correlates of depression in brain-damaged patients. Implications for a neurology of depression. Arch Gen Psychiatry 1981;38(12):1344–54.

156. Ross ED, Orbelo DM, Cartwright J et al. Affective-prosodic deficits in schizophrenia: comparison to patients with brain damage and relation to schizophrenic symptoms [corrected]. J Neurol Neurosurg Psychiatry 2001;70(5):597–604.

168. Ross ED, Stewart RS. Pathological display of affect in patients with depression and right frontal brain damage. An alternative mechanism. J Nerv Ment Dis. 1987;175(3):165–72.

157. Freeman TW, Hart J, Kimbrell T, Ross ED. Comprehension of affective prosody in veterans

169. Kinnier Wilson SA. Original papers: some problems in neurology – No. II. – Pathological laughing and crying. J Neurol Psychopathol. 1924;4(16):299–333.

197


170. Lieberman A, Benson DF. Control of emotional expression in pseudobulbar palsy. A personal experience. Arch Neurol. 1977;34(11):717–19.

178. Rehak A, Kaplan JA, Weylman ST et al. Story processing in right-hemisphere brain-damaged patients. Brain Lang. 1992;42(3):320–36.

171. Winner E, Gardner H. The comprehension of metaphor in brain-damaged patients. Brain 1977; 100(4):717–29.

179. Schneiderman EI, Murasugi KG, Saddy JD. Story arrangement ability in right brain-damaged patients. Brain Lang. 1992;43(1):107–20.

172. Caramazza A, Berndt RS, Basili AG, Koller JJ. Syntactic processing deficits in aphasia. Cortex 1981;17(3):333–48.

180. Marini A, Carlomagno S, Caltagirone C, Nocentini U. The role played by the right hemisphere in the organization of complex textual structures. Brain Lang. 2005;93(1):46–54.

173. Delis DC, Wapner W, Gardner H, Moses JA, Jr. The contribution of the right hemisphere to the organization of paragraphs. Cortex 1983;19(1): 43–50. 174. Brownell HH, Potter HH, Michelow D, Gardner H. Sensitivity to lexical denotation and connotation in brain-damaged patients: a double dissociation? Brain Lang. 1984;22(2):253–65. 175. Brownell HH, Potter HH, Bihrle AM, Gardner H. Inference deficits in right brain-damaged patients. Brain Lang. 1986;27(2):310–21. 176. Foldi NS. Appreciation of pragmatic interpretations of indirect commands: comparison of right and left hemisphere brain-damaged patients. Brain Lang. 1987;31(1):88–108. 177. Hough MS. Narrative comprehension in adults with right and left hemisphere brain-damage: theme organization. Brain Lang. 1990;38(2): 253–77.

198

181. Mitchell RL, Crow TJ. Right hemisphere language functions and schizophrenia: the forgotten hemisphere? Brain 2005;128(Pt 5):963–78. 182. Van Lancker DR, Kempler D. Comprehension of familiar phrases by left- but not by right-hemisphere damaged patients. Brain Lang. 1987;32(2):265–77. 183. Van Lancker D. The neurology of proverbs. Behav Neurol. 1990;3:169–87. 184. Mashal N, Faust M, Hendler T, Jung-Beeman M. Hemispheric differences in processing the literal interpretation of idioms: converging evidence from behavioral and fMRI studies. Cortex 2008;44(7): 848–60. 185. Borod JC, Andelman F, Obler LK, Tweedy JR, Welkowitz J. Right hemisphere specialization for the identification of emotional words and sentences: evidence from stroke patients. Neuropsychologia 1992;30(9):827–44.

Section I


Chapter

Praxis

14

Kenneth M. Heilman

There are two major cognitive control systems that help the human program movements. One system helps determine when to move and the other how to move. Akinesia, or hypokinesia, is a disorder in the “when” or “action-intentional system.” Some of the other disorders of the action-intentional system include motor impersistence, defective response inhibition, and motor perseveration. Although these disorders are caused by brain damage and are terribly disabling, this chapter will focus on the disorders of the “how” system. The term apraxia was originally used by Steinthal in 1871 [1] to describe a misuse of tools and objects, a disorder of the “how” system. Although the term apraxia, derived from Greek, literally means “without action,” the word akinesia is used currently to describe the failure to initiate an action in the absence of weakness. The term apraxia has been used for a variety of how-movement disorders including disorders of gait, speech and eye control, but this chapter will focus on apraxia of the upper limbs. Apraxia of the forelimbs can be task specific or general. Task-specific apraxias include dressing apraxia and constructional apraxia; these specific forms of apraxia will not be discussed in this chapter, which instead will focus on the general forms of apraxia. As noted by Geschwind [2, 3], who helped to re-establish interest in apraxia, these disorders are in part defined by what they are not. For example, there are many sensory, motor and cognitive disorders that might impair a person’s ability to correctly make skilled purposeful movements, including: weakness, sensory loss, abnormal and involuntary movements such as tremors, dystonia, chorea, ballismus, athetosis, myoclonus, loss of coordination such as ataxia, as well as seizures. Patients with severe cognitive, memory

and attentional disorders may also have difficulty performing skilled acts, because they do not understand, forget, or get distracted. The presence of these more elemental motor, sensory and cognitive disorders do not, however, preclude that a patient can also have limb apraxia. Unfortunately, the presence of these disorders might prevent the examiner from adequately testing for apraxia.

Clinical relevance Apraxia often goes unrecognized by patients as well as physicians and there are several possible reasons for its poor recognition. In regard to the patient, apraxia is often associated with left hemispheric injury such as that produced by diseases such as stroke. Since many of these patients have a hemiparesis of their preferred right arm and hand, when these patients attempt to perform skilled acts with their non-preferred left arm and learn that they are impaired, they may attribute their poor performance to pre-morbid clumsiness of their non-dominant left forelimb. However, many apraxic patients who do not have a right hemiplegia but who are impaired when attempting to perform learned skilled movement with their preferred right upper limb still fail to recognize their deficits; this unawareness of deficits appears to be a form of anosognosia. Not only do patients often fail to complain about the deficits associated with apraxia, but many health professionals also fail to test for limb apraxia. Limb apraxia has been noted to be a heterogeneous group of disorders with a variety of different clinical presentations; unfortunately, there is a paucity of standardized clinical tests that can be used to assess for these disorders.


199


For many years neurologists, neuropsychologists, speech pathologists, and other clinicians thought that limb apraxia was a rare disorder seen only in the laboratory by a handful of academicians, and that these disorders did not interfere with performing activities of daily living or instrumental activities. However, it is now widely recognized that apraxia is a major cause of disability which can interfere with a patient’s ability to perform both basic and instrumental activities of daily living. Additionally, apraxia can occur with a variety of diseases that cause damage to the brain, the most common perhaps being stroke and degenerative dementias, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, such as corticobasal degeneration.

The apraxias Hugo Liepmann, a student of Carl Wernicke, made important contributions to the understanding of apraxia that parallel the paradigm shifts made by Wernicke in the study of aphasia. In a series of papers written between 1900 and 1920, Liepmann described three major forms of apraxia: ideomotor apraxia, which was also called ideo-kinetic apraxia in Liepmann’s terminology [4]; ideational apraxia; and limbkinetic apraxia, also referred to by some investigators as melokinetic or innervatory apraxia. Studies in our laboratory introduced two other forms: conceptual apraxia and dissociation apraxia. We have discussed each of these forms of apraxia elsewhere [5], discussing the means of their testing, the abnormal behaviors that characterize them, and their pathophysiology. In this chapter, we also discuss the signs and pathophysiology of these apraxic disorders but use a processing approach. Like many other cognitive activities, performing skilled purposeful movements requires the sequential and/or parallel activation of distributed modular networks. Degradation of the different modules or disconnections between modules in these networks induces specific forms of apraxia, and these forms of apraxia will be discussed in the following sections.

Conceptual apraxia Definition and description Human forelimbs perform several functions of major importance, interacting and altering the environment as well as helping to take care of others and oneself. In

200

order to be successful at these motor-action endeavors, a person must have motives and goal-oriented behaviors. Apathy, abulia, and akinesia are major causes of disability but, as mentioned earlier, these actionintentional system (i.e., “when”) disorders will not be discussed here. When attempting to alter the environment, one needs to decide what needs to be altered and “how” it will be altered. Thus, a person has to know if he or she will need a tool-implement to help accomplish their goals, the type of tool that would be needed, and how this tool will be moved by the person to accomplish this goal. In regard to tool knowledge, patients with conceptual apraxia might not know the mechanical advantage afforded by specific tools and implements. For example, an individual may be shown a nut on a bolt that is not fully tightened; when that individual next is shown a hammer, handsaw, chisel, pliers, and wrench and asked to select the correct tool to complete the job, he or she might incorrectly select the handsaw. Some patients with a milder form of conceptual apraxia might be able to select the correct tool (e.g., wrench); however, if this tool is not present in their tool chests and they therefore must use another tool, they might then select the incorrect tool. For example, an individual might be presented with a wooden board in which a nail has been driven partially and with a tool chest in which there is no hammer; instead of selecting pliers or wrench to pound in this nail, the individual might select the handsaw. In general, the highest level of tool conceptual knowledge allows individuals to create a new tool to solve a mechanical problem; conceptual apraxia is characterized in some patients by the loss of this ability [6, 7]. After a person is given, correctly selects, or devises a tool to use for a task, he or she then must select and perform the action that is associated with that tool. For example, if a person wants to insert a nail into a board then that person has to make pounding motions, not slicing or sawing movements; if, instead, a person wants to cut something then he or she must make slicing rather than pounding movements. As will be discussed below, patients with ideomotor apraxia make movement errors but the clinician can usually detect that the intent of the movement is correct. In contrast, patients with conceptual apraxia make content-movement errors, such that when asked to pantomime a specific transitive movement and shown a partially driven-in nail, the patient pantomimes the

Chapter 14: Praxis

movements associated with using another tool, such as slicing. Some patients with severe conceptual apraxia will make errors even when given the tool; for example, even when shown a hammer or even when holding the hammer the patient makes slicing movements.

Testing Unfortunately, there is a paucity of standardized tests that are available to assess for conceptual apraxia. The Florida Action Recall Test (FLART) [8], developed to assess conceptual apraxia, consists of 45 line drawings of objects or scenes for which an action with a tool is required. First, the patient must decide what in the scene needs to be altered. Next, the subject must imagine the proper tool with which to make these alterations and then pantomime its use. There are several types of errors that may be made by patients. They may fail to know which elements of the scene need to be altered, which tool allows a person to make those alterations, and/or the correct actions associated with the use of a tool. For example, a patient shown a partially driven-in nail might make no movement and state “I do not know what to do” or instead make slicing movement rather than pounding movements. Both of these errors are conceptual errors. However, a patient might make pounding movements but either hold his hand in an incorrect posture or fail to make flexion-extension or radial-ulnar movements at the wrist. These latter errors are considered evidence for an ideomotor apraxia (discussed below) and not a sign of conceptual apraxia. In today’s “bean counter” controlled practice of medicine, physicians and neuropsychologists often cannot afford to observe patients when they are performing basic or instrumental activities of daily living; however, observations of these activities often best allow the clinician to detect the presence of conceptual apraxia. For example, we observed a patient with a hemispheric stroke after he was brought a meal on a tray that was placed next to his bed [9]. Before the patient got his tray, we placed some extra implements, such as a toothbrush, on his tray along with the silverware. The first thing this patient did was to take a sugar packet, tear it open, and pour it into his iced tea. Although there was a long teaspoon on his tray, he picked up a knife and placed it in his glass of tea. Rather than stirring the sugar by moving the knife he instead rotated the glass. While unorthodox, these actions did allow him to accomplish his mission. On his dinner

plate there was creamed corn; when he attempted to eat his creamed corn, he picked up the toothbrush, rather than a fork, and was unsuccessful, leading him to use his fingers to get this item into his mouth. In order to make certain that this patient did not have a visual agnosia (which could have interfered with his object and food item recognition), we asked him to name all the utensils on his tray – he had no difficulty doing so.

Pathophysiology Conceptual apraxia is reported among persons with degenerative dementias such as Alzheimer’s disease (AD) [6] and in the semantic dementia subtype of frontotemporal lobar degeneration [10]. In addition, a study of patients with right and left hemisphere strokes revealed that right-handed patients with left hemisphere strokes may demonstrate conceptual apraxia [7]. Mechanical knowledge, at least in part, is learned throughout life and thus is likely to be a form of memory. Warrington and Shallice [11] reported that whereas some patients had degradation of semantic memories of living things, others had degradation of semantic memories of non-living things. In our study of patients with conceptual apraxia due to stroke, many of the participants with left hemisphere lesions who demonstrate conceptual apraxia had intact verbal comprehension, an observation suggesting that tool-action semantic representations are independent of lexical-semantics. Unfortunately, when we attempted to localize the region of the left hemisphere that when damaged was most likely to lead to conceptual apraxia, we were unable to localize it [7]. Some of the patients with conceptual apraxia following left hemisphere strokes had temporoparietal injury, others had frontal injury, and still others a combination of frontal and temporoparietal injury. Failure to find a significant specific locus for conceptual apraxia suggests that either we had an insufficient number of subjects or that mechanical knowledge is widely distributed neuroanatomically. Support for the latter possibility comes from a functional magnetic resonance imaging study of conceptual mechanical knowledge in normal subjects [12], in which investigators observed activation in multiple areas of the left hemisphere, including the parietal-temporal-occipital junction, inferior frontal and anterior dorsal premotor areas.

201


If mechanical knowledge is stored in the left hemisphere of right-handed people, then disconnection of the cerebral hemispheres due to a callosal lesion in a right-handed person might produce signs of conceptual apraxia when that individual attempts to use his left hand to solve mechanical problems. Liepmann and Maas reported patient Ochs [13], an individual who appeared to have a callosal disconnection and whose many left upper extremity errors appeared to be content errors. Unfortunately, Ochs had a right hemiparesis from a brainstem lesion and thus the performance of his right and left hand could not be compared. The patient reported by Watson and Heilman [14], who sustained an infarction of her corpus callosum, initially made content errors with her left but not her right hand and arm. If the content errors performed by this woman’s left forelimb were only in response to verbal commands it might have suggested that language speech commands could not get access to the right hemisphere; however, this woman also made content errors when holding the actual tools or implements in her left hand. Her right hand performance, in these same conditions, however, was flawless.

Ideational apraxia Definition and description The term ideational apraxia has been used to describe many different forms of apraxic disorders. For example, De Renzi and Lucchelli [15] defined ideational apraxia as failure to correctly use actual tools and implements. In their article entitled “Ideational Apraxia,” they noted that patients with lesions of their left inferior parietal lobe made spatial errors when attempting to use actual tools and implements. However, Poizner et al. [16] demonstrated that patients with ideomotor apraxia are often impaired when using tools and objects. Unfortunately, when Heilman first described dissociation apraxia he called it ideational apraxia; conceptual apraxia also has been called ideational apraxia [9, 12]. Despite the overlapping use of these terms, these are presently recognized as distinct types of apraxia. The latter type of apraxia was described in the preceding section of this chapter and dissociation apraxia will be discussed later in this chapter. The remainder of this section focuses specifically on ideational apraxia.

202

Many goal-oriented behaviors require that a person perform a series of acts to accomplish a goal. For example, a person making a ham and cheese sandwich to bring to work for lunch ordinarily follows a series of steps when doing so. First, two slices of bread are cut from the loaf. Mustard and/or mayonnaise are then put on the slices of bread. Next, the ham, cheese, and lettuce are placed on one slice of this bread, and then covered with the other piece of bread. Finally, the sandwich is cut in half and put into a vinyl sandwich bag. According to Liepmann’s definition [17], a person with ideation apraxia demonstrates problems properly sequencing these acts; for example, cutting the bread before placing the mustard, ham, and cheese on it.

Pathophysiology Patients with frontal lobe injuries often have trouble with sequencing; however, De Renzi and co-workers [18] noted that this sequencing disorder was more commonly associated with left inferior parietal than frontal injury. After degeneration of the medial temporal lobes, AD involves degeneration of the inferior parietal lobes; consistent with the findings of De Renzi and colleagues [18], Crutch et al. [19] observed that patients with AD often had ideational apraxia.

Ideomotor apraxia Definition and description After a person decides what tool or implement they need to use to accomplish each act in a goal, the next step is to use this tool or implement to accomplish the desired task. In order to correctly perform the required actions, an individual needs to know: (1) how to hold the tool; (2) how to direct the tool to the location where the action of the tool is required; (3) how to move their forelimb through space so that the tool-implement can correctly move on the target upon which it is acting; (4) how fast to move the tool; and (5) how much force with which to use the tool. After having selected the correct tool for the job and upon knowing the type of action needed to use the tool effectively to accomplish the goal, a patient with ideomotor apraxia might: (1) fail to hold her hand correctly (i.e., make a postural error); (2) fail to move her forelimb to the target of the tool’s action or fail to maintain the correct spatial orientation; (3) move the incorrect joints of the limb involved or not properly

Chapter 14: Praxis

coordinate multiple joint movements; and (4) use the incorrect speed or force.

Testing When testing patients for ideomotor apraxia, if possible, both the right and the left forelimbs should be tested. In general, there are two types of gestures or movements that a person can make with their forelimb, transitive and intransitive. Transitive movements are those that are used with tools and implements. Intransitive movements are those usually used to communicate with others. For example, when standing at the side of the road, if a person makes a fist and points his thumb in the direction to which he wants to travel then that is understood as a sign that he is requesting someone to stop and give him a ride (hitchhiking). This is an intransitive gesture. When the policeman puts his open hand up in the air with his palm facing a driver it means that he wants the driver to stop his car. This is another intransitive gesture. In contrast, asking a person to pretend she is using a pair of scissors to cut in half a piece of paper she will be pantomiming a transitive act. In general, when assessing patients for ideomotor apraxia, testing patients by asking them to pantomime transitive acts is much more likely to detect ideomotor apraxia then testing them performing intransitive acts. While having patients pantomime transitive acts is the most sensitive means of assessing for ideomotor apraxia, patients should be asked to imitate the examiner performing both meaningful and meaningless gestures. Additionally, being allowed to see pictures of tools or even to hold actual tools or objects and to demonstrate how to use these tools and implements is valuable. It also is valuable to determine whether a patient can name transitive pantomimes made by the examiner and is able to discriminate between well- and poorly performed transitive pantomimes made by the examiner. Patients with ideomotor apraxia may produce several types of movement errors, including postural, allocentric orientation, and egocentric movement errors. Each of these is considered further here.

can be observed in these patients: postural or internal configuration errors, spatial movement errors, and errors of spatial orientation. When using a tool or implement, the hand has to be held in a certain posture. Goodglass and Kaplan [20] noted that when patients with ideomotor apraxia are asked to perform a pantomime of a transitive act they often use a body part, such as the finger or the hand, as the tool. For example, when patients with ideomotor apraxia are asked to show the examiner how they would use a screwdriver they might use their forefinger as the shaft of the screwdriver; when asked to pantomime using a pair of scissors, they may use their fingers as if they were the blades. These movements are emblems of the tool and are not the correct pantomime. When given the command to pretend that they are using a pair of scissors, many normal people make similar “body part as tool” errors. Thus, it is important that patients be instructed not to use a body part as a tool. We have found that, unlike normal subjects who improve with these instructions, patients with ideomotor apraxia often continue using their body parts as tools [21]. However, when patients can be convinced not to use their body parts as tools, patients with ideomotor apraxia often fail to correctly position their arms, hands, and fingers.

Allocentric orientation errors When asked to pantomime the use of the tool (e.g., “show me how you would cut a piece of paper in half by using a pair of scissors”) normal individuals orient the pantomimed tool to an imaginary target of the tool’s action. Patients with ideomotor apraxia often fail to correctly orient their forelimbs to an imaginary target. For example, when pantomiming the use of scissors to cut a piece of paper in half, most normal subjects will keep the blades of the scissor oriented in a sagittal plane; in contrast, patients with ideomotor apraxia may orient the scissors laterally so that they are in the coronal plane or even fail to maintain any consistent plane of movement [22].

Egocentric movement errors Postural errors When attempting to perform skilled transitive acts, patients with ideomotor apraxia primarily make spatial errors. There are three types of spatial errors that

A tool must be moved in certain directions with respect to the object upon which this tool is acting in order for this tool to perform its intended action. When attempting to pantomime or even use actual

203


tools, patients with ideomotor apraxia often incorrectly move the tool through space. The core concept of the movement may be correct, but other, more refined, elements are incorrect. For example, when patients with ideomotor apraxia are asked to pantomime hammering a nail into a board, these patients will often demonstrate pounding-like movements by flexing and extending their arm at the elbow and shoulder. However, correctly using a hammer to pound a nail into a board requires when extending the arm at the elbow to also flex or ulnar-deviate the wrist; failing to move the wrist results in the head of the hammer not coming down upon the nail [22, 23]. Some egocentric movement errors associated with ideomotor apraxia are the result of incorrectly stabilizing some joints and moving the incorrect joints. For example, by trying to rotate a screwdriver on axis by using only the wrist joint, the screwdriver will not rotate on axis and instead makes circular movements. However, many transitive movements require the coordinated movements of multiple joints (e.g., slicing) and patients with ideomotor apraxia often have difficulty coordinating these multiple joint movements.

Pathophysiology Callosal disconnection One of the first people to intensively investigate the pathophysiology of ideomotor apraxia was Hugo Liepmann. In one of his most important reports, Liepmann and Maas [13] described a 70-year-old man whose post-mortem examination revealed an infarction in the distribution of the left anterior cerebral artery which damaged the anterior two-thirds of the corpus callosum. Unfortunately, this patient also had a lesion of his left pons that caused a right hemiparesis. Prior to this patient’s death, Liepmann and Maas noted that when attempting to write or perform skilled movements to command with his left hand this patient demonstrated an inability to correctly perform skilled movements. Liepmann was a student of Carl Wernicke and was aware that the left hemisphere mediated language. Thus, injury to the corpus callosum, the major interhemispheric connecting system, could have isolated the left hemisphere language systems from the motor systems in the right hemisphere that control the left hand and arm. Liepmann and Maas, however, rejected this language disconnection hypothesis

204

because this patient was unable not only to correctly perform skilled purposeful gestures to command but also to use real implements/tools with his left forelimb. Based on these observations, Liepmann and Maas posited that the left hemisphere of right-handed people not only mediates language-speech but also contains movement formulae, the spatial-temporal movement representations that are important for programming purposeful learned skilled movements. They therefore suggested that the callosal injury sustained by their patient prevented movement representations in his left hemisphere from gaining access to the motor systems in his right hemisphere. Liepmann and Maas’ callosal disconnection study played an important role in developing an understanding of the role of the corpus callosum in interhemispheric communication as well as the role of the left hemisphere in the control of movements of the ipsilateral left forelimb. Unfortunately the case they described was less than optimal for this purpose. Their patient’s stroke, which appeared to be in the distribution of the anterior cerebral artery, not only damaged the anterior portion of the corpus callosum but also damaged the superior and medial portions of the left frontal lobe. As we will discuss below, damage to the left medial frontal lobe, including the supplementary motor area, can induce an ideomotor apraxia of both the right and left hands [24]. To demonstrate that the patient reported by Liepmann and Maas had a ideomotor apraxia of his left hand because he had a callosal disconnection, Liepmann and Maas needed to demonstrate that their patient did not have an ideomotor apraxia of his right forelimb; unfortunately, this patient also had a brainstem infarction that caused a right hemiparesis and thus he could not be tested for this finding. Another major problem with Liepmann and Maas’ report is that their patient (who had a callosal lesion) often made what appeared to be content errors; as discussed above, content errors suggest a conceptual apraxia rather than an ideomotor apraxia. Another patient with apraxia from a callosal disconnection was described by Geschwind and Kaplan [25]. Their patient had a left hemisphere glioblastoma and in the peri-operative period he developed an infarction in the distribution of the anterior cerebral artery that injured the anterior four-fifths of his corpus callosum. This patient was able to use his right hand flawlessly, but could not correctly use his left hand in

Chapter 14: Praxis

response to verbal commands. He was, however, able to imitate and use actual objects normally with his left forelimb; thus, he could not be classified as having an ideomotor apraxia but instead appeared to have a verbal dissociation apraxia. The signs and mechanism of dissociation apraxia are discussed in a subsequent section. Gazzaniga and his co-workers [26] studied several epileptic patients who had surgical disconnection of their corpus callosum. Like Geschwind and Kaplan’s patient, these patients were able to imitate and use actual implements with their left forelimb. Thus, these investigators concluded that callosal damage induced a language disconnection. Gazzaniga et al. [26] suggested that if patients had impaired imitation and trouble using actual objects this apraxia would be the result of extracallosal damage. Watson and Heilman [14] reported a woman with a subarachnoid hemorrhage who appeared to contradict the assertion of Gazzaniga et al. [26] that extracallosal damage induces ideomotor apraxia with impairment of imitation and actual object use. This woman’s subarachnoid hemorrhage caused a spasm of the anterior cerebral artery, which caused an infarction of the body of her corpus callosum. Magnetic resonance imaging of this patient’s brain revealed no evidence of any extracallosal damage [27]. Unlike Geschwind and Kaplan’s [25] patient, who was only impaired in pantomiming commands with his left forelimb, this woman was impaired in performing transitive pantomimes and intransitive movements with her left upper limb to command, but she also had trouble imitating the examiner and using actual objects with her left forelimb. In addition, her spatial movement errors were typical of those observed with ideomotor apraxia. In contrast to the apraxia observed when she was using her left forelimb, her ability to pantomime transitive movements and to imitate and use actual objects with her right forelimb was flawless. Graff-Radford et al. [28] and Lausberg et al. [29] have reported patients that replicated the finding of Watson and Heilman [14, 27]. These patients with callosal disconnection also demonstrated left, but not right, ideomotor apraxia making spatial errors with pantomimes, imitation, and actual object use. The patients with callosal disconnection reported by Watson and Heilman [14, 27], Graff-Radford et al. [28], and Lausberg et al. [29] might have differed from those reported by Geschwind and Kaplan [25]

and Gazzaniga et al. [26] because these two groups of patients had differences in their brain organizationlaterality. Liepmann [17] reported that left hemisphere lesions are most likely to cause ideomotor apraxia in right-handed individuals. However, Liepmann also noted that whereas about 95% of patients with large left hemisphere lesions are aphasic, only about 50% have ideomotor apraxia [17]. The fact that there are a lower percentage of left hemisphere-damaged patients who have ideomotor apraxia than have aphasia suggests that a substantial percentage of right-handed people either have movement representations stored in both hemispheres or instead have movement representations stored in the right hemisphere. Apraxia in righthanded patients from right hemisphere injury has been reported [30]; however, this is rare. The majority of people who do not have apraxia from a large left hemisphere lesion therefore probably have movement representations stored in both hemispheres. When a patient has movement representations in both hemispheres and they have an injury to the anterior portions of their corpus callosum, he or she should have the clinical picture described by Geschwind and Kaplan [25]: when using the left forelimb to pantomime to command, the movement is impaired as a result of disconnection of the language-dominant left hemisphere from the left hand-controlling right hemisphere. However, the left hand is able to be used by such individuals to perform imitation and to use actual objects because these actions can be performed without language and because the movement representations necessary for their performance are stored in their right hemispheres. In contrast, the patients reported by Watson and Heilman [14, 27], Graff-Radford et al. [28], and Lausberg et al. [29] appear to have their movement representation restricted to their left hemisphere; thus, callosal disconnection prevented both language and movement formulae from reaching the right hemisphere. These patients therefore made errors when pantomiming to command, imitating, and using actual objects, i.e., they demonstrated unilateral ideomotor apraxia.

Intrahemispheric disconnection As mentioned above, Liepmann [17] noted that about 50% of patients with large left hemisphere damage will have an ideomotor apraxia. Unlike patients with

205


callosal lesions (who have this apraxia restricted to their left forelimb), ideomotor apraxia can be observed in both hands among patients without a hemiparesis. Both Liepmann [17] and Geschwind [2, 3] noted that it was primarily lesions in the region of the left supramarginal gyrus that induce ideomotor apraxia. To account for the development of ideomotor apraxia following injury to this region, Geschwind [2, 3] proposed a disconnection hypothesis. In the subcortical white matter of the supramarginal gyrus is the arcuate fasciculus. This fasciculus is the white matter pathway that connects Wernicke’s area, important in language comprehension, to the left hemisphere’s convexity premotor areas. The premotor cortex of the left hemisphere projects to the right hemisphere’s premotor cortex and both premotor cortices project to the motor cortex on the same side. According to Geschwind’s [2, 3] disconnection model, injury to the region of the supramarginal gyrus interrupts the arcuate fasciculus; thus, when a person with injury to this region hears a command, he is unable to transfer this information to the premotor cortices and hence unable to correctly carry out the command.

Inferior parietal lobe Geschwind’s [2, 3] verbal disconnection hypothesis cannot explain why patients with lesions in the region of the supramarginal gyrus cannot correctly imitate or correctly use actual objects. An alternative explanation is that the region of the inferior parietal lobe contains the multimodal (visuo-kinesthetic) movement representations (spatial-temporal movement representations) and that degradation of these representations of skilled movements induces apraxia [31, 32]. Unlike Geschwind’s [2, 3] disconnection hypothesis, this representational hypothesis can account for why injury to this area would also impair imitation and the use of actual objects. If a patient has a degradation of a movement representation, then – in addition to being unable to produce the behavior that this representation programs – such a patient also should have trouble discriminating correctly versus incorrectly performed pantomimes. Therefore, we tested this representation hypothesis of ideomotor apraxia by assessing the ability of apraxic patients, who suffered with anterior versus posterior left hemisphere strokes, to discriminate correctly from incorrectly performed pantomimes of transitive movements. We found that patients with anterior left

206

hemisphere lesions could correctly discriminate between pantomimes of these types whereas those with posterior lesions were impaired, thereby supporting the representational hypothesis. Recently, functional imaging studies have also provided converging evidence that movement representations are stored in the inferior parietal lobe [33]. Lissauer [34] noted that patients with ventral temporal-occipital lesions had trouble identifying objects (visual object agnosia) and Balint [35] noted that patients with dorsal parietal-occipital lesions have trouble determining the position of objects in relation to the body (optic ataxia and psychic paralysis of gaze). Ungerleider and Haxby [36] called these the “what” and “where” visual systems. Watson et al. [37] suggested and provided support for the postulate that in humans the integration of the areas important in stimulus localization (e.g., the dorsal visual [“where”] system) and stimulus identification (the ventral [“what”] system) takes place in the inferior parietal lobe. The synthesis of these systems would appear to be critical for developing the correct postures and body-centered (egocentric) joint movements when pantomiming the use of a tool or implements as well as for directing the subject’s hand and arm to the location where the action is directed. Injury to the left inferior parietal cortex would impair these functions and patients with inferior parietal injuries do demonstrate both postural and orientation errors [22].

Premotor cortex The movement representations we discussed above that are stored in the inferior parietal lobe are stored in a polymodal (visual-kinesthetic) three-dimensional spatial-temporal code [5]. In some respects, this code could be considered similar to sheet music. Sheet music provides the piano player with a program that denotes the sequences of spatial movements required to be made by the pianist’s fingers and the duration of each movement as well as the duration between movements. The corticospinal neurons, found primarily in Brodmann’s area 4 (primary motor cortex), might be thought of as being similar to the piano keys. These corticospinal neurons activate the motor nerves in the spinal cord, which in the metaphor we have been using might be the felt hammers in the piano. The felt hammer hits the wires that make the sound and the motor nerves when active make specific muscle groups contract.

Chapter 14: Praxis

At one time it was thought that each site of the motor cortex activated one muscle that moved a joint in a specific direction, but more recent studies show the primary motor cortex can influence the speed or movement as well as its direction through space [38]. Other investigators have suggested that it might be joint angle that is coded and programmed in the primary motor cortex [39]. For the purpose of our discussion of ideomotor apraxia, the functional organization of the corticospinal system is not critical. However, in order for the corticospinal system to provide the motor units with the correct firing patterns, this system must get instructions from another portion of the brain. Thus, the spatial-temporal knowledge (sheet music) stored in the parietal lobe that guides purposeful voluntary movements have to be transformed into motor programs (the piano player) and these motor programs have to activate the motor cortex using specific firing patterns. The premotor cortex, which is anterior to the motor cortex, can be divided into two major divisions: a lateral portion and a medial portion. Each of these major subdivisions of the premotor area can also be further divided into subunits. These subunits include rostral and caudal subregions. Medially, the premotor cortex is divided into the caudally situated supplementary motor area (SMA) and the rostrally located pre-SMA. The lateral portions of the premotor cortex are divided into ventral and dorsal subregions, and each of these dorsal and ventral subregions is divided further into caudal and rostral portions. Picard and Strick [40] noted that the more rostral portions do not have strong direct connections with the motor cortex and appear to be heavily connected with regions of the prefrontal cortex. According to these investigators, the role of the rostral premotor area is primarily executive-planning functions rather than motor control. In contrast, the more caudal portions (such as SMA and caudal lateral premotor cortex) appear to play a critical role in mediating and programming skilled movements. Whereas electrical stimulation of the primary motor cortex induces simple movements such as flexion of the thumb, stimulation of the supplementary motor area induces complex movements that may include the entire forelimb. The role of the lateral versus medial caudal premotor cortex (SMA) in controlling purposeful skilled movements has still not been entirely elucidated. There is, however, evidence for the hypothesis that SMA

primarily programs the aspects of skilled movement that are entirely internally initiated (self-directed actions) whereas the lateral premotor cortex is more involved with movements that are directed by external sensory (e.g., visual) stimuli [41]. Some investigators find that the lateral premotor cortex also might activate these movements [42]. Thus, the medial premotor cortex (SMA) may be more important in programming the egocentric aspects of skilled movements and the lateral premotor cortex the allocentric (target) aspects. The connectivity of the SMA also places it in a good anatomic position to act as the piano player. It receives projections from parietal neurons, which contain the spatial temporal movement representations (the sheet music) and project to corticospinal motor neurons (the piano keys). Physiological studies have revealed that the neurons in the SMA discharge before neurons in the primary motor cortex [43]. Functional imaging studies (measuring alterations of blood flow, which indirectly reflects synaptic activity), revealed that single simple repetitive movements such as finger flexion increase activation of the primary motor cortex contralateral to the finger that is flexing. In contrast, blood flow increases in both the contralateral motor cortex and in the supplementary motor area when subjects make complex purposeful movements. Finally, when normal subjects think about/plan making complex movements but do not make actual movements, blood flow increases in the SMA but not the primary motor cortex [44, 45]. This series of studies provide evidence that in normal subjects the SMA is critical in programming complex purposeful voluntary movements – in the metaphor begun earlier in this section, SMA is the pianist. In regard to ideomotor apraxia, Watson et al. [24] reported several patients with left-sided medial frontal lesions involving the SMA who demonstrated an ideomotor apraxia when tested with either arm. Unlike patients with parietal lesions, these patients with SMA injury could discriminate between well and incorrectly performed pantomimes. Patients with corticobasal degeneration often suffer with an ideomotor apraxia and Leiguarda et al. [46] suggested that these patients’ deficits may also be related to dysfunction of the supplementary motor area. Imaging studies appear to support this hypothesis [47]. We observe that most of our patients with corticobasal degeneration are able to discriminate wellperformed from incorrectly performed pantomimes of

207


transitive movements, supporting the hypothesis that these patients’ movement representations are intact and that their disability might be related to dysfunction of the supplementary or convexity premotor areas. Returning to our metaphor, it appears that information from the sheet music gets to the pianist by means of vision; how then does the spatial-temporal movement information needed to perform transitive acts get from the parietal lobe to the premotor areas? Additionally, can a disconnection between these two regions also induce an ideomotor apraxia? Based on the work of Schmahmann et al. [48], the pathway that connects the supramarginal gyrus and premotor cortex is the superior longitudinal fasciculus. Although Schmahmann et al. [48] described this white matter pathway in rhesus monkeys, studies in humans using diffusion tensor imaging tractography [49] also appear to demonstrate a similar white matter pathway. If the white matter connections between these two critical areas are interrupted then these patients should also have an ideomotor apraxia. Pramstaller and Marsden [50] reviewed the reports of 82 patients with apraxia from subcortical lesions. These investigators found that the majority of these patients sustained large lesions with damage to the basal ganglia and/or thalamus together with the white matter. The injured portions of white matter included the internal capsule as well as the periventricular and peristriatal white matter, interrupting association fibers in the superior longitudinal fasciculus. Discrimination between correctly and incorrectly performed pantomimes might be performed by a visuo-spatial analysis that does not require motor programming. Thus, a disconnection between the stored spatial-temporal movement representations in the parietal lobe and the regions that translate these representations to movement programs in the premotor cortex should induce an ideomotor apraxia with intact discrimination. Hanna-Pladdy et al. [51] compared the performance on praxis performance and discrimination tasks in patients with left hemisphere cortical and subcortical lesions. The patients with cortical lesions demonstrated production deficits, as well as impaired gesture discrimination. Whereas the patients with subcortical injuries also exhibited apraxic production deficits they had normal discrimination. Unfortunately, at the time the Hanna-Pladdy et al. study was performed the exact white matter pathways that induced these deficits could not be

208

determined, but now with diffusion tensor imaging the white matter pathways that when damaged induce ideomotor apraxia can be examined.

Dissociation apraxia Definition, description, and testing In some circumstances, a person might be required to perform a learned action in response to a command, or by seeing a tool, or by observing another person perform an action. There are patients who are unable to correctly pantomime transitive movements to command using either forelimb, but who are able to correctly pantomime when seeing the tool or implement, to imitate normally, and to use actual objects normally. As mentioned, this disorder is now called verbal dissociation apraxia [5]. De Renzi et al. [52] also reported similar patients, but also described patients who were unable to correctly pantomime transitive gestures in response to seeing tools but who were able to do so in response to commands. Heilman et al. [5] suggested that verbal dissociation apraxia was induced by dissociation between lexical-semantic language representations and movement representations and that visual-object dissociation apraxia reported by De Renzi et al. [52] was caused by a functional dissociation between object recognition units and movement representations. However, in both disorders the movement representations and their connections to premotor and motor cortex were intact. These are not common disorders, and the loci of lesion that induces these forms of intrahemispheric dissociation apraxias are not known. Patients with ideomotor apraxia typically are more impaired when performing to command than when imitating. When a patient has degraded movement representations, observing an examiner make movements provides patients with movement information that is not available from their own degraded movement representations. However, there are several reports of patients who were more impaired when imitating an examiner perform a gesture than when performing to command or actually using tools and implements [53–56]. Whereas some patients demonstrated that the imitation of novel gestures was more impaired than previously learned gestures [53], other patients were more impaired when imitating meaningful gestures than meaningless gestures [57]. Some aphasic patients have more problems with imitation

Chapter 14: Praxis

than spontaneous speech, and this disorder has been called conduction aphasia; since patients with this form of apraxia have more problems with visual imitation of gesture than performing gestures to command, this disorder has been called conduction apraxia [56]. However, another term that describes these modality-specific dissociation disorders would be “visual-imitative dissociation apraxia.” The mechanism of this visual-motor imitative disorder is not known. When patients with this disorder perform to commands their pantomimes are relatively intact, suggesting that there is no degradation of their movement representations and that their premotor areas do have the ability to translate these visualkinesthetic movement representations into motor programs and thereby to innovate the motor cortex. Thus, the inability to imitate viewed gestures might suggest a failure of the visual perceptual systems to successfully access the areas of the brain that program movements. Support for this postulate comes from the report of Merians et al. [58], who wrote about a patient with a left occipital and inferior temporal lobe lesion that spared the inferior parietal cortex. This patient performed well to verbal command but was impaired when imitating. In contrast, three patients with ideomotor apraxia whose lesions included the left parietal cortex had the most severe deficits when pantomiming to verbal command and improved pantomime performance with imitation. The observation that there is, in some patients, dissociation between imitation of meaningful and meaningless gestures suggest that there are at least two routes for imitation. Meaningful and previously learned movement might be imitated by accessing movement representations and meaningless movements might directly access the premotor areas that alter this visual input into motor programs. As mentioned, Geschwind and Kaplan [25] reported a patient with a corpus callosum disconnection who, when performing pantomimes to verbal command with his left forelimb, was apraxic but was able to perform normally with the right forelimb. This patient could imitate and use actual objects normally with both hands. Although this patient’s behavior is similar to the patients with the intrahemispheric verbal dissociation apraxia described above, unlike the patients with intrahemispheric verbal dissociation apraxia that involves both forelimbs, the callosal verbal dissociation apraxia seen in this patient only involved the left forelimb.

Limb-kinetic apraxia Definition, description, and testing Limb-kinetic apraxia is characterized by a loss of dexterity or deftness such that patients with this disorder are impaired at making precise, independent but coordinated finger movements. One of the simplest and most sensitive means of testing patients for limbkinetic apraxia is to have the patients attempt to rotate a coin, such as a nickel, between the forefinger, middle finger and thumb, as rapidly as possible. Many patients with ideomotor apraxia will be unable to rotate the coin, others will drop it frequently, and still others perform this movement slowly [59]. Again using the metaphor begun earlier in this chapter, after the piano player reads the music and hits the proper piano keys in the proper sequence and duration, the piano key must move the hammers that hit the strings. If the sheet music is the movement program stored in the parietal lobe, the piano player is the motor program performed by the supplementarypremotor area, the hammer is the motor neurons, and the strings are the muscles, then the piano keys, which activate the hammers (lower motor neurons), is the corticospinal system.

Pathophysiology Lawrence and Kuypers [60] demonstrated that destruction of the pyramidal neurons in the brainstem (corticospinal tract) in monkeys did not cause paralysis but did induce a loss of deftness, in this case independent and precise finger movement –which are the signs of a limb-kinetic apraxia. Other investigators report that damage to the primary motor area or its projections to the motor neurons in the spinal cord does not cause a paralysis, and instead results in a specific deficit in fine manual actions –what Liepmann [17] termed limb-kinetic apraxia [61–64]. Hannah-Pladdy and co-workers [59] found that right-handed patients with left hemisphere lesions not only demonstrated a limb-kinetic apraxia of their right (contralateral) hand but also frequently exhibit a loss of deftness of their ipsilateral (left) hand. In contrast, patients with right hemisphere lesions may have a limb-kinetic apraxia of their left hand but usually perform normally with their right (ipsi-lesional) hand. Thus, it appears that in right-handed people the left hemisphere corticospinal system influences the deftness of the left hand more than vice versa, but the

209


means by which this asymmetry of control is mediated is not fully known. It is possible that the left hemisphere’s motor cortex influences the right hemisphere by transferring information by way of the corpus callosum or influences the left hand by means of ipsilateral pathways. Support for the callosal hypothesis comes from the report of a right-handed man who infarcted the anterior and middle parts of his corpus callosum [65]. This man lost agility and deftness in his left hand, including the ability to make fast and nimble finger movements of his left hand, and these investigators thought that this patient had a melokinetic (limb-kinetic) apraxia induced by a hemispheric disconnection.

Treatment Recently, a consensus conference was held to review the treatment for limb apraxia [66]. The investigators

and clinicians participating in this conference concluded, “despite evidence that several types of limb apraxia significantly impact functional abilities, surprisingly few studies have focused on development of treatment paradigms.” The successful therapies for ideomotor apraxia as reviewed by Buxbaum et al. [66] used a variety of different strategies including: multiple cues, error correction, conductive education, where treatment is focused on a task analysis of the movements with articulationverbalization of the task elements, the use of compensatory strategies to help perform activities of daily living, and imitation with errorless learning. In regard to limb-kinetic apraxia, Quencer and coworkers [67] demonstrated that patient with Parkinson’s disease (PD) often demonstrate limb-kinetic apraxia. Gebhardt et al. [68] demonstrated that whereas dopaminergic agents improve the bradykinesia associated with PD, the limb-kinetic apraxia

Figure 14.1. Cartoon of the praxis system and the injuries that can induce the different forms of apraxia. The right hemisphere is on the top half and the left hemisphere on the bottom half of this cartoon of the brain. O-R-U = Object recognition units. These visual representations are stored in the ventral occipital-temporal cortex. L-S = The lexical-semantic network. The other modular networks are labeled. The arrows represent the pathways that connect these modular networks. The lines with letters attached represent either damage to a network or disconnection between the networks. Damage to the different networks and their connections induce different forms of apraxia, including: A = ideomotor apraxia with impaired pantomime to command, imitation, tool-implement use and impaired discrimination; B = intrahemispheric disconnection ideomotor apraxia, with intact discrimination; C = premotor ideomotor apraxia with same symptoms as B; D = callosal (disconnection) interhemispheric ideomotor apraxia and/or callosal interhemispheric conceptual apraxia; E = intrahemispheric limb-kinetic apraxia; F = interhemispheric disconnection limb-kinetic apraxia; G = visual intrahemispheric dissociation apraxia; H = verbal intrahemispheric dissociation apraxia; I = conceptual apraxia. Some patients have movement representations in both hemispheres (right hemisphere movement representations are illustrated in this cartoon as a cloud). In these patients a callosal disconnection, J = verbal dissociation apraxia of the left, but not right, hand.

210

Chapter 14: Praxis

does not improve with this treatment. A search of PubMed did not reveal any other studies where investigators attempted to treat limb-kinetic apraxia. In addition, there are at present no studies demonstrating treatments of either conceptual or ideational apraxia.

Conclusion In this chapter, several types of limb apraxia were discussed. The cartoon in Figure 14.1 displays the systems that mediate purposeful, skilled movements and the injuries that can induce the different forms of limb apraxia discussed in this review. Patients with conceptual apraxia have lost the knowledge of the mechanical advantage offered by tools and might make errors such as selecting the wrong tool for a specific task, using the incorrect action with a tool, and be unable to correctly use alternative tools, as well as being unable to create tools. Patients with ideational apraxia are impaired at sequencing a series of independent acts that lead to a goal (e.g., making a sandwich). Patients with ideomotor apraxia primarily make spatial errors. The errors may be postural, or may consist of egocentric and allocentric movement errors. There are several forms of dissociation apraxia in which patients cannot perform correct purposeful movements in response to a stimulus in a specific modality (speech commands), but can correctly perform these movements in response to a stimulus in another modality (e.g., seeing the object with which a tool interacts). Finally, limbkinetic (melokinetic, innervatory) apraxia is characterized by a loss of hand–wrist deftness. Within each of these five major categories of limb apraxia there are subtypes. For example, there are patients with ideomotor apraxia who cannot discriminate well-performed movements from incorrectly performed movements and there are other patients who can normally discriminate. Some of these forms and subtypes of apraxia can be caused by disconnection and others by degradation or destruction of critical brain representations.

References 1. Steinthal H. Abriss der Sprachwissenschaft. Berlin: F. Dümmlers; 1871. 2. Geschwind N. Disconnexion syndromes in animals and man. I. Brain. 1965;88(2):237–94. 3. Geschwind N. Disconnexion syndromes in animals and man. II. Brain. 1965;88(3):585–644.

4. Goldenberg G. Apraxia and beyond: life and work of Hugo Liepmann. Cortex 2003;39(3):509–24. 5. Heilman KM, Rothi LG. Apraxia. In Heilman KM, Valenstein E, editors. Clinical Neuropsychology. 4th edition. Oxford: Oxford University Press; 2003, pp. 215–35. 6. Ochipa C, Rothi LJ, Heilman KM. Conceptual apraxia in Alzheimer’s disease. Brain 1992;115(4): 1061–71. 7. Heilman KM, Maher LM, Greenwald ML, Rothi LJ. Conceptual apraxia from lateralized lesions. Neurology 1997;49(2):457–64. 8. Schwartz RL, Adair JC, Raymer AM et al. Conceptual apraxia in probable Alzheimer’s disease as demonstrated by the Florida Action Recall Test. J Int Neuropsychol Soc. 2000;6(3):265–70. 9. Ochipa C, Rothi LJ, Heilman KM. Ideational apraxia: a deficit in tool selection and use. Ann Neurol. 1989; 25(2):190–3. 10. Hodges JR, Bozeat S, Lambon Ralph MA, Patterson K, Spatt J. The role of conceptual knowledge in object use evidence from semantic dementia. Brain 2000;123(9): 1913–25. 11. Warrington EK, Shallice T. Category specific semantic impairments. Brain 1984;107(3):829–54. 12. Ebisch SJ, Babiloni C, Del Gratta C et al. Human neural systems for conceptual knowledge of proper object use: a functional magnetic resonance imaging study. Cereb Cortex 2007;17(11):2744–51. 13. Liepmann H, Maas O. Fall von linksseitiger agraphie und apraxie bei rechsseitiger lahmung. Zeitschrift Psychol Neurol. 1907;10:214–27. 14. Watson RT, Heilman KM. Callosal apraxia. Brain 1983;106(2):391–403. 15. De Renzi E, Lucchelli F. Ideational apraxia. Brain 1988;111(5):1173–85. 16. Poizner H, Clark MA, Merians AS et al. Joint coordination deficits in limb apraxia. Brain 1995; 118(1):227–42. 17. Liepmann H. Apraxia. Erbgn der ges Med. 1920;1: 516–43. 18. De Renzi E, Faglioni P, Lodesani M, Vecchi A. Performance of left brain-damaged patients on imitation of single movements and motor sequences. Frontal and parietal-injured patients compared. Cortex 1983;19(3):333–43. 19. Crutch SJ, Rossor MN, Warrington EK. The quantitative assessment of apraxic deficits in Alzheimer’s disease. Cortex 2007;43(7): 976–86. 20. Goodglass H, Kaplan E. Disturbance of gesture and pantomime in aphasia. Brain 1963;86:703–20.

211


21. Raymer AM, Maher LM, Foundas AL, Heilman KM, Rothi LJ. The significance of body part as tool errors in limb apraxia. Brain Cogn. 1997;34(2): 287–92. 22. Rothi LJG, Mack L, Verfaellie M, Brown P, Heilman KM. Ideomotor apraxia – error pattern-analysis. Aphasiology 1988;2(3–4):381–7. 23. Poizner H, Mack L, Verfaellie M, Rothi LJ, Heilman KM. Three-dimensional computer graphic analysis of apraxia. Neural representations of learned movement. Brain 1990;113(1):85–101. 24. Watson RT, Fleet WS, Gonzalez-Rothi L, Heilman KM. Apraxia and the supplementary motor area. Arch Neurol. 1986;43(8):787–92.

37. Watson RT, Valenstein E, Day A, Heilman KM. Posterior neocortical systems subserving awareness and neglect. Neglect associated with superior temporal sulcus but not area 7 lesions. Arch Neurol. 1994;51(10): 1014–21. 38. Georgopoulos AP, Lurito JT, Petrides M, Schwartz AB, Massey JT. Mental rotation of the neuronal population vector. Science 1989;243(4888):234–6. 39. Scott SH, Kalaska JF. Reaching movements with similar hand paths but different arm orientations. I. Activity of individual cells in motor cortex. J Neurophysiol. 1997;77(2):826–52. 40. Picard N, Strick PL. Imaging the premotor areas. Curr Opin Neurobiol. 2001;11(6):663–72.

25. Geschwind N, Kaplan E. A human cerebral deconnection syndrome. A preliminary report. Neurology 1962;12:675–85.

41. Larsson J, Gulyas B, Roland PE. Cortical representation of self-paced finger movement. Neuroreport 1996;7(2):463–8.

26. Gazzaniga MS, Bogen JE, Sperry RW. Dyspraxia following division of the cerebral commissures. Arch Neurol. 1967;16(6):606–12.

42. Weeks RA, Honda M, Catalan MJ, Hallett M. Comparison of auditory, somatosensory, and visually instructed and internally generated finger movements: a PET study. Neuroimage 2001;14(1 Pt 1):219–30.

27. Watson RT, Heilman KM, Bowers D. Magnetic resonance imaging (MRI, NMR) scan in a case of callosal apraxia and pseudoneglect. Brain 1985;108(2): 535–6. 28. Graff-Radford NR, Welsh K, Godersky J. Callosal apraxia. Neurology 1987;37(1):100–5.

43. Deecke L, Lang W, Uhl F et al. Movement-related potentials and magnetic fields: new evidence for SMA activation leading MI activation prior to voluntary movement. Electroencephalogr Clin Neurophysiol Suppl. 1999;50:386–401.

29. Lausberg H, Cruz RF, Kita S, Zaidel E, Ptito A. Pantomime to visual presentation of objects: left hand dyspraxia in patients with complete callosotomy. Brain 2003;126(2):343–60.

44. Babiloni C, Carducci F, Del Gratta C et al. Hemispherical asymmetry in human SMA during voluntary simple unilateral movements. An fMRI study. Cortex 2003;39(2):293–305.

30. Rapcsak SZ, Gonzalez Rothi LJ, Heilman KM. Apraxia in a patient with atypical cerebral dominance. Brain Cogn. 1987;6(4):450–63.

45. Thobois S, Dominey PF, Decety J et al. Motor imagery in normal subjects and in asymmetrical Parkinson’s disease: a PET study. Neurology 2000;55(7):996–1002.

31. Heilman KM, Rothi LJ, Valenstein E. Two forms of ideomotor apraxia. Neurology 1982;32(4):342–6. 32. Rothi LJ, Heilman KM, Watson RT. Pantomime comprehension and ideomotor apraxia. J Neurol Neurosurg Psychiatry 1985;48(3):207–10. 33. Hermsdorfer J, Terlinden G, Muhlau M, Goldenberg G, Wohlschlager AM. Neural representations of pantomimed and actual tool use: evidence from an event-related fMRI study. Neuroimage 2007; 36(Suppl. 2):T109–18. 34. Lissauer H. Ein Fall von Seelenblindheit nebst einem Beitrage zur Theorie derselben. Eur Arch Psychiatry Clin Neurosci. 1890;21(2):222–70. 35. Balint R. Seelenlahmung des “Schuens” optische Ataxie, raumliche Storung der Aufmerksamkeit. Mschr Psychiat Neurol. 1909;25:51–66. 36. Ungerleider LG, Haxby JV. ‘What’ and ‘where’ in the human brain. Curr Opin Neurobiol. 1994;4(2): 157–65.

212

46. Leiguarda R, Lees AJ, Merello M, Starkstein S, Marsden CD. The nature of apraxia in corticobasal degeneration. J Neurol Neurosurg Psychiatry 1994; 57(4):455–9. 47. Peigneux P, Salmon E, Garraux G et al. Neural and cognitive bases of upper limb apraxia in corticobasal degeneration. Neurology 2001;57(7):1259–68. 48. Schmahmann JD, Pandya DN, Wang R et al. Association fibre pathways of the brain: parallel observations from diffusion spectrum imaging and autoradiography. Brain 2007;130(Pt 3):630–53. 49. Catani M, ffytche DH. The rises and falls of disconnection syndromes. Brain 2005;128(Pt 10): 2224–39. 50. Pramstaller PP, Marsden CD. The basal ganglia and apraxia. Brain 1996;119(Pt 1):319–40. 51. Hanna-Pladdy B, Heilman KM, Foundas AL. Cortical and subcortical contributions to ideomotor apraxia:

Chapter 14: Praxis

analysis of task demands and error types. Brain 2001; 124(Pt 12):2513–27. 52. De Renzi E, Faglioni P, Sorgato P. Modality-specific and supramodal mechanisms of apraxia. Brain 1982; 105(Pt 2):301–12. 53. Goldenberg G, Hagmann S. The meaning of meaningless gestures: a study of visuo-imitative apraxia. Neuropsychologia 1997;35(3):333–41. 54. Peigneux P, Van Der Linden M, Andres-Benito P et al. [A neuropsychological and functional brain imaging study of visuo-imitative apraxia]. Rev Neurol. (Paris) 2000;156(5):459–72. 55. Mehler M. Visuo-imitative apraxia. Neurology 1987; 37(Suppl. 1):129. 56. Ochipa C, Rothi LJ, Heilman KM. Conduction apraxia. J Neurol Neurosurg Psychiatry 1994;57(10):1241–4. 57. Tessari A, Canessa N, Ukmar M, Rumiati RI. Neuropsychological evidence for a strategic control of multiple routes in imitation. Brain 2007;130(Pt 4): 1111–26. 58. Merians AS, Clark M, Poizner H et al. Visual-imitative dissociation apraxia. Neuropsychologia 1997;35(11): 1483–90. 59. Hanna-Pladdy B, Mendoza JE, Apostolos GT, Heilman KM. Lateralised motor control: hemispheric damage and the loss of deftness. J Neurol Neurosurg Psychiatry 2002;73(5):574–7. 60. Lawrence DG, Kuypers HG. The functional organization of the motor system in the monkey. II. The effects of lesions of the descending brain-stem pathways. Brain 1968;91(1):15–36.

61. Denny-Brown D, Botterell EH. The motor functions of the agranular frontal cortex. Res Publ Assoc Res Nerv Ment Dis. 1948;27:235–345. 62. Travis AM. Neurological deficiencies after ablation of the precentral motor area in Macaca mulatta. Brain 1955;78(2):155–73. 63. Kermadi I, Liu Y, Tempini A, Rouiller EM. Effects of reversible inactivation of the supplementary motor area (SMA) on unimanual grasp and bimanual pull and grasp performance in monkeys. Somatosens Mot Res. 1997;14(4):268–80. 64. Rouiller E, Yu X, Moret V et al. Dexterity in adult monkeys following early lesion of the motor cortical hand area: the role of cortex adjacent to the lesion. Eur J Neurosci. 1998;10(2):729–40. 65. Verstichel P, Meyrignac C. [Left unilateral melokinetic apraxia and left dynamic apraxia following partial callosal infarction]. Rev Neurol. (Paris) 2000;156(3): 274–7. 66. Buxbaum LJ, Haaland KY, Hallett M et al. Treatment of limb apraxia: moving forward to improved action. Am J Phys Med Rehabil. 2008;87(2): 149–61. 67. Quencer K, Okun MS, Crucian G et al. Limb-kinetic apraxia in Parkinson disease. Neurology 2007; 68(2):150–1. 68. Gebhardt A, Vanbellingen T, Baronti F, Kersten B, Bohlhalter S. Poor dopaminergic response of impaired dexterity in Parkinson’s disease: bradykinesia or limb kinetic apraxia? Mov Disord. 2008;23(12): 1701–6.

213

Section I


Chapter

Visuospatial function

15

Doron Merims and Morris Freedman

In this chapter, we discuss the neuroanatomy underlying visuospatial function. Our focus will include the anatomical organization of visuospatial processing, visuospatial syndromes relevant to clinical disorders, as well as specific neurologic diseases affecting visuospatial function.

Visuospatial processing The organization of visual processing in the brain involves two general components. The first of these transmits information from the retina to the striate cortex, and the second includes neurons that leave the striate cortex to project to various regions in the interconnected hierarchical network of extrastriate cortical areas [1]. The first component of the visual system starts with the optic nerves, which consist mainly of axons originating in the ganglion layer of the retina. The optic nerves converge to form the optic chiasm. The fibers lying medially in the optic nerves cross the chiasm and continue in the optic tract on the contralateral side of the brain, while the lateral fibers do not cross and continue in the optic tract on the ipsilateral side. The optic tract ends in the lateral geniculate body of the thalamus. Visual information continues along the geniculocalcarine tract (optic radiation) to the striate cortex [2]. The primary visual area, also called the striate cortex, corresponds to Brodmann’s area (BA) 17 and is located in the depths of the calcarine fissure, mainly on the medial surface of the occipital lobe. The primary visual area contains well-developed outer and internal granular layers (II and IV). The internal granular layer of the primary visual area receives fibers from the lateral geniculate body via the optic radiation [2]. The unimodal visual association areas in the human brain occupy

peristriate cortex that corresponds to BA 18 and 19 and parts of the fusiform, inferior temporal and middle temporal gyri (BA 37, 20 and 21) [3]. Lesions in the pathway to the striate cortex result in a contralateral visual field defect that affects all aspects of vision. The deficits are thus specific for location but not for modality. Lesions in the areas that receive projections from the striate cortex may cause impairment in different modalities of the visual system and are less specific for location [1]. Schneider [4] described two different types of visual impairment in the hamster due to cortical and tectal ablations. Ablating the superior colliculus abolished the ability to orient toward an object, but not the ability to identify it, while ablation of the visual cortical areas (BA 17 and 18) had the opposite effect. Ungerleider and Mishkin [5] distinguished between two different visual pathways originating in the occipital cortex, the ventral and dorsal streams. The superior longitudinal fasciculus follows a dorsal path, traversing the posterior parietal region in its course to the frontal lobes. The dorsal stream is responsible for spatial localization (i.e., object location) and is alternatively known as the “where” stream. The inferior longitudinal fasciculus projects to the inferior temporal area; this ventral stream has a role in visual object recognition, and is known as the “what” stream. In their theory of perception and action, Goodale and Milner [6] proposed that the ventral stream plays a major role in perceptual identification of objects, whereas the dorsal stream mediates the required sensorimotor transformations for visually guided actions directed at these objects. The role of right and left hemispheres in visuospatial function was investigated by Delis and colleagues [7]. They compared the performance of patients with left hemisphere damage to patients with right


214

Chapter 15: Visuospatial function

hemisphere lesions and normal controls. Patients and normal controls were asked to remember visual hierarchical stimuli consisting of larger forms constructed of smaller forms. An example of a stimulus was a large letter (“M”) created out of many copies of a small letter (“z”). The major difference between the groups was their ability to remember the two levels of hierarchical stimuli on a forced-choice recognition test. Patients with right hemisphere damage made significantly more errors than control subjects in remembering the larger forms relative to the smaller forms. In contrast, patients with left hemisphere damage made significantly more errors than control subjects in remembering the smaller forms relative to the larger forms. Ng and colleagues [8] supported the concept that both hemispheres participate in visuospatial processing in a study using functional magnetic resonance imaging (fMRI) in ten right-handed normal volunteers, as well as lesion analyses in patients with focal parietal damage. The fMRI was done while the normal volunteers were performing a spatial processing task and showed robust bilateral cortical activation in both superior parietal lobes. However, the right parietal lobe showed earlier and stronger signal change. Lesion analysis of 17 patients indicated that damage to either the right or left parietal lobe led to impaired judgment of line orientation, but relatively greater difficulty was found in the right parietal lesion sample. These studies support the conclusion that the right cerebral hemisphere, and in particular the parietal lobe, plays a special role in visuospatial function.

Visuospatial clinical syndromes Neglect Neglect is a failure to report, respond or orient to novel or meaningful stimuli presented to the side opposite a brain lesion, when this failure cannot be attributed to sensory or motor dysfunction [9]. Neglect reflects a lateralized disruption of spatial attention. The left neglect syndrome is characterized by a reduction of neural resources that can be mobilized by sensory events located on the left and by motor plans directed towards the left. When neglect is severe, the patient may behave as if half the environment has ceased to exist [10]. Neglect can be either sensory or motor. Sensory neglect manifests by a deficit in awareness of stimuli contralateral to a lesion that does not involve sensory

projection systems or the primary cortical sensory areas to which they project. Motor neglect is characterized by failure to respond to a stimulus even though the patient is aware of the stimulus and has the strength to respond [9]. Patients with neglect may be slower to initiate a motor response to targets appearing in left hemispace (directional hypokinesia). Patients with directional hypokinesia were found to have a lesion involving the ventral lateral putamen, the claustrum, and the white matter subjacent to the frontal lobe [11]. Ghacibeh and colleagues [12] examined the effect of repetitive transcranial magnetic stimulation (rTMS) on the right frontal and right parietal areas during a line bisection task in healthy volunteers. They used a task that dissociated motor-intentional from sensory-attentional neglect. Right frontal rTMS caused motor-intentional neglect, whereas right parietal rTMS caused sensory-attentional neglect. Lesions in other brain areas also may cause neglect. The area that is most commonly involved is the right posterior parietal lobe, especially the inferior parietal area. The most common cause is stroke [13, 14] and thus a major portion of the data regarding the neuroanatomy of neglect is derived from patients who have had focal cerebral infarcts. The anatomical correlates of visual neglect were investigated in 110 right-handed stroke patients with lesions confined to the right hemisphere. Neglect was found to be associated more frequently with lesions posterior to the Rolandic fissure, as compared with frontal lesions. When the cerebral lesion is confined to deep structures, neglect occurs more frequently when nuclei such as the thalamus and the basal ganglia are damaged. Conversely, lesions limited to the subcortical white matter are rarely associated with neglect [13]. Using intra-operative direct electrical stimulation during tumor resection, Thiebaut de Schotten and colleagues [15] described two patients who underwent surgical resection of a low-grade glioma. In one patient, the glioma was centered on the caudal part of the right temporal lobe. In the second patient, the glioma was centered on the right inferior parietal lobule. Both patients showed a rightward deviation on line bisection upon stimulation of two cortical sites: the supramarginal gyrus (SMG) and the caudal portion of the superior temporal gyrus (cSTG). In addition, the second patient showed a maximal rightward deviation upon stimulation of a restricted subcortical region on the floor of the surgical cavity that corresponded to a portion of the superior occipitofrontal fasciculus

215


connecting the parietal to the frontal lobe. The findings suggest that the SMG, the cSTG, and a poorly known parietal-frontal pathway, the superior occipitofrontal fasciculus, but not the rostral superior temporal gyrus, are critical to the symmetrical processing of the visual scene in humans. Watson and Heilman [16] described three patients with right thalamic hemorrhage, contralateral motor neglect, and limb akinesia. These patients also had anosognosia and emotional flattening. Ischemic stroke to the right medial thalamus may also cause hemispatial neglect [17]. Mort and colleagues [18] used high-resolution MRI protocols to map the lesions of 35 patients with neglect and either right middle cerebral artery (MCA) or right posterior cerebral artery (PCA) stroke. For patients with MCA stroke, the critical area involved in all patients with neglect was the angular gyrus on the lateral surface of the inferior parietal lobe. The superior temporal gyrus was involved only in half of these patients. Eight MCA neglect patients had frontal involvement, with lesions overlapping in the inferior frontal gyrus, but the same overlap region was also involved in four MCA patients without neglect. Park and colleagues [19] examined 45 patients with right or left PCA territory infarctions. The overall frequency of hemispatial neglect was 42.2% and did not significantly differ between right (48.0%) and left (35.0%) PCA groups, but the severity of neglect was significantly greater in those with right PCA territory lesions. Isolated occipital lesions did not cause neglect; however, injury to both the occipital lobe and the splenium of the corpus callosum did produce this syndrome. Bird and colleagues [20] showed that, in patients with neglect after right PCA territory infarction, the region maximally involved was the white matter of the occipital lobe, but there also was a high degree of overlap extending anteriorly into the ventral medial temporal lobe. Using MRI, Committeri and colleagues [21] demonstrated the anatomical segregation of personal and extrapersonal neglect. They found that awareness of extrapersonal space is based on the integrity of right frontal and superior temporal regions whereas the right inferior parietal regions (supramarginal gyrus, post-central gyrus, and especially the white matter medial to them) are crucial areas for the awareness of personal space. Common but less crucial regions for both personal and extrapersonal awareness were located in the temporo-perisylvian cortex.

216

The presence of visual neglect in the studies cited above was identified primarily by patient performance on “pencil and paper” tests such as line bisection [22] and cancellation tasks [3]. On the line bisection task, the patient is asked to divide a line by placing a mark at its central point. Patients with neglect displace the mark ipsilateral to their lesion. On cancellation tests, patients are asked to cross out letters, numbers, or symbols, such as stars. The severity of neglect can be quantified by the number of target objects that are missed [22, 23]. The presence of neglect can also be determined by performance on different drawing tasks such as drawing a clock or a flower. On these tasks, patients with neglect ignore the left side of the image. On clock drawing, for example, left hemiinattention often results in omission of numbers on the left [24].

Simultanagnosia Simultanagnosia is a disorder characterized by the inability to see more than one object at a time [25]. Patients have difficulty describing a complex scene and may report only one or a few components of the visual array. Simultanagnosia is one of the three components of Balint’s syndrome, which also includes optic ataxia (deficient visually guided reaching), and oculomotor apraxia (impaired visual scanning) [26]. Simultanagnosia typically occurs following bilateral lesions in the superior occipitoparietal regions. Rizzo and Hurtig [27] described three patients with simultanagnosia caused by bilateral superior occipital lobe strokes. These patients had no abnormalities in visual acuity or visual fields to explain their impairment. A striking example of this syndrome was recently reported by Smith and colleagues [28] in an 87-yearold artist who had a presumed top of the basilar stroke secondary to atrial fibrillation. During the first 4 weeks following her stroke, there was a change in her drawings, with selective attention to the left lower quadrant and important aspects of the whole image missing. Subsequently, she improved to the point where there was no major difference from her style of painting compared with before the stroke. The authors interpreted her changed paintings post-stroke as showing selective inattention to the whole of the object. This transient inability to perceive the overall figure or scene was thought to represent simultanagnosia. The localization of her lesion was not determined by neuroimaging.


Transient Balint’s syndrome was reported in a 74-year-old woman who received non-ionic contrast media during renal angiography. The contrast material was noted in the bilateral parietooccipital cortices on the initial computed tomography (CT) scan and disappeared after clinical resolution of the symptoms [29]. Coslett and Lie [25] described a patient with profound simultanagnosia and optic ataxia in the presence of bilateral posterior parietal infarcts and white matter hyperintensities. The patient could not report more than one attribute of an object; for example, he could not name the color of the ink in which words were written despite being able to name the word correctly. These investigators suggested that, in patients with simultanagnosia, the inability to offer explicit information about object identity, attributes, or location reflects a failure to link spatial representations computed in the parietal lobe to information about object identity and perceptual attributes stored in the temporal lobe. They suggested the presence of at least two subtypes of dorsal simultanagnosia: one characterized by an early visual attention impairment that may be related to lesions involving the superior parietooccipital junction bilaterally, and another reflecting impairments in the binding of information computed in the dorsal and ventral visual streams. Patients with this “binding deficit” simultanagnosia may have lesions involving the inferior parietal lobes bilaterally. Another group of patients with simultanagnosia appear to have a lesion restricted to the left occipitotemporal junction [30]. Simultanagnosia may also be a feature of degenerative brain disorders such as posterior cortical atrophy [31, 32], corticobasal degeneration [33], and Alzheimer’s disease (AD) [34]. In addition to simultanagnosia following ischemic stroke [28, 35], the syndrome may appear after brain hemorrhage [36], with brain tumors [37], and with infections including progressive multifocal leukoencephalopathy associated with acquired immunodeficiency syndrome (AIDS) and subacute sclerosing panencephalitis [38].

Visuospatial memory Studies on visuospatial memory have distinguished between visuospatial working memory and memory for visuospatial information. With regard to working memory, an fMRI study in 11 healthy subjects suggested that an area in the superior frontal sulcus plays a predominant role in visuospatial working memory

[39]. Other studies, using positron emission tomography (PET) in humans, suggest that the neural systems involved in working memory for spatial location and object identification are functionally segregated, with a dorsal frontal region being important for spatial location and a more ventral region (involving the middle, inferior, and orbital frontal areas) being critical for object identification [40]. A widely known study of memory for visuospatial information is that of Maguire and colleagues [41]. These investigators examined 16 London taxi drivers, who, through their daily work, acquired a substantial amount of large-scale spatial information (as evidenced by passing the licensing examinations). These taxi drivers were compared with a group of comparison subjects who did not drive taxis. The volume of the posterior hippocampus (as assessed using quantitative MRI) was larger among the taxi drivers whereas anterior hippocampal volume was larger among the comparison subjects. Additionally, posterior hippocampal volume correlated with the amount of time spent as a taxi driver. In another study, Iaria and colleagues [42] used a virtual radial maze task and fMRI to investigate the modulation of brain activity while healthy subjects spontaneously adopted different navigational strategies. Subjects were categorized as using a non-spatial strategy if they associated the arms of the maze with numbers or letters, or they counted the arms clockwise or counterclockwise from a single starting point. They were categorized as using a spatial memory strategy if they used at least two landmarks and did not mention a non-spatial strategy. Subjects using a spatial memory strategy showed activation of the right hippocampus in the early phase of performance, whereas those using a non-spatial strategy showed a sustained increase in activity within the caudate nucleus in the later stages and no increase in hippocampal activity. In a subsequent study, Bohbot and colleagues [43] used voxel-based morphometry to identify brain regions co-varying with the navigational strategies used by healthy subjects. They used the MRI scans of subjects tested previously in the study by Iaria and colleagues [42] and found that those who adopted a spatial memory strategy had significantly more gray matter in the hippocampus and less gray matter in the caudate nucleus compared with those who used a non-spatial strategy. In addition, the gray matter in the hippocampus was negatively correlated with the gray matter of the caudate nucleus. The

217


authors suggested that a competitive interaction exists between the hippocampus and the caudate, one or the other being optimal for different tasks. Gray matter regions anatomically connected to the hippocampus, such as the amygdala, parahippocampal, perirhinal, entorhinal, and orbitofrontal cortices were found to co-vary with gray matter in the hippocampus. Bohbot and colleagues [43] suggested that the correspondence between navigational strategies and gray matter density found in their study has implications for clinical intervention aimed at recovering function in patients with hippocampal or caudate dysfunction. Another dissociation, supported by lesion studies, divides visuospatial memory into two categories: allocentric and egocentric. The allocentric system refers to the spatial location of objects in relation to each other. It has been suggested that the hippocampus is involved in allocentric spatial memory, and functions to consolidate allocentric information into long-term memory [44]. The egocentric system, which refers to the location of an object in relation to the observer, is thought to be mediated by the posterior parietal cortex [45]. The amygdala also may be involved in visuospatial memory. In one study, quantitative MRI measurement of hippocampal sclerosis in patients suffering from temporal lobe epilepsy failed to find a correlation between the right hippocampus and visuospatial memory. Instead, a correlation was found between the volume of the right amygdala and visuospatial memory [46].

Depth perception and stereopsis Depth perception can be achieved, to a certain degree, with monocular vision by use of depth cues such as motion parallax (a depth cue that results from one’s motion) and the obscuration of distant objects by nearer ones. However, for maximal three-dimensional visuospatial processing, the brain uses the difference between both eyes (disparity) as a cue for evaluation of depth [47]. Stereopsis is the perception of depth arising from these small differences between the images in the two eyes. Tsao and colleagues [48] used fMRI to show that a cluster of areas at the parietooccipital junction is specialized for stereopsis. Similarly, Merboldt and colleagues [49] showed with fMRI that stereoscopic depth perception relies on the recruitment of neuronal populations in higher-order visual areas of the parietal cortex rather than in primary visual areas. The finding that

218

transient activity caused by the recognition of a minor change (view angle) of the visual percept is localized to the intraparietal sulcus suggests that this process represents an early search for binocular disparity, which precedes or even initiates depth perception.

Cerebral akinetopsia Akinetopsia is the inability to perceive visual motion [50] and like many visuospatial deficits can be functionally disturbing. Blanke and colleagues [51] reported a 41-year-old patient with akinetopsia accompanied by dog phobia. MRI showed bilateral parietal lobe strokes, more evident on the left and with extension toward the occipital lobe. The patient could recognize a dog, but would constantly misperceive its position and direction of motion. However, the patient also had difficulty walking on or crossing a crowded street even without dogs present, and his functional impairment could not be solely attributed to dog phobia. The lesion was largely restricted to the parietal lobes, a component of the dorsal stream of the visual system that is responsible for spatial processing. Using focal electrical stimulation in a patient undergoing invasive monitoring for epilepsy, Blanke and colleagues [52] studied whether extrastriate cortex was involved in the unidirectional motion blindness. Findings suggested that unilateral electrical stimulation in the posterior temporal lobes, more specifically the middle temporal gyrus (area hMT+, also referred to as V5), may diminish the capacity to discriminate motion in the contralateral visual field. Beckers and Zeki [53] studied the effect of deactivation of areas V1 and V5 in normal subjects using transcranial magnetic stimulation (TMS). Stimulation of V5 induced severe impairment in perception of the direction of motion. TMS of V1 also showed impairment in motion perception but to a lesser degree than was apparent in V5.

Neurological conditions and visuospatial dysfunction This section will consider visuospatial impairment in common neurologic diseases such as AD and Parkinson’s disease (PD). Less common disorders such as Huntington’s disease (HD) and Williams syndrome (WMS) will also be described to emphasize the variety of etiologies that may affect the visuospatial system.


Alzheimer’s disease

Basal ganglia lesions

Although memory loss is the most prominent feature of AD, visuospatial function is also impaired, even in the early stages of the disease [54]. Using PET and tests to assess spatial vision and object recognition, Fujimori and colleagues [55] showed that visuospatial disturbances were significantly correlated with lower metabolic rate of both inferior parietal lobules in patients with mild to moderate AD. More specifically, object recognition deficits were significantly correlated with lower metabolic rate in the right middle temporal gyrus and the right inferior parietal lobule. Grossi and colleagues [56] performed a longitudinal study of a patient with selective, progressive impairment of topographical orientation. Six years after the onset of this disturbance, and three years after the first evaluation, the patient developed typical cognitive impairments of AD with PET findings of bilateral hypoperfusion in parietotemporal areas. Although not an autopsy-proven case of AD, this patient may represent a highly focal variant of AD, with visuospatial impairment as the dominant and presenting symptom.

Su and colleagues [61] studied 37 patients with basal ganglia hemorrhage and found that visuospatial function and memory were the most affected cognitive domains. The explanation for visuospatial dysfunction associated with basal ganglia disorders may be disruption of the cortical-striatal circuits involving parietal and temporal cortices that may lead to impairment in visuospatial analysis [62]. In addition, striatal damage has been found to selectively impair performance based on egocentric (body-centered) rather than allocentric (object-centered) spatial cues [63]. Lineweaver and colleagues [64] compared the visuospatial performance of patients with HD, a disease that primarily affects the basal ganglia, to performance in patients with AD. Speed, but not accuracy, of mental rotation decreased with increasing angle of orientation in patients with HD. In contrast, accuracy but not speed of rotation decreased with increasing angle of orientation in patients with AD. The slowing exhibited by HD patients may be mediated by damage to the basal ganglia, whereas the spatial manipulation deficit of AD patients may reflect pathology in parietal and temporal lobe cortices important for visuospatial processing [64]. Lawrence and colleagues [65] showed that patients with HD exhibited deficits on tests of spatial recognition and impaired reaction times on visual search. HD patients were also impaired on spatial but not visual object working memory, and showed impaired pattern–location associative learning. On two visuospatial recognition memory tasks, one assessing memory for hand positions (egocentric) and the other assessing memory for spatial locations (allocentric), HD patients were impaired relative to matched healthy controls on both. Correlation analyses indicated that performance of HD patients on the Hand Position Memory task, but not the Spatial Location Memory task, was associated with global cognitive impairment [66].

Posterior cortical atrophy Posterior cortical atrophy (PCA) is a clinically homogeneous but pathologically heterogeneous syndrome in which the onset of a progressive dementia is characterized by visual deficits. AD is the most common pathological correlate of PCA [57], although this syndrome is also associated with progressive subcortical gliosis and Creutzfeldt–Jakob disease [58]. McMonagle and colleagues [59] compared cognitive performance of patients with PCA with that of patients with probable AD and normal controls. Patients were included in the PCA group if they showed gradual onset of progressive cognitive impairment with prominent visuospatial dysfunction. The PCA patients had marked impairment on visuospatial tasks with poor reading and writing in the presence of relatively preserved memory, in striking contrast to the patients with AD. The most common visual symptoms among PCA patients were simultanagnosia and optic ataxia; complete Balint’s syndrome was detected in five individuals. Unilateral neglect and visual field defects were found less commonly. PET studies in patients with PCA have shown hypometabolism in the occipitoparietal cortices, more prominent on the right [60].

Dementia with Lewy bodies and Parkinson’s disease with dementia Dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD) can be considered to lie on the same spectrum of neurodegeneration, and their cognitive impairments have much in common. In particular, visual perception impairments are similar in

219


patients with DLB and PDD [67]. In both diseases, visual perception is more impaired if visual hallucinations are present [68].

Dementia with Lewy bodies In contrast to their relatively mild episodic memory deficits, the visuospatial abilities of patients with DLB are profoundly impaired, and significantly worse than those of patients with AD [69, 70]. Tiraboschi and colleagues [71] collected first-visit data of 23 pathologically proven DLB and 94 AD cases. Whereas visual hallucinations at presentation were more specific for DLB (99%), visuospatial impairment was observed in 74% of the DLB cases and found to be the most sensitive symptom. Visual hallucinations at presentation were the best positive predictor of DLB at autopsy, and lack of visuospatial impairment was the best negative predictor. The best model for differentiating DLB from AD in the earliest stages of disease was found to include visual hallucinations and visuospatial dysfunction but not extrapyramidal symptoms. Lobotesis and colleagues [72] compared regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT) in DLB patients, AD patients, and normal age-matched control subjects. Both DLB and AD subjects had significantly reduced rCBF in parietal and temporal regions compared with control subjects. A significant difference between DLB and AD was in the occipital regions, with the DLB patients showing a greater rCBF deficit. Harding and colleagues [73] studied the pathology of 63 cases with Lewy body (LB) pathology and described consistent association between the presence of visual hallucinations and cortical pathology. The overall LB burden was significantly greater in the parahippocampal and inferior temporal cortices in cases with early hallucinations. Higher LB densities were found in the inferior temporal cortex in cases with DLB than in cases with PDD. Cases with hallucinations had significantly more LB/field on average than those without hallucinations in the parahippocampus and amygdala, but not in the frontal, anterior cingulate or inferior temporal cortices. Abnormalities in the occipital and temporoparietal areas in patients with DLB may explain the prominent visuospatial deficits in these patients.

Parkinson’s disease with dementia Visuospatial deficits in PD are clearly related to dementia and progression of the disease [74]. Witt and

220

colleagues [75] evaluated the influence of the subthalamic nucleus (STN) in extrapersonal space orientation using STN deep brain stimulation (DBS) in PD as a reversible model of functional ablation. They examined 12 patients with PD one year after implantation of DBS electrodes in the STN after overnight withdrawal of L-dopa. Patients were tested with both stimulators turned on, the right only, the left only, or none at all. No asymmetries in spatial orientation were found when both stimulators were off, when both stimulators were on, and when only the right stimulator was on. When only the left subthalamic stimulation was switched on, the reaction times of both hands to visual stimuli in left extra-personal hemispace increased significantly, and the line bisection test showed a significant shift to the right. These results lead to the conclusion that the STN and its cortical projections may influence the network involved in visuospatial orientation.

Williams syndrome WMS is a rare genetic condition characterized by mild to moderate cognitive and behavioral abnormalities including unusually heightened drive toward social interaction. In addition, there are distinctive facial features, growth delay, cardiovascular anomalies, and occasional hypercalcemia. The etiology relates to microdeletions on chromosome 7q11.23 [76, 77]. The main visuospatial deficit in WMS is in spatial localization [78, 79]. Paul and colleagues [78] showed that patients with WMS perform markedly worse than healthy controls on a location-matching task. However, their performance on a face-matching task was similar to controls. These investigators suggested that patients with WMS might have selective involvement of the dorsal stream of visual processing. Chiang and colleagues [80] compared 3D T1-weighted brain MRI scans of patients with WMS with healthy controls and found marked volume reductions of the parietal and occipital lobes, thalamus, basal ganglia, and midbrain in WMS. Using fMRI in WMS patients, Meyer-Lindenberg and colleagues [81] found isolated hypoactivation in the parietal portion of the dorsal visual stream with normal activation in the ventral visual stream. Using high-resolution structural MRI, they also found symmetrical reduction in gray matter; one such area, the parietooccipital region/intraparietal sulcus, is immediately adjacent to the dorsal visual stream. The authors suggested that the


visuoconstructive deficit in WMS could be attributed to impaired input from this structurally altered region.

Mitochondrial myopathies Mitochondrial myopathies are clinically heterogeneous disorders that can affect multiple organ systems. The Kearns–Sayre syndrome (KSS) is the bestknown example of a mitochondrial myopathy, and is characterized by onset before age 15, progressive external ophthalmoplegia, and pigmentary degeneration of the retina, with other systemic manifestations [82]. Chronic progressive external ophthalmoplegia (CPEO) is a closely related disorder. KSS and CPEO patients were compared with healthy control subjects matched for age, sex, and education with a neuropsychological test battery covering verbal skills, verbal and visual memory, visuospatial perception, visual construction, attention, abstraction, and flexibility [83]. The patients with KSS or CPEO did not have dementia, but there was evidence of neuropsychological dysfunction, suggesting selective impairment of visuospatial perception and executive function. A specific pattern of cognitive deficits implicating parietooccipital and prefrontal dysfunction was suggested [83]. In an earlier study by Turconi and colleagues [84], 16 patients with mitochondrial encephalomyopathy showed no global cognitive impairment but did score lower on non-verbal versus verbal tasks. Visuospatial skills and short-term memory were selectively impaired. SPECT scans were carried out on 12 of the patients, and the most frequent finding was hypoperfusion in both temporal lobes [84].

Conclusion Impairment of visuospatial function is common with focal brain lesions, as well as more widespread disorders such as neurodegenerative diseases. Knowledge of the neuroanatomy underlying deficits in visuospatial function is critical for understanding the mechanisms leading to the disability experienced by patients with visuospatial dysfunction. This understanding may in turn provide insights for better assessment and management strategies of affected patients.

Acknowledgments During the preparation of this work, M. Freedman held a research grant from the Ontario Mental Health

Foundation and was supported by the Saul A. Silverman Family Foundation, Toronto, Ontario, Canada, as part of a Canada International Scientific Exchange Program (CISEPO) project.

References 1. Barton JS, Rizzo M, Eslinger PJ. Visual dysfunction. In Rizzo M, Eslinger PJ, editors. Principles and Practice of Behavioral Neurology and Neuropsychology. Philadelphia, PA: W.B. Saunders; 2004, pp. 267–84. 2. Clemente DC. Development and gross anatomy of the central nervous system. In Gray H, Clemente CD, editors. Anatomy of the Human Body. 30th American edition. Philadelphia, PA: Lea & Febiger; 1985, pp. 933–1148. 3. Mesulam MM. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000. 4. Schneider GE. Two visual systems. Science 1969; 163(870):895–902. 5. Ungerleider L, Mishkin M. Two cortical visual systems. In Ingle D, Goodale MA, Mansfield RJW, editors. Analysis of Visual Behavior. Cambridge, MA: MIT Press; 1982, p. 834. 6. Goodale MA, Milner AD. Separate visual pathways for perception and action. Trends Neurosci. 1992;15(1): 20–5. 7. Delis DC, Robertson LC, Efron R. Hemispheric specialization of memory for visual hierarchical stimuli. Neuropsychologia 1986;24(2):205–14. 8. Ng VW, Eslinger PJ, Williams SC et al. Hemispheric preference in visuospatial processing: a complementary approach with fMRI and lesion studies. Hum Brain Mapp. 2000;10(2):80–6. 9. Heilman KM, Watson RT, Valenstein E. Neglect and related disorders. In Heilman KM, Valenstein E, editors. Clinical Neuropsychology. 4th edition. Oxford: Oxford University Press; 2003, pp. 296–346. 10. Mesulam MM. Spatial attention and neglect: parietal, frontal and cingulate contributions to the mental representation and attentional targeting of salient extrapersonal events. Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1325–46. 11. Sapir A, Kaplan JB, He BJ, Corbetta M. Anatomical correlates of directional hypokinesia in patients with hemispatial neglect. J Neurosci. 2007;27(15): 4045–51. 12. Ghacibeh GA, Shenker JI, Winter KH, Triggs WJ, Heilman KM. Dissociation of neglect subtypes with transcranial magnetic stimulation. Neurology 2007; 69(11):1122–7.

221


13. Vallar G, Perani D. The anatomy of unilateral neglect after right-hemisphere stroke lesions. A clinical/ CT-scan correlation study in man. Neuropsychologia 1986;24(5):609–22.

30. Bauer RM, Demery JA. Agnosia. In Heilman KM, Valenstein E, editors. Clinical Neuropsychology. 4th edition. Oxford: Oxford University Press; 2003, pp. 236–95.

14. Vallar G. Extrapersonal visual unilateral spatial neglect and its neuroanatomy. Neuroimage 2001;14(1 Pt 2):S52–8.

31. Graff-Radford NR, Bolling JP, Earnest FT et al. Simultanagnosia as the initial sign of degenerative dementia. Mayo Clin Proc. 1993;68(10):955–64.

15. Thiebaut de Schotten M, Urbanski M, Duffau H et al. Direct evidence for a parietal-frontal pathway subserving spatial awareness in humans. Science 2005;309(5744):2226–8.

32. Yoon SJ, Park JM, Na DL. Simultanagnosia in posterior cortical atrophy. J Neurol Neurosurg Psychiatry 2002; 72(2):269.

16. Watson RT, Heilman KM. Thalamic neglect. Neurology 1979;29(5):690–4.

33. Mendez MF. Corticobasal ganglionic degeneration with Balint’s syndrome. J Neuropsychiatry Clin Neurosci. 2000;12(2):273–5.

17. Watson RT, Valenstein E, Heilman KM. Thalamic neglect. Possible role of the medial thalamus and nucleus reticularis in behavior. Arch Neurol. 1981; 38(8):501–6.

34. Mendez MF, Turner J, Gilmore GC, Remler B, Tomsak RL. Balint’s syndrome in Alzheimer’s disease: visuospatial functions. Int J Neurosci. 1990;54(3–4): 339–46.

18. Mort DJ, Malhotra P, Mannan SK et al. The anatomy of visual neglect. Brain 2003;126(Pt 9):1986–97.

35. Kanwisher N. Neural events and perceptual awareness. Cognition 2001;79(1–2):89–113.

19. Park KC, Lee BH, Kim EJ et al. Deafferentationdisconnection neglect induced by posterior cerebral artery infarction. Neurology 2006;66(1):56–61.

36. Gillen JA, Dutton GN. Balint’s syndrome in a 10-yearold male. Dev Med Child Neurol. 2003;45(5):349–52.

20. Bird CM, Malhotra P, Parton A et al. Visual neglect after right posterior cerebral artery infarction. J Neurol Neurosurg Psychiatry 2006;77(9):1008–12. 21. Committeri G, Pitzalis S, Galati G et al. Neural bases of personal and extrapersonal neglect in humans. Brain 2007;130(Pt 2):431–41. 22. Halligan P, Wilson B, Cockburn J. A short screening test for visual neglect in stroke patients. Int Disabil Stud. 1990;12(3):95–9. 23. Ruff RM, Evans RW, Light RH. Automatic detection vs controlled search: a paper-and-pencil approach. Percept Mot Skills. 1986;62(2):407–16. 24. Freedman M, Leach L, Kaplan E et al. Focal brain damage. In Freedman M, editor. Clock Drawing: A Neuropsychological Analysis. New York, NY: Oxford University Press; 1994, pp. 98–127. 25. Coslett HB, Lie G. Simultanagnosia: when a rose is not red. J Cogn Neurosci. 2008;20(1):36–48. 26. Moreaud O. Balint syndrome. Arch Neurol. 2003;60(9): 1329–31. 27. Rizzo M, Hurtig R. Looking but not seeing: attention, perception, and eye movements in simultanagnosia. Neurology 1987;37(10):1642–8. 28. Smith WS, Mindelzun RE, Miller B. Simultanagnosia through the eyes of an artist. Neurology 2003;60(11): 1832–4. 29. Merchut MP, Richie B. Transient visuospatial disorder from angiographic contrast. Arch Neurol. 2002;59(5): 851–4.

222

37. Naccache L, Slachevsky A, Levy R, Dubois B. Simultanagnosia in a patient with right brain lesions. J Neurol. 2000;247(8):650–1. 38. Yapici Z. Subacute sclerosing panencephalitis presenting with Balint’s syndrome. Brain Dev. 2006; 28(6):398–400. 39. Courtney SM, Petit L, Maisog JM, Ungerleider LG, Haxby JV. An area specialized for spatial working memory in human frontal cortex. Science 1998; 279(5355):1347–51. 40. Courtney SM, Ungerleider LG, Keil K, Haxby JV. Object and spatial visual working memory activate separate neural systems in human cortex. Cereb Cortex 1996;6(1):39–49. 41. Maguire EA, Gadian DG, Johnsrude IS et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci USA 2000;97(8):4398–403. 42. Iaria G, Petrides M, Dagher A, Pike B, Bohbot VD. Cognitive strategies dependent on the hippocampus and caudate nucleus in human navigation: variability and change with practice. J Neurosci. 2003;23(13): 5945–52. 43. Bohbot VD, Lerch J, Thorndycraft B, Iaria G, Zijdenbos AP. Gray matter differences correlate with spontaneous strategies in a human virtual navigation task. J Neurosci. 2007;27(38):10,078–83. 44. Holdstock JS, Mayes AR, Cezayirli E et al. A comparison of egocentric and allocentric spatial memory in a patient with selective hippocampal damage. Neuropsychologia 2000;38(4):410–25.


45. Vallar G, Lobel E, Galati G et al. A fronto-parietal system for computing the egocentric spatial frame of reference in humans. Exp Brain Res. 1999;124(3): 281–6. 46. Pegna AJ, Caldara-Schnetzer AS, Perrig SH et al. Is the right amygdala involved in visuospatial memory? Evidence from MRI volumetric measures. Eur Neurol. 2002;47(3):148–55. 47. Barlow HB, Blakemore C, Pettigrew JD. The neural mechanism of binocular depth discrimination. J Physiol. 1967;193(2):327–42. 48. Tsao DY, Vanduffel W, Sasaki Y et al. Stereopsis activates V3A and caudal intraparietal areas in macaques and humans. Neuron 2003;39(3): 555–68. 49. Merboldt KD, Baudewig J, Treue S, Frahm J. Functional MRI of self-controlled stereoscopic depth perception. Neuroreport 2002;13(14):1721–5. 50. Zihl J, von Cramon D, Mai N. Selective disturbance of movement vision after bilateral brain damage. Brain 1983;106(Pt 2):313–40. 51. Blanke O, Vaclavik V, Landis T, Safran AB. Dog phobia in a motion-blind patient. Cogn Neuropsychiatry 2003;8(3):211–21. 52. Blanke O, Landis T, Safran AB, Seeck M. Direction-specific motion blindness induced by focal stimulation of human extrastriate cortex. Eur J Neurosci. 2002;15(12):2043–8. 53. Beckers G, Zeki S. The consequences of inactivating areas V1 and V5 on visual motion perception. Brain 1995;118(Pt 1):49–60. 54. Kaskie B, Storandt M. Visuospatial deficit in dementia of the Alzheimer type. Arch Neurol. 1995;52(4):422–5. 55. Fujimori M, Imamura T, Hirono N et al. Disturbances of spatial vision and object vision correlate differently with regional cerebral glucose metabolism in Alzheimer’s disease. Neuropsychologia 2000;38(10): 1356–61. 56. Grossi D, Fasanaro AM, Cecere R, Salzano S, Trojano L. Progressive topographical disorientation: a case of focal Alzheimer’s disease. Neurol Sci. 2007;28(2): 107–10. 57. Tang-Wai DF, Graff-Radford NR, Boeve BF et al. Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy. Neurology 2004;63(7): 1168–74. 58. Victoroff J, Ross GW, Benson DF, Verity MA, Vinters HV. Posterior cortical atrophy. Neuropathologic correlations. Arch Neurol. 1994;51(3):269–74. 59. McMonagle P, Deering F, Berliner Y, Kertesz A. The cognitive profile of posterior cortical atrophy. Neurology 2006;66(3):331–8.

60. Nestor PJ, Caine D, Fryer TD, Clarke J, Hodges JR. The topography of metabolic deficits in posterior cortical atrophy (the visual variant of Alzheimer’s disease) with FDG-PET. J Neurol Neurosurg Psychiatry 2003;74(11):1521–9. 61. Su CY, Chen HM, Kwan AL, Lin YH, Guo NW. Neuropsychological impairment after hemorrhagic stroke in basal ganglia. Arch Clin Neuropsychol. 2007;22(4):465–74. 62. Amick MM, Schendan HE, Ganis G, Cronin-Golomb A. Frontostriatal circuits are necessary for visuomotor transformation: mental rotation in Parkinson’s disease. Neuropsychologia 2006;44(3):339–49. 63. Mijovic-Prelec D, Bentley P, Caviness VS, Jr. Selective rotation of egocentric spatial representation following right putaminal hemorrhage. Neuropsychologia 2004;42(13):1827–37. 64. Lineweaver TT, Salmon DP, Bondi MW, Corey-Bloom J. Differential effects of Alzheimer’s disease and Huntington’s disease on the performance of mental rotation. J Int Neuropsychol Soc. 2005;11(1):30–9. 65. Lawrence AD, Watkins LH, Sahakian BJ, Hodges JR, Robbins TW. Visual object and visuospatial cognition in Huntington’s disease: implications for information processing in corticostriatal circuits. Brain 2000;123(Pt 7):1349–64. 66. Davis JD, Filoteo JV, Kesner RP, Roberts JW. Recognition memory for hand positions and spatial locations in patients with Huntington’s disease: differential visuospatial memory impairment? Cortex 2003;39(2):239–53. 67. Mosimann UP, Mather G, Wesnes KA et al. Visual perception in Parkinson disease dementia and dementia with Lewy bodies. Neurology 2004; 63(11):2091–6. 68. Cormack F, Aarsland D, Ballard C, Tovee MJ. Pentagon drawing and neuropsychological performance in Dementia with Lewy bodies, Alzheimer’s disease, Parkinson’s disease and Parkinson’s disease with dementia. Int J Geriatr Psychiatry 2004;19(4):371–7. 69. Salmon DP, Galasko D, Hansen LA et al. Neuropsychological deficits associated with diffuse Lewy body disease. Brain Cogn. 1996;31(2):148–65. 70. Calderon J, Perry RJ, Erzinclioglu SW et al. Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2001;70(2):157–64. 71. Tiraboschi P, Salmon DP, Hansen LA et al. What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia? Brain 2006;129(Pt 3): 729–35.

223


72. Lobotesis K, Fenwick JD, Phipps A et al. Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 2001;56(5):643–9. 73. Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002;125(Pt 2): 391–403. 74. Levin BE, Llabre MM, Reisman S et al. Visuospatial impairment in Parkinson’s disease. Neurology 1991;41(3):365–9. 75. Witt K, Kopper F, Deuschl G, Krack P. Subthalamic nucleus influences spatial orientation in extrapersonal space. Mov Disord. 2006;21(3):354–61. 76. Amenta S, Sofocleous C, Kolialexi A et al. Clinical manifestations and molecular investigation of 50 patients with Williams syndrome in the Greek population. Pediatr Res. 2005;57(6):789–95.

79. Nakamura M, Watanabe K, Matsumoto A et al. Williams syndrome and deficiency in visuospatial recognition. Dev Med Child Neurol. 2001;43(9): 617–21. 80. Chiang MC, Reiss AL, Lee AD et al. 3D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry. Neuroimage 2007;36(4):1096–109. 81. Meyer-Lindenberg A, Kohn P, Mervis CB et al. Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron 2004;43(5):623–31. 82. DiMauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol. 1985;17(6):521–38.

77. Hirota H, Matsuoka R, Kimura M et al. Molecular cytogenetic diagnosis of Williams syndrome. Am J Med Genet. 1996;64(3):473–7.

83. Bosbach S, Kornblum C, Schroder R, Wagner M. Executive and visuospatial deficits in patients with chronic progressive external ophthalmoplegia and Kearns–Sayre syndrome. Brain 2003;126(Pt 5): 1231–40.

78. Paul BM, Stiles J, Passarotti A, Bavar N, Bellugi U. Face and place processing in Williams syndrome: evidence for a dorsal-ventral dissociation. Neuroreport 2002; 13(9):1115–9.

84. Turconi AC, Benti R, Castelli E et al. Focal cognitive impairment in mitochondrial encephalomyopathies: a neuropsychological and neuroimaging study. J Neurol Sci. 1999;170(1):57–63.

224

(A)

(B)

(C)

(D)

(E)

Figure 2.1. General structure of the brain (A). Major areas considered in this chapter include the brainstem and cerebellum (B), diencephalon (C), limbic and paralimbic structures (D), basal ganglia (see Figure 2.5), and cerebral cortex (E).



Cut edge of midbrain Parahippocampal gyrus

Temporal lobe



Fornix


Anterior commissure


Hypothalamus


Mammillary body

Hippocampus

Figure 2.6. Limbic and paralimbic areas (green shading) viewed parasagittally. The top panel depicts these areas as if viewed through the left hemisphere. The bottom panel illustrates these areas in greater detail. Reprinted from Purves D, Augustine GJ, Fitzpatrick D et al. (editors), Neuroscience, 2nd edition; 2001, with permission from Sinauer Associates.

Figure 2.8. Lobar divisions of the cerebral hemispheres (left lateral view).

Figure 2.9. Brodmann’s areas in the human brain. Reprinted with permission from Mark Dubin, PhD, Department of Molecular, Cellular & Developmental Biology, University of Colorado at Boulder (http://spot.colorado.edu/∼dubin/talks/brodmann/brodmann.html).

Figure 2.11. Orthogonal frontal projection of the cerebral and cerebellar arteries in situ, together with some bony landmarks and the lateral ventricles. Labeled structures include: 1 – Calvaria (inner border). 2 – Medial occipital artery, parieto-occipital branch. 3 – Trunk of the corpus callosum. 4 – Lateral ventricle. 5 – Insula. 6 – Medial occipital artery. 7 – Superior cerebellar artery, medial branch. 8 – Lateral occipital artery. 9 – Free margin of the lesser wing of the sphenoid bone. 10 – Middle meningeal artery, intraosseous part (in-constant). 11 – Middle meningeal artery, frontal branch. 12 – Middle meningeal artery, parietal branch. 13 – Superior margin of petrous part of the temporal bone. 14 – Superior cerebellar artery, lateral branch. 15 – Posterior cerebral artery. 16 – Superior cerebellar artery. 17 – Basilar artery. 18 – Anterior inferior cerebellar artery. 19 – Posterior inferior cerebellar artery, medial branch. 20 – Posterior inferior cerebellar artery, lateral branch. 21 – Posterior inferior cerebellar artery. 22 – Vertebral artery, intracranial part. 23 – Maxillary artery, pterygoid part. 24 – Middle meningeal artery. 25 – Superficial temporal artery. 26 – Maxillary artery, manidibular part. 27 – Vertebral artery, atlantal part. 28 – External carotid artery. 29 – Facial artery. 30 – Vertebral artery, cervical part. 31 – Paracentral artery. 32 – Pericallosal artery. 33 – Callosomarginal artery. 34 – Middle cerebral artery, terminal part. 35 – Middle cerebral artery, insular part. 36 – Anterior cerebral artery, post-communicating part. 37 – Anterior communicating artery. 38 – Anterior cerebral artery, pre-communicating part. 39 – Middle cerebral artery, sphenoid part. 40 – Internal carotid artery, cavernous part. 41 – Internal carotid artery, petrous part. 42 – Internal carotid artery, cervical part. 43 – Common carotid artery. Reprinted from Nieuwenhuys R, Voogd J, Huijzen CV. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008, with permission from Springer Science+Business Media.

Figure 2.12. Orthogonal lateral projection of the cerebral and cerebellar arteries, together with external and bony landmarks. Some neural structures are illustrated in outline; in the center, two lines tangential to the anterior and posterior commisures (AC and PC, respectively) are seen: the one passing above the AC and beneath the PC is part of the bicommissural line of Talairach (BC); the other tangent is part of the ¨ upper horizontal line of Kronlein (CH). Additional abbreviations include: CM – canthus-meatus line; FH – horizontal line of Frankfurt; GI – glabella-inion line; VCA – vertical tangent to anterior commissure; and VCP – vertical tangent to posterior commissure. Labeled structures include: 1 – Central sulcus. 2 – Pericallosal artery. 3 – Callosomarginal artery. 4 – Corpus callosum. 5 – Outline of ventricles. 6 – Outline of insula. 7 – Anterior cerebral artery. 8 – Middle cerebral artery, frontal trunk. 9 – Anterior commissure. 10 – Middle cerebral artery, parietal trunk. 11 – Middle cerebral artery, temporal trunk. 12 – Posterior commissure. 13 – Medial occipital artery. 14 – Lateral occipital artery. 15 – Superior cerebellar artery, medial branch. 16 – Superior cerebellar artery, lateral branch. 17 – Superior cerebellar artery. 18 – Posterior cerebral artery. 19 – Posterior communicating artery. 20 – Internal carotid artery, cerebral part. 21 – Internal carotid artery, cavernous part. 22 – Siphon point. 23 – Middle cerebral artery, sphenoid part. 24– Ektocanthion (Canthus externus). 25 – Glabella. 26 – Orbital (on infraorbital margin). 27 – Internal carotid artery, petrous part. 28 – Basilar artery. 29 – Superior margin of petrous part of the temporal bone. 30 – Anterior inferior cerebellar artery. 31 – Porion (on supramental margin). 32 – Fourth ventricle. 33– Posterior inferior cerebellar artery, medial branch. 34 – Posterior inferior cerebellar artery, lateral branch. 35 – Posterior inferior cerebellar artery. 36 – Vertebral artery, intracranial part. 37 – Vertebral artery, atlantal part. 38 – Internal carotid artery, cervical part. 39 – Maxillary artery. 40 – Middle meningeal artery. 41 – External carotid artery. 42 – Vertebral artery, cervical part. 43 – Common carotid artery. 44 – Spinal cord. 45 – Inion (external occipital protuberance). Reprinted from Nieuwenhuys R, Voogd J, Huijzen CV. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008, with permission from Springer Science+Business Media.

Figure 2.13. The ventricular system, including the lateral ventricles (dark blue, rostral), third ventricle (purple), cerebral aqueduct (green), fourth ventricle (light blue, caudal), and choroid plexus (red). Adapted from 3D Brain from G2C Online (www.g2conline.org), produced by the Dolan DNA Learning Center, Cold Spring Harbor Laboratory.

(A)

(B)

(C)

(F)

(D)

(G)

(E)

(H)

Figure 3.1. A, Posterior, and B, right lateral surface reconstructions of the human cerebellum derived from MRI images. The named fissures are demarcated in color, and the fissures and lobules are identified. C, Surface reconstruction of the cerebellum seen from the oblique posterior view, with lobules demarcated. Parasagittal images of human cerebellum on MRI 2 mm lateral to midline in D, and 18 mm lateral to midline in E. Fissures are color coded according to the convention used in A and B, and the lobules are designated. F, Superior (SCP), middle (MCP), and inferior (ICP) cerebellar peduncles in human identified with diffusion spectrum imaging, overlaid on diffusion-weighted image of cerebellum and brainstem. G, Cryosection image of post-mortem human cerebellum in the coronal plane 52 mm behind the anterior commissure – posterior commissure (AC-PC), with deep cerebellar nuclei identified: D – dentate nucleus, E – emboliform nucleus, F – fastigial nucleus, G – globose nucleus. H, Diagram of a single cerebellar folium is shown sectioned in its longitudinal axis (diagram right) and transversely (left) to depict the histology of the cerebellar cortex. Purkinje cells are red; superficial and deep stellate, basket, and Golgi cells are black; granule cells and ascending axons and parallel fibers are yellow; mossy and climbing fibers are blue. Also shown are the glomeruli with mossy fiber rosettes, claw-like dendrites of granule cells, and Golgi axons. (A, B, D, E, G reproduced from Schmahmann JD, Doyon J, Toga A, Evans A, Petrides M. MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; Copyright Elsevier, 2000, with permission from Elsevier; C from Makris N, Schlerf JE, Hodge SM et al. MRI-based surface-assisted parcellation of human cerebellar cortex: an anatomically specified method with estimate of reliability. Neuroimage 2005;25(4):1146–60, with permission from Academic Press; F reproduced from Granziera C, Schmahmann JD, Hadjikhani N et al. Diffusion spectrum imaging shows the structural basis of functional cerebellar circuits in the human cerebellum in vivo. PLoS One 2009;4(4):e5101, with permission; H reproduced from Williams PL, Bannister LH, Berry MM et al. (editors). Gray’s Anatomy. 38th edition. New York, NY: Churchill Livingstone; 1995; Copyright Elsevier, 1995, with permission from Elsevier. Redrawn from Eccles JC, Ito M, Szentágothai J. The Cerebellum as a Neuronal Machine. Berlin: Springer-Verlag; Copyright Elsevier, 1967.

(A)

(D)

(B)

(C)

Figure 3.2. Activation Likelihood Estimation (ALE) activation maps for the domains of A, spatial cognition, B, motor tapping with the right hand, and C, language tasks drawn from a meta-analysis of functional imaging studies [26]. The right cerebellum is depicted on the right. The results are overlaid upon an image of the cerebellum in the coronal plane at y = −70 from the MRI Atlas of the Human Cerebellum [7], and the cerebellar fissures and lobules at this level are identified in D. Reproduced from Schmahmann JD, Doyon J, Toga A, Evans A, Petrides M. MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press; Copyright Elsevier, 2000, with permission of Elsevier; and with permission of Academic Press from Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage 2009;44(2):489–501.

Figure 3.3. Representative rostral (y = −44) to caudal (y = −76) coronal sections through a human cerebellum showing activation patterns in a functional magnetic resonance imaging experiment in a single subject [28]. Tasks investigated sensorimotor function (finger tapping, red), language (verb generation, blue), spatial cognition (mental rotation, green), working memory (n-back task, purple), and emotional processing (viewing images from the International Affective Picture System, yellow). Lobules V, VI, Crus I (Cr I), Crus II (Cr II), VIIB and VIII are labeled. The right and left cerebellar hemispheres are as indicated. Reproduced with permission of Masson Spa from Stoodley CJ, Schmahmann JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex 2010;48(7):831–844.

Figure 4.2. Diffusion tensor image showing the arcuate fasciculus. Note the additional fascicle extending to Geschwind’s territory in the inferior parietal cortex, not recognized by traditional neuroanatomic investigation. Reproduced from Catani M, Jones DK, Ffytche DH. Perisylvian language networks of the human brain. Ann Neurol. 2005;57(1):8–16, with permission from John Wiley & Sons, Inc.

IPs/SPL

FEF

VFC (IFg/MFg)

TPJ (IPL/STG) Top-down control L FEF

R FEF

Novelty R VFC

L VFC

Circuit breaker

Stimulusresponse selection L TPJ

R IPs

L IPs

R TPJ

Behavioral valence Visual areas Stimulus-driven control

Figure 8.10. Illustration of a neuroanatomic model of attentional control. Top: diagram indicating brain regions involved in the control of attention. Bottom: Schematic of the mechanisms of a model of attentional control [43]. The dorsal network (IPs-FEF), indicated by the black arrows, is involved in the top-down, or “goal-directed,” control of attention. The ventral network (TPJ-VFC), indicated by the gray arrows, is involved in bottom-up, or “stimulus-driven,” control of attention. The dorsal system is also modulated by bottom-up information, with the TPJ communicating with the IPs and acting as a “circuit breaker” allowing salient bottom-up information to interrupt voluntary, top-down orienting, in turn reorienting attention to salient aspects of the environment. Abbreviations: IPs: intraparietal sulcus; SPL: superior parietal lobule; FEF: frontal eye field; TPJ: temporoparietal junction; IPL: inferior parietal lobule; STG: superior temporal gyrus; VFC: ventral frontal cortex; IFg: inferior frontal gyrus: MFg: middle frontal gyrus; L: left; R: right. Adapted from Corbetta M, Shulman GL. Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci. 2002;3(3):201–15, with permission from Macmillan Publishers Ltd.

Figure 12.2. Lateral view of the left hemisphere indicating the perisylvian area. The illustration shows Broca’s area in the frontal operculum and Wernicke’s area in the superior temporal gyrus and the corresponding Brodmann’s areas. Reprinted with permission from Mark Dubin, PhD, Department of Molecular, Cellular & Developmental Biology, University of Colorado at Boulder (http://spot.colorado.edu/∼dubin/talks/ brodmann/brodmann.html).

(A)

(B)

(C)

Figure 12.4. Examples of language mapping in the frontal lobe (A) and the combined temporal and parietal lobes (B). Yellow and green circles represent numbered electrocortical stimulation mapping (ESM) language sites and clean ESM sites, respectively. Red boxes represent expression fMR imaging activations. Blue boxes represent comprehension fMR imaging activations. The frontal lobe slices are shown with an ESM radius of 5 mm (determined to produce the highest sensitivity with the least cost to specificity) and temporoparietal lobe slices are shown with an ESM radius of 9 mm. A: For frontal lobe mapping, these brain slices demonstrate that red (expression) activations tend to overlap with, or are adjacent to, essential (yellow) ESM sites, but avoid non-essential (green) ESM sites. Blue activations in the frontal lobe also appear predictive. B: In most cases of temporoparietal lobe mapping, such as the one illustrated here, comprehension fMR imaging activations matched well with ESM language sites (yellow) in the temporoparietal lobes and did not overlap with clean ESM sites (green). Very little expression fMR imaging activations are seen in the temporoparietal lobe region and the reason why such tasks as verbal object naming and word generation do not accurately predict language sites in these regions. C: These maps were obtained in an individual case in which preoperative fMR imaging was the least effective at accurately predicting whether a given cortical area would be involved in language function. In this case, only two of the three essential ESM sites overlapped with fMR imaging activations, and only two of seven of the clean ESM sites completely avoided fMR imaging activations. Reproduced from Pouratian N, Bookheimer SY, Rex DE, Martin NA, Toga AW. Utility of preoperative functional magnetic resonance imaging for identifying language cortices in patients with vascular malformations. J Neurosurg. 2002;97(1):21–32, with permission of Journal of Neurosurgery Publishing Group.

Figure 12.6. Diffusion tensor imaging pathways in conduction aphasia. Reproduced from Catani M, Jones DK, Ffytche DH. Perisylvian language networks of the human brain. Ann Neurol. 2005;57(1):8–16, with permission from John Wiley & Sons, Inc.

(a)

(b)

Figure 16.5. White matter tractography may be used to label brain voxels according to the white matter structure of which they form a part. (a) Image tractograms of the projection (green), association (red) and callosal (blue) fibers are mapped into the brain space, indicating their position with respect to other brain regions, and include the anterior region of corona radiata (acr), external capsule (ec), internal capsule (ic), and posterior region of corona radiata (pcr). (b) A similar procedure has been used to label various white matter tracts, including the corpus callosum (purple), superior longitudinal fasciculus (yellow), cingulum (green), uncinate fasciculus (dark red), inferior occipito-frontal fasciculus (orange), inferior longitudinal fasciculus (brown), corticobulbar tract (light blue), corticospinal tract (white), fornix and stria terminalis (light yellow). Tract positions are shown in several sagittal and axial slices. Reprinted from Lazar M. Mapping brain anatomical connectivity using white matter tractography. NMR Biomed 2010;23:821–35, with permission of John Wiley & Sons Ltd.

(A)

(B)

(C)

(D)

(E)

(F)

Figure 18.1. Graphic illustrations of relationships between mood and affect. In each panel, the Y-axis represents the valence of emotion and emotional feeling and the X-axis represents time (days to weeks or longer). Mood is represented by a thick solid line and affect is represented by a thin dotted line. The amplitude of each line reflects the intensity of emotion and emotional feeling. (A) Mood is euthymic (from Greek eu “normal” + thymia “state of mind”) – that is, the emotional climate is temperate and stable over days to weeks. Affect varies around that mood, with clearly identifiable shifts between positive (e.g., happiness) and negative (e.g., irritation, frustration, anger) of modest intensity occurring during any given day. (B) Mood is dysphoric (from Greek dusphoros “hard to bear”), i.e., persistently sad or sad/irritable most of the day nearly every day for several weeks. Affect continues to vary around that mood, but it is restricted to emotions and emotional feelings that are predominantly negative and whose amplitudes are attenuated. (C) Mood varies from persistently and excessively positive (i.e., euphoric and expansive) for a week or longer to excessively negative (i.e., sad). Affect is labile and intense when superimposed on persistently and excessively positive mood and its valence and amplitude are more restricted when superimposed on persistently and excessively negative mood. (D) Moderate affective lability superimposed on euthymic mood. (E) Severely pathological affect (i.e., pathological laughing and crying) superimposed on euthymic mood. (F) Severely pathological affect (i.e., pathological laughing and crying) superimposed on dysphoric mood (i.e., major depressive episode).

Figure 18.2. Graphic illustrations of several types of mood and affect. The Y-axis represents the valence of emotion and emotional feeling and the X-axis represents time (days to weeks or longer). Moods are represented by thick solid lines and affects are represented by thin dotted lines, the intensity of which are reflected by their amplitudes. This graphic offers a visual representation of the concepts of mood and affect: mood is a slow-frequency phenomenon (background, emotional “climate”) and affect is a fast frequency phenomenon (foreground, emotional “weather”).

Figure 18.5. A schematic representation of many of the structures and circuits supporting emotional generation, expression, experience, and control and their functional relationships. Glutamatergic, presumed excitatory projections are shown in green, GABAergic projections are shown in orange, and modulatory projections in blue. In the model proposed here, dysfunction in the amygdala and/or the medial prefrontal network results in dysregulation of transmission throughout an extended brain circuit that stretches from the cortex to the brainstem, generating emotion and its expression through motoric, visceral, autonomic, endocrine, and neurochemical effectors. Intra-amygdaloid connections link the basal and lateral amygdaloid nuclei to the central and medial nuclei of the amygdala. Parallel and convergent efferent projections from the amygdala and the medial prefrontal network to the hypothalamus, periaqueductal gray, nucleus basalis, locus coeruleus, dorsal raphe, and medullary vagal nuclei organize neuroendocrine, autonomic, neurotransmitter and behavioral responses to stressors and emotional stimuli. Structures of the default system (or network) support emotional experience. The amygdala and medial prefrontal network interact with the cortico-striatal-pallidal-thalamic loop, through prominent connections both with the accumbens nucleus and medial caudate, and with the mediodorsal and paraventricular thalamic nuclei, to control and limit responses. Abbreviations: 5-HT – serotonin; ACh – acetylcholine; BNST – bed nucleus of the stria terminalis; Cort. – corticosteroid; CRH – corticotrophin releasing hormone; Ctx – cortex; NorAdr – norepinephrine; PAG – periaqueductal gray; PVH – paraventricular nucleus of the hypothalamus; PVZ – periventricular zone of hypothalamus; VTA – ventral tegmental area. Reprinted from Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology 2010;35(1):192–216, with permission.

(A)

(B)

Figure 26.3. An example of diffusion tensor imaging (DTI) as applied to the study of traumatic brain injury (TBI) (axial T1-weighted image with DTI overlaid). White matter tractography using TBI is used here to visualize the anterior forceps of the corpus callosum in a male who experienced multiple concussions due to blast forces. This case is provided courtesy and with the permission of Dr. Rajendra Morey, Duke University and Mid-Atlantic Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 6, Durham, North Carolina.

Figure 18.6. Results from a study examining the effects on brain activation and emotion of systematic variations in the goal and content of reappraisal strategies. A: Regardless of whether the goal is to increase or decrease emotion, lateral prefrontal and anterior cingulate cortices are activated. B: When the goal is to decrease emotion, right dorsolateral and ventrolateral prefrontal as well as right orbitofrontal cortex is more active than are left-hemispheric structures (left panel). By contrast, when the goal of control is to increase emotion, left lateral and dorsomedial prefrontal cortical regions are differentially recruited when imagining worsening experiences and outcomes (right panel). Abbreviations: LPFC, lateral prefrontal cortex; MPFC, medial prefrontal cortex; ACC, anterior cingulate cortex; OFC, orbitofrontal cortex. Adapted from Ochsner KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci. 2005;9(5):242–9, with permission.

Figure 27.1. Functional magnetic resonance imaging (fMRI) using a light pain stimulation paradigm, which produced bilateral thalamic activation.

(A)

(B)

Figure 27.2. Magnetic resonance imaging (MRI) of a man with remote traumatic brain injury (TBI). High-resolution T2-weighted imaging (A), diffusion tensor imaging (DTI) with color-coded fractional anisotropy (FA) mapping (B), and fiber tracking (C) based on the identification of the region of interest (boxed area in A).

(C)

Figure 27.4. Functional magnetic resonance imaging (fMRI) of a visual task. In this example, a 40-year-old subject was asked to fixate on a small fixation cross while concentric circles expanded from this central point at a rate of 8 Hz for 20 seconds. This 20-second period was followed by a rest condition when the subject was presented the same stimulus with eyes closed. This cycle was repeated three times.

(A)

(B)

(C)

(E)

(F)

(G)

(D)

Figure 27.6. Examples of various diffusion tensor images generated using data acquired from a 30-year-old healthy adult.

Figure 27.7. Typical patterns of cerebral metabolism as imaged using fluorodeoxyglucose positron emission tomography (FDG-PET) among persons with mild, moderate, and severe Alzheimer’s disease (AD). FDG-PET scans are displayed as three-dimensional stereotactic surface projection (SSP) maps normalized to pons generated with the software program Neurostat. Maps are shown with relative cerebral metabolism or statistical significance increasing on the color scale from the lowest values shown in blue to the highest values in red and white. For orientation, a reference brain is shown in row A with regions of interest in dementia evaluations in color; orange areas usually hypometabolic in AD, blue and purple areas typically hypometabolic in frontotemporal dementia. Row B shows the pattern of metabolism in 27 normal elderly subjects. This is used for statistical comparisons with metabolism in individual patients (rows D, F, and H). There are increasing severity and extent of cerebral glucose hypometabolism as AD progresses from mild (rows C and D) and moderate (rows E and F) to severe (rows G and H). Reproduced from Foster NL, Wang AY, Tasdizen T et al. Realizing the potential of positron emission tomography with 18F-fluorodeoxyglucose to improve the treatment of Alzheimer’s disease. Alzheimers Dement. 2008;4(1 Suppl. 1):S29–36, with permission from Elsevier.

Figure 27.8. Statistical parametric mapping of metabolic activity using fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with relatively common neurodegenerative disorders. Statistical parametric mapping of regions of decreased metabolic activity (relative to the global mean, thresholded at p ⬍ 0.001 with cluster cut-off of 20 voxels) are overlaid onto a single subject T1 magnetic resonance image. Abbreviations: PD – Parkinson’s disease; MSA – multisystem atrophy; PSP – progressive supranuclear palsy; CBD – corticobasal degeneration; DLB – dementia with Lewy bodies; AD – Alzheimer’s disease; FTD – frontotemporal dementia. Reproduced from Teune LK, Bartels AL, de Jong BM et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord. 2010;25(14):2395–404, with permission from John Wiley and Sons.

Figure 28.4. Sleep architecture presented in a bipolar montage. The stages of sleep are identified by their typical EEG findings and cycle throughout the night among lighter (Stages 1 and 2) and deeper (Stages 3, 4, and REM) stages of sleep. Stage 1 sleep (top left) is characterized by loss of the posterior dominant rhythm, further diminishment of movement and muscle artifact and increasing diffuse slowing of background activity. Stage 2 sleep (top right) is characterized by the appearance of sleep spindles and K-complexes. Stages 3 and 4 sleep (bottom left) are characterized by various percentages of higher amplitude delta range activity. REM sleep (bottom right) is characterized by a low-voltage, irregular background with multiple rapid eye movements. Muscle artifact is virtually absent during normal REM sleep.

Figure 28.5. Normal posterior dominant rhythm with attenuation upon eye opening (black arrow) and reappearance with eye closure (purple arrow).

Figure 28.7. Widespread, or diffuse, beta activity.

Figure 28.14. Photoparoxysmal response.

Figure 29.4. Scalp topography of posterior-dominant alpha. A flat projection of the top of the head is shown and the circles indicate approximate electrode locations (nose is up in figure). The power distribution across electrodes exhibits a typical posterior dominance for alpha, mapped at 10 Hz.

Figure 29.8. Time, frequency, and time–frequency representations. The signal in the left column is a mixture of two pure tones (20 and 80 Hz). The signal in the right column is the same complex tone as the left, but amplitude modulated at 5 Hz. Top panels: Time domain; Bottom panels: Frequency domain (FFT); Middle panels: Time–frequency domain (Short-Time Fourier Transform). The reds in the color scale indicate greater spectral power. Note that for the stationary signal on the left, a simple frequency representation (middle panel) conveys as much information as the time–frequency representation (bottom). For the non-stationary signal on the right, however, the amplitude modulation effect is lost in the FFT (middle panel), but captured effectively in the time–frequency representation (bottom panel).

Figure 29.9. Examples of time–frequency transformations. Top panel: Original signal in the time domain. The signal is linearly decreasing in frequency across time (i.e., it is a chirp signal). Middle panel: Short-time Fourier Transform of chirp. Bottom panel: Pseudo-Wigner Distribution of chirp. Note the increased frequency resolution of the Pseudo-Wigner Distribution. Reds in the color scale indicate greater spectral power.

Figure 29.10. Magnetic response to visually cued index finger flexions. Top panel: Averaged evoked field (EF) (101 trials) from a single channel over the right hemisphere. Time zero indicates movement onset. The evoked responses seen in the immediate post-movement period are known as motor evoked fields (MEF, or MEP for EEG recordings) and reflect the somatosensory feedback from motor cortex and from the peripheral sensation of movement. Bottom panel: Wavelet-based time-frequency transformation of same trials in same channel used to create averaged EF (color scale: blues indicate event-related de-synchronization (ERD) and reds indicate event-related synchronization (ERS)). Note the prominent beta-band changes in the panel, including ERD in the pre- and peri-movement period and then ERS following the ERD. The power increase from the evoked response in the top panel is evident immediately following movement onset at the lower frequencies (⬍10 Hz). The ERD/ERS in the beta-band is difficult to visualize in the averaged evoked response, although a small change in amplitude may be discerned.

Figure 29.11. Subdividing the spectral response into evoked and induced components. The data illustrated in Figure 29.10 are shown here, focusing more clearly on the relevant time and frequency windows. Top panel: evoked power, relative to pre-movement baseline period (−3 to −2 s); Middle panel: relative induced power; Bottom panel: phase-locking factor. Color scales: reds indicates greater power (top two panels) or phase-locking (bottom panel) – blues indicate lower power or phase-locking.

Figure 29.12. Distributed source analysis of the visual evoked magnetic field and electric potential at 100 ms (M/P100) produced by averaging EEG and MEG data to repeated presentations of a central visual fixation crosshair. A cortically constrained minimum norm solution was used for source reconstruction in this case.

Figure 29.14. Independent component analysis of a 248-channel MEG dataset from a child with medial temporal lobe epilepsy. The first 20 (of 248) ICA components are illustrated (top: waveforms; bottom: topography). Component 14 shows a spike at approximately 232 seconds from the initiation of recording. The spike shows a dipole-like phase-reversal over the left temporal cortex in the topography. Follow-on source analysis revealed a hippocampal origin. Also of interest are component 16, which reflects eyeblinks, and component 19, a magnetocardiographic artifact (note the broad phase-reversal over the left and right sensors reflecting a very distant source). A significant amount of slowing in the MEG record (mixed delta/theta) is also seen in the first 10 components. Color scale: reds are positive and blues negative component values.

(A)

(B)

(C)

(D)

Figure 31.1. Lymphomatosis cerebri. A: Coronal brain autopsy sections showed no mass lesions or hemorrhages, and no obvious abnormalities of the white matter except for very subtle discoloration best seen in the left inferior frontal gyrus (arrow). B: Whole mount sections stained with hematoxylin and eosin (H&E) (left) and CD45 for lymphocytes (right) showed that the densest lymphoma cell infiltrates were found in this same abnormal left inferior frontal gyrus, where they filled the subgyral white matter, with relative sparing of the overlying cortical gray matter. C: High-power photomicrograph of the white matter showing clusters of lymphoma cells that permeated, splayed, and disrupted the myelinated fibers, seen as elongate linear strands (Luxol fast blue-periodic acid Schiff (LFB-PAS)). D: High-power photomicrograph of the white matter from the same area as seen in Figure 31.1C, showing better preservation of axons. Anti-neurofilament immunostaining with light hematoxylin counterstain.

(A)

(B)

(C)

(D)

(E)

(F)

Figure 31.2. Lymphomatosis cerebri. A: Low-power photomicrograph illustrating that less-dense lymphomatous infiltrates could also be found in the cerebellar white matter (WM), where they again favored white matter over the cerebellar gray matter (GM) or molecular layer (ML). Meningeal involvement was focally identified (arrow). Hematoxylin and eosin (H&E) stain. B: Low power photomicrograph showing that in the subcortical gray matter areas the preference of the cells for white matter over gray matter still existed. Note extensive involvement of the white matter, with virtual stoppage cells where the gray matter of the putamen (P) meets the adjacent white matter (arrows); H&E stain used in this photomicrograph. C: High-power photomicrograph illustrates that while some degree of perivascular accumulation of lymphoma cells was found, individual cell permeation by the cytologically malignant cells (D: arrows) was more typical. E: Lymphoma cells were immunoreactive for CD20, a B-cell marker; CD20 immunostaining with light hematoxylin counterstain. F: Only a few accompanying non-neoplastic T-cells were identified; CD3 immunostaining with light hematoxylin counterstain.

(A)

(B)

(C)

(D)

(E)

(F)

(G)

(H)

Figure 31.3. Mycosis fungoides. A: Low-power photomicrograph of the skin from the lower extremities demonstrated increased numbers of lymphocytes within the upper dermis that were cytologically atypical, features diagnostic for mycosis fungoides. Hematoxylin and eosin (H&E) stain. B: At the same magnification and in the same region, the atypical lymphocytes are easily highlighted by their strongly positive reaction for CD8, an immunomarker for suppressor T-cells. Cases of mycosis fungoides with CD8+ predominance are far fewer than those with CD4+ strong staining. CD8 immunostaining with light hematoxylin counterstain. C: Same region of skin immunostained with CD4 shows that CD4-positive helper T-cells are far less frequent. CD4 immunostaining with light hematoxylin counterstain. D: Low power photomicrograph taken from the white matter of the cerebral hemispheres shows cytologically atypical lymphocytes that percolate through the white matter, yielding only subtle hypercellularity and only focal angiocentric arrangement (arrow). H&E stain. E: High-power magnification revealed the individual neoplastic T-cells of mycosis fungoides with classic “cerebriform,” folded and grooved nuclei (arrow). H&E stain. F: Immunohistochemical staining for CD8 highlighted these individual tumor cells far better in the white matter than did routine H&E staining. G: High-power photomicrograph of one of the mycosis fungoides cells in white matter immunostained for CD8. H: Leptomeningeal involvement could also be discerned in some areas. H&E stain.

(A)

(B)

(C)

(D)

(E)

(F)

Figure 31.4. Intravascular lymphoma. A: Magnetic resonance imaging (MRI) performed soon after diagnosis reveals multiple bilateral areas of increased T2 signal in the cerebral white matter (illustrated) as well as in the pons and cerebellar hemispheres. B: Fluid-attenuated inversion recovery (FLAIR) imaging similarly demonstrates multiple foci with ill-defined borders scattered throughout the supratentorial region. The lesions principally occupy the white matter, but some cortical involvement is also present. Probable restrictive diffusion was noted, with definitive enhancement (not shown). C: T2-weighted MRI scan performed hours prior to demise shows even more extensive white matter lesions; these proved to be white matter infarctions devoid of intravascular tumor cells at the time of autopsy. D: FLAIR (pictured), diffusion, and post-contrast images prior to demise are similar in appearance to the MRI performed soon after diagnosis, despite the absence of tumor cells at autopsy. E and F: Coronal brain autopsy sections at the level of the mamillary bodies (E) and occipital horns (F) showed no mass lesions or hemorrhages, although obvious abnormalities of the white matter were seen bilaterally in the cerebral white matter as grayish areas of partial cavitation, indicative of multifocal white matter infarctions (arrows).

(A)

(B)

(C)

(D)

(E)

(F)

(G)

(H)

Figure 31.5. Intravascular lymphoma. A: Low-power photomicrograph of the pre-mortem brain biopsy revealed that vessels of all sizes were packed with lymphoma cells; lymphoma was confined to the intralumenal space. Hematoxylin and eosin (H&E) stain. B: Medium-power photomicrograph shows that even individual small capillaries contained single lymphoma cells; no infarction of surrounding brain was found on the small biopsy sections (H&E stain). C: High-power photomicrograph illustrates the extreme cytological atypia of the individual lymphoma cells within blood vessels (H&E stain). D: These cells, including those in capillaries, were highlighted by their strong immunoreactivity for CD20 (CD20 immunostaining for B-cell lymphocytes, with light hematoxylin counterstain). E: Whole-mount section of the cerebral white matter discloses the discrete white matter areas of pallor and infarction (H&E stain). F: Whole-mount section of the lower spinal cord revealed multifocal areas of infarction, correlating with the patient’s lower extremity weakness noted in life (luxol fast blue-periodic acid Schiff stain for myelin). G: On lower power microscopic sections, infarcted white matter lesions could be recognized by their vacuolization, partial cavitation, and pallor (upper left in photograph; H&E stain). H: On high-power magnification, nearby blood vessels (seen at low power in block G) contained no residual intralumenal lymphoma cells after the patient’s chemotherapy treatment. Only reactive, perivascular non-neoplastic lymphocytes remained at autopsy near the infarcts.

Section I


Chapter

Executive function

16

David B. Arciniegas

Executive function refers to a complex set of processes that manage and control other, relatively basic, cognitive functions [1, 2] and that support purposeful goaldirected behaviors [2–5]. These processes are engaged most fully when confronting novel problems or situations for which no previously established routines exist [5, 6]. By facilitating pattern identification, strategy development, and problem solving, executive function enables an individual to respond flexibly and adaptively to the environment, to develop goals and anticipate their consequences, and to direct cognition, emotion, and behavior in the service of goal attainment [7, 8]. The broad anatomic areas contributing to the networks upon which executive functions are predicated render them vulnerable to disruption by many conditions affecting the brain [2, 9–17]. When the function of these networks is compromised, executive dysfunction ensues. This dysfunction may manifest as limited conceptualization and abstraction, cognitive inflexibility, impaired control of attention, working memory, declarative memory, language, praxis, calculation, and visuospatial function and other cognitive abilities, impaired decision-making and judgment (including impulsivity, disinhibition, and carelessness), difficulty setting goals, organizing, maintaining, and shifting plans, and difficulty with error detection and correction [5]. Deficits in executive function compromise an individual’s ability to meet the demands of everyday life in a flexible and adaptive manner, even when basic cognitive functions are relatively preserved [18–20]. Accordingly, an understanding of the phenomenology and neuropathophysiology of executive function and dysfunctions is required of subspecialists in Behavioral Neurology & Neuropsychiatry (BN&NP) [21]. Toward

that end, this chapter reviews conceptual issues and definitions of executive function. It is argued that executive function is a multidimensional construct and it is suggested that subspecialists in BN&NP regard executive function principally as a cognitive domain. The neuroanatomy and neurochemistry of executive function is reviewed, beginning with early formulations of frontal lobe functioning and ending with a description of the distributed neural networks supporting executive function. Finally, neuropsychological tests and bedside assessments of executive function are identified and discussed briefly.

Conceptual issues and definitions The referents of executive function offered in the medical and psychology literatures are diverse [5, 22] and consensus is lacking on a definition of this cognitive domain [2, 5, 22]. Royall et al. (2002) [2], writing on behalf of the American Neuropsychiatric Association Committee on Research (ANPA CoR), suggest that the historical foundations for the concept of executive function derive from the application of systems engineering descriptions of the 1960s to the study of human cognitive processes [23] and the seminal analyses of higher cortical function performed by Luria [24, 25]. Among the earliest and clearest descriptions of this area of cognition is Luria’s (1962) [24] characterization of the prefrontal cortices as regions of the brain responsible for integrating and attaching informative or regulatory significance to selected elements of incoming stimuli (i.e., establishing “the provisional basis of action”). He suggested that this information is processed “with the intimate participation of the frontal lobes” in a manner that fosters “complex


225


programs of behavior; the constant monitoring of the performance of these programs and the checking of behavior with comparison of actions performed and the original plans; [and] the provision of a system of “feedback” on the basis of which complex forms of behavior are regulated” (translated in [26], p. 248). This system was conceptualized as supporting the “general organization of behavior” [26] through programming, regulation, and verification [25]. Over the following decades, general descriptions of executive functions arose in the context of theories describing the psychological mechanisms and cerebral loci of control over specific cognitive processes. Norman and Shallice (1986) [6, 27] described a “supervisory system” for attentional control (i.e., executive control of attention) that is used in situations in which routine or automatic processes are inadequate (contention scheduling). Building upon the filter model proposed by Broadbent (1958) [28], it was suggested that the supervisory attentional system facilitates target selection from amongst multiple competing inputs, monitors for and corrects errors, and resolves response conflicts. Posner and Rothbart (1998, 2009) [29, 30], reviewing the literature on attention and self-regulation from a developmental perspective, extended this view to include effortful control of mental events (i.e., a category of mental events that is contrasted with those that are automatically, or nonvolitionally, activated by internal or external stimuli). The concept of a supervisory (executive) system subsequently expanded to encompass cognitive processes responsible for supplanting automatic responses with strategies necessary for volitional goal-directed behavior, especially in novel or complex circumstances, and for monitoring their effectiveness [5]. Baddeley (1986) [31] posited a role for a “central executive” that regulates and manipulates information held in working memory (i.e., the phonological loop, the visuospatial “sketchpad,” and the episodic buffer that integrates short- and long-term memory). Mesulam (2000) [32] suggests that the role of the central executive applies most directly to the volitional manipulation of information held in working memory, reflecting the “top-down” influence (i.e., supramodal role) of lateral prefrontal cortices on the orchestration of working memory in all domains of information processing. The referent of the central executive was subsequently clarified by Stuss and Alexander. (2007) [33] as several separate processes: facilitation (energizing) of neural systems involved in decision-making

226

(contention scheduling), response initiation, monitoring of task activity and timing (e.g., error detection), and adjustment of behavior. In the context of developing a conceptual model of attention-deficit hyperactivity disorder, Barkley (1997) [34] integrated definitions of executive function offered by others [35–38]. He suggests that executive function comprises self-directed (cognitive) actions, the organization of behavioral contingencies across time, the use of self-directed speech, rules, or plans, deferred gratification, and goal-directed, futureoriented, purposive or intentional actions. These domain- or condition-specific control functions form the background for broader, albeit still cognitively focused, models of executive function. Zelazo et al. (1997) [39] describe executive function as a macro-construct that spans four phases of problem solving: representation, planning, execution, and evaluation. Similarly, the American Psychiatric Association (1994, 2000) [40, 41] describes executive function as involving conceptualization (i.e., thinking abstractly) and the ability to plan, initiate, sequence, monitor, and stop complex behavior. Miyake et al. (2000) [42] describe executive function as the processes involved in the continuous monitoring and modification of information in working memory (updating), the capacity to supersede automatic responses (inhibition), and the capacity to flexibly alternate between different tasks or mental states (shifting). Baron (2004) [8] suggests that executive functions are metacognitive capacities that facilitate stimulus perception, adaptive responding, flexibility (i.e., changing responses), anticipating future goals and consequences integrating responses rationally, and using such capacities to achieve goals. More recently, Banich (2009) [43] described executive function as a multidimensional construct encompassing the set of abilities required to guide effortful behavior toward a goal in non-routine situations. These abilities include prioritizing and sequencing behavior, inhibiting familiar or stereotyped behaviors, generating and maintaining an attentional set focused on contextually relevant information, providing resistance to distracting or task-irrelevant information, switching between goals, using information in the service of decision-making, categorization and abstraction, and managing novel information and/or situations. These executive functions are organized into a “cascade-of-control” model involving four distinct and

Chapter 16: Executive function

interactive information-processing steps mediated by discrete prefrontal cortices: establishing a bias toward task-relevant processes, biasing to task-relevant representations, selecting information that guides responding, and evaluating responses. The concept of executive function, or at least the language used to describe it, sometimes extends beyond cognition to include volition [4], initiation [2, 44], emotional evaluation and regulation [45–47], insight [48–53] and theory of mind (i.e., insight into thoughts and feelings of other people) [47, 54, 55]. For example, Lezak (1995, 2004) [4, 56] suggests that there are at least four general components of executive function: volition, planning, purposive active, and effective performance. In this view, executive function explains not “what” or “how much” an individual does something (e.g., a cognitive task, a behavior) but instead “whether” and “how” it is done. Royall et al. (2002) [2] suggest that this simple dichotomy usefully divides the broad array of cognitive, emotional, and behavioral functions in which prefrontal systems participate into executive and non-executive types. A more recent multi-perspective approach undertaken by Packwood et al. (2011) [22] reviewed 60 studies on executive function. Although all of the studies reviewed purported to study “executive function,” the authors identified 68 sub-components (i.e., specific processes) referred to by this term. Latent semantic analysis (to account for semantic overlap) and hierarchical cluster analysis (to account for psychometric overlap) reduced the referents of executive function to 18 clusters of clinically identifiable processes and abilities (Table 16.1). They suggested that this relatively large number of abilities comprising executive function reflects a tendency in the clinical neuropsychological literature to rest definitions of executive functions on behaviors (or deficits) revealed by test performances. Even if these 18 clusters can be organized into a smaller number of core abilities, such as those described by Lezak [4, 56], this analysis makes clear that executive function is not a unidimensional construct – i.e., there is no single “central executive” or simple homunculus-like supervisory system [22, 33, 46, 57].

Defining executive function for clinical practice The cognitive neuroscience literature, from which much of the preceding review is drawn, takes a broad

Table 16.1. Clusters of executive functions and their constituents as described by Packwood et al. (2011) [22].

Cluster

Elements

1

Working memory, efficient retrieval of works from memory, temporal coding, concentration, performing a sequence of actions

2

Strategy generation, conceptualization, attentional set formation, set maintenance

3

Executive memory (as demonstrated by verbal and non-verbal fluency tasks)

4

Goal-setting, “central executive” function

5

Impulsivity

6

Initiation

7

Inhibition, interference control, response control, mental control, visual search, sustained attention (vigilance)

8

Freedom from/resistance to distraction

9

Problem solving, controlling actions

10

Planning/goal management, developing a plan, executing a plan

11

Organization

12

Strategy use, self-generative behavior, self-monitoring, selective attention, set shifting, attentional control (shifting attention), cue-directed attention

13

Cognitive flexibility

14

Concept formation

15

Abstraction

16

Spontaneous verbal formation, fluency, response generation, response control (i.e., response suppression, response modulation), verbal efficiency

17

Information processing, sequencing

18

Perseveration, reasoning

view of executive function. By many of these accounts [2, 4, 22, 29, 30, 34, 44–47], initiation, emotional regulation, comportment, and behavioral control all fall within the category of executive function. For academic purposes (i.e., studying information processing and control systems in theory and in the human brain), such a broad view of executive function is useful to the extent that it facilitates identification of general mechanisms of control over information processing in the human brain. Clinicians, especially subspecialists in BN&NP, also recognize that cognitive control processes contribute to emotional and behavioral regulation. However, regulation of non-cognitive functions is

227


conceptualized [58–64] and assessed separately from cognition [65–69]. Similarly, cognitive impairments commonly co-occur with disturbances of emotion and behavior, but disturbances of emotion and behavior (e.g., disorders of motivation, disorders of mood and affect, impaired comportment, impulsivity, agitation, aggression) are diagnosed separately from cognitive disorders, including the dysexecutive syndrome [14, 41, 70, 71]. In clinical practice, executive function is regarded as a cognitive domain, understood to be a multidimensional (i.e., non-unitary) construct, and assessed separately from emotion and behavior [41, 72–75] (see Chapter 23). Within the domain of executive function are complex sets of cognitive processes involved in the management and control of other, relatively basic, aspects of information processing. These processes and their outcomes support purposeful goal-directed behaviors, especially those required to address novel problems or situations for which no previously established routines exist, and interact with the processes and outcomes of systems involved in the regulation of emotion and behavior. The merits of “splitting” control processes into cognitive (i.e., executive) and non-cognitive (i.e., emotional and behavioral) types are debatable and are subjects of disagreement within and between researchers and clinicians. Additional theoretical and experimental research is needed to determine whether a unified account of cognitive, emotional, and behavioral control process in the human brain is tenable [2, 22, 43, 75]. Since a widely accepted, theoretically comprehensive, and experimentally supported account that integrates control processes across cognition, emotion, and behavior is not available presently, executive function is considered in this chapter and volume to be a domain of cognition.

Neuroanatomy of executive function There is a longstanding tradition amongst clinicians and neuroscientists of attributing executive function to the frontal lobes, describing them as “frontal lobe functions,” and referring to their disturbances as “frontal lobe syndromes” or “frontal lobe disorders” [2, 9, 20, 24, 26, 32, 43, 75, 76]. Neuroanatomic and neuroimaging studies performed over the last several decades suggest that this tradition requires reconsideration. Executive function requires the integrated actions of the frontal-subcortical circuits, open-loop

228

connections to other neocortical areas, limbic and paralimbic structures, thalamic nuclei, pontocerebellar networks, modulatory neurochemical projections from mesencephalic and ventral forebrain structures, and the white matter connections within and between all of these areas [2, 32, 75, 77–80] (see also Chapter 5). As such, executive dysfunction is more accurately understood as dysfunction within or across these networks [81]. Understanding this revised view of the neuroanatomy of executive function necessitates reviewing briefly the history of ideas on this subject and findings from modern neuroanatomic studies.

Early observations on frontal function In his review of disturbances associated with lesions of the frontal region, Luria (1962, 1980) [24, 26] credits Gratiolet (1861) [82] with first describing the frontal lobes as the site of the “regulating mind.” He then describes decades of research in the late 1800s and early 1900s involving stimulation and extirpation of the frontal lobes in animals, and identifies Jackson [83], Bianchi [84, 85], Bekheterev [86], and Pavlov [87] as key contributors to the foundation upon which modern views of the neuroanatomy of executive function rests. Jackson (1884) [83] identified the prefrontal regions as the highest and most complex motor centers that indirectly represent movements of all parts of the body. Bianchi (1895, 1920) [84, 85], through ablation studies of animals, identified the role of the frontal lobes in coordinating motor and sensory elements, using the products of the sensory zones to create mental syntheses (i.e., integrative function), and relate to sensorimotor zones in the same manner that motor systems relate to subcortical nuclei. He observed that bilateral extirpation (i.e., lesion or resection) of the frontal lobes results in behavioral disorganization and lack of adaptation to new conditions. Bekhterev (1907) [86], summarizing observations begun in the 1880s, observed disintegration of goaldirected behavior following extirpation of the frontal lobes, including loss of the regulatory activity required to correctly evaluate external impressions and purposively direct movements in accordance with the evaluation. Pavlov (1949) [87], through studies involving extirpation of the frontal lobes in dogs, regarded the prefrontal cortices as integrators of goal-directed movement. He introduced the concept of the “motor


analyzer,” referring to the cortical motor areas that served as an afferent analyzing apparatus of impulses received from all other parts of the brain, especially the kinesthetic signals providing information on the course of a movement and its effects. He regarded the frontal lobes as an essential component, and the most complex aspect, of the cortical division of the motor analyzer and hypothesized that they facilitate the selection of goal-directed movements. Pavlov’s concept of a “motor analyzer” informed subsequent works (summarized in [24, 26]) on the regulatory functions served by the prefrontal cortices. These works identified the prefrontal cortices as subserving complex forms of motor operations and the evaluating of the effects of action, and suggested that their destruction precludes selective goal-directed behavior. The works of Gratiolet (1861) [82], Jackson (1884) [83], Bianchi (1895, 1920) [84, 85], Bekhterev (1907) [86], Pavlov (1949) [87] and other investigators [24, 26] established the importance of the prefrontal cortices in the integration, coordination, and inhibitory functions as well as evaluation (i.e., selfobservation) of movements and bodily activities.

Prefrontal cortices Luria (1962, 1980) [24, 26] emphasized connections between prefrontal cortices and other areas as illuminating their role in the functional organization of the cerebral hemispheres. He anchored his review of the functional anatomy of the prefrontal cortices to the work of Brodmann (1909, 1914) [88, 89] (Figure 16.1). He recognized that the prefrontal divisions of the cortex differ in a number of respects from the motor and premotor areas, including the structure of the second and their association layers, in which giant pyramidal Betz cells are absent (Figure 16.2), as well as the system of vertical connections between the prefrontal divisions of the cortex and the thalamus. He identified Brodmann’s areas (BA) 9, 10, 11, 24, 44, 45, and 46 as subdivisions of the prefrontal cortices possessing specific afferent-efferent connections to other brain areas, especially non-motor association (i.e., mediodorsal) divisions of the thalamus. For example, Luria noted connections between the oculomotor area (BA8) and posterior visual cortices (BA18, 19), and connections between dorsolateral prefrontal areas (BA10, 45, 46) and parietotemporal regions (BA22, 37, 39, and 42). On the basis of their regionally specific connections, he considered

the prefrontal regions to be the cortical portions of Pavlov’s cortical analyzer. He also suggested that these regions play an important role in the organization of movement in light of their receipt of afferent impulses from “all of the more important parts of the brain” (in [26], p. 260). This characteristic suggested to him that these prefrontal regions “must be instrumental in the sorting of these impulses and in the transmission of them to the system of the motor analyzer” (in [26], p. 260). He also noted the close connections between the mediobasal cortical divisions and the structures of the limbic region, hypothalamic region, reticular formation, and “other nervous apparatuses concerned with interoception.” On the basis of these connections, he posited a role for the mediobasal cortical regions in the regulation of body states and “active states of the individual” (in [26], pp. 262–263). Integrating his analyses of the structure and function of all of these prefrontal regions, Luria (1962, 1980) [24, 26] suggested that these regions synthesize information about the outside world as well as internal body states, support the complex programming of behavior, monitoring performance of these programs, comparing actions performed to previously established plans, and that they establish a system of feedback for regulating behavior. These seminal observations inform subsequent works clarifying the neuroanatomy underlying the synthesis and control of information processing within the human brain and the information programming, regulation, and verification required for purposeful self-directed action – that is, executive function.

Functional subdivisions of the prefrontal cortices Subsequent works (summarized in [32, 46, 90–95]) clarified the anatomic and functional subdivisions of the prefrontal cortices (Figure 16.3). Mesulam (2000) [32] suggested that these regions may be divided into three distinct sectors: motor-premotor, heteromodal (lateral prefrontal), and paralimbic (anterior cingulate and orbitofrontal).

Motor-premotor sector The motor association areas anterior to BA4 (motor cortex or M1) are the principal source of cortical projections into BA4 [32]. The motor association areas include premotor cortex (lateral aspect of BA6),

229


Figure 16.1. Brodmann’s areas (BA) of the human brain. Reprinted from Nieuwenhuys R, Voogd, J., van Huijzen, C. The Human Central Nervous System. 4th edition. 2008, p. 502, with permission from Springer Science+Business Media.

supplementary motor area (medial aspect of BA6), supplementary eye fields (dorsomedial BA8) and frontal eye fields (lateral BA8), and the posterior portions of Broca’s area (BA44). These areas, along with BA4, comprise the motor-premotor sector. The motor association components of this sector are involved in the programming and control of movement, including differential responding to sensory stimuli, integration of visual and motor acts (i.e., hand–eye coordination), imagining movement, movement selection, motor programming/planning, sequencing goal-directed movements, coordinating multi-step

230

movement strategies, initiating and maintaining motor output, and encoding procedural learning [32]. These functions apply to the segment of the motorpremotor sector referred to as Broca’s area (BA44 and adjacent heteromodal cortex), which is understood most usefully as a motor association area supporting language. This area generates articulatory sequences with meaning-appropriate syntactic structure, making grapheme-to-phoneme transformations, even when articulatory output is imaginary, and deciphering (analyzing, interpreting) the meaning of syntactically complex sentences [32]. This area is distinct


Figure 16.2. A map of granular and agranular cortical areas in the human brain. Reprinted from Nieuwenhuys R, Voogd, J., van Huijzen, C. The Human Central Nervous System. 4th edition. 2008, p. 505, with permission from Springer Science+Business Media.

5

1 2

2

3 3 1

2

4

3

5 4 1

5

1 2

(C)

2

2

2

1

3

5 1

1 Heterotypical, agranular cortex (motor cortex) 2 Homotypical cortex, frontal type 3 Homotypical cortex, parietal type 4 Homotypical cortex, polar type 5 Heterotypical, granular cortex (primary sensory cortical areas)

4

1

4

5

4 1

(B)

2

5

3

1 2

I

I

II

II

IIIa

III

IIIb

IV

IIIc

V

IV

VIa

V

VIb

VI

1

2

3

4

from other subdivisions of the motor-premotor sector only in its application to language-related processes; its programming and regulating functions on the motor aspects of language are the same as those of the other motor-premotor sector components.

Heteromodal sector The heteromodal sector is extensive, encompassing BA9–10, anterior BA11–12, and BA45–47. These areas are characterized by isocortical architecture, with a six-layer cortex of high neuronal density and granular bands in layers 2 and 4 (see Figure 16.2). This region receives neural inputs from unimodal sensory association areas, all other heteromodal association areas,

5

(A)

and paralimbic cortices [32] and is interconnected with other prefrontal regions [46]. Neurons in these areas may respond preferentially to modality-specific information, but these are intermixed with others that respond to many sensory modalities (i.e., multimodal neurons). As a transmodal zone at the fifth and sixth synaptic levels, the lateral prefrontal heteromodal cortices integrate information across sensory and motor domains, facilitate attentional tuning by biasing information processing at unimodal cortices, activate representational networks and suppress others, exert a top-down influence on working memory activity in neurons in active areas, and orchestrate network interactions. These lateral prefrontal heteromodal cortices

231


Figure 16.3. Subdivisions of Brodmann’s areas (BA) in the prefrontal regions surface-rendered onto the orbital (a) and medial (b) surface and illustrated on a drawing of the lateral (c) of the human brain. Abbreviations: AON, anterior olfactory nucleus; 32ac, dorsal anterior cingulate area; c, caudal; d, dorsal; l, lateral; Iai, intermediate agranular insula area; Ial, lateral agranular insula area; Iam, medial agranular insula area; Iapm, posteromedial agranular insula area; m, medial; p, polar; pl, posterolateral; r, rostral; s, sulcal; v, ventral. Letters A, B, a, b, and c represent subdivisions of the BA with which they are associated; an exception to this convention is 14c, referring to the caudal aspect of this area. Adapted from Ramnani N, Owen AM. Anterior prefrontal cortex: insights into function from anatomy and neuroimaging. Nat Rev Neurosci 2004;5:184–94., with permission from Macmillan Publishers Ltd.

also are involved in inhibiting context-inappropriate responses by engaging and supporting information processing in a manner that supplants customary (i.e., automatic) responses to stimuli. As reviewed in Banich (2009) [43], the functional roles of the various subsections of the heteromodal sector are subjects of controversy. The inferolateral areas (BA45, 57) may contribute to maintaining information in working memory whereas the mid-dorsolateral prefrontal areas (BA9, 46) perform executive operations on that information [96]. Anterior regions (BA10p) may be involved more closely with the use of internally generated information [97] or the coordination of information processing and information transfer within actively engaged heteromodal cortices [93]. Posterior prefrontal areas engage in processing of environmental (i.e., sensory) information [93, 97]. Christoff and Gabrieli (2000) [97] suggest that dorsolateral and frontopolar regions are recruited serially when a reasoning or memory task requires evaluation of internally generated

232

information. There also may be hemispheric differences in the function of the dorsolateral heteromodal sectors, with the left subserving task generation (or task setting) and the right supporting performance monitoring [33]. Banich (2009) [43] suggests that the posterior dorsolateral prefrontal cortex biases attention toward task-relevant processes, thereby providing freedom from distraction produced by automatic engagement of task-irrelevant processes, whereas the mid-dorsolateral prefrontal cortex selects specific representations identified as task-relevant.

Paralimbic sector The paralimbic sector, located in the ventral and medial parts of the frontal lobes, includes the anterior cingulate complex (BA23, 32), parolfactory gyrus (gyrus rectus, BA25), and posterior orbitofrontal regions (BA11–13) [32]. This sector is characterized by a gradual architectonic transition from primitive allocortex to granular isocortex (homotypical cortex)


[81] (see Figure 16.2). These areas provide transmodal nodes for binding visceral and emotional states to cognition (i.e., thoughts, memories, experiences) and for prioritizing information processing on the behavioral relevance of a stimulus over its physical characteristics. Mesulam (2000) [32] notes that there is a tendency in the literature to refer to these areas as “medial frontal cortex” (or medial prefrontal cortex) and to use that term as if it denotes a distinct and uniform neuroanatomic area. The structures comprising the medial prefrontal cortex include portions of both the heteromodal sector (BA9, 10) as well as the paralimbic sector, including cingulate complex (BA24, 25, 32, 33) and medial orbitofrontal cortices (BA11–13). Disruption of the function or structure of the medial prefrontal cortex therefore may produce disturbances of cognition, motivation, comportment, and emotion, alone or in combination, depending on the site of lesion. Use of the term “medial prefrontal cortex” therefore is discouraged in favor of referring to specific element(s) of this area and the circuits and networks into which they are incorporated. There are two major divisions of the anterior cingulate cortex: dorsal cognitive division (BA24, 24a’-b’, and 32’), also referred to as the cognitive effector region, and the rostral-ventral affective division (subgenual cingulate (BA25), adjacent (caudal) portions of BA32 (pregenual cingulate), area 33, and the rostral portions of AC cortex, subcallosal areas 24a and 24b) [32, 98]. The dorsal cognitive division contributes to an attentional network and is reciprocally connected with the heteromodal (i.e., dorsolateral prefrontal) sector, parietal cortex (BA7), and the premotor and supplementary motor areas [99–102]. This division of the anterior cingulate cortex contributes to sensory and response selection, monitoring competition, complex motor control, novelty, error detection, working memory, motivation, and anticipation of cognitively demanding tasks [103]. In the Banich (2009) model of executive function, posterior portions of the dorsal anterior cingulate are involved in late-stage aspects of selection, are especially sensitive to response-related factors, and are most activated when stimuli lead to competing responses. Anterior regions of the dorsal anterior cingulate cortex are involved in response evaluation, and become more active when the probability of error increases [104]. The rostral-ventral affective division of the AC cortex comprises the subgenual cingulate (BA25), adjacent (caudal) portions of BA32 (pregenual cingulate),

area 33, and the rostral portions of AC cortex, subcallosal areas 24a and 24b [99–102]. This division of the anterior cingulate cortex connects extensively with the amygdala and midbrain periaqueductal gray, and also connects to autonomic brainstem motor nuclei. It contributes to the regulation of autonomic and endocrine functions, conditioned emotional learning, vocalizations associated with expressing internal states, assessments of motivational content, and assigning emotional valence to internal and external stimuli [99]. The orbitofrontal elements of the paralimbic sector are anatomically and functionally complex. Posterior portions of the orbitofrontal cortex abut the caudal portion of the subcallosal area of the cingulate complex, piriform olfactory cortex, anterior olfactory nucleus, and insula, reciprocally connect with the hypothalamus, and receive input from primary olfactory cortex, amygdala, nucleus basalis, and hippocampus [32, 105–107]. These connections render this area behaviorally “limbic” in character. By contrast, the lateral orbitofrontal cortex (BA11, inferior aspects of BA10 and 47) is more densely connected with gustatory, somatic and visual sensory areas, temporal pole, premotor regions, cingulate, and the amygdala [106, 107]. The orbitofrontal cortices (and connected subgenual cingulate cortex) are activated by pleasant touch, painful touch, visual stimuli, rewarding and aversive taste, and odor, consistent with lower primate studies and human neuroimaging findings identifying connections between orbitofrontal and sensorimotor cortices [108, 109]. The medial orbitofrontal cortex activates in association with reward and deactivates in response to punishment, whereas the lateral orbitofrontal cortex activates in response to punishment and deactivates in response to reward. In O’Doherty et al. (2001) [110], the magnitude of these changes correlated with the magnitude of the reward or punishment. Elliot et al. (2000) [111] suggest that the lateral orbitofrontal cortex is likely to be activated when a response previously associated with reward has to be suppressed. The balance of activity between medial and lateral orbitofrontal cortices facilitates the decoding and representation of reinforcers, learning and reversing associations related to reinforcers, goal-directed action by encoding predictive stimulus-outcome relationships that bias response selection, and controlling and correcting reward-related and punishment-related behavior [110–114]. It is not clear whether these functions are mediated by bilateral orbitofrontal cortices

233


Figure 16.4. Diagram of frontal-subcortical circuits. The specific elements and pathways vary, especially the motor circuit and the anterior cingulate circuit (for which the striatal and pallidal components are more complex). Adapted from Arciniegas DB, Beresford TP. Neuropsychiatry: an Introductory Approach. Cambridge: Cambridge University Press; 2001.

or whether they are fully or partially lateralized (e.g., in relation to interpreting, learning, and responding in a manner consistent with the reward or punishing features of stimuli) [110, 111, 115–118]. In either case, the functions they serve are integrated with the cognitive (i.e., executive) control functions served by the heteromodal sector as well as the motivational and attentional functions of the anterior cingulate complex [110, 114, 116–118].

Frontal-subcortical circuits Within premotor-motor, heteromodal, and paralimbic sectors, several specific subregions contribute to discrete, parallel, and reciprocally interactive frontalsubcortical circuits [77, 78, 119, 120]. These prefrontal cortical subregions are organized into “closed loop” circuits composed of discrete segments of the striatum, globus pallidus, substantia nigra, and thalamus, each of which is designed similarly (Figure 16.4). The anatomy and neurochemistry of these circuits is reviewed in detail in Chapter 5; accordingly, a brief summary of these circuits emphasizing their connections with other brain areas and the implications of those connections on executive function is offered here. Each basal ganglia-thalamocortical circuit receives corticostriatal inputs from cortical areas that are functionally related and, usually, interconnected. Information entering these circuits at the level of the prefrontal cortex and/or striatum is formatted for executive action and funneled through the subsequent

234

segments of each circuit [32, 77, 78, 119, 120]. This information is integrated progressively as passage is made through the pallidum and thalamus before projecting back to the area of prefrontal cortex in which the circuit originates. The prefrontal cortical areas receive “open-loop” inputs and reciprocally project to adjacent functionally related prefrontal cortices as well as other cortical areas whose activity they modulate, synthesize, and monitor. The striatal portions of these circuits also receive inputs from the specific prefrontal subregions defining the circuit to which they belong and also from multiple functionally related cortices outside that circuit (i.e., open-loop afferent projections). The motor circuit originates and terminates in the supplementary motor area and incorporates information from adjacent premotor association areas (arcuate premotor area, motor cortex) as well as somatosensory cortex. This circuit is involved in the executive control of voluntary movement, and its principal efferents are to motor cortex. The oculomotor circuit originates and terminates in the frontal eye fields, and incorporates information from adjacent prefrontal cortices as well as the posterior parietal cortices. The frontal eye field may be subdivided into smooth eye movement and saccadic subregions, the related subcortical elements of which facilitate executive control of these functions. The dorsolateral prefrontal circuit originates and terminates in BA9 and 10, and receives inputs from dorsolateral BA46, parietal area BA7a, as well as the dorsal parafascicular thalamus, medial pars compacta


of the substantia nigra, dorsal raphe, and central midbrain tegmentum [77, 78, 119]. Afferent and efferent connections from the prefrontal cortical origin of this circuit are also made with the orbitofrontal and cingulate cortices, heteromodal parietal cortex, auditory and visual association cortices, retrosplenial cortex, parahippocampal gyrus, and presubiculum [119]. The dorsal caudate, which is the striatal portion of this circuit, also receives afferents from parietal, temporal, and occipital cortices as well as the substantia nigra and mediodorsal thalamus. This frontal-subcortical circuit is associated with the cognitive operations described as executive functions in the clinical practice of BN&NP [78, 119]. It is integrated into the other functions of the heteromodal sector, and thereby contributes to processing information about the outside environment, the internal milieu, and the individual’s emotional and motivational state and facilitates the development of action plans that are integrated with those developed in the motor-, oculomotor-, lateral orbitofrontal-, and anterior cingulate-subcortical circuits [119]. The lateral orbitofrontal circuit originates and terminates in BA10 and 11, and receives input from BA12 and superior temporal area BA22, as well as entorhinal cortex, amygdala, rostromedial parafascicular thalamus, dorsal raphe, and central midbrain tegmentum [77, 78, 119]. The prefrontal cortical segment of this circuit also receives input from and projects to the dorsolateral prefrontal cortex, temporal pole, and amygdala [119], and the ventral caudate (its striatal element) receives afferents from the superior temporal cortices, amygdala, mediodorsal thalamus, substantia nigra, ventral tegmental area, and midbrain raphe nuclei [119]. Connections between this circuit and the dorsolateral prefrontal circuit contribute to executive function by integrating cognitive operations with social information and assessments of the reinforcing qualities of the stimuli and/or contexts in which information processing occurs. The anterior cingulate-subcortical circuit originates and terminates in BA24. It is reciprocally connected with dorsolateral prefrontal cortices and the amygdala, and receives afferents from the ventral tegmental area as well [77, 78, 119]. The nucleus acumens/ventral striatum is the first subcortical node in this circuit. In addition to receiving input from BA24, it makes afferent and efferent connections with medial orbitofrontal cortex, amygdala, perirhinal and entorhinal cortex, hippocampal subiculum, posterior

insula, the premotor and supplementary motor areas, parietal cortex (BA7), and mediodorsal nucleus of the thalamus, substantia nigra, ventral tegmental area, and dorsal raphe nucleus [99–102, 119]. Unlike the other frontal-subcortical circuits, the striatal, pallidal, and mediodorsal thalamic elements of this circuit also receive open loop afferents from paralimbic and upper brainstem areas and make efferent connections with these areas as well [119]. As noted earlier, BA24 (dorsal cognitive division of the anterior cingulate) contributes to an attentional network, sensory and response selection, monitors competition, complex motor control, novelty, error detection, working memory, and motivation, and anticipates cognitively demanding tasks [103].

Association pathways The subdivisions of the prefrontal cortex as well as the striatal elements of the frontal-subcortical circuits receive inputs from other brain areas through several association pathways and interhemispheric prefrontal cortical connections comprise the anterior portions of the corpus callosum (Figure 16.5; see also Chapter 4) [121, 122]. Afferent connections to prefrontal areas provide information regarding ongoing motor, sensory, association, limbic, subcortical, cerebellar, and other processes, and prefrontal efferents provide a means of regulating information processing in (i.e., exerting executive control over) other brain regions [121]. The superior longitudinal fasciculus (SLF) links the parietal and frontal cortices, and the occipitofrontal fasciculus (also known as the fronto-occipital fasciculus) links dorsal and medial occipitoparietal regions with a large area of the dorsolateral prefrontal cortex. In the rhesus monkey, this fasciculus has been subdivided into three divisions (SLF I, II, and III) [121]. SLF I connects the superior parietal lobule and adjacent medial parietal cortex with supplementary motor area, dorsal BA6, and BA8Ad. SLF II originates in the caudal part of the inferior parietal lobule and adjacent occipitoparietal region and projects to posterior dorsolateral prefrontal areas (dorsal BA6, 8, mid-dorsolateral BA9/46 and 46). SLF III originates in the rostral inferior parietal lobule (human supramarginal gyrus) and adjacent parietal opercular region and terminates in ventral BA6, adjacent BA44 (human pars opercularis), frontal opercular region (gustatory area), and ventral portion of BA9/46.

235


Figure 16.5. White matter tractography may be used to label brain voxels according to the white matter structure of which they form a part. (a) Image tractograms of the projection (green), association (red) and callosal (blue) fibers are mapped into the brain space, indicating their position with respect to other brain regions, and include the anterior region of corona radiata (acr), external capsule (ec), internal capsule (ic), and posterior region of corona radiata (pcr). (b) A similar procedure has been used to label various white matter tracts, including the corpus callosum (purple), superior longitudinal fasciculus (yellow), cingulum (green), uncinate fasciculus (dark red), inferior occipito-frontal fasciculus (orange), inferior longitudinal fasciculus (brown), corticobulbar tract (light blue), corticospinal tract (white), fornix and stria terminalis (light yellow). Tract positions are shown in several sagittal and axial slices. Reprinted from Lazar M. Mapping brain anatomical connectivity using white matter tractography. NMR Biomed 2010;23:821–35, with permission of John Wiley & Sons Ltd. This figure is presented in color in the color plate section.

The arcuate fasciculus originates in the caudal superior temporal gyrus, arches around the caudal portion of the Sylvian fissure, and then follows a horizontal course (parallel with the superior longitudinal fasciculus) that terminates in the lateral prefrontal cortex (BA8d). The mid-portion of the superior temporal gyrus and adjacent cortex of superior temporal sulcus give rise to fibers that run in the extreme capsule and terminate in lateral and anterior prefrontal areas (BA45, 46, 8Ad, 9, and 10). The uncinate fasciculus connects the rostral superior temporal, inferior temporal cortices, and temporal proisocortex with the lateral, medial, and posterior orbitofrontal cortices. Fibers from the parahippocampal region form a discrete bundle running lateral and ventral to the extreme capsule and claustrum; a portion of these fibers contribute to the uncinate fasciculus as it projects toward the ventral prefrontal cortices and others (originating in the caudal parahippocampal region) enter the extreme capsule and terminate in BA9, 9/46, and 46 [121]. Together, these two fiber pathways from the parahippocampal region comprise

236

the ventral limbic pathway. The dorsal limbic pathway (cingulum bundle, or cingulum in humans) originates in the rostral and caudal cingulate cortex (BA24 and 23, respectively) and retrosplenial cortex (BA30) and connects to the mid-dorsolateral prefrontal areas BA9, 9/46, and 46 [121] as well as the orbitofrontal cortex (BA11) and medial surface of the frontal lobe (BA32).

Frontocerebellar interactions Connections between the cerebellum and cerebrum are organized in discrete parallel anatomic circuits (see Chapter 3). These circuits include a two-stage feedforward corticopontine pathway, which projects from cerebral cortex through the nuclei of the basis pontis to the cerebellum, and a two-stage feedback system from the cerebellar nuclei through the thalamus to the cerebral cortex. Inputs from prefrontal, posterior parietal, superior temporal, and dorsal parastriate association areas as well as paralimbic areas (i.e., posterior parahippocampus, anterior inferior cingulate gyrus, and anterior insular cortex) project via the


corticopontine to lobules VI and VII of the cerebellum via the corticopontine pathway [123–125]. Ventral portions of the dentate nucleus convey information from these cerebellar regions to cerebral cortical association areas via the two-stage cerebellothalamocortical pathway [124, 126, 127], whereas limbic and paralimbic cortices are interconnected with the cerebellar vermis and fastigial nucleus [128]. Cerebrocerebellar connections are predominantly contralateral (i.e., right cerebral hemisphere to left cerebellum and vice versa). Through these cerebrocerebellar connections, the cerebellum contributes to the regulation of movement, cognition, and emotion. Schmahmann and colleagues (2008) [124, 129–132] suggest that the uniform histology and specificity of connections to cerebral regions permits the cerebellum to perform similar operations on sensorimotor, cognitive, affective, and behavioral information processing. More specifically, they suggest that the cerebellum acts as an oscillation dampener that maintains function in equilibrium around a homeostatic baseline, which smoothes performance and modifies it according to context. Analogous to the role of the cerebellum in the regulation of the rate, force, rhythm, and accuracy of motor function, it regulates the speed, capacity, consistency, and appropriateness of cognitive and emotional processes, including executive function.

Neurochemical modulation Glutamate and gamma-aminobutyric acid Glutamate is the principal excitatory neurotransmitter in the central nervous system, and gammaaminobutyric acid (GABA) is the principal inhibitory neurotransmitter. As such, these neurotransmitters are the fundamental currency of excitation and inhibition in the neural systems supporting executive function [78, 120]. Within the direct pathway of the frontalsubcortical circuits, glutamatergic projections from the prefrontal cortices to the striatum (caudate, putamen, ventral striatum/nucleus accumbens) and from the thalamus to the prefrontal cortices facilitate information processing at their targets. GABA-ergic projections from the striatum to the globus pallidus interna/substantia nigra pars reticulata (GPi/SNr) and from the GPi/SNr to the thalamus inhibit the function of their targets. Dopamine type 1 receptors (D1 receptors) are expressed in the direct pathway and substance P is co-localized with its GABA-ergic projections to

the pallidum. Within the indirect circuit, GABA-ergic projections from the striatum to the globus pallidus externa (GPe) and from the GPe to the subthalamic nucleus inhibit their targets, and glutamatergic projections from the subthalamic nucleus to the GPi/SNr facilitate activity of the latter structure. In the indirect pathway, dopamine type 2 receptors (D2 receptors) are expressed and enkephalin is co-localized with its GABA-ergic pallidal projections. Glutamate and GABA also modulate the activity of other modulatory neurotransmitter systems projecting to the prefrontal cortices, striatum, thalamus, and the networks into which they are incorporated [133–135]. Interactions between these systems create complex corticostriatal-thalamocortical feedback loops that regulate the level of activity within these networks and thereby guard against overstimulation [134].

Catecholamines Dopamine and norepinephrine (catecholamines) project into and modulate the networks upon which executive function is predicated [133, 136]. The prefrontal cortices receive dopaminergic inputs from the ventral tegmental area, and the striatum receives dopaminergic projections from the substantia nigra pars compacta (SNpc), the retrorubral region, and the ventral tegmental area [95, 137]. These dopaminergic cell groups also receive projections from the prefrontal cortices, thereby providing a mechanism for reciprocal control of the dopaminergic tone in these systems. Noradrenergic neurons from the locus coeruleus project to widespread areas of neocortex, limbic and paralimbic cortices, hypothalamus, cerebellum, and brainstem. Prefrontal cortical regions also project to the locus coeruleus and modulate its activity [133]. Catecholamines modulate signal-to-noise ratio quadratically (i.e., along an inverted U-shaped curve) in information processing systems [32, 133, 138– 142]. Mid-range cerebral catecholamine levels allow information processing networks to optimize processing of signal (information to which processing resources are directed) and, through active inhibition at the neural level, to minimize noise (information to which resources are not directed). When cerebral catecholamine levels are low, signal-to-noise ratio is reduced as a result of inadequate signal generation. When levels of cerebral catecholamines are high, signal-to-noise ratios are low as a result of excessive

237


noise. In other words, systems that require inhibition in order for optimally efficient information processing to take place remain active, thereby becoming sources of competition for information processing resources (i.e., “noise”). Dopamine also exhibits complex and differential effects on activity within the frontal-subcortical circuits and appears to play an important role in reward and reinforcement [133, 143, 144]. The effects of dopamine and norepinephrine on information processing systems vary with the types of receptors at which these neurotransmitters act and their locations within these systems [133]. Additionally, dopamine and norepinephrine interact with other neurotransmitter systems [135, 145, 146] and thereby also indirectly modulate the activity of frontalsubcortical circuits and the networks into which they are incorporated [133, 134].

Acetylcholine The cerebral cholinergic system is composed of eight distinct nuclear groups (designated Ch1 through Ch8) whose efferent projections remain segregated into discrete pathways to their neuroanatomic targets [95, 147–151]. As reviewed in Arciniegas (2011) [152], Ch1 (septal nucleus) and Ch2 (vertical limb of the diagonal band or Broca) project via the fornix to the hippocampus. Ch3 (horizontal limb of the diagonal band or Broca) projects via the olfactory tract to the olfactory bulb. Ch4 (nucleus basalis of Meynert) projects to the amygdala via the ventral amygdalofugal striatal terminalis; to the medial orbitofrontal, subcallosal area, cingulate and pericingulate gyri, and the retrosplenial cortices via the medial pathway (within the cingulum); to the insular and frontoparietal opercular cortices, superior temporal gyrus, and insula via the perisylvian division of the lateral pathway; to the dorsal frontoparietal network, middle and inferior temporal gyri, inferotemporal cortex, parahippocampal cortex, and possibly the amygdala via the capsular division of the lateral pathway. Ch5 (pedunculopontine nucleus) and Ch6 (laterodorsal tegmental nucleus), collectively designated Ch5–6, project to thalamus, cerebellum, globus pallidus, subthalamic nucleus, substantia nigra (pars compacta), the medullary reticular formation and spinal cord, and provide lesser contributions to the striatum (caudate and putamen). Ch7 (medial habenula) projects to the interpeduncular nucleus via the fasciculus retroflexus, and Ch8 (parabigeminal nucleus) projects to the superior colliculus

238

and, to a lesser extent, the thalamus. There are lesser connections from Ch1–4 and Ch8 to the thalamus and from Ch5–6 to the cerebral cortex. Intrinsic cholinergic interneurons in the striatum (caudate and putamen) provide the majority of the acetylcholine required for striatal function, with lesser contributions supplied by Ch4 and Ch5–6. The cerebellum also contains cholinergic neurons that are localized predominantly in the vermis, flocculus, and tonsilla, and acetylcholine appears to be a primary neurotransmitter in vestibulocerebellar pathways and a modulator of cerebrocerebellar networks. Cholinergic neurons, especially those in Ch4, also receive input from prefrontal regions, including the orbitofrontal cortices [133]. Through their effects on these anatomic targets (at multiple types of muscarinic and nicotinic receptors) as well as through their interactions with other neurotransmitter systems (especially glutamatergic, GABAergic, and dopaminergic neurons), cerebral cholinergic systems directly and indirectly influence many aspects of cognition, including arousal [153, 154], attention [155–157], working memory [153, 158], declarative memory [157, 159, 160], language [161, 162], and executive function [163–166]. The effects of acetylcholine on central nervous system functioning are understood most simply as modulating the efficiency of intraneuronal signaling through facilitation or inhibiting of neuronal responses to other neurotransmitters via generation of excitatory or inhibitory pre- and post-synaptic potentials [135]. As with catecholamines, the effect of acetylcholine on information processing networks is quadratic, with normal function at mid-range levels and dysfunction arising from either cholinergic deficits or excesses [152].

Serotonin The dorsal and medial raphe nuclei are the principal sources of serotonergic input to the cerebral hemispheres, and their afferents project widely through the cerebral hemispheres [95, 145]. As reviewed in Nieuwenhuys et al. (2008) [95], these nuclei also have relatively more focal projections, with the dorsal raphe afferents targeting the olfactory bulb, amygdala, entorhinal cortex, striatum, and lateral geniculate body and the median raphe nuclei targeting the hippocampus, basal forebrain, and septum. The cerebellum is densely innervated by the median raphe nucleus and the nucleus raphe magnus. Afferents from these nuclei also specifically target the substantia nigra,


locus coeruleus, pedunculopontine and laterodorsal tegmental nuclei (Ch5–6), resulting in an interconnected network between these modulatory neurotransmitter nuclei. The dorsal raphe nucleus receives projections from the heteromodal and paralimbic prefrontal cortices [133], and both the dorsal and medial raphe nuclei receive modulatory inputs from limbic and paralimbic cortices [133, 167]. The effects of serotonin on cerebral information processing systems are highly complex and vary with the types and locations of serotonin receptors at which this neurotransmitter acts [145]. In concert with other brainstem neurotransmitter nuclei, the serotonergic nuclei contribute to regulation of sleep/wake cycles. Serotonergic neurons modulate the function of the prefrontal cortices, striatum, cerebellum, and spinal cord. The reciprocity of connections between the interactions between the upper brainstem raphe nuclei and the paralimbic sector (including the subcortical structures incorporated into paralimbic sector circuits) suggest a more prominent role for serotonin in the modulation of activity within these systems. However, there are serotonergic inputs to the dorsolateral prefrontal cortices, in which serotonin type 1A, type 2A, and type 3A receptors (5-HT1A, 5-HT2A, and 5-HT3A, respectively) are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons. As reviewed in Puig and Gulledge (2011) [168], the role of 5-HT on the function of prefrontal cortices and the networks in which they participate remains uncertain. This reflects the complexity of the subdivisions of the prefrontal cortex and the microcircuitry within those areas, as well as sophisticated patterns of serotonin receptor subtype expression among different populations of prefrontal neurons. Based on their own studies and reviews of this literature, these authors concluded that serotonin predominantly reduces activity of pyramidal neurons via stimulation of 5-HT1A receptors, and simultaneously excites the membranes of large ensembles of these neurons through 5-HT2A. The net effect of these influences is serotonin inhibiting the activity of individual neurons but exciting the network as a whole. Fink and Gothert (2007) [145] and Bymaster et al. (2003) [146] also note that there are highly complex interactions between serotonin and the other neurotransmitter systems modulating prefrontal function. Through action at serotonin receptors located on nonserotonergic neurons (i.e., heteroreceptors), serotonin modulates cholinergic, noradrenergic, dopaminergic,

and GABA-ergic neurotransmission. Depending on the serotonin receptor type and its pre- or postsynaptic location, the modulation effected by serotonin may be facilitatory or inhibitory (i.e., promoting or decreasing release of other neurotransmitters, respectively). The complex interactions and balance between actions at these serotonin receptors modulate activity patterns within the prefrontal cortices, striatum, thalamus, the networks into which they are incorporated, as well as the ascending neurotransmitter systems that support them, and thereby influence executive function.

Executive function, frontal networks, and the dysexecutive syndrome Executive function requires the integrated actions of the frontal-subcortical circuits, open-loop connections to other neocortical areas, limbic and paralimbic structures, thalamic nuclei, pontocerebellar networks, modulatory neurochemical projections from mesencephalic and ventral forebrain structures, and the white matter connections within and between all of these areas [2, 32, 75, 77–80] (see also Chapter 5). Executive function therefore results from interactions across these networks and is not a product of the frontal lobes alone [46, 75, 81, 169]. As a consequence of the distributed anatomy of executive function, lesion to (or dysfunction of) any element within the networks supporting this cognitive domain may produce executive dysfunction. The vulnerability of executive function to disruption by a broad array of neuroanatomically and etiologically diverse conditions [2, 9–17] supports this view of the neuroanatomy of executive function (see also Chapter 5). On the basis of such observations, Mesulam (2002) [81] suggests that the concept of “frontal lobe syndrome” be replaced by “frontal network syndrome.” He suggests that the use of this term will prevent considerable clinical confusion by acknowledging that the lesion responsible for it may be located anywhere within the distributed networks supporting executive function. A similar argument suggests that the absence of a literal “central executive” (as described by Baddeley (1986) [31]) precludes the possibility of a dysexecutive syndrome [33, 57]. The preceding reviews of the phenomenology and neuroanatomy of executive function support the view that executive function is not a unitary construct [4, 22, 33, 46, 56, 57], and that there is no

239


single “central executive” or simple homunculus-like supervisory system [22, 33]. Instead, executive function is composed of a complex and multidimensional set of abilities, subsets of which are vulnerable to concurrent disruption by a single injury or disease process. Given that a syndrome (from Greek, syn “together” + dromos “course”) is defined by a constellation of cooccurring symptoms and signs whose onset is linked and whose course is coupled [170–172], any individual experiencing impairments in two or more clinically identifiable executive abilities (see Table 16.1) due to a neurological or psychiatric condition and whose impairments follow such a course can be regarded correctly as experiencing a dysexecutive syndrome. Describing the clinical presentation of patients with executive function impairments as a dysexecutive syndrome has several advantages over their description as a “frontal network syndrome.” Phenomenologic description separates the discussion of psychological function from its neuroanatomy, which continues to be misunderstood by many non-specialist clinicians. Referring to frontal networks is intended to resolve such misunderstanding by emphasizing the interaction between frontal and other regions of the brain supporting executive function. However, common clinical experience suggests that the use of “frontal” in this description tends to anchor diagnostic considerations to conditions affecting the frontal lobes and to prompt confusion (especially among patients and families) when it is suggested that frontal lesions or dysfunction may be absent among persons suffering from a “frontal network syndrome.” This problem may be avoided by applying the term dysexecutive syndrome to the clinical presentation of individuals with executive dysfunction [173, 174]. Once offered and explained, this phenomenologic description can be augmented by a discussion of the distributed neuroanatomy of executive function that includes, but does not overemphasize, the role of the frontal lobes as well as the conditions that produce executive dysfunction.

Neuropsychological assessment issues There is a tendency in the clinical neuropsychological literature to define executive function based on the behaviors (or deficits) revealed by performance on one or more “executive” tasks [5, 22] and to construct theories about cognitive domain that are anchored to a single test. As noted by Strauss and colleagues (2006) [5]

240

and Royall et al. (2002) [2], and as demonstrated by Packwood et al. (2011) [22] and Pickens et al. (2010) [175], there is no consensus on the best test with which to assess executive function, and no single neuropsychological test serves adequately as the “gold standard” for its assessment. Rabin et al. (2005) [176] surveyed the practices of clinical neuropsychologists in the USA and Canada (members of the International Neuropsychological Society, National Academy of Neuropsychology, and Division 40 of the American Psychological Association) and identified the 40 most commonly used executive functioning assessment instruments; the ten instruments used most often by these neuropsychologists are presented in Table 16.2. The abilities assessed by these instruments are many and varied, and there is relatively modest overlap between many of them. That all of these measures are regarded as tests of executive function reiterates the point that executive function is composed of a constellation of processes that may be impaired singly or in combination in any given individual. Such observations prompted Strauss et al. (2006) [5] to eschew reliance on a single assessment (i.e., Wisconsin Card Sorting Test, Stroop Test) and to incorporate multiple measures into the assessment of executive function. The use of several relatively simple tests that concurrently assess multiple aspects of executive function is recommended by Miyake et al. (2000) [42], Strauss et al. (2006) [5], and the ANPA CoR [2]. Matching the executive process of interest (Table 16.1) with instruments that evaluate those processes (Table 16.2) is essential [5]. Incorporating measures that converge on some executive abilities increases confidence in the interpretation of findings (e.g., strengths and impairments). At the same time, using measures that provide complementary assessments decreases the risk of missing clinically important executive impairments. Since executive function also depends upon nonexecutive cognitive processes (e.g., visual and/or auditory processing, working memory, language, motor function), concurrently evaluating the “basic” cognitive functions upon which performance on the executive function tests selected relies is essential. Executive function is most engaged when an individual confronts novel problems or situations for which no previously established routines exist [5, 6]. Consequently, many commonly used instruments are “one shot” tests for any particular patient [5, 177], especially those involving pattern identification,


Table 16.2. The ten most commonly used neuropsychological tests of executive function based on the survey of assessment practices of clinical neuropsychologists in the USA and Canada performed by Rabin et al. (2005) [176]. Also noted are the cognitive processes assessed by these tests, based on the reviews of Strauss et al. (2006) [5] and Packwood et al. (2011) [22].

Instrument

Processes assessed

Wisconsin Card Sorting Test

Conceptualization, set maintenance, set shifting, feedback utilization

Rey–Osterrieth Complex Figure Test

Attention, visual working memory, visual and spatial memory, visual-spatial construction, organization, strategy generation, planning

Halstead–Reitan Category Test

Abstraction, cognitive flexibility, non-verbal reasoning

Trail Making Test

Attention, processing speed, set shifting, cognitive flexibility

Controlled Oral Word Association Test

Phonemic fluency under restricted search conditions (response generation, response control, verbal efficiency), set shifting (switching)

Block Design (subtest of the Weschler Adult Intelligence Scale–Revised/Wechsler Adult Intelligence Scale-III/Wechsler Abbreviated Scale of Intelligence)

Spatial perception, visual working memory, motor skills, mental rotation (visual abstraction, cognitive flexibility, problem solving)

Weschler Adult Intelligence Scale–Revised/Wechsler Adult Intelligence Scale–III

Verbal intelligence quotient (IQ), performance IQ, full scale IQ, verbal comprehension, working memory, perceptual organization, and processing speed

Stroop Test

Working memory, processing speed, semantic activation, set maintenance, freedom from/resistance to distraction, inhibition, interference control, response control, mental control

Picture Arrangement (subtest of the Weschler Adult Intelligence Scale–Revised/Wechsler Adult Intelligence Scale–III/Wechsler Abbreviated Scale of Intelligence)

Visual perception, verbal comprehension, organization, concept formation, planning, social knowledge

Porteus Maze Test

Visual perception, visual attention, planning, strategy generation, inhibition, visuomotor integration

strategy development, and/or novel problem solving. Once patterns, strategies, or effective problem-solving approaches are learned, they may be re-applied during subsequent administration of these measures [5, 177], potentially resulting in the false appearance of cognitive improvement or masking of cognitive decline. This problem may be mitigated to some extent by using multiple assessments for each executive process of interest and/or tests for which multiple forms exist.

Bedside assessment of executive function Assessment of executive function is an essential element of a comprehensive BN&NP subspecialty evaluation [21]. This assessment is described in Chapter 23, to which readers are referred for detailed review and explanation. Briefly, the clinical interview seeks to identify problems in the performance of everyday tasks that may reflect disturbances in executive function. Although such disturbances may manifest in a broad variety of daily tasks, executive function is

strongly correlated with functional capacities, including medical and financial decision-making as well as instrumental activities of daily living (e.g., housework, technology use, transportation, shopping, meal preparation) [19]. When patients or those observing them report difficulty performing such tasks, clinical assessment for executive dysfunction should be undertaken. Among adults capable of reliable self-report, subjectively experienced executive function impairments may be assessed by the Behavior Rating Inventory of Executive Function–Adult Version (BRIEF–A) [7]. This measure also includes an informant report form for use when the rated individual is unable to complete the self-report form or is not capable of reliable self-report. It provides an assessment of working memory, self-monitoring, planning and organizing, shifting, initiation, task monitoring, inhibition, emotional control, which are organized into a Behavioral Regulation Index, Metacognition Index, and Global Executive Composite. Additionally, the BRIEF–A also produces three validity scales (Negativity, Inconsistency, and Infrequency) that facilitate its interpretation. A

241


Table 16.3. Examples of commonly used bedside assessments of executive function.

Measure

Comments

Frontal Assessment Battery

This brief assessment of executive function includes tests of similarities, lexical fluency, complex motor sequencing, sensitivity to interference, inhibitory control (go no-go), and environmental autonomy; its administration with the Mini-Mental State Examination (MMSE) and a clock drawing task creates a comprehensive brief cognitive screening examination; normative data are available to guide interpretation

Executive Interview (EXIT-25)

A useful and more comprehensive extended screening examination of executive function

Behavioral Dyscontrol Scale-2

Assesses nine areas of frontally mediated cognition; these items comprise three factors: motor programming, environmental autonomy, and fluid intelligence (the capacity to think logically and solve problems in novel situations independent of previously acquired knowledge)

The Executive Clock Drawing Task (CLOX)

A structured clock drawing task designed specifically to elicit executive impairments and to discriminate between executive and non-executive constructional failure

similar measure is the Frontal Systems Behavior Scale (FrSBe) [178], formerly known as the Frontal Lobe Personality Scale (FLoPS) [179], which is a self- and informant-based rating of executive dysfunction, apathy, and disinhibition. There are several relatively brief bedside assessments of executive function which subspecialists in BN&NP are encouraged to consider using in everyday clinical practice (Table 16.3) [180–184]. These measures provide a method of structured assessment of executive function, the results of which are quantifiable and normatively interpretable. From both a test construction and administration perspective, these are relatively brief and simple tests of executive function that concurrently assess multiple aspects of executive function. Their use in clinical practice is consistent with the aforementioned recommendations to deploy executive function assessments with these characteristics [2, 5, 42]. When coupled with the qualitative assessments of executive function and comprehensive mental status examination described in Chapter 23, these are useful tools for subspecialists in BN&NP to incorporate into the assessment of persons with neurological and psychiatric conditions at risk for executive dysfunction.

Conclusion Executive function refers to a complex set of cognitive processes that permit management and control of other, relatively basic, aspects of information processing and facilitate purposeful goal-directed behaviors. These functions are used most when attempting to solve novel problems and when no previously established routines exist, thereby providing the capacity for

242

flexible and adaptive responding to the challenges of everyday life. Executive function is not solely a product of frontal lobe activity, but instead requires the integrated actions of the frontal-subcortical circuits, openloop connections to other neocortical areas, limbic and paralimbic structures, thalamic nuclei, pontocerebellar networks, modulatory neurochemical projections from mesencephalic and ventral forebrain structures, and the white matter connections within and between all of these areas. The distributed structural and functional anatomy of executive function renders it vulnerable to disruption by many conditions affecting the brain. Deficits in executive function compromise an individual’s ability to meet the demands of everyday life in a flexible and adaptive manner, even when basic cognitive functions are relatively preserved. Assessment of executive function therefore is an essential element of the examination of persons evaluated by subspecialists in BN&NP and related disciplines in the clinical neurosciences. Advanced functional neuroimaging methods are poised to improve identification of the neural substrates of executive function at the single-patient level, although these are predominantly research tools presently. Rehabilitative interventions and pharmacotherapies for executive dysfunction are emerging areas of neurotherapeutics (see Chapter 33), and the evidence base supporting their use in clinical practice is developing rapidly. There also may be a role for the application of procedural interventions such as transcranial magnetic stimulation or transcranial direct current stimulation in the treatment of impaired executive function (see Chapter 38). Armed with an understanding of the phenomenology, neurobiology, assessment, and


treatments of executive function and dysfunction, subspecialists in BN&NP and related clinical disciplines are well positioned to improve the lives of persons experiencing executive dysfunction due to neurological and/or psychiatric conditions.

References 1. Shallice T. Fractionation of the supervisory system. In Stuss DT, Knight RT, editors. Principles of Frontal Lobe Function. Oxford: Oxford University Press; 2002, pp. 261–77. 2. Royall DR, Lauterbach EC, Cummings JL et al. Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2002;14(4):377–405. 3. Luria AR. Higher Cortical Functions in Man. New York, NY: Basic Books; 1966. 4. Lezak MD. Neuropsychological Assessment. 4th edition. Oxford: Oxford University Press; 2004. 5. Strauss E, Sherman EMS, Spreen O. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. 3rd edition. Oxford: Oxford University Press; 2006.

depression patients: a longitudinal, naturalistic study. J Affect Disord. 2012;136(3):328–39. 14. Rascovsky K, Hodges JR, Knopman D et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134(Pt 9):2456–77. 15. Reed BR, Mungas DM, Kramer JH et al. Profiles of neuropsychological impairment in autopsy-defined Alzheimer’s disease and cerebrovascular disease. Brain 2007;130(Pt 3):731–9. 16. Troster AI. Neuropsychological characteristics of dementia with Lewy bodies and Parkinson’s disease with dementia: differentiation, early detection, and implications for “mild cognitive impairment” and biomarkers. Neuropsychol Rev. 2008;18(1):103–19. 17. McDonald BC, Flashman LA, Saykin AJ. Executive dysfunction following traumatic brain injury: neural substrates and treatment strategies. NeuroRehabilitation 2002;17(4):333–44. 18. Royall DR, Chiodo LK, Polk MJ. Correlates of disability among elderly retirees with “subclinical” cognitive impairment. J Gerontol A Biol Sci Med Sci. 2000;55(9):M541–6.

6. Shallice T. From Neuropsychology to Mental Structure. Cambridge: Cambridge University Press; 1988.

19. Royall DR, Lauterbach EC, Kaufer D et al. The cognitive correlates of functional status: a review from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2007;19(3):249–65.

7. Roth RM, Isquith PK, Gioia GA. BRIEF-A: Behavior Rating Inventory of Executive Function – Adult Version. Lutz, FL: Psychological Assessment Resources; 2005.

20. Fogel BS. The significance of frontal system disorders for medical practice and health policy. J Neuropsychiatry Clin Neurosci. 1994;6(4):343–7.

8. Baron IS. Neuropsychological Evaluation of the Child. Oxford: Oxford University Press; 2004.

21. Arciniegas DB, Kaufer DI, Joint Advisory Committee on subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13.

9. Salloway SP. Diagnosis and treatment of patients with “frontal lobe” syndromes. J Neuropsychiatry Clin Neurosci. 1994;6(4):388–98. 10. Schillerstrom JE, Horton MS, Royall DR. The impact of medical illness on executive function. Psychosomatics 2005;46(6):508–16. 11. Schillerstrom JE, Horton MS, Schillerstrom TL et al. Prevalence, course, and risk factors for executive impairment in patients hospitalized on a general medicine service. Psychosomatics 2005;46(5): 411–17.

22. Packwood S, Hodgetts HM, Tremblay S. A multiperspective approach to the conceptualization of executive functions. J Clin Exp Neuropsychol. 2011;33(4):456–70. 23. Miller GA. Plans and the Structure of Behavior. New York, NY: Holt; 1960. 24. Luria AR. Higher Cortical Functions in Man. Moscow: Moscow University Press; 1962.

12. Brissos S, Dias VV, Soeiro-de-Souza MG, Balanza-Martinez V, Kapczinski F. The impact of a history of psychotic symptoms on cognitive function in euthymic bipolar patients: a comparison with schizophrenic patients and healthy controls. Rev Bras Psiquiatr. 2011;33(4):353–61.

26. Luria AR. Higher Cortical Functions in Man. 2nd edition. New York, NY: Basic Books; 1980.

13. Xu G, Lin K, Rao D et al. Neuropsychological performance in bipolar I, bipolar II and unipolar

27. Norman DA, Shallice T. Attention to action: willed and automatic control of behavior. In Davidson RJ,

25. Luria AR, Haigh B. The Working Brain: An Introduction to Neuropsychology. New York, NY: Basic Books; 1973.

243


Schwartz GE, Shapiro DE, editors. Consciousness and Self-Regulation. New York, NY: Plenum Press; 1986, pp. 1–14. 28. Broadbent DE. Perception and Communication. New York, NY: Pergamon Press; 1958. 29. Posner MI, Rothbart MK. Attention, self-regulation and consciousness. Philos Trans R Soc Lond B Biol Sci. 1998;353(1377):1915–27. 30. Posner MI, Rothbart MK. Toward a physical basis of attention and self regulation. Phys Life Rev. 2009;6(2): 103–20. 31. Baddeley AD. Working Memory. Oxford: Clarendon Press; 1986. 32. Mesulam M-M. Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system, and hemispheric specializations. In Mesulam MM, editor. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 1–120. 33. Stuss DT, Alexander MP. Is there a dysexecutive syndrome? Philos Trans R Soc Lond B Biol Sci. 2007;362(1481):901–15. 34. Barkley RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull. 1997;121(1):65–94. 35. Denckla MB. Measurement of executive function. In Lyon GR, editor. Frames of Reference for the Assessment of Learning Disabilities: New Views on Measurement Issues. Baltimore, MD: Paul H. Brookes Publishing Co.; 1994, pp. 117–42. 36. Stuss DT, Benson DF. The Frontal Lobes. New York, NY: Raven Press; 1986. 37. Torgesen JK. Issues in the assessment of executive function: an information-processing perspective. In Lyon GR, editor. Frames of Reference for the Assessment of Learning Disabilities: New Views on Measurement Issues. Baltimore, MD: Paul H. Brookes Publishing Co.; 1994, pp. 143–62. 38. Welsh MC, Pennington BF. Assessing frontal-lobe functioning in children: views from developmental psychology. Develop Neuropsychol. 1988;4(3):199–230. 39. Zelazo PD, Carter A, Reznick JS, Frye D. Early development of executive function: a problem-solving framework. Rev Gen Psychol. 1997;1(2):198–226. 40. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: DSM–IV. Washington, DC: American Psychiatric Association; 1994. 41. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision: DSM–IV–TR.

244

Washington, DC: American Psychiatric Association; 2000. 42. Miyake A, Friedman NP, Emerson MJ et al. The unity and diversity of executive functions and their contributions to complex “Frontal Lobe” tasks: a latent variable analysis. Cogn Psychol. 2000;41(1):49–100. 43. Banich MT. Executive function: the search for an integrated account. Curr Dir Psychol Sci. 2009; 18(2):89–94. 44. Chan RC, Shum D, Toulopoulou T, Chen EY. Assessment of executive functions: review of instruments and identification of critical issues. Arch Clin Neuropsychol. 2008;23(2):201–16. 45. Ochsner KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci. 2005;9(5):242–9. 46. Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001;24:167–202. 47. Spinella M. Measuring the executive regulation of emotion with self-rating scales in a nonclinical population. J Gen Psychol. 2007;134(1):101–11. 48. Young DA, Davila R, Scher H. Unawareness of illness and neuropsychological performance in chronic schizophrenia. Schizophr Res. 1993;10(2):117–24. 49. Mohamed S, Fleming S, Penn DL, Spaulding W. Insight in schizophrenia: its relationship to measures of executive functions. J Nerv Ment Dis. 1999;187(9):525–31. 50. McEvoy JP, Apperson LJ, Appelbaum PS et al. Insight in schizophrenia: its relationship to acute psychopathology. J Nerv Ment Dis. 1989;177(1): 43–7. 51. Lysaker P, Bell M. Insight and cognitive impairment in schizophrenia. Performance on repeated administrations of the Wisconsin Card Sorting Test. J Nerv Ment Dis. 1994;182(11):656–60. 52. David A, van Os J, Jones P et al. Insight and psychotic illness. Cross-sectional and longitudinal associations. Br J Psychiatry 1995;167(5):621–8. 53. Cuesta MJ, Peralta V, Caro F, de Leon J. Is poor insight in psychotic disorders associated with poor performance on the Wisconsin Card Sorting Test? Am J Psychiatry 1995;152(9):1380–2. 54. Aboulafia-Brakha T, Christe B, Martory MD, Annoni JM. Theory of mind tasks and executive functions: a systematic review of group studies in neurology. J Neuropsychol. 2011;5(Pt 1):39–55. 55. Muller U, Liebermann-Finestone DP, Carpendale JI, Hammond SI, Bibok MB. Knowing minds, controlling actions: the developmental relations between theory of mind and executive function from 2 to 4 years of age. J Exp Child Psychol. 2012;111(2):331–48.


56. Lezak MD. Neuropsychological Assessment. 3rd edition. New York, NY: Oxford University Press; 1995. 57. Stuss DT, Shallice T, Alexander MP, Picton TW. A multidisciplinary approach to anterior attentional functions. Ann N Y Acad Sci. 1995;769:191–211. 58. Ballard C, Day S, Sharp S, Wing G, Sorensen S. Neuropsychiatric symptoms in dementia: importance and treatment considerations. Int Rev Psychiatry 2008;20(4):396–404. 59. Aarsland D, Bronnick K, Ehrt U et al. Neuropsychiatric symptoms in patients with Parkinson’s disease and dementia: frequency, profile and associated care giver stress. J Neurol Neurosurg Psychiatry 2007;78(1):36–42. 60. Kao AW, Racine CA, Quitania LC et al. Cognitive and neuropsychiatric profile of the synucleinopathies: Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. Alzheimer Dis Assoc Disord. 2009;23(4):365–70. 61. Adams SJ, O’Brien TJ, Lloyd J et al. Neuropsychiatric morbidity in focal epilepsy. Br J Psychiatry 2008; 192(6):464–9. 62. Robinson RG. The Clinical Neuropsychiatry of Stroke. 2nd edition. Cambridge: Cambridge University Press; 2006. 63. Arciniegas DB, Silver JM. Pharmacotherapy of neuropsychiatric disturbances. In Zasler ND, Katz DI, Zafonte RD, editors. Brain Injury Medicine: Principles and Practice. New York, NY: Demos Medical Publishing; 2007, pp. 963–94. 64. Figved N, Klevan G, Myhr KM et al. Neuropsychiatric symptoms in patients with multiple sclerosis. Acta Psychiatr Scand. 2005;112(6):463–8. 65. Cummings JL, Mega M, Gray K et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44(12):2308–14. 66. de Medeiros K, Robert P, Gauthier S et al. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. Int Psychogeriatr. 2010;22(6):984–94. 67. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799–812.

impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56(9): 1133–42. 71. Kozora E, Filley CM. Cognitive dysfunction and white matter abnormalities in systemic lupus erythematosus. J Int Neuropsychol Soc. 2011;17: 385–92. 72. Weintraub S. Neuropsychological assessment of mental state. In Mesulam M-M, editor. Principles of Behavioral and Cognitive Neurology. Oxford: Oxford University Press; 2000, pp. 121–73. 73. Cummings JL, Mega MS. Neuropsychiatry and Behavioral Neuroscience. Oxford: Oxford University Press; 2003. 74. Faber RA. The neuropsychiatric mental status examination. Semin Neurol. 2009;29(3):185–93. 75. Alvarez JA, Emory E. Executive function and the frontal lobes: a meta-analytic review. Neuropsychol Rev. 2006;16(1):17–42. 76. Malloy PF, Richardson ED. Assessment of frontal lobe functions. J Neuropsychiatry Clin Neurosci. 1994;6(4): 399–410. 77. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–81. 78. Mega MS, Cummings JL. Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci. 1994;6(4):358–70. 79. Schmahmann JD, Pandya DN, Wang R et al. Association fibre pathways of the brain: parallel observations from diffusion spectrum imaging and autoradiography. Brain 2007;130(Pt 3):630–53. 80. Koziol LF, Budding DE, Chidekel D. From movement to thought: executive function, embodied cognition, and the cerebellum. Cerebellum 2012;11(2): 505–25. 81. Mesulam M-M. The human frontal lobes: transcending the default mode through contingent encoding. In Stuss DT, Knight RT, editors. Principles of Frontal Lobe Function. Oxford: Oxford University Press; 2002, pp. 8–30.

68. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76.

82. Gratiolet P-L. Observations sur le poids et la forme du cerveau, lués a` la Société d’anthropologie, dans la séance du 18 avril 1861. Paris: Typographie Hennuyer; 1861.

69. Derogatis LR. SCL-90-R Symptom Checklist-90-R: Administration, Scoring, and Procedures Manual. 3rd edition. Minneapolis, MN: NCS Pearson; 1994.

83. Jackson JH. The Croonian Lectures on evolution and dissolution of the nervous system. Br Med J. 1884;1(1214):660–3.

70. Petersen RC, Stevens JC, Ganguli M et al. Practice parameter: early detection of dementia: mild cognitive

84. Bianchi L. The functions of the frontal lobes. Brain 1895;18(4):497–522.

245


85. Bianchi L. La meccanica del cervello e la funzione dei lobi frontali. Torino: Fratelli Bocca; 1920. 86. Bekhterev VM. Fundamentals of Brain Function. St. Petersburg, Russia: Brokhauz i Efron; 1907. 87. Pavlov IP. Complete Collected Works. Moscow: Izd-vo Akademii Nauk SSSR; 1949. 88. Brodmann K. Physiologie des gehirns. In Von Bruns O, editor. Neue Deutsche Chirurgie. Stuttgart: Enke; 1914, pp. 85–426. 89. Brodmann K. Vergleichende Lokalisationslehre der Großhirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth; 1909. 90. Mesulam MM. Principles of Behavioral Neurology. Philadelphia, PA: F.A. Davis; 1985. 91. Petrides M, Pandya DN. Comparative architectonic analysis of the human and macaque frontal cortex. In Boller F, Grafman J, editors. Handbook of Neuropsychology. Amsterdam: Elsevier Health Sciences; 1994, pp. 17–58. 92. Mesulam MM. From sensation to cognition. Brain 1998;121(Pt 6):1013–52. 93. Ramnani N, Owen AM. Anterior prefrontal cortex: insights into function from anatomy and neuroimaging. Nat Rev Neurosci. 2004;5(3):184–94. 94. Ongur D, Ferry AT, Price JL. Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol. 2003;460(3):425–49. 95. Nieuwenhuys R, Voogd J, Huijzen Cv. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008. 96. Petrides M. Lateral prefrontal cortex: architectonic and functional organization. Philos Trans R Soc Lond B Biol Sci. 2005;360(1456):781–95. 97. Christoff K, Gabrieli JDE. The frontopolar cortex and human cognition: evidence for a rostrocaudal hierarchical organization within the human prefrontal cortex. Psychobiology 2000;28(2):168–86. 98. Mega MS, Cummings JL, Salloway S, Malloy P. The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci. 1997;9(3):315–30. 99. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118(Pt 1):279–306. 100. Barbas H, Pandya DN. Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey. J Comp Neurol. 1989;286(3):353–75. 101. Morecraft RJ, Van Hoesen GW. Frontal granular cortex input to the cingulate (M3), supplementary (M2) and primary (M1) motor cortices in the rhesus monkey. J Comp Neurol. 1993;337(4):669–89.

246

102. Morecraft RJ, Geula C, Mesulam MM. Architecture of connectivity within a cingulo-fronto-parietal neurocognitive network for directed attention. Arch Neurol. 1993;50(3):279–84. 103. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000;4(6):215–22. 104. Milham MP, Banich MT. Anterior cingulate cortex: an fMRI analysis of conflict specificity and functional differentiation. Hum Brain Mapp. 2005;25(3):328–35. 105. Mayberg HS, Liotti M, Brannan SK et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999;156(5):675–82. 106. Cavada C, Company T, Tejedor J, Cruz-Rizzolo RJ, Reinoso-Suarez F. The anatomical connections of the macaque monkey orbitofrontal cortex. A review. Cereb Cortex 2000;10(3):220–42. 107. Carmichael ST, Price JL. Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys. J Comp Neurol. 1995;363(4):615–41. 108. Rolls ET. The orbitofrontal cortex and reward. Cereb Cortex 2000;10(3):284–94. 109. Rolls ET, Critchley HD, Mason R, Wakeman EA. Orbitofrontal cortex neurons: role in olfactory and visual association learning. J Neurophysiol. 1996;75(5):1970–81. 110. O’Doherty J, Kringelbach ML, Rolls ET, Hornak J, Andrews C. Abstract reward and punishment representations in the human orbitofrontal cortex. Nat Neurosci. 2001;4(1):95–102. 111. Elliott R, Dolan RJ, Frith CD. Dissociable functions in the medial and lateral orbitofrontal cortex: evidence from human neuroimaging studies. Cereb Cortex 2000;10(3):308–17. 112. Ostlund SB, Balleine BW. The contribution of orbitofrontal cortex to action selection. Ann N Y Acad Sci. 2007;1121:174–92. 113. Furuyashiki T, Gallagher M. Neural encoding in the orbitofrontal cortex related to goal-directed behavior. Ann N Y Acad Sci. 2007;1121:193–215. 114. Wallis JD. Neuronal mechanisms in prefrontal cortex underlying adaptive choice behavior. Ann N Y Acad Sci. 2007;1121:447–60. 115. Davidson RJ. Anterior cerebral asymmetry and the nature of emotion. Brain Cogn. 1992;20(1):125–51. 116. Akitsuki Y, Sugiura M, Watanabe J et al. Context-dependent cortical activation in response to financial reward and penalty: an event-related fMRI study. Neuroimage 2003;19(4):1674–85. 117. Remijnse PL, Nielen MM, Uylings HB, Veltman DJ. Neural correlates of a reversal learning task with an


affectively neutral baseline: an event-related fMRI study. Neuroimage 2005;26(2):609–18. 118. Hornak J, O’Doherty J, Bramham J et al. Reward-related reversal learning after surgical excisions in orbito-frontal or dorsolateral prefrontal cortex in humans. J Cogn Neurosci. 2004;16(3):463–78. 119. Cummings JL. Anatomic and behavioral aspects of frontal-subcortical circuits. Ann N Y Acad Sci. 1995;769:1–13. 120. Lichter DG, Cummings JL. Frontal-subcortical Circuits in Psychiatric and Neurological Disorders. New York, NY: Guilford Press; 2001. 121. Petrides M, Pandya DN. Association pathways of the prefrontal cortex and functional observations. In Stuss DT, Knight RT, editors. Principles of Frontal Lobe Function. Oxford: Oxford University Press; 2002, pp. 31–50. 122. Lazar M. Mapping brain anatomical connectivity using white matter tractography. NMR Biomed. 2010;23(7):821–35. 123. Schmahmann JD, Pandya DN. The cerebrocerebellar system. Int Rev Neurobiol. 1997;41:31–60. 124. Schmahmann JD. From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Hum Brain Mapp. 1996;4(3): 174–98.

133. Arnsten AFT, Robbins TW. Neurochemical modulation of prefrontal cortical function in humans and animals. In Stuss DT, Knight RT, editors. Principles of Frontal Lobe Function. Oxford: Oxford University Press; 2002, pp. 51–84. 134. Chow TW, Cummings JL. Frontal-subcortical circuits. In Miller BL, Cummings JL, editors. The Human Frontal Lobes: Functions and Disorders. 2nd edition. New York, NY: Guilford Press; 2007, pp. 25–43. 135. Di Chiara G, Morelli M. Dopamine-acetylcholine-glutamate interactions in the striatum. A working hypothesis. Adv Neurol. 1993;60:102–6. 136. Arnsten AF. Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs 2009;23(Suppl. 1):33–41. 137. Simon H, Scatton B, Moal ML. Dopaminergic A10 neurones are involved in cognitive functions. Nature 1980;286(5769):150–1. 138. Kroener S, Chandler LJ, Phillips PE, Seamans JK. Dopamine modulates persistent synaptic activity and enhances the signal-to-noise ratio in the prefrontal cortex. PLoS One 2009;4(8):e6507. 139. O’Donnell P. Dopamine gating of forebrain neural ensembles. Eur J Neurosci. 2003;17(3):429–35.

125. Schmahmann JD, Pandya DN. Anatomic organization of the basilar pontine projections from prefrontal cortices in rhesus monkey. J Neurosci. 1997;17(1): 438–58.

140. Gu Q. Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neuroscience 2002;111(4):815–35.

126. Kelly RM, Strick PL. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci. 2003;23(23):8432–44.

141. Kischka U, Kammer T, Maier S et al. Dopaminergic modulation of semantic network activation. Neuropsychologia 1996;34(11):1107–13.

127. Leiner HC, Leiner AL, Dow RS. Does the cerebellum contribute to mental skills? Behav Neurosci. 1986;100(4):443–54.

142. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 2007;10(3):376–84.

128. Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci. 2004;16(3):367–78.

143. Pine A, Shiner T, Seymour B, Dolan RJ. Dopamine, time, and impulsivity in humans. J Neurosci. 2010; 30(26):8888–96.

129. Schmahmann JD, Pandya DN. Disconnection syndromes of basal ganglia, thalamus, and cerebrocerebellar systems. Cortex 2008;44(8):1037–66.

144. St Onge JR, Floresco SB. Dopaminergic modulation of risk-based decision making. Neuropsychopharmacology 2009;34(3):681–97.

130. Schmahmann JD. An emerging concept. The cerebellar contribution to higher function. Arch Neurol. 1991;48(11):1178–87.

145. Fink KB, Gothert M. 5-HT receptor regulation of neurotransmitter release. Pharmacol Rev. 2007;59(4):360–417.

131. Schmahmann JD. Dysmetria of thought: clinical consequences of cerebellar dysfunction on cognition and affect. Trends Cogn Sci. 1998;2(9):362–71.

146. Bymaster FP, Felder CC, Tzavara E et al. Muscarinic mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 2003;27(7):1125–43.

132. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain 1998;121(Pt 4):561–79.

147. Selden NR, Gitelman DR, Salamon-Murayama N, Parrish TB, Mesulam M-M. Trajectories of cholinergic

247


pathways within the cerebral hemispheres of the human brain. Brain 1998;121(Pt 12):2249–57. 148. Jaarsma D, Ruigrok TJ, Caffe R et al. Cholinergic innervation and receptors in the cerebellum. Prog Brain Res. 1997;114:67–96. 149. Mesulam M-M. Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus of the human brain. In Bloom FE, Kupfer DJ, editors. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1994, pp. 135–46. 150. de Lacalle S, Hersh LB, Saper CB. Cholinergic innervation of the human cerebellum. J Comp Neurol. 1993;328(3):364–76. 151. Herkenham M, Nauta WJ. Efferent connections of the habenular nuclei in the rat. J Comp Neurol. 1979; 187(1):19–47. 152. Arciniegas DB. Cholinergic dysfunction and cognitive impairment after traumatic brain injury. Part 1: The structure and function of cerebral cholinergic systems. J Head Trauma Rehabil. 2011;26(1):98–101. 153. Everitt BJ, Robbins TW. Central cholinergic systems and cognition. Annu Rev Psychol. 1997;48:649–84. 154. Mesulam MM. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000. 155. Arciniegas D, Adler L, Topkoff J et al. Attention and memory dysfunction after traumatic brain injury: cholinergic mechanisms, sensory gating, and a hypothesis for further investigation. Brain Inj. 1999;13(1):1–13.

162. Klein RB, Albert ML. Can drug therapies improve language functions of individuals with aphasia? A review of the evidence. Semin Speech Lang. 2004; 25(2):193–204. 163. Thienel R, Kellermann T, Schall U et al. Muscarinic antagonist effects on executive control of attention. Int J Neuropsychopharmacol. 2009;12(10):1307–17. 164. Robbins TW, Roberts AC. Differential regulation of fronto-executive function by the monoamines and acetylcholine. Cereb Cortex 2007;17(Suppl. 1): i151–60. 165. Livingstone PD, Srinivasan J, Kew JN et al. Alpha7 and non-alpha7 nicotinic acetylcholine receptors modulate dopamine release in vitro and in vivo in the rat prefrontal cortex. Eur J Neurosci. 2009;29(3): 539–50. 166. Livingstone PD, Wonnacott S. Nicotinic acetylcholine receptors and the ascending dopamine pathways. Biochem Pharmacol. 2009;78(7):744–55. 167. Mesulam M-M. Attentional networks, confusional states, and neglect syndromes. In Mesulam MM, editor. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 174–256. 168. Puig MV, Gulledge AT. Serotonin and prefrontal cortex function: neurons, networks, and circuits. Mol Neurobiol. 2011;44(3):449–64. 169. Stuss DT, Knight RT. Principles of Frontal Lobe Function. Oxford: Oxford University Press; 2002. 170. Fundukian LJ. The Gale Encyclopedia of Medicine. 4th edition. Detroit: Gale; 2011.

156. Freo U, Pizzolato G, Dam M, Ori C, Battistin L. A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials. J Neural Transm. 2002;109(5–6):857–70.

172. Miller BF. Encyclopedia & Dictionary of Medicine, Nursing, and Allied Health. 7th edition. Philadelphia, PA: Saunders; 2003.

157. Baxter MG, Chiba AA. Cognitive functions of the basal forebrain. Curr Opin Neurobiol. 1999;9(2): 178–83.

173. Baddeley A, Wilson B. Frontal amnesia and the dysexecutive syndrome. Brain Cogn. 1988;7(2): 212–30.

158. Ellis KA, Nathan PJ. The pharmacology of human working memory. Int J Neuropsychopharmacol. 2001;4(3):299–313.

174. Baddeley A. The central executive: a concept and some misconceptions. J Int Neuropsychol Soc. 1998;4(5): 523–6.

159. Hasselmo ME. The role of acetylcholine in learning and memory. Curr Opin Neurobiol. 2006;16(6): 710–15.

175. Pickens S, Ostwald SK, Murphy-Pace K, Bergstrom N. Systematic review of current executive function measures in adults with and without cognitive impairments. Int J Evidence Based Healthcare 2010; 8(3):110–25.

160. Aigner TG. Pharmacology of memory: cholinergic-glutamatergic interactions. Curr Opin Neurobiol. 1995;5(2):155–60. 161. Hutsler JJ, Gazzaniga MS. Acetylcholinesterase staining in human auditory and language cortices: regional variation of structural features. Cereb Cortex 1996;6(2):260–70.

248

171. Mosby Inc. Mosby’s Medical Dictionary. 8th edition. St. Louis, MO: Mosby; 2009.

176. Rabin LA, Barr WB, Burton LA. Assessment practices of clinical neuropsychologists in the United States and Canada: a survey of INS, NAN, and APA Division 40 members. Arch Clin Neuropsychol. 2005;20(1): 33–65.


177. Lowe C, Rabbitt P. Test/re-test reliability of the CANTAB and ISPOCD neuropsychological batteries: theoretical and practical issues. Cambridge Neuropsychological Test Automated Battery. International Study of Post-Operative Cognitive Dysfunction. Neuropsychologia 1998;36(9):915–23. 178. Stout JC, Ready RE, Grace J, Malloy PF, Paulsen JS. Factor analysis of the frontal systems behavior scale (FrSBe). Assessment 2003;10(1):79–85.

181. Royall DR, Mahurin RK, Gray KF. Bedside assessment of executive cognitive impairment: the executive interview. J Am Geriatr Soc. 1992;40(12): 1221–6. 182. Grigsby J, Kaye K, Robbins LJ. Reliabilities, norms and factor structure of the Behavioral Dyscontrol Scale. Percept Mot Skills 1992;74(3 Pt 1): 883–92.

179. Grace J, Stout JC, Malloy PF. Assessing frontal lobe behavioral syndromes with the frontal lobe personality scale. Assessment 1999;6(3):269–84.

183. Kaye K, Grigsby J, Robbins LJ, Korzun B. Prediction of independent functioning and behavior problems in geriatric patients. J Am Geriatr Soc. 1990;38(12): 1304–10.

180. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment Battery at bedside. Neurology 2000;55(11):1621–6.

184. Royall DR, Cordes JA, Polk M. CLOX: an executive clock drawing task. J Neurol Neurosurg Psychiatry 1998;64(5):588–94.

249

Section I


Chapter

Comportment

17

Michael Henry Rosenbloom, Oliver Freudenreich, and Bruce H. Price

In neurology, there are many different types of “blind spots.” The simplest example is the physiological visual blind spot formed by ganglion cell axons exiting the retina. A more extreme case is an occipital lobe lesion in which the blind spot encapsulates an entire contralateral visual field. The blind spots of neurology are by no means confined to the visual system. For example, the hemineglect syndrome is a condition in which a right parietal lobe lesion results in asomatognosia and anosognosia. Each of these clinical situations involves a perceptual modality that renders the patient oblivious to a particular sensory experience. But consider the following scenario: a brain lesion that results in an inability to perceive social cues, uncontrolled profanity, and impulsivity, ultimately letting slip “the animal propensities” normally suppressed by an intact cerebral cortex – in other words, a brain lesion that changes one’s personality. Such a presentation represents a neurological syndrome affecting the most complex mental processes such as insight, judgment, self-awareness, empathy, and social adaptation. The most famous case resulting in compromise of these complex mental processes is that of Phineas Gage, a 25-year-old construction foreman employed by Rutland and Burlington Railroad. In September 1848, chance and human error led to the occurrence of an unfortunate but instructive scenario. Gage was in charge of delivering blasts to level the uneven rocky terrain in order to facilitate laying new rail tracks. He would drill holes into the stone, fill the space with explosive powder, cover the powder with sand, and then use a tamping iron to prepare for the blast. One day, he forgot to sandwich the sand between the tamping iron and the explosive powder. The result was the

propulsion of a tamping iron, three feet seven inches long, through Phineas’s left cheekbone, into the frontal lobes and through his skull, eventually landing approximately 25–30 yards behind him. Despite the obvious trauma to the skull and underlying cortex, Gage still managed to talk and even walk away from the accident with the assistance of his fellow workers. Dr. John Harlow, Gage’s personal physician, made the following observations [1]: “[He is] fitful, irreverent, indulging at times in the grossest profanity which was not previously his custom, manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operation, which are no sooner arranged than abandoned . . . A child in his intellectual capacity and manifestations, he has the animal passions of a strong man.”

Gage’s subsequent medical recovery and preservation of intellectual functions belied a profound disintegration of personality in which “Gage was no longer Gage” [1]. As a result of these personality changes, Gage became unreliable on the job, and his employers eventually dismissed their once “most efficient and capable man” [1]. Subsequently, Gage was unable to maintain any consistent employment, and toured with circuses including Barnum and Bailey for a period of time until his death from status epilepticus. As a consequence of his accident, Phineas Gage had acquired a “blind spot” for behavior and social interaction. His ability for insight, judgment, self-awareness, empathy, and social adaptation was compromised, forever obliterated by a turbo-charged projectile that destroyed much of his prefrontal cortex. The main conclusion derived from Gage’s case was that frontal lobe damage leads to dramatic alterations of strategic


250

Chapter 17: Comportment

thinking, personality, emotional integration, and conduct while leaving language, memory, and sensorymotor functions intact [2]. Dr. Harlow, Gage’s physician, eloquently depicted the functional consequences of his patient’s lesion. A term that encapsulates these compromised functions is comportment.

Definition of comportment According to the Oxford English Dictionary, the word “comportment” first was used in the English language in 1599, and is defined presently as “social bearing, carriage, demeanor, deportment, behavior, outward conduct, and course of action” [3]. A more neurologically based definition of comportment is the complex mental processes that include insight, judgment, self-awareness, and social adaptation [2]. At the same time, comportment does not include cognitive functions such as memory, language, planning, set-shifting, and attention. Comportment can be better understood through analysis of its individual components: insight, judgment, self-awareness, social adaptation, and empathy.

Insight Insight allows for an awareness of one’s social behavior as well as the severity of one’s disease. Patients with prefrontal lobe pathology have a profound dissociation between knowing how to behave in a particular situation and behaving in a manner that comports with that knowledge. In the clinical setting, patients with schizophrenia and frontotemporal dementia (FTD) frequently lack insight into the fact that they suffer from a disease. The most extreme case of denial of disease or anosognosia is the right inferior parietal lobe syndrome associated with a left hemineglect.

Judgment Comportment also includes judgment, which is related to insight. Judgment involves making appropriate decisions under certain circumstances. Poor judgment is commonly seen in patients with prefrontal lesions who act in an inappropriately friendly manner to strangers or make inappropriate remarks. Illustrative cases include a 63-year-old woman who developed intimate relations with strangers after suffering prefrontal injury from an operation for an olfactory groove meningioma [2]. Furthermore, the ability to understand a complex situation, to have

empathy, and to catch the punch line of a joke is dependent on judgment [2].

Self-awareness Perhaps the most complex constituent of comportment is self-awareness. This component enables an individual to distinguish him- or herself from the environment, and allows for personal autonomy. Commonly, patients with frontal lobe damage develop imitation and/or utilization behaviors. These phenomena result from a loss of this ability to separate the self from the environment. In an experiment involving two patients with left inferior prefrontal lesions after tumor resections, Lhermitte found that the individuals exhibited a tendency to imitate the examiner’s gestures, and their behaviors were heavily influenced by external stimuli in a non-clinical environment [4]. One subject even went so far as to give the examiner an injection after a syringe was placed near her. The mechanism behind this utilization behavior is thought to result from a loss of personal autonomy, creating what is known as the environmental dependency syndrome. Intact prefrontal regions function to prevent such enslavement to the surrounding environment.

Social adaptation Social adaptation refers to social learning from both positive and negative experiences. Social learning is dependent on the ability to interpret and respond to social cues. Individuals must be able to weigh decisions that may result in reward versus punishment. Furthermore, social adaptation is dependent on counterfactual thinking, in which an individual will compare the actual outcome from an action with a hypothetical outcome if the alternative decision was chosen. For example, the guest who makes a blunt observation about the host’s improperly fitting dress may elicit social awkwardness from other individuals, and this negative result will presumably deter any further mistakes by the guest. In normal subjects, the feeling of responsibility for a negative result leads to feelings of regret, an important factor in social adjustment. The ability to adapt socially depends on recognizing mental states based on social cues (i.e., facial expression, voice pitch, and body gestures). This ability to interpret the mental states of others in order to

251


predict and explain behavior is described in the cognitive neuroscience literature as theory of mind [5]. Failure to perceive or infer accurately what others feel may lead to the expression of inappropriate behavior as well as a failure to modify one’s own behavior based on social cues [6]. Neurodevelopmental disorders such as autism, and traumatic brain injury to frontal regions are associated with impaired ability to recognize the mental states of others [5].

Empathy Empathy refers to the ability to recognize mental states of others, and is critical for social adaptation. Social psychologists describe empathy as consisting of a cognitive part responsible for the intellectual/imaginative apprehension of another’s mental state, and an affective part responsible for an emotional response to others’ emotions [7]. Thus, empathy refers to the ability to understand and share the feelings of others. Empathy derives from three main cognitive steps [8]. The first step involves the sharing of another’s emotion. The second requires recognition that an internally represented emotion is located outside of oneself. The final step depends on the intentional suppression of one’s own viewpoint to accurately infer the other’s perspective [8]. Loss of empathy is an early symptom of FTD, a focal neurodegenerative disorder involving the frontal and temporal lobes [8]. Many functional neuroimaging studies have been performed to establish a functional localization of empathy. One network involves the amygdala, cingulate, and orbitofrontal cortices involved in perception and emotion regulation [5]. Another network involves the dorsolateral and ventromedial prefrontal regions engaged in holding and manipulating this information [5]. Comportment therefore is very much a function of the gestalt of insight, judgment, self-awareness, social adaptation, and empathy. As human beings we have the capacity for comportment, but we are also prone to the occasional situation where our decisions lack judgment and insight. The band Main Ingredient captures this concept in the lyrics from their 1972 hit single, “Everybody plays the fool, sometime/There’s no exception to the rule.” Whether it is the basic faux pas at the cocktail party or the romantic relationship where a person exhibits less than the desired empathy and sensitivity, there is a wide margin of normal error regarding the functions of comportment. However, the factor

252

that distinguishes a normal individual from a patient with a prefrontal lesion is the ability to adapt and learn from mistakes. Accordingly, the Phineas Gages of the world will always be prone to repeating the same errors despite negative experiences.

Functional neuroanatomy of comportment The case of Phineas Gage has served as the guiding compass towards our understanding of the prefrontal cortex as a region critical for comportment. Modern neuroimaging using the skull of Gage has shown bihemispheric prefrontal lesions involving the orbitofrontal cortex, the medial frontal cortex, and the anterior cingulate gyrus (Figure 17.1) [9]. The prefrontal cortex can be subdivided both anatomically and functionally. Anatomically, the three major anatomical divisions include: (1) orbitofrontal cortex, (2) superior medial (anterior cingulate) cortex, and (3) dorsolateral cortex [10]. Functionally, the prefrontal cortex consists of two axes, one for working memory, executive function, and attention, and the other for comportment [2]. The dorsolateral prefrontal cortex is the anatomical region responsible for the first axis, whereas the medial frontal and orbitofrontal cortices are mainly involved in comportment, influencing both affect and behavior (Figure 17.2) [2]. The orbitofrontal and medial frontal cortices have multiple connections by which they influence comportment, and each serves as the origin for a frontalsubcortical circuit. Each of these pathways has subcortical projections that project to the thalamus via the basal ganglia by direct and indirect pathways [11]. The direct pathway has two consecutive inhibitory GABAergic connections that cause disinhibition of the thalamus, whereas the indirect pathway has an excitatory glutamatergic pathway that has an overall inhibitory affect on the thalamus [12]. Eventually, the thalamus provides a feedback loop terminating in the cortical region from which the circuit originated. Furthermore, each circuit has both efferent and afferent connections with other cortical regions. For instance, the orbitofrontal cortex sends projections to and receives connections from the dorsolateral prefrontal region [12]. Cortico-cortical connections communicate by glutamatergic pathways. The orbitofrontal and medial frontal cortices exhibit extensive limbic connectivity [13]. This chapter will focus on these two frontal circuits.


Figure 17.1. Trajectory of the tamping rod used by Phineas Gage through his skull and brain. Reproduced from Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. The return of Phineas Gage: clues about the brain from the skull of a famous patient. Science. 1994;264(5162):1102–5 with permission from the American Association for the Advancement of Science.

Figure 17.2. General characteristics of prefrontal circuits. Image courtesy of Robert Baden.

Orbitofrontal circuit The orbitofrontal circuit (OFC) consists of four main components: (1) orbitofrontal cortex; (2) ventral caudate; (3) medial globus pallidus; and (4) ventral anterior and medial dorsal thalamus (Figure 17.3). The orbitofrontal circuit begins with projections from the cortex to the subcortical region of the ventral caudate [12]. Information is eventually sent

to the ventral anterior and medial dorsal thalamus via the medial globus pallidus [12]. Eventually, the information is relayed back to the orbitofrontal cortex [12]. Each of the four components of the OFC receives afferents from the amygdala. Furthermore, the orbitofrontal cortex sends inputs to the preoptic region of the lateral hypothalamus, which is critical for the hormonal modulation of emotions [6].

253


Figure 17.3. Diagram of the orbitofrontal circuit.

The circuit’s main function is the pairing of thoughts, memories, and experiences with corresponding visceral and emotional states [2]. The OFC is uniquely suited to evaluate the costs and benefits of specific behavioral responses to the environment, particularly in situations where those reinforcers must be inferred from minimal or complex input [11]. Thus, this circuit is heavily involved in the process of decision-making, weighing actions that may result in reward versus those that may result in punishment. In addition, the OFC represents both concrete primary, unlearned reinforcers, such as touch and taste, and more abstract secondary, learned reinforcers emanating from visual, auditory, olfactory, and multimodal sources. The medial orbitofrontal cortex is involved in monitoring and decoding reward whereas the lateral orbitofrontal cortex evaluates punishment, motivating behavioral change [11]. There is also an anteriorposterior gradient in which the reward value for more concrete, primary reinforcing factors such as touch and taste are encoded in the posterior OFC while the value of more complex secondary reinforcing factors such as money are encoded in the anterior OFC [8]. Since the orbitofrontal circuit includes both cortical and subcortical regions, any disruption of the pathway at the level of the orbitofrontal cortex, the

254

basal ganglia, or the thalamus may result in comportmental dysfunction. Furthermore, most disease processes are not purely confined to the orbitofrontal regions, and thus there is no such thing as a pure orbitofrontal syndrome. The orbitofrontal region is prone to injury from closed head trauma, anterior communicating aneurysm rupture, and subfrontal meningioma [12]. Degenerative processes such as FTD may also involve the orbitofrontal cortices as well as other regions of the prefrontal cortex. Occasionally Creutzfeldt–Jakob disease and herpes encephalitis can affect the orbitofrontal cortices [12]. Neuropsychiatric disorders of the orbitofrontal regions including obsessive-compulsive disorder are associated with increased metabolism of the orbitofrontal cortex [12]. Disease processes involving the subcortical projections of the OFC include Huntington’s disease, neuroacanthocytosis, post-encephalic Parkinson’s disease, and thalamic infarcts. In general, patients with orbitofrontal lesions are socially disabled, and manifest interpersonal disinhibition, impulsive decision-making, lack of consideration, and impaired judgment. The ability to infer rewards and punishment from subtle environmental cues is critical for emotion recognition and social adaptation. Patients with OFC lesions show deficits in both the production and recognition of emotional expression from the face, voice, or gestures [6]. Beer and colleagues [14] found that five patients with focal bilateral OFC damage were significantly worse than normal controls at identifying self-conscious emotions (i.e., embarrassment, shame), but not other emotions (anger, disgust, fear, happiness, sadness, contempt, surprise, or amusement) [14]. Blair and Cipolotti [15] found that a patient suffering from a unilateral right orbitofrontal lesion was not only impaired in recognizing angry and disgusted facial expressions, but also had a lower autonomic response to these expressions than did controls [15]. Patients with bilateral orbitofrontal lesions have been found to have mindreading and theory of mind deficits, whereas patients with unilateral damage of the left dorsolateral prefrontal cortex performed normally on these tasks [5]. The inability to weigh actions that result in reward versus those that result in punishment also relates to the ability to feel regret. Regret is a cognitively mediated emotion triggered by our ability to reason counterfactually or compare what is with what might have been [16]. In a study comparing OFC patients with normal controls in the performance of a simple


Figure 17.4. Diagram of the medial frontal circuit.

gambling task, Camille and colleagues found that patients with orbitofrontal lesions were neither able to anticipate the negative consequences of their choices nor experience regret [16]. These patients did not modify their gambling based on feedback, and continued to make the same gambling errors in the experiment, ending up with greater net losses compared with controls [16]. Thus patients with orbitofrontal lesions are unable to learn from mistakes. The feeling of regret reinforces the decisional learning process, and without this capacity, individuals fail to make the necessary practical adjustments. In summary, patients with OFC lesions develop a range of comportmental deficits. A triad of these deficits has been described as altered emotional experience with blunting and lability, deficient decisionmaking, and impaired goal-directed behavior with general disorganization [11].

Medial frontal circuit The medial frontal circuit begins in the cortex of the anterior cingulate region and includes the nucleus accumbens, globus pallidus, substantia nigra, and the medial dorsal nucleus of the thalamus (Figure 17.4) [12]. As in the OFC, the medial dorsal nucleus of the thalamus provides feedback to the circuit’s origin from

the frontal cortex. Furthermore, the anterior cingulate cortex has both efferent and afferent connections to the dorsolateral prefrontal cortex and the amygdala [12]. The cingulate cortex may be a critical area in directing vigilance toward events of emotional or motivational significance [6]. Lesions of the medial frontal cortex result in an amotivational state consisting of motor, cognitive, affective, emotional, and motivational apathy [11]. The medial prefrontal cortex also processes the affective, evaluative, and attentional aspects of pain perception [17]. Infarction in the territory of the anterior cerebral artery is among the most common causes of medial frontal injury [12]. In addition, gliomas, multiple sclerosis, encephalitides, and FTD can also impair function of the medial frontal cortex and its connections [12]. In addition to motivation and pain perception, the medial prefrontal cortex appears to play a critical role in theory of mind. A review of recent functional neuroimaging studies on the localization theory of mind concluded that the medial prefrontal cortex was activated in almost 90% of these paradigms [18]. Clinically, these findings are of little surprise, as FTD patients with degeneration of the medial prefrontal cortex have been found to exhibit a selective drop in empathetic concern as rated by spouses and long-term caregivers [19]. Functional neuroimaging studies also suggest that the cingulate cortex is part of a neural circuit responsible for the generation of emotions related to empathy. Studies have mainly focused on how the response in the cingulate cortex in a subject undergoing noxious stimuli is similar to that elicited when others undergo the same painful stimuli. In one study, participants received painful stimuli in one set of trials, and, in a second set, received a signal that their partner who was present in the same room would receive the same noxious stimuli [20]. The anterior medial cingulate cortex as well as the anterior insula and cerebellum were activated in both conditions [20]. Another investigation revealed increased activity in the anterior cingulate cortex in subjects during the application of painful pinprick stimuli as well as when these subjects observed others undergo the same stimulation [21]. Analogous functional neuroimaging studies have been performed while subjects viewed pictures of people suffering and imagined themselves in the same position. In one recent study, participants were shown pictures of people with their hands or feet in painful situations and asked to imagine themselves or another

255


individual in the same situation [22]. Functional magnetic resonance imaging (fMRI) revealed increased activation in the anterior medial cingulate cortex, the parietal operculum, and the anterior insula. In another study, subjects were exposed to videos of patients acting as if they were undergoing a painful auditory treatment for a neurological disease with either a positive (treatment success) or a negative outcome (treatment failure) [17]. Participants were asked to imagine the feelings of the patient and to imagine themselves in the patient’s situation. Empathic concern (as elicited by empathy scores) was stronger when patients focused on the feelings of others, whereas adopting the selfperspective led to stronger personal distress. Empathy scores (as measured by the Interpersonal Reactivity Index [23, 24]) correlated with activity in the anterior medial cingulate cortex, the insular cortices, and the fusiform gyrus [17]. During the task of perspectivetaking, the anterior medial cingulate cortex was again activated, along with the middle insula, lateral premotor areas, and both parietal cortices [17]. Finally, the medial prefrontal cortex may play a role in the response to violent behavior. In a study requiring healthy individuals to imagine scenes in which they witnessed the assault of their mother in an elevator under three different conditions: (1) passively watching the assault; (2) being restrained by one of the perpetrators; and (3) violently attacking the perpetrators, positron emission tomography (PET) scans showed reduced activation of the medial prefrontal cortex in all three scenarios [25].

Prefrontal and temporal circuits Although comportment is largely a function of the prefrontal circuits, these pathways do not exist in isolation, and are dependent on connections with areas such as the limbic system and the dorsolateral prefrontal cortex. The orbitofrontal cortex has both afferent and efferent connections with the dorsolateral prefrontal cortex, temporal pole, and amygdala [12]. The amygdala likely plays a role in social judgment similar to that of the orbitofrontal cortex. The role of the amygdala is thought to involve evaluation of a stimulus’s emotional significance and the determination of an appropriate behavioral response. For instance, patients with bilateral damage to the amygdalae typically rate people as more approachable and trustworthy [26]. A case study of patient N. M., who had bilateral amygdala damage, was found to be impaired in

256

recognizing fear from facial expressions [27]. In addition, studies have shown elevated activation in the right amygdala during emotion recognition [28]. Diseases that commonly affect comportment such as autism and FTD frequently compromise both frontal and temporal structures. Thus the circuitry responsible for social cognition involves diffuse connections within the prefrontal cortex as well as to the temporal cortex [5].

Measuring comportment The complex functions associated with comportment make it difficult to objectively measure this capacity. The components of comportment such as insight, judgment, self-awareness, social adaptation, and empathy are difficult to assess in isolation. Moreover, comportment can vary in normal individuals, as everyone has occasional lapses in insight and judgment. Furthermore, the hospital or clinical environment is an artificial setting where patients’ responses to tests of judgment may be inapplicable to the real world. Informal ways of assessing comportment include observing the way an individual dresses him- or herself, or whether or not there is insight into the disease. Few bedside neuropsychological tests are geared to detecting orbitofrontal deficits, although some patients with lesions in this region may have difficulty with set shifting on the Wisconsin Card Sorting Test [12]. However, this test primarily focuses on the assessment of dorsolateral prefrontal cortical function. Unlike memory or executive function, there are no objective tests to measure comportment. Hypothetical problems geared to assessing social judgment do not appear to have a high sensitivity for comportment and have little predictive value. For example, a commonly presented scenario requires a patient to make judgments in the event that a fire breaks out in a theater. However, the real-life relevance of responses to this situation is questionable. To illustrate, patient E.V.R., a 44-year-old accountant who developed problems with decision-making and social learning following resection of a bilateral orbitofrontal meningioma, performed well on hypothetical tasks requiring judgment [13]. He created satisfactory and logical assessments of dilemmas such as a poor father with three starving children stealing from a grocery store, and a psychiatrist refusing to treat a patient who had killed a person for food while stranded on a deserted island


[13]. Social judgment may often seem to be intact in the artificial environment of a clinic, and these patients often appear normal when presented with challenging ethical questions in a controlled setting. However, patients such as E.V.R. would likely act in a much different manner when challenged in the real world. Thus, comportment may be one of those higher mental facilities that warrant testing outside the clinic or hospital and within the patient’s own environment. Lhermitte’s study of his two patients with prefrontal lobe injury is a perfect example of how deficits, which in this case was self-awareness, were best elicited in a non-clinical environment [4]. There are also no standard questionnaires that specifically address comportment. The Neuropsychiatric Inventory (NPI) [29] was developed to provide a means of objectively characterizing neuropsychiatric symptoms among persons with dementias, including Alzheimer’s disease (AD) and FTD, and has enjoyed widespread use. This inventory mainly focuses on symptoms of apathy, agitation, anxiety, irritability, dysphoria, disinhibition, delusions, hallucinations, and euphoria [29]. Patients with FTD may exhibit these symptoms more often than AD patients, but unfortunately the NPI does not provide any insight into comportment. There are measures that do permit the assessment of comportment, although these often are limited to the individual processes that comprise it (i.e., insight, judgment, self-awareness, social adaptation, and empathy). For example, a study of persons with probable AD required subjects to self-estimate their ability to perform tasks requiring memory, attention, generative behavior, naming, visuospatial skill, limb praxis, mood, and uncorrected vision pre- and posttesting [30]. Probable AD patients tended to overestimate their memory performance compared with controls [30]. From this study, the investigators developed an anosognosia ratio for their subjects, finding that probable AD patients had falsely elevated self-assessment scores for visuospatial and memory task both pre- and post-testing. Perhaps this is one technique that might be used to measure insight, but it would still fail to distinguish between posterior cortical processes such as AD from frontal cortical processes such as FTD or traumatic brain injury (TBI). Several scales measuring insight have been used in schizophrenia, including the Insight and Treatment Attitude Questionnaire (ITAQ) – the score being dependent on a patient’s agreement to psychiatric

treatment – the Scale to Assess Unawareness of Mental Disorder (SUMD), with subscores resulting from a patient’s awareness and attribution of their symptoms [31, 32], and the Self-Awareness of Deficits Interview [33], which uses an interview-rated semi-structured interview to assess such problems. Several scales have also been developed to measure empathy. The earliest examples included the Questionnaire Measure of Emotional Empathy [34] and the Balanced Emotional Empathy Scale [35]. More comprehensive scales such as the Interpersonal Reactivity Index (IRI) [23, 24] measure perspective taking, empathic concern (the capacity to feel warm, concerned, compassionate feelings for others), fantasy items (ability to identify with fictional characters), and personal distress (occurrence of self-oriented response to others’ negative experiences) [7]. The IRI has been used to quantify empathy in studies of patients with dementia and TBI [8]. The Empathy Quotient (EQ) [7], developed for the assessment of individuals with autism, is a recent scale that is sensitive to lack of empathy [7].

Disease processes affecting comportment A variety of diseases that preferentially affect the prefrontal cortex and that result in increased aggression, loss of empathy, and disinhibition have provided neurologists with insight into the brain structures responsible for comportment. Developmental disorders such as autism and Asperger’s Syndrome (AS) may result in abnormalities in connections between the frontal circuits and the temporal lobe. Degenerative processes such as FTD cause progressive dysfunction of all three prefrontal circuits. Physical injury to the prefrontal cortex either from trauma or tumor resection offer further clues to the cortical areas and pathways necessary for maintaining social cognition and behavior. Finally, schizophrenia results in functional impairment of social cognition. The pathogenesis of these four processes as well as relevant functional neuroimaging studies will be discussed in this section.

Frontotemporal dementia In his paper, “On the Relationship Between Senile Cerebral Atrophy and Aphasia” [36], Arnold Pick described a 41-year-old woman who “became careless, clumsy . . . did not change her clothes or the

257


bedding, and stopped combing her hair . . . did not initiate conversation, repeated questions, tended to give stereotypical answers, and often perseverated . . . she had unusual fits of anger, verbally abuse and hit her children or whatever was nearby, including cattle.” This was the index report of a tau-positive dementia illness, which came to be named Pick’s Disease, and is now known as FTD. Pick’s clinical observations are still relevant today for considering FTD, a symmetrical bifrontal variation of the frontotemporal lobar dementias (FTLD) in which pathology may show tau, ubiquitin, transactive response DNA-binding protein with Mr 43 kDa (TDP43), fused in sarcoma (FUS), or the absence of intraneuronal inclusions [11]. FTD is one of the degenerative syndromes under the category of FTLD, the others being progressive non-fluent aphasia, which involves the left frontal lobe, and semantic dementia, which involves the anterior temporal lobes. For the purpose of this discussion, we will focus on FTD [11]. FTD is a degenerative condition that usually affects patients 45– 65 years of age, and consists of circumscribed degeneration of the prefrontal and anterior temporal lobes [37]. FTD is the third most common degenerative dementia behind AD and dementia with Lewy bodies [11]. The most common presenting symptom of FTD is behavioral change. Core diagnostic features for the behavioral variant of FTD (bvFTD) include decline in social cognition, impairment in regulation of personal conduct, emotional blunting, loss of insight, and utilization behavior [38]. Furthermore, bvFTD patients tend to overeat in a gluttonous manner [11]. The key components of comportment are the earliest and most prominently affected. In terms of social adaptation, patients lose respect for personal boundaries, frequently becoming overfriendly with complete strangers [11]. Patients have impaired ability to comprehend and express emotion [11]. Loss of empathy is one of the earliest and most distressing symptoms of bvFTD [8]. Patients have impaired recognition of both facial and vocal expressions of emotion, leading to difficulty inferring what other people feel or think [37]. Self-awareness is compromised, resulting in utilization behavior [37]. Interestingly, patients with predominantly right frontal atrophy exhibit greater behavioral change than those with left side atrophy. Structural neuroimaging typically shows bilateral atrophy (often right greater than left) of the dorsolateral, orbitofrontal, insular, and medial frontal

258

cortices [11]. Functional neuroimaging reveals hypometabolism (often left greater than right) of the anterior temporal cortex, amygdala, and insular cortex [11]. Post-mortem studies in patients with bvFTD confirm involvement predominantly of the orbitofrontal and anterior temporal cortices in socially disinhibited patients, and predominant dorsolateral involvement in those presenting with apathy [37]. Numerous studies have examined the relationship between comportmental deficits and prefrontal pathology. Patients with bvFTD perform worse on tests of emotion perception than dementia control groups without OFC damage [11]. Patients also demonstrate interpersonal coldness and poor perspective-taking. In a study of 123 patients, Rankin et al. [8] correlated empathy scores of FTLD, AD, corticobasal degeneration, and progressive supranuclear palsy as demonstrated by the Empathic Concern and Perspective-Taking Scale with anatomical findings using MRI with voxel-based morphometry. Empathy scores correlated with the volume of right temporal structures in semantic dementia and with orbitofrontal/ventral striatal volume in bvFTD. Lower levels of empathy corresponded most significantly with atrophy of the right temporal pole, the right anterior fusiform gyrus, and the right medial inferior frontal cortex. Thus, the study suggested right anterior and medial frontal regions predominantly mediate empathetic behavior [8].

Traumatic and other acquired brain injuries In his best-selling novel, Everything is Illuminated [39], Jonathan Safran Foer recounts the story of a sawmill worker, the “Kolker,” who suffers a horrible accident while working in the fictional shtetl of Trachimibrod. One day, a disk saw blade from a chaff splitter spins from its bearings, racing through the mill and eventually imbedding itself permanently in the Kolker’s skull as he swallows a cheese sandwich. The local physician evaluates him and finds that although the Kolker appears physically intact, he has an overwhelming urge to use profanity. Over time, he becomes “undeniably different,” beating his wife repeatedly until a wall is erected to separate the two at home [39]. Despite the extraordinary nature of Foer’s descriptions, the character of the Kolker bears contemporary relevance, and is reminiscent of many patients suffering from prefrontal lesions secondary to trauma and surgery.


Like the Kolker and Phineas Gage, many victims of TBI emerge as altered individuals with an increased tendency toward aggression and violence. The OFC is a region highly susceptible to traumatic injury. Such injury may result from blunt force, intracranial hemorrhage, and/or contusion. Case studies as far back as 1835 have reported the onset of antisocial personality traits after frontal injury, particularly in the OFC [40]. German researchers described personality changes in World War I and World War II veterans with orbitofrontal lesions [40]. The Vietnam Head Injury Study (VHIS), which investigated violent and aggressive behavior in 279 head-injured veterans, found that 14% of subjects with battleinduced frontal lobe injury engaged in fights or damaged property compared with 4% of controls without head injury [41]. The study further demonstrated a significant association between increased aggression and focal mediofrontal and orbitofrontal injury as shown by brain computed tomography (CT) scan [41]. This study, however, did not make mention of a history of aggression and violence prior to head injury. A more recent case study described a 35-yearold security guard, who after sustaining bilateral orbitofrontal lesions after an attack by a gang, engaged in frequent fights with co-workers and made sexually inappropriate overtures toward women [42]. Beer and colleagues [14] reported a group of five patients with focal bilateral OFC damage who were significantly worse than normal controls at identifying self-conscious emotions (embarrassment, shame), but not other emotions (anger, disgust, fear, happiness, sadness, contempt, surprise, or amusement) [14]. Besides blunt head trauma, surgical operations may also result in profound behavioral changes. As mentioned earlier in this chapter, Eslinger and Damasio described the case of E.V.R., a 44-year-old accountant who developed a large bilateral orbitofrontal meningioma and severe comportmental dysfunction following the tumor resection with bilateral ablation of the orbital and lower medial frontal cortices [13]. After the surgery, he engaged in reckless partnerships with individuals of questionable reputability. Employers complained about his tardiness and disorganization. His personal life slowly disintegrated, and his wife left home with his children, filing for divorce after 17 years of marriage. Yet E.V.R. was found to have a superior range IQ. Furthermore, he performed well on tests

sensitive to frontal lobe dysfunction such as the Wisconsin Card Sorting Test, memory tasks, and set shifting [13]. Interestingly, when given hypothetical scenarios with social problems such as whether a father is justified in stealing food to provide for his family, he responded appropriately. Despite this ability to solve hypothetical problems, E.V.R. appeared to have lost the ability to analyze and integrate real-life situations. E.V.R.’s case is novel in the sense that his illness did not manifest itself as the impulsiveness, disinhibition, or lack of restraint found in many TBI patients, but instead by poor decision-making in social contexts. Prefrontal lesions that occur in childhood may also have profound social consequences, as some affected patients fail to develop skills necessary for insight, social judgment, and foresight. Price and colleagues presented a case study of two patients with early frontal lobe pathology [43]. The first was a 31-year-old man who had suffered a left perinatal subdural hematoma requiring surgical evacuation, and who subsequently developed serious behavioral problems by the age of eight. He failed to respond to parental discipline, and later was imprisoned eight times on charges of assault, forgery, grand larceny, drug involvement, and lewd behavior. On neuropsychological testing, he had a normal IQ, but had severe deficits on the Trail Making Test, the Stroop Test, the Wisconsin Card Sorting Test, the Luria hand-motor sequence, auditory go-nogo testing, and visual-verbal tests. MRI showed bilateral lesions extending from the superior medial prefrontal cortex to the caudate nuclei [43]. The other patient was a 26-year-old woman who had suffered a right frontal hematoma secondary to a car accident at the age of four. The patient later became notorious for her sexual promiscuity and bravado, frequently engaging in drug use as well. She displayed inappropriate and negligent care of her infant. She would also make poor decisions such as wandering alone through a local cemetery where she was raped on two different occasions by the same man [43]. This patient was found on neuropsychological testing to have a full scale IQ of 78 with moderate impairment in mental flexibility, abstract reasoning, the Trail Making Test, the Stroop Test, word list generation, and visual-verbal tests. MRI showed abnormal T1 and T2 signal intensities in both prefrontal regions, with dilation of the frontal horns of the lateral ventricles [43]. In both these cases, early bilateral prefrontal lesions resulted in lifelong social learning deficits. Neither patient was able to make necessary adjustments based on negative social

259


experiences. Consequently, one patient ended up committing repeated crimes and the other made repeated self-endangering decisions. In general, most of these patients have lesions that involve large regions of the prefrontal cortex and their connections, extending beyond both the medial frontal and orbitofrontal regions. Taken together, these observations clearly emphasize the role of the prefrontal cortex in comportment. A deeper philosophical question is: how does loss of comportment result in a life of crime and violence? The lack of social adaptation and empathy are key factors in the development of antisocial personality, leading to failure to recognize the suffering inflicted upon others by antisocial acts.

Schizophrenia Schizophrenia is a brain disorder with the hallmarks of psychosis and thought disorganization. Emil Kraepelin’s term for schizophrenia, dementia praecox, signifies the early recognition of a disease that ultimately results in intellectual dysfunction, impaired judgment, and functional decline. Individuals with schizophrenia experience positive symptoms, consisting of hallucinations, delusions, and disorganization of speech, as well as negative symptoms including blunted affect, alogia, avolition-apathy, anhedonia, and asociality [44]. Furthermore, cognitive deficits are core features of schizophrenia, primarily involving attention, verbal learning and memory, and executive function. In these key areas of cognition, patients generally show impairments between 1.5–2 deviations below healthy controls [45]. Memory and executive dysfunction may resemble that seen in FTD, which has also been correlated with hypoperfusion of the frontotemporal cortices on functional neuroimaging with single-photon emission computed tomography (SPECT) [46]. Social cognition, reasoning and problem solving, and speed of information processing are other cognitive domains that are usually measurably impaired in schizophrenia. Approximately 75% of persons with schizophrenia demonstrate impairments on standard comprehensive neuropsychological batteries [47]. Many pathological and functional neuroimaging studies demonstrate an association between schizophrenia and dysfunction of brain structures involved in comportment. Using computational morphometry, Marcelis and colleagues [48] identified several clusters of gray matter volume reduction

260

among subjects with schizophrenia when compared with control subjects; these reductions were in the cingulate gyrus, inferior frontal gyrus, insula, and amygdala [48]. Besides these anatomical variations in schizophrenia, neurochemical variations in dopamine activity may also contribute to the dysfunction of prefrontal circuits, as the cingulate cortex receives a large projection of dopaminergic afferents [18]. On clinical evaluation, patients with schizophrenia manifest marked impairments in various aspects of comportment, including insight (particularly into one’s illness), empathy, and social cognition. Lack of insight has long been considered an important clinical feature of schizophrenia. For instance, the International Pilot Study of Schizophrenia (IPSS) found the “lack of insight” item on a psychopathological inventory to be the most frequently identified problem among persons with schizophrenia [49]. This impairment of insight contributes to poor adherence to antipsychotic medication and contributes to an overall poor prognosis [50]. It has been suggested that poor insight among persons with schizophrenia may be a result of executive dysfunction, but many studies examining the association between insight and cognition have failed to show a consistent relationship [51]. However, a recent meta-analysis confirmed a relationship between insight and impairment in set shifting and error monitoring as assessed by the Wisconsin Card Sorting Test, although the correlation was weak (r = 0.17) [52]. Lysaker and colleagues administered the Delis–Kaplan Executive Function System to 53 subjects with schizophrenia and found that awareness of symptoms was related to performance on verbal fluency, Stroop Test, Tower of Hanoi, and word context measures [53]. The assessment of insight in persons with schizophrenia is complicated by the dynamic nature of this faculty, which may be influenced by treatment and affective state. Unlike patients with FTD who have more static insight impairments, those with schizophrenia have been noted to have improved insight after treatment with antipsychotics [54]. Furthermore, insight has been shown to vary depending on the patient’s affective state. For instance, patients with acute mania (which can occur in schizoaffective disorder) are notorious for having very poor insight during the acute episode [55]. Conversely, major depression has consistently been associated with better insight than other psychiatric disorders [56]. Freudenreich and colleagues studied 122 stable


outpatients with schizophrenia, of whom 62% had at least partial awareness of symptoms [57]. Only dysphoric affect predicted the degree of insight into the pathological nature of the patients’ symptoms. Finally, insight into illness may be also be influenced by cultural factors such as a resistance to being labeled with a mental illness or an unwillingness to take medications with a variety of side effects. Such denial of illness is a well-known psychological phenomenon in clinical medicine that can be seen in diseases unrelated to the brain (e.g., denial in patients following myocardial infarction). Consequently, insight in schizophrenia cannot be understood as being a dichotomous variable in which the patient either does or does not have insight. Both dimensional models of insight (i.e., full insight, varying degrees of partial insight, no insight) and more complex, multidimensional conceptual models of insight have developed. David proposed a tridimensional model that conceives of insight as being comprised of three dimensions: (1) ability to recognize the pathological nature of psychological experiences (e.g., hallucinations); (2) recognition that one suffers from a mental illness; and (3) acknowledgment of the need for treatment [58]. In addition to insight deficits, many persons with schizophrenia also demonstrate impairments in the theory of mind, another likely sequel of prefrontal dysfunction. Much of the testing to support this conclusion has revolved around having patients use physical cues such as eye appearance to judge an individual’s affective state. Russell and colleagues studied subjects with schizophrenia taking antipsychotic medications whose IQ scores were similar to those of control subjects, and he assessed their ability to ascertain emotional states based on pictures of eyes [59]. Subjects with schizophrenia made more errors in mental state attribution and were found to have decreased fMRI blood-oxygen-level-dependent signal response in the left middle and inferior frontal cortex and insula compared with controls [59]. In a PET study, persons with schizophrenia receiving antipsychotic medications were matched with normal controls for verbal IQ and performed a non-verbal attribution of intention task as well as two matched physical logic tasks [60]. When compared with the control subjects, performance on these tasks was lower among those with schizophrenia; additionally, the latter group did not demonstrate blood flow responses in the right middle front gyrus [60].

Although persons with schizophrenia may not have obvious neuroimaging abnormalities such as those seen in FTD or TBI patients, the condition clearly affects insight and social cognition. An interesting aspect of schizophrenia is that it is one of the few comportmental disorders that can be modulated with pharmacologic treatment. Further functional and anatomical investigations are necessary to further delineate the dysfunctional circuits that result in the disorganization of both thought as well as social adaptation in these patients. A certain degree of mystery still surrounds the mechanisms underlying schizophrenia, as in autism spectrum disorders, the last topic of this section.

Autism spectrum disorders In contrast to conditions affecting comportment that are acquired in adulthood, autism and AS (referred collectively to as autism spectrum disorders, or ASD) are developmental disorders that involve dysfunction in social interaction and empathy. These patients exhibit impairment in the interpretation of non-verbal behaviors (i.e., facial expressions, body posture, and gestures), fail to develop appropriate peer relationships, and lack social and emotional reciprocity [61]. The principal difference between high-functioning autism (i.e., autism with normal performance on measures of intellectual functioning) and AS is that autism is associated with language and cognitive delays [61]. Both autism and AS cause dysfunction in social cognition. Persons with these disorders do not attend normally to the affective component of facial expression [62]. In fact, Schultz and colleagues found that the brain activity of AS individuals regarding facial features was similar to that produced by these subjects viewing non-human objects [63]. Furthermore, these patients are unable to adequately perceive information about what others may think or feel, and they have impaired theory of mind. Loveland and colleagues [64] found that children and adolescents with autism were less accurate than controls in detecting whether videotaped children were willing to share candy [64]. Consequently, this failure to assess the social cues of others can lead to the expression of inappropriate behavior as well as failure to modify behavior based on social cues. Structurally, both the frontal and temporal cortices appear to be involved in autism. In a study using voxelbased morphometry, reductions in gray matter volume in the medial frontal regions were detected [65].

261


Kwon and colleagues studied males with high functioning autism, AS, and age-matched controls. Males with either autism or AS had decreased gray matter density in the ventromedial regions of the temporal cortices when compared with controls [66]. In addition, the AS group was noted to have less gray matter density in the body of the cingulate gyrus when compared with those in the autism and control groups. Post-mortem studies of autism have shown a variety of subtle findings, including abnormal gyrification of the parietal lobe; decreased volumes of the corpus callosum, anterior cingulate, inferior frontal gyrus, and occipitotemporal junction; hypoplasia of the cerebellar vermis; and tightly packed cells in the cerebellar nuclei, amygdala, and hippocampus [6]. The amygdala appears to be consistently involved in autism. Adolphs and colleagues found that individuals with autism and those with damage to the amygdala make similar abnormal judgments of trustworthiness and approachability from faces (i.e., trusting a face with a “negative expression”) and make similar errors in recognizing emotional expression from faces [67]. Furthermore, studies of monkeys show that bilateral medial temporal lobe lesions result in reduced eye contact, inexpressive faces, decreased social encounters, and lack of play, all suggestive of an autism-like syndrome [68]. There is no single, well-accepted neuroanatomical model for autism [6]. The condition is a disorder of social cognition, which implies a neuroanatomical basis consisting of a ventral (emotion) circuit including the amygdala, anterior cingulate, OFC, and mediodorsal thalamus, and a dorsal (processing) circuit that involves the hippocampus, anterior thalamic nuclei, parietal cortex, and dorsolateral prefrontal cortex [6]. Ornitz hypothesized involvement of cerebellum, parietal cortex, brainstem, thalamus, and striatum on the basis of poor sensory modulation and selective attention in these patients [69]. Delong suggested that autism resulted from bilateral dysfunction of medial temporal lobe structures such as the hippocampus [70]. Damasio and Maurer proposed that autism resulted from dysfunction of the mesolimbic (dopaminergic) brain areas [71]. Functional MRI studies of autistic patients have suggested a neural network involving the superior temporal gyrus, amygdala, and OFC [72]. BaronCohen and colleagues [72] performed fMRI studies of persons with autism performing a theory of mind task in which subjects were required to judge from a

262

person’s eyes what that individual was thinking. Not only were subjects with autism less accurate than the control subjects when judging emotion, but they also failed to activate the amygdala relative to the control subjects [72]. Critchley et al. [73] performed functional neuroimaging on persons with autism spectrum disorders during the implicit processing of facial emotions. Results revealed absent activity in the left cerebellum and left amygdalohippocampal regions in the subject group compared with the control group [73]. Clinically, autism is a developmental disease of comportment, and it stands as a clear example of how the structures responsible for comportment are not confined to the prefrontal cortex, but also depend heavily on limbic structures. The early onset of autism and its profound behavioral consequences are both related to the fact that these individuals do not learn or are unable to use effectively the rules of social interaction.

Conclusion An understanding of comportment is an understanding of the qualities that define us as social beings. Successful careers, marital relationships, parental bonding, and lifelong friendships develop as a result of intact insight, judgment, self-awareness, social adaptation, and empathy. The circuitry subserving comportment, however, remains only vaguely defined, and consists of broad pathways that shuttle impulses between the frontal, temporal, and subcortical structures. On a larger scale, comportmental dysfunction has significant ramifications for society. Many individuals with violent and antisocial behavior have dysfunction of the prefrontal cortex. For instance, individuals with antisocial personality disorder have been shown to have reduced overall prefrontal gray matter volume on MRI volumetric studies compared with control subjects [74]. Furthermore, a PET study of 41 individuals charged with murder or manslaughter demonstrated significant bilateral prefrontal hypometabolism compared with control subjects during a frontal lobe activation task [75]. It is the integrity of these regions that may distinguish the good citizen from the sociopath. The importance of comportment in everyday function also becomes clear in illnesses that compromise the function of the prefrontal circuits. Diseases of comportment, which often culminate in increased aggression, loss of empathy, and disinhibition, challenge the very notion of true love between the patient and his


family. Whereas diseases such as amyotrophic lateral sclerosis or cancer result in distortion and atrophy of the physical body, diseases of comportment acquired during adulthood profoundly alter patients’ behaviors, changing the very psychological characteristics that previously defined them as individuals. Thus, it is the comportmental axis of the prefrontal cortex that is responsible in many ways for our humanity. Knowledge of comportmental function leads to broader questions about good and evil. Are acts of theft and physical violence abstract psychological qualities of a criminal mind, or are they a function of abnormalities in the prefrontal circuitry? On a larger scale, could one reduce the disregard for humanity by the perpetrators of the Nazi or Rwanda genocides to an abnormality or a functional misfiring within the prefrontal cortex? These broad questions currently seem unfathomable, but collaborative efforts between neurologists, psychiatrists, philosophers, ethicists, religious authorities, and psychologists are instrumental in arriving at solutions regarding aggressive and violent behavior. Case studies of patients with FTD and TBI with the aid of functional imaging have allowed for neuroanatomical localizations of higher mental functions such as empathy and social adaptation. With more sophisticated studies of comportment, it may even be possible to consider the eventual likelihood of modifying these circuits. Modern advances in technology have served to recharacterize conditions such as FTD, TBI, autism spectrum disorders, and schizophrenia as anatomical and functional disorders of the brain structures responsible for comportment. The unfortunate truth is that neurologists currently serve as observers of these conditions and have limited ability to modify comportmental deficits. However, the ability to define abstract processes such as empathy and social adaptation in terms of complex neural circuitry is a resounding step forward. Perhaps one day, neurologists and psychiatrists will see diseases such as FTD and schizophrenia in the same light as Parkinson’s disease, a disorder that can be eloquently modified by pharmacologic, electrical, and surgical intervention.

References 1. Harlow JM. Passage of an iron rod through the head. J Neuropsychiatry Clin Neurosci. 1999;11(2):281–3. 2. Mesulam MM. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000. 3. Simpson JA, Weiner ESC, editors. The Oxford English Dictionary. 2nd edition. Oxford: Oxford University Press; 1989. 4. Lhermitte F, Pillon B, Serdaru M. Human autonomy and the frontal lobes. Part I: Imitation and utilization behavior: a neuropsychological study of 75 patients. Ann Neurol. 1986;19(4):326–34. 5. Lee KH, Farrow TF, Spence SA, Woodruff PW. Social cognition, brain networks and schizophrenia. Psychol Med. 2004;34(3):391–400. 6. Bachevalier J, Loveland KA. The orbitofrontalamygdala circuit and self-regulation of social-emotional behavior in autism. Neurosci Biobehav Rev. 2006;30(1):97–117. 7. Lawrence EJ, Shaw P, Baker D, Baron-Cohen S, David AS. Measuring empathy: reliability and validity of the Empathy Quotient. Psychol Med. 2004;34(5):911–19. 8. Rankin KP, Gorno-Tempini ML, Allison SC et al. Structural anatomy of empathy in neurodegenerative disease. Brain 2006;129(Pt 11):2945–56. 9. Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. The return of Phineas Gage: clues about the brain from the skull of a famous patient. Science 1994;264(5162):1102–5. 10. Stuss DT, Benson DF. The Frontal Lobes. New York, NY: Raven Press; 1986. 11. Miller BL, Cummings JL. The Human Frontal Lobes: Functions and Disorders. 2nd edition. New York, NY: Guilford Press; 2007. 12. Cummings JL. Anatomic and behavioral aspects of frontal-subcortical circuits. Ann N Y Acad Sci. 1995;769:1–13. 13. Eslinger PJ, Damasio AR. Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology 1985;35(12):1731–41. 14. Beer JS, Heerey EA, Keltner D, Scabini D, Knight RT. The regulatory function of self-conscious emotion: insights from patients with orbitofrontal damage. J Pers Soc Psychol. 2003;85(4):594–604. 15. Blair RJ, Cipolotti L. Impaired social response reversal. A case of ‘acquired sociopathy’. Brain 2000;123(Pt 6):1122–41.

Acknowledgments Dr. Price is supported in part by the Sidney R. Baer Jr. Foundation.

16. Camille N, Coricelli G, Sallet J et al. The involvement of the orbitofrontal cortex in the experience of regret. Science 2004;304(5674):1167–70.

263


17. Lamm C, Batson CD, Decety J. The neural substrate of human empathy: effects of perspective-taking and cognitive appraisal. J Cogn Neurosci. 2007;19(1): 42–58. 18. Brunet-Gouet E, Decety J. Social brain dysfunctions in schizophrenia: a review of neuroimaging studies. Psychiatry Res. 2006;148(2–3):75–92. 19. Lough S, Kipps CM, Treise C et al. Social reasoning, emotion and empathy in frontotemporal dementia. Neuropsychologia 2006;44(6):950–8. 20. Singer T, Seymour B, O’Doherty J et al. Empathy for pain involves the affective but not sensory components of pain. Science 2004;303(5661):1157–62. 21. Morrison I, Lloyd D, di Pellegrino G, Roberts N. Vicarious responses to pain in anterior cingulate cortex: is empathy a multisensory issue? Cogn Affect Behav Neurosci. 2004;4(2):270–8.

32. Amador XF, Strauss DH, Yale SA et al. Assessment of insight in psychosis. Am J Psychiatry 1993;150(6): 873–9. 33. Fleming JM, Strong J, Ashton R. Self-awareness of deficits in adults with traumatic brain injury: how best to measure? Brain Inj. 1996;10(1):1–15. 34. Mehrabian A, Epstein N. A measure of emotional empathy. J Pers. 1972;40(4):525–43. 35. Mehrabian A. Manual for the Balanced Emotional Empathy Scale (BEES). http://www.kaaj.com/?PMU ?psych/scales/emp.html ¨ 36. Pick A. Uber die Beziehungen der senilen Hirnatrophie zur Aphasie. Prager medicinische Wochenschrift 1892;17:165–7. 37. Neary D, Snowden J, Mann D. Frontotemporal dementia. Lancet Neurol. 2005;4(11):771–80.

22. Jackson PL, Brunet E, Meltzoff AN, Decety J. Empathy examined through the neural mechanisms involved in imagining how I feel versus how you feel pain. Neuropsychologia 2006;44(5):752–61.

38. Rascovsky K, Hodges JR, Kipps CM et al. Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions. Alzheimer Dis Assoc Disord. 2007;21(4): S14–18.

23. Davis M. A multidimensional approach to individual differences in empathy. JSAS Catalog Select Doc Psychol. 1980;10(85).

39. Foer JS. Everything is Illuminated: A Novel. 1st Perennial edition. New York, NY: Perennial; 2003.

24. Davis MH. Measuring individual-differences in empathy – evidence for a multidimensional approach. J Personal Soc Psychol. 1983;44(1):113–26.

40. Blumer D, Benson DF. Personality changes with frontal and temporal lobe lesions. In Benson DF, Blumer D, editors. Psychiatric Aspects of Neurological Disease. New York, NY: Grune & Stratton; 1975.

25. Pietrini P, Guazzelli M, Basso G, Jaffe K, Grafman J. Neural correlates of imaginal aggressive behavior assessed by positron emission tomography in healthy subjects. Am J Psychiatry 2000;157(11):1772–81.

41. Grafman J, Schwab K, Warden D et al. Frontal lobe injuries, violence, and aggression: a report of the Vietnam Head Injury Study. Neurology 1996;46(5):1231–8.

26. Wood JN. Social cognition and the prefrontal cortex. Behav Cogn Neurosci Rev. 2003;2(2):97–114.

42. Stein DJ, Moeller FG. The man who turned bad. CNS Spectr. 2005;10(2):88–90.

27. Sprengelmeyer R, Young AW, Schroeder U et al. Knowing no fear. Proc Biol Sci. 1999;266(1437): 2451–6.

43. Price BH, Daffner KR, Stowe RM, Mesulam MM. The comportmental learning disabilities of early frontal lobe damage. Brain 1990;113(Pt 5):1383–93.

28. Kosaka H, Omori M, Murata T et al. Differential amygdala response during facial recognition in patients with schizophrenia: an fMRI study. Schizophr Res. 2002;57(1):87–95.

44. Freedman R. Schizophrenia. N Engl J Med. 2003;349(18):1738–49.

29. Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997;48(5 Suppl. 6):S10–16. 30. Barrett AM, Eslinger PJ, Ballentine NH, Heilman KM. Unawareness of cognitive deficit (cognitive anosognosia) in probable AD and control subjects. Neurology 2005;64(4):693–9. 31. McEvoy JP, Apperson LJ, Appelbaum PS et al. Insight in schizophrenia. Its relationship to acute psychopathology. J Nerv Ment Dis. 1989;177(1): 43–7.

264

45. Bilder RM, Goldman RS, Robinson D et al. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 2000;157(4):549–59. 46. de Vries PJ, Honer WG, Kemp PM, McKenna PJ. Dementia as a complication of schizophrenia. J Neurol Neurosurg Psychiatry 2001;70(5):588–96. 47. Palmer BW, Heaton RK, Paulsen JS et al. Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology 1997;11(3):437–46. 48. Marcelis M, Suckling J, Woodruff P et al. Searching for a structural endophenotype in psychosis using


computational morphometry. Psychiatry Res. 2003;122(3):153–67. 49. WHO. Report of the International Pilot Study of Schizophrenia. Geneva: World Health Organization; 1973.

63. Schultz RT, Gauthier I, Klin A et al. Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Arch Gen Psychiatry 2000;57(4):331–40.

50. Day JC, Bentall RP, Roberts C et al. Attitudes toward antipsychotic medication: the impact of clinical variables and relationships with health professionals. Arch Gen Psychiatry 2005;62(7):717–24.

64. Loveland KA, Pearson DA, Tunali-Kotoski B, Ortegon J, Gibbs MC. Judgments of social appropriateness by children and adolescents with autism. J Autism Dev Disord. 2001;31(4):367–76.

51. Marková I. Insight in Psychiatry. Cambridge: Cambridge University Press; 2005.

65. McAlonan GM, Daly E, Kumari V et al. Brain anatomy and sensorimotor gating in Asperger’s syndrome. Brain 2002;125(Pt 7):1594–606.

52. Aleman A, Agrawal N, Morgan KD, David AS. Insight in psychosis and neuropsychological function: meta-analysis. Br J Psychiatry 2006;189:204–12. 53. Lysaker PH, Whitney KA, Davis LW. Awareness of illness in schizophrenia: associations with multiple assessments of executive function. J Neuropsychiatry Clin Neurosci. 2006;18(4):516–20. 54. McEvoy JP, Johnson J, Perkins D et al. Insight in first-episode psychosis. Psychol Med. 2006;36(10): 1385–93. 55. Ghaemi SN, Rosenquist KJ. Is insight in mania state-dependent? A meta-analysis. J Nerv Ment Dis. 2004;192(11):771–5.

66. Kwon H, Ow AW, Pedatella KE, Lotspeich LJ, Reiss AL. Voxel-based morphometry elucidates structural neuroanatomy of high-functioning autism and Asperger syndrome. Dev Med Child Neurol. 2004;46(11):760–4. 67. Adolphs R. The neurobiology of social cognition. Curr Opin Neurobiol. 2001;11(2):231–9. 68. Bachevalier J, Mishkin M. Effects of selective neonatal temporal lobe lesions on visual recognition memory in rhesus monkeys. J Neurosci. 1994;14(4):2128–39. 69. Ornitz EM. The functional neuroanatomy of infantile autism. Int J Neurosci. 1983;19(1–4):85–124.

56. Amador XF, Flaum M, Andreasen NC et al. Awareness of illness in schizophrenia and schizoaffective and mood disorders. Arch Gen Psychiatry 1994;51(10): 826–36.

70. DeLong GR. Autism, amnesia, hippocampus, and learning. Neurosci Biobehav Rev. 1992;16(1):63–70.

57. Freudenreich O, Deckersbach T, Goff DC. Insight into current symptoms of schizophrenia. Association with frontal cortical function and affect. Acta Psychiatr Scand. 2004;110(1):14–20.

72. Baron-Cohen S, Ring HA, Wheelwright S et al. Social intelligence in the normal and autistic brain: an fMRI study. Eur J Neurosci. 1999;11(6):1891–8.

58. David AS. Insight and psychosis. Br J Psychiatry 1990;156:798–808. 59. Russell TA, Rubia K, Bullmore ET et al. Exploring the social brain in schizophrenia: left prefrontal underactivation during mental state attribution. Am J Psychiatry 2000;157(12):2040–2. 60. Brunet E, Sarfati Y, Hardy-Bayle MC, Decety J. Abnormalities of brain function during a nonverbal theory of mind task in schizophrenia. Neuropsychologia 2003;41(12):1574–82. 61. Rapin I. Autism. N Engl J Med. 1997;337(2):97–104. 62. Baskin JH, Sperber M, Price BH. Asperger syndrome revisited. Rev Neurol Dis. 2006;3(1):1–7.

71. Damasio AR, Maurer RG. A neurological model for childhood autism. Arch Neurol. 1978;35(12):777–86.

73. Critchley HD, Daly EM, Bullmore ET et al. The functional neuroanatomy of social behaviour: changes in cerebral blood flow when people with autistic disorder process facial expressions. Brain 2000;123(Pt 11):2203–12. 74. Raine A, Lencz T, Bihrle S, LaCasse L, Colletti P. Reduced prefrontal gray matter volume and reduced autonomic activity in antisocial personality disorder. Arch Gen Psychiatry 2000;57(2):119–27; discussion 28–9. 75. Raine A, Phil D, Stoddard J, Bihrle S, Buchsbaum M. Prefrontal glucose deficits in murderers lacking psychosocial deprivation. Neuropsychiatry Neuropsychol Behav Neurol. 1998;11(1):1–7.

265

Section I


Chapter

Emotion

18

David B. Arciniegas

. . . from nothing else but the brain come joy, delights, laughter and sports, and sorrows, griefs, despondency, and lamentations . . . By this we distinguish objects of relish and disrelish . . . And by the same organ we become mad and delirious, and fears and terrors assail us . . . All these things we endure from the brain . . . Hippocrates, On the Sacred Disease, 4th century BC (in [1], p. 159).

Emotions and emotional feelings arise through the integrated processing of bodily sensations, environmental events, thoughts and recollections, and they shape new learning, facilitate decision-making, and guide behavior [2–6]. In most circumstances, emotions and emotional feelings promote learning, adaptation, and survival. The generation and expression of emotions are fundamental (i.e., evolutionarily preserved and relatively primitive) neurobehavioral functions that are expressed similarly between individuals, across cultures, and over the lifespan [7–10]. As noted by LeDoux (1991) [11] and Ekman (1999) [9], the generation of emotion is predicated on evolutionarily preserved neural circuits that respond rapidly to primitive sensory events. By contrast, nuanced emotional experience, its interpretation in oneself and others, and context-relevant emotional control are among the most complex and evolutionarily advanced neurobehavioral functions of humans [12, 13]. When disease or injury compromises normal emotional generation, expression, experience, or control, the effects on patients, families, and societies are adverse and substantial [14–19]. Theoretical and neuroscientific accounts of emotion have advanced substantially over the last 50 years, and especially the last two decades [4, 6, 9–11, 13,

20–33]. These advances are reshaping the way in which disturbances of emotional generation, expression, experience and control are studied, evaluated, and treated. They challenge the use of layman’s terms to describe emotions and emotional feelings, necessitate the development of a coherent nosology for diagnosis of emotional disturbances [6, 17, 24, 34, 35], and undermine the historical research tradition of regarding cognition and emotion as fully separable neurobehavioral processes [4, 13, 27]. Likewise, historical attribution of emotional generation, expression, experience, and control to specific structures or regions, especially the “limbic system,” has been replaced by discussion of integrated pathways and distributed neural networks supporting these functions [29–32, 36–40]. Despite these advances, or perhaps because of them, the student of this subject reading this literature is likely to find inconsistencies in the terms used to describe emotion and emotional disturbances as well as their phenomenologic and neurobiological referents. An attempt must be made to offer an account of the phenomenology and neurobiology of emotional generation, expression, experience, and control that facilitates the evaluation and treatment of persons with disturbances of these neuropsychiatric functions. Toward that end, this chapter attempts a synthesis and necessary simplification of this literature modeled on ones performed previously by the author and his collaborators [17, 41–45]. Definitions of emotion, emotional feelings, mood, and affect, are offered first. The manner in which these terms are applied clinically is discussed briefly. The putative structural and functional neuroanatomies of emotional generation, expression, experience, and control are reviewed next. Finally, the relationships between disturbances in the


266

Chapter 18: Emotion

integrated pathways and distributed neural networks supporting these neuropsychiatric functions and the clinical phenomena encountered in the practice of Behavioral Neurology & Neuropsychiatry (BN&NP) are considered.

Emotion and emotional feelings Although “emotion” and “feeling” are often used synonymously in common and clinical parlance, their psychophysiologic referents are distinct. Emotion (from Latin ex “out” + movere “move”) describes a neural impulse that moves an organism to action, prompting automatic reactive behaviors adapted through evolution and experience as mechanisms to meet survival needs [2, 4, 46, 47]. Damasio (1994, 2003) [4, 46] and Prinz (2004) [25] describe emotion as a coordinated constellation of brain–body interactions, comprising facial expressions, vocalizations, gestures, body posture, behaviors, autonomic activity, visceral activity, neurohormonal, and neurotransmitter processes that occur automatically as reactions to specific types of external or internal, including imagined, stimuli. The use of the term “emotion” in this manner echoes the work of James (1890) [8], Lange (1885) [48], and Darwin (1890) [7] in its emphasis on the interaction between the brain and the body – especially the viscera and endocrine systems – involved in the generation and expression of the class of behaviors to which this term is applied. This view makes the occurrence of emotions necessary for the development of emotional feelings [4], and allows for the possibility that emotions can occur outside of conscious awareness – that is, in the absence of a corresponding emotional feeling. In this chapter, this class of brain–body interactions, their neural representations, and their expression (i.e., is limited to ex-movere phenomena) will be described as emotion. Feeling (from Old English felan “to touch, perceive”) describes a broad class of subjective psychological phenomena (qualia). Emotional feelings are a subset of this class that are associated with emotions [2, 4, 46, 47, 49]. For example, “hot,” “cold,” and “pain” are subjective experiences (i.e., feelings) reflecting conscious awareness of elementary sensation. By contrast, sadness, happiness, and fear are emotional feelings whose occurrence represents concurrent conscious awareness of automatic reactive brain–body interactions (i.e., ex-movere, or emotional, processes) and the mental images with which they are

(or will become) associated [4, 46]. In this chapter, this class of subjective experiences will be described as emotional feelings – that is, the subset of feelings that are associated with brain–body interactions, their neural representations, and their expression. By this account, emotional feelings necessitate the occurrence of an emotion – although the ex-movere phenomena with which they are associated may be subtle and/or opaque to detection by casual observation.

Categories of emotions and emotional feelings One of the most contentious subjects in the psychology of emotion is the manner in which emotions and emotional feelings are categorized. Proponents of onedimensional valence theories suggest that there are two basic classes of emotion and emotional feeling: positive and negative [50, 51]. Bi-dimensional theories suggest that emotions and emotional feelings are distinguished on the basis of valence (good or bad) and arousal (energized or enervated) [52, 53]. In these theories, these core emotions (or “core affects”) are contrasted with the prototypical emotional episodes to which they contribute – that is, events involving emotions and feelings about a specific person, condition, event, or thing. Componential appraisal theories approach the categorization of emotions and emotional feelings from the opposite extreme, suggesting that there is a relatively large number of emotional feelings constituted by conscious and unconscious integration of appraisal and response processes [54–58]. Other theories postulate a relatively small number of basic (i.e., fundamental, discrete) emotions and emotional feelings.

Basic emotions Basic emotions (expression, objective phenomena) and emotional feelings (experience, subjective phenomena) are similar between individuals and across cultures [7, 9, 10, 20–22, 59, 60]. These basic, or discrete, emotions and emotional feelings elicit changes in cognition (e.g., narrowing of attention), judgment (e.g., the risk perceived in the environment), behavior (action tendency), and physiology (e.g., visceral, autonomic, and endocrine activity) that are adapted to facilitate a response to the types of environmental changes that elicit the emotional event [61]. The basic emotions and emotional feelings are characterized by the universality of their antecedents,

267


Table 18.1. Correspondence between adaptive behaviors and basic emotions described by Plutchik (1980, 1984) [21, 22].

Adaptive behavior

Basic emotion

Destruction

Anger

Protection

Fear

Reintegration

Sadness

Reproduction

Joy

Rejection

Disgust

Orientation

Surprise

Exploration

Expectancy

Incorporation

Acceptance

unbidden occurrence, function as distinctive universal signals, physiology, function as automatic stimulus appraisers, appearance developmentally and in other primates, and also the distinctive thoughts, memories, images, and subjective experiences with which they are associated [9]. Ekman (1999) [9] emphasizes that the term “basic” in this context is used to identify the emotions possessing the aforementioned characteristics and their evolutionary-derived adaptive value for dealing with fundamental life tasks. Ekman (1972) [20] described six basic emotions that are identifiable in the facial expressions of individuals of all cultural and linguistic backgrounds: anger, fear, sadness, happiness, disgust, and surprise. There is relatively wide agreement on the primacy of this set of emotions and emotional feelings and the ease of their identification by most healthy individuals [31, 32]. Plutchik (1980, 1984) [21, 22] suggested that emotions represent basic adaptations that promote survival, and paired each of eight adaptive behaviors with a corresponding basic emotion and emotional feeling (Table 18.1). This approach added expectancy and acceptance to the set of basic emotions described by Ekman (1972) [20]. Ekman (1999) [9] subsequently revised the basic set to include the 15 emotions and emotional feelings listed in Box 18.1. Each of these terms denotes a family of related emotions and emotional feelings, a suggestion that serves in part to supplant the earlier suggestion of Ekman and Friesen (1975) [62] that complex, or compound, emotions and emotional feelings may arise through the co-occurrence of two or more basic ones. Ekman (1999) [9] acknowledged that this list does not include love (romantic or parental), hate, grief, or jealousy, and suggested that

268

Box 18.1. The 15 families of basic emotions and emotional feelings described by Ekman (1999) [9]. Amusement Anger Contempt Contentment Disgust Embarrassment Excitement Fear Guilt Pride in achievement Relief Sadness/distress Satisfaction Sensory pleasure Shame

these phenomena are better understood as emotional plots – phenomena that are more specific and enduring than the basic emotions and are specific contexts in which some, but not all, of the basic emotions and emotional feelings can be expected to occur.

Modal emotions and emotional feelings The basic emotions described by Ekman (1972, 1999) [9, 20] vary substantially in the frequency with which they occur in most healthy persons [56]. Additionally, the relatively small number of basic emotions – even if they are understood as categories of emotion and emotional feeling – seems inconsistent with most people’s everyday experiences of emotions and emotional feelings. Those experiences involve blendings and nuanced variations of emotional experience and expression (appraisal-outcome profiles) that are not captured adequately by the limited number of terms used to describe basic emotions and emotional feelings [54]. Scherer et al. (2004) [56] therefore suggests that a complete account of emotions and emotional feelings acknowledges that there are many distinct appraisaloutcome profiles but that only a limited number of these occur frequently in everyday life. Despite major differences in the theoretical approach used by these authors, the set of frequently occurring (i.e., “modal”) emotions and emotional feelings is similar in content and breadth to the basic emotions described by Ekman (1972) [20]. For example, Scherer et al. (2004) [56] obtained descriptors and brief narratives about a recent

Chapter 18: Emotion

Box 18.2. The 10 most frequently reported categories of emotion and emotional feeling. These categories are listed in order of descending frequency, and only the first eight were reported by 40 or more subjects (≥3.9%). Anger Anxiety Contentment Frustration Happiness Irritation Joy Sadness Stress Despair

emotional event from 1030 subjects. These individuals were asked to characterize: the situational context of the experience; the duration of the emotional feeling; the origin or cause of the event; the nature of a potential interaction partner with whom the experience was shared; the intensity of the feeling; the bodily symptoms experienced; the types of expressive reactions shown; the type of verbal utterance produced; changes in voice and speech patterns; and attempts to control the emotion. The subjects used approximately 775 different words, word combinations, and phrases to characterize the emotions and emotional feelings relevant to the events they described. Even when those terms were aggregated into groups of descriptively similar emotional events, 38 distinct categories emerged. Additionally, multiple positive, negative blends, and mixed blends were reported. The ten most frequently reported categories of emotions and emotional feelings observed in this study are listed in Box 18.2. The ten most commonly reported categories of emotions and emotional feelings were organized into six “families:” happiness (comprising happiness, joy, and contentment), anger (comprising anger, irritation, and frustration), anxiety, sadness, stress, and despair. Responses falling into the happiness and anger categories were more frequent (by a factor of four) than all other emotions and emotional feelings. Among the others, anxiety was more common than sadness, both of which were more common than stress or despair. Scherer et al. (2004) [56] acknowledge that “stress” is not usually discussed as an emotion or emotional feeling in the psychological literature, but that it occurred

Table 18.2. Emotional categories and the action tendencies with which they are associated.

Emotional category

Action tendency

Aim of the action tendency

Anger

Agonistic

Removal of obstruction, regaining control

Arrogance

Dominating

Retaining control

Desire

Approach

Access and consummatory activity

Disgust

Rejecting

Removal of object, distancing from self

Enjoyment

Being-with

Contact and interaction

Fear

Avoidance

Protection, limiting access to oneself

Humility

Submitting

Deflecting pressure

Indifference

Non-attending

Selecting (or not)

Interest

Attending

Identification

Resignation

Submitting

Deflecting pressure

Sadness

Reacquiring

Finding and reunifying

Shock

Interrupting

Behavioral reorientation

Surprise

Interrupting

Behavioral reorientation

more frequently than many of the other basic emotions described by Ekman (1972, 1999) [9, 20] and descriptions of its characteristics were distinctive enough to necessitate its identification as such in this dataset. These observations about the relative frequencies of emotions and emotional feelings also suggest that the “happy–sad” continuum used in much of the social-psychological research on emotion does not accurately reflect the everyday emotional life of most healthy people. Instead, Scherer et al. (2004) [56] suggest that a “happy–angry” continuum typifies everyday emotional expression and experience and that sadness, anxiety, stress, and despair are – quite fortunately – relatively low-frequency emotional events.

Action tendencies Another approach to categorizing emotions and emotional feelings organizes them by the action tendencies with which they are associated (Table 18.2) [63– 65]. The theory underlying this categorization suggests that cognitive appraisal of the event cueing an emotion (i.e., the physiologic responses to that event) generates consistent action tendencies. In other words, emotions arise because events are appraised cognitively as favorable or harmful to one’s own interests. This theory views emotions and emotional feelings as directing the

269


tendency of an individual to engage in specific types of behaviors, consistent with the behaviorist tradition out of which it developed. Although the correspondence between action tendencies and emotions is probably not as strict as this theory suggests, many of its concepts (i.e., “approach” and “avoidance” types of emotions) are used commonly in the emotion literature. Accordingly, subspecialists in BN&NP are well served to be familiar with this categorization of emotion and emotional feelings.

Dimensions of emotions and emotional feelings Each category of emotion and emotional feeling also may be characterized according to frequency, valence (evaluation-pleasantness), intensity, arousal (or activating) qualities, potency (or control), and unpredictability [57, 66–70]. The importance of considering frequency in the description of emotion and emotional feelings is embedded in the preceding discussion of modal emotions. The intensity of emotional expression and experience refers to the strength of the physiologic response and automatic reactive behaviors (i.e., ex-movere phenomena) as well as the emotional feeling with which they are associated. Valence describes the positive or negative characteristics of an emotional event. Arousal represents the degree of alertness, excitement, or engagement associated with an emotional event and the object (internal or external) that incites it. Potency refers to the individual’s sense of power or control over emotional events. Unpredictability is a term used to differentiate between emotions and emotional feelings that do or do not reflect an urgent reaction to a novel stimulus or an unfamiliar situation [57]. There is a lack of consensus on the number and usefulness of these dimensions of emotion and emotional feeling. However, their common use as qualifiers of emotional events in the clinical and research literature suggests that subspecialists in BN&NP will benefit from being familiar with their intended referents. Clinicians also may be aware of the tendency in the behavioral (and neuroimaging) research literature to associate positively valenced emotions and emotional feelings with approach behavior and negatively valenced emotions with avoidance behavior [32, 71, 72]. While the simplicity of a unidimensional approach to the description of emotional events is appealing, the relationships between valence and

270

approach-avoidance are not straightforward [61, 63– 65] (see Table 18.2). For example, most clinicians and researchers regard anger as a negatively valenced emotion that tends to produce approach behavior toward the object inciting it. Sadness generally is regarded as a negatively valenced emotion; although it may result in interpersonal withdrawal (i.e., avoidance behaviors) it also, and perhaps more commonly, results in behavior directed at finding or reunifying with the object of sadness or loss [64, 65, 73]. Similarly, sadnessrelated behaviors such as crying tend to elicit approach behaviors from others [74, 75]. The extent to which emotion and emotional feeling confer action tendencies among not only the person engaged in an emotional event but also those with whom they interact complicates the relationship between valence and approach-avoidance. Consistent with this suggestion, meta-analysis of approach-avoidance models in the study of emotions offers mixed support for their theoretical and clinical usefulness [61]. Finally, “state” and “trait” are also used commonly as dimensions of emotions and emotional feelings [76–80]. Emotional states are transitory emotions and emotional feelings, or relatively discrete emotional episodes. The referent of emotional states varies depending on the literature (or specific study) in which they are described, sometimes referring to momentary shifts in emotion and emotional feeling and at other times describing episodes of depression or anxiety lasting weeks or longer. Regardless of their specific duration, emotional states are distinguished from emotional traits, which refer to innate tendencies to experience certain types of emotions and emotional feelings. Emotional traits, or temperaments, are moderately heritable, observable early in childhood, crystallize during the second and third years of life, and remain relatively stable throughout life thereafter (see Chapter 19). Unlike emotional states, which vary over time and with the context in which they develop, emotional traits contribute to personality and may bias individuals toward the development of a variety of psychiatric conditions, including depression and anxiety disorders [81–84].

Mood and affect For the last 25 years, mood and affect have been defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) [34, 35, 85] according to the durations of the emotions and emotional feelings

Chapter 18: Emotion

Table 18.3. The relationships between emotion, emotional feeling, mood, and affect. Mood refers to pervasive and slowly changing emotions and emotional feelings (the “emotional climate”). Affect refers to relatively brief emotions and emotional feelings (the “emotional weather”). The expressed (literally ex-movere, or emotion) elements of both the “climate” and the “weather” can be assessed by interview and/or observation. Information about emotional feelings requires self-report on those experiences.

Emotion (expression)

Emotional feeling (experience)

Mood

Pervasive and sustained autonomic activity, visceral activity, neurohormonal, neurochemical processes, body posture, gestures, behaviors, facial expressions, vocalizations (ex movere phenomena that are present most of the day, nearly every day, over a period of days to weeks)

Emotion-related sensorimotor phenomena and associated cognitions that are present most of the day, nearly every day, over a period of days to weeks; these establish tendencies with which self and others are experienced (i.e., coloring of perception of the world)

Affect

Transient autonomic activity, visceral activity, neurohormonal, neurochemical processes, body posture, gestures, behaviors, facial expressions, vocalizations, the occurrence of which is superimposed and may be modified by the emotional background in which they occur (i.e., mood)

Transient emotion-related sensorimotor phenomena and associated cognitions (a momentary subjectively experienced feeling state)

comprising them. This approach has its origins in the transition between DSM–III [85] and DSM–III– R [34]. Prior to publication of the latter edition of the DSM, major depressive disorder, dysthymia, bipolar disorder, and cyclothymia were classified as “affective disorders.” In order to clarify that the cardinal feature of these conditions is mood disturbance, mood was defined as “a pervasive and sustained emotion that, in the extreme, markedly colors the person’s perception of the world” (in [34], p. 401) and these conditions were reclassified as “mood disorders.” The sustained and pervasive emotion and emotional feeling that defined mood were contrasted with affect, which was defined as a “pattern of observable behaviors that is the expression of a subjectively experienced feeling state . . . Affect is variable over time, in response to changing emotional states, whereas mood refers to a pervasive and sustained emotion” (in [34], p. 391). These definitions of mood and affect include both ex-movere elements (i.e., “emotion” in the mood definition, and “observable behaviors” in the affect definition) and also emotional feelings/subjective appraisals (i.e., “perception of the world” in the mood definition, “subjectively experienced feeling state” in the affect definition). However, the referents of the objective and subjective elements of these definitions were often conflated such that “mood” was regarded only as a subjectively experienced feeling state and “affect” only as the pattern of observable behaviors through which mood was expressed. This conflation was not the intent of the DSM Work Group charged with the task of developing the mood disorders classification and defining mood and affect (personal communication, Robert L. Spitzer, MD, Chair of the Work Group to Revise DSM–III and

Special Advisor to the Task Force on DSM–IV; August 15, 2005). Accordingly, in the DSM–IV [86], the distinction between mood and affect was clarified by the use of analogy: “In contrast to affect, which refers to more fluctuating changes in emotional “weather,” mood refers to a more pervasive and sustained emotional “climate” (in [86], p. 768). Ekman (1999) [9] echoes the temporal definition of mood as a relatively long duration phenomenon, and the temporal distinction between mood and affect (and use of this meteorological analogy to distinguish between them) is maintained in current editions of the DSM [35]. Given that mood and affect are distinguished from one another on temporal grounds, a careful reading of their current DSM-based definitions [34, 35, 86] makes clear that both encompass subjective (experienced) and objective (expressed) components (Table 18.3). Mood describes the emotional background – including pervasive and sustained emotions and also emotional feelings – on which transient emotions and emotional feelings are superimposed. Consistent with the meteorological analogy for mood and affect, the emotional weather of the moment occurs in the context of the emotional climate and may be either restricted or amplified by it.

Clinical implications These definitions of mood and affect direct the differential diagnostic considerations for disorders of mood and affect. These are considered briefly here and explored further in Chapters 23 and 34.

Mood disorders The development of functionally impairing pervasive and sustained disturbances of emotion and

271


Table 18.4. Mood disorders, their cardinal features, and associated symptoms described in the DSM–IV–TR.

Condition

Cardinal feature(s)

Associated features

Major depressive episode

Most of the day, nearly every day for at least 2 weeks the patient reports feeling “sad” or “empty” or is observably sad (e.g., tearfulness); or most of the day, nearly every day for at least 2 weeks the patient reports, or others observe, markedly diminished interest or pleasure in all, or almost all, activities

Pervasive and sustained mood disturbance-related cognitions (feelings of worthlessness, excessive or inappropriate guilt, difficulty concentrating, indecisiveness, thoughts of death), behavior (psychomotor agitation or retardation), and physical function (appetite or weight loss or gain, insomnia or hypersomnia, fatigue or loss of energy)

Dysthymic disorder

Most of the day, for more days than not, over at least 2 years, depressed mood is reported by the patient or observed by others

Mood disturbance-related cognitions (feelings of hopelessness, low self-esteem, poor concentration, indecisiveness) and physical function (poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue)

Manic episode

Over at least 1 week, the patient reports and/or others observe mood to be abnormally and persistently elevated (euphoric, unusually good, cheerful, high), expansive (unceasing and indiscriminate enthusiasm), or irritable

Mood disturbance-related cognitions (inflated self-esteem, grandiosity, flight of ideas, racing thoughts, distractibility), behaviors (excessively talkative, pressured speech, increased goal-directed behavior, excessive involvement in pleasurable high-risk behaviors, psychomotor agitation), and physical functions (decreased need for sleep) are present “to a significant degree”

Hypomanic episode

Throughout at least 4 days, mood is persistently elevated, expansive, or irritable in a manner that is clearly different from the usual non-depressed mood

Mood disturbance-related cognitions (inflated self-esteem, grandiosity, flight of ideas, racing thoughts, distractibility), behaviors (excessively talkative, pressured speech, increased goal-directed behavior, excessive involvement in pleasurable high-risk behaviors, psychomotor agitation), and physical functions (decreased need for sleep) are present “to a significant degree”

Cyclothymic disorder

For at least 2 years, there are numerous subjectively reported or observed periods of persistent elevation, expansiveness, or irritability as well as numerous periods of persistent and excessive sadness; during these 2 years, the person has not been without such symptoms for more than 2 months at a time

During periods of persistently elevated, expansive, or irritable mood, there are mood disturbance-related cognitive, behavioral, and physical symptoms of the types described in hypomanic episode; during periods of persistently and excessive sadness, there are mood disturbance-related cognitive, behavioral, and physical symptoms of the types described (but subthreshold) for major depressive episode

emotional feelings suggests a mood disorder such as major depression, dysthymia, mania, hypomania, or cyclothymia. For each of these conditions, the cardinal feature is a disturbance of emotional expression and experience that is present most of the day, nearly every day, for a period of days to weeks or longer (Table 18.4). As Holtzheimer and Mayberg (2011) [87] suggest, the cardinal feature of such states is not defined by their emotional content per se but instead by both a susceptibility to entering an abnormal emotion state and also an inability to disengage from it. As noted in Table 18.4, the emotional “climate shift” of a mood disorder is also accompanied by sustained mood disturbance-related changes in physical function, behavior, and cognition. The latter commonly involve distortions of the content or significance of their objects (e.g., self, others, things, events) in a manner reflecting the valence of the mood disturbance. In this context, most things – not merely

272

a stimulus inciting a transient emotion and emotional feeling – are experienced in a manner that reflects the valence and intensity of the emotional climate shift: oneself, other people, and everyday events are experienced as unduly negative by persons in the midst of a depressive episode or irritable mania and positively by persons in a euphoric mania. In other words, the mood disturbance “markedly colors the person’s perception of the world” (in [34]). Given the DSM–IV–TR definition of mood, the rationale for considering disorders involving persistent and excessive anxiety (e.g., generalized anxiety disorder, post-traumatic stress disorder) as categorically distinct from “mood disorders” is unclear – except, perhaps, for obliging the longstanding clinical tradition of doing so. This tradition is being reconsidered presently [88], and may result in the incorporation of anxiety into the types of emotions and emotional feelings entailed by mood disorders.

Chapter 18: Emotion

Table 18.5. Disorders of affect and their cardinal features.

Disorder of affect

Cardinal feature(s)

Pathological laughing and crying

Frequent, brief, uncontrollable, stereotyped, functionally impairing episodes of laughing and/or crying that are excessive in relation to the stimuli that incite them, reflect a change in customary affect, neither reflect nor produce a disturbance of mood

Affective lability

A tendency to be easily overcome by emotions and emotional feelings (from Late Latin labilis “apt to slip”); the emotions and emotional feelings may be excessively intense relative to the stimuli that incite them and fluctuate easily or rapidly, but they are neither entirely uncontrollable nor stereotyped; may reflect temperament or acquired cerebral pathology

Pathological euphoria (euphoria sclerotica)

Frequent inappropriate cheerfulness and bemused indifference to the affective significance of personal circumstances or life events

Witzelsucht

An uncontrollable tendency to make puns, comments, or jokes and/or to act in a manner that the actor experiences as humorous but that is facetious, childish, latently hostile, and socially inappropriate; it involves an admixture of irritability and mirth (from German witzeln “jokes” + sucht “addiction, obsession”)

Essential crying

A lifelong and hereditary propensity to cry easily

Ictal laughing (gelastic epilepsy)

Recurrent unprovoked complex partial seizures featuring ictal laughing

Dacrystic (or quiritarian) epilepsy

Recurrent unprovoked complex partial seizures featuring ictal crying

Affective placidity

A partial or complete deficit of normal emotional responsiveness, including responses to stimuli with high evolutionarily influenced emotional salience (i.e., threat objects, desire objects)

Disorders of affect Functionally impairing moment-to-moment disturbances of emotional expression and experience are disorders of affect (Table 18.5). This category of clinical conditions includes disorders of affective excess such as pathological laughing and crying (also known as pseudobulbar affect, emotional incontinence, and involuntary emotional expression disorder) [17, 42, 43, 89, 90], pathological euphoria (euphoria sclerotica) [91–93], essential crying [90, 94], witzelsucht [43, 95, 96], and affective lability [24, 67, 70, 97, 98]. The cardinal feature of each of these disorders is a relatively brief disturbance of emotion and emotional feeling [17, 99], thereby distinguishing them from mood disorders. However, they differ from each other with respect to their frequency, valence, intensity, activating qualities, potency, and unpredictability. Although the ex-movere phenomena (i.e., facial expressions, vocalizations, gestures, body posture, behaviors, autonomic activity, visceral activity, neurohormonal, and neurotransmitter changes) associated with any particular momentary emotional episode in a person with a disorder of affect may be very intense, their occurrence does not entail between-episode disturbances in emotion, emotional feelings, physical function, behavior, and cognition [43]. However, disorders of affect may co-occur with mood disorders (e.g., pathological crying and major

depressive episode [100, 101], affective lability during the euthymic period of bipolar disorder [24, 97, 102]) and their treatments are distinct [17]. Accordingly, careful evaluation of both the emotional “weather” and “climate” among persons presenting with these types of disorders of affect is essential. Affective placidity refers to a partial or complete deficit of normal emotional responsiveness, including normal evolutionarily influenced responses to stimuli with high emotional salience [43, 103]. As such, it is a disorder of affective deficit, and is most commonly associated with conditions in which diminished motivation and/or Klüver–Bucy-like syndromes develop. Paroxysms of laughing and crying also may occur as ictal manifestations of complex partial seizures [104–106]. The classic clinico-neuropathological association for gelastic epilepsy (ictal laughing) is hypothalamic hamartomas among adolescent males; however, such patients are encountered rarely in clinical practice.

Key clinical questions about mood and affect Distinguishing between mood disorders and disorders of affect requires attention to both the ex-movere phenomena and the subjective qualities of both mood and

273


Figure 18.1. Graphic illustrations of relationships between mood and affect. In each panel, the Y-axis represents the valence of emotion and emotional feeling and the X-axis represents time (days to weeks or longer). Mood is represented by a thick solid line and affect is represented by a thin dotted line. The amplitude of each line reflects the intensity of emotion and emotional feeling. (A) Mood is euthymic (from Greek eu “normal” + thymia “state of mind”) – that is, the emotional climate is temperate and stable over days to weeks. Affect varies around that mood, with clearly identifiable shifts between positive (e.g., happiness) and negative (e.g., irritation, frustration, anger) of modest intensity occurring during any given day. (B) Mood is dysphoric (from Greek dusphoros “hard to bear”), i.e., persistently sad or sad/irritable most of the day nearly every day for several weeks. Affect continues to vary around that mood, but it is restricted to emotions and emotional feelings that are predominantly negative and whose amplitudes are attenuated. (C) Mood varies from persistently and excessively positive (i.e., euphoric and expansive) for a week or longer to excessively negative (i.e., sad). Affect is labile and intense when superimposed on persistently and excessively positive mood and its valence and amplitude are more restricted when superimposed on persistently and excessively negative mood. (D) Moderate affective lability superimposed on euthymic mood. (E) Severely pathological affect (i.e., pathological laughing and crying) superimposed on euthymic mood. (F) Severely pathological affect (i.e., pathological laughing and crying) superimposed on dysphoric mood (i.e., major depressive episode). This figure is presented in color in the color plate section.

affect. These features of mood are identified by asking: (1) How does the patient feel emotionally most of the time? (2) How does the patient appear to feel emotionally most of the time? Clinician observation and patient self-observation may be sufficient to answer the latter question; however, it is prudent to ask a reliable informant to answer this question about the patient as well. Questions about affect include: (1) How does the patient feel emotionally now? (2) How does the patient appear to feel emotionally now? (3) What

274

moment-to-moment variability, if any, is there in how the patient feels or appears to feel emotionally? Figures 18.1 and 2 offer a graphic representation of the emotional phenomena to which these questions pertain and to which clinical attention is directed. Additional comments on the evaluation of emotion, emotional feeling, mood, and affect are offered in Chapter 23, and overviews of the treatment of mood disorders and disorders of affect are presented in Chapter 34.

Chapter 18: Emotion

Figure 18.2. Graphic illustrations of several types of mood and affect. The Y-axis represents the valence of emotion and emotional feeling and the X-axis represents time (days to weeks or longer). Moods are represented by thick solid lines and affects are represented by thin dotted lines, the intensity of which are reflected by their amplitudes. This graphic offers a visual representation of the concepts of mood and affect: mood is a slow-frequency phenomenon (background, emotional “climate”) and affect is a fast frequency phenomenon (foreground, emotional “weather”). This figure is presented in color in the color plate section.

Neurobiology of emotion and emotional feelings The phenomenologies of emotional generation, expression, experience, and control reflect their putative neurobiologies. With emotion defined as the coordinated constellation of brain–body interactions, comprising facial expressions, vocalizations, gestures, body posture, behaviors, autonomic activity, visceral activity, neurohormonal, and neurotransmitter processes that occur automatically as reactions to specific types of external or internal, including imagined, stimuli (i.e., ex-movere phenomena) [4, 25, 46], the neuroanatomy of emotional generation and expression comprises a network of central, autonomic, and peripheral nervous system structures capable of supporting these functions. Since emotional feelings represent concurrent conscious awareness of automatic reactive brain–body interactions (i.e., ex-movere, or emotional, processes) and the mental images with which they are (or will become) associated [4, 46], the neuroanatomy of emotional experience includes systems capable of representing brain–body interactions and linking them with cognition. A neuroanatomic account of emotional control, or regulation, incorporates neural – especially prefrontal – systems capable of modulating those involved in emotional generation, expression, and experience [13, 33]. The concept of the “limbic system” pervades descriptions of the neuroscience of emotion, and traditional teaching in neurology and psychiatry regards it as the neural basis of emotion and emotional feelings. The term “limbic system” refers to a set of structures at the border (from Latin limbus “border, edge,

fringe”) between the telencephalon and diencephalon on the medial aspect of each hemisphere. Although descriptions of the limbic system and its elements vary between authors, most include at least the structures identified in Figure 18.3 [36, 107]. However, there are disagreements about the validity of this concept, its neuroanatomic referents, and its heuristic value [11, 36, 107–116]. Nieuwenhuys and colleagues (2008) [107] identify three essential criticisms of the limbic system concept in the literature: (1) lack of an adequate empirical definition; (2) blurring of the conceptual boundaries between the limbic system and the rest of the brain as integrated systems serving emotion and cognition; and (3) persistent uncertainty regarding the superior and inferior ends of this system. They suggest that the first and second of these criticisms are not tenable given that strict structural and functional criteria for the limbic system permits tract-tracing and immunohistochemical technique-based discrimination of this system from classical sensory and motor systems. They argue that the ongoing evolution of the anatomy of the limbic system does not undermine this concept, as “it is the very nature of living concepts to evolve” (in [107], p. 941). Perhaps most persuasively, they note that there is no functional system in the brain possessing sharp and distinct boundaries throughout – e.g., the demarcation between “sensibility” and “motricity” in neocortical circuitry is not invariant. Just as the concepts of somatosensory, auditory, visual, and voluntary motor systems remain valid and useful, the concept of the limbic system retains heuristic value as well. Most current formulations of the neurobiological bases of emotions and emotional feelings are grounded

275




Cut edge of midbrain Temporal lobe


Figure 18.3. Limbic and paralimbic areas viewed parasagittally. The top panel depicts these areas as if viewed through the left hemisphere. The bottom panel illustrates these areas in greater detail. Reprinted from Purves D, Augustine GJ, Fitzpatrick D et al., editors. Neuroscience. 2nd edition, 2001, with permission from Sinauer Associates.


Parahippocampal gyrus

Fornix


Anterior commissure


Hypothalamus


Mammillary body

Hippocampus

historically in theories about the limbic system that have evolved over the last one and a half centuries. However, those developed over the last decade [6, 13, 28–30, 38, 87, 117–119] focus on selective distributed neural networks supporting emotional generation and expression, emotional experience, and control of these phenomena rather than on the limbic system per se. In order to provide a foundation for modern neurobiological models of emotion and emotional feelings, an overview of the history and evolution of ideas about the limbic system is required.

276

A historical perspective on the limbic system Broca described the grand lobe limbique (“the great limbic lobe”) in 1878 [120]. This lobe comprises the cingulate and parahippocampal gyri, and was defined on the basis of its structure rather than its function. Nieuwenhuys et al. (2008) [107] suggest that during the last decades of the nineteenth and first decades of the twentieth centuries, most neuroanatomists conceptualized Broca’s limbic lobe as an element of the rhinencephalon in light of evidence demonstrating its abundant olfactory inputs.

Chapter 18: Emotion

Wilson (1924) [121], while not addressing “limbic” anatomy directly, examined the neuroanatomy of pathological laughing and crying and its bearing on the emotion hypotheses of James (1890) [8], Lange (1885) [48], and Sergi (1894) [122]. The common theme across these hypotheses was the primacy of brain–body interactions in emotion, and the secondary (and cortically based) nature of emotional feelings. Wilson appears to have agreed with the James–Lange hypothesis with respect to the essential role of emotional motor systems and the central representation of visceral systems in the genesis of emotional feelings among healthy individuals. However, he presented clinico-pathological examples demonstrating dissociation between emotional expression and volitional faciorespiratory motor function as well as several instances in which emotional display and emotional feeling dissociated. He also noted exceptional cases in which emotional displays occurred in the absence of a corresponding emotional feeling. Although he admonished clinicians working with persons with pathological laughing and crying “to be assured of the fact that the emotional display is a genuine manifestation of feeling” more often than not (in [121], p. 310), he challenged the James–Lange hypothesis by demonstrating that the mechanisms of emotional expression and emotional experience are distinct and dissociable. With regard to the mechanisms of emotional expression, Wilson (1924) [121] outlined a theory for the automatic function of facial and respiratory mechanisms in the act of laughing and weeping (physiological and pathological). He argued that the seventh cranial nerve nucleus and the motor nuclei of the ninth, tenth, and eleventh cranial nerves (i.e., nucleus ambiguus), “certain upper cervical spinal groups,” including the phrenic nerve nuclei at cervical levels 3–5, and, possibly, one or more medullary respiratory centers operated in concert to effect emotional expression. He opined that “for simplicity’s sake, we may allude it as the faciorespiratory mechanism” (in [121] p. 322) whose normal activities are involuntary and that it is amenable, at best, to a limited degree of voluntary control. In other words, laughter may be “stifled” and tears may be “restrained” but the fasciorespiratory mechanism tends to be engaged automatically and irresistibly in both normal and pathological states. Based on the work of Spencer (1894) [123], Wilson identified two tracts as central to the automatic expression of emotion. One arises from the under-surface of

the frontal lobe and is involved in the acceleration of emotional expression, and another arises from sensory cortex and is required for its arrest [121]. He suggested that these pathways converge in the midline proximate to the subthalamic nucleus and tegmentum, the appropriate excitation and inhibition of which modulates the expression of emotion. He elected not to address directly the connections between the fasciorespiratory mechanism and the central representation (and control) of the visceral system, and indicated that the neuroanatomy of those functions were “not at present, unfortunately, capable of the same objective examination” (in [121], p. 315). Wilson (1924) [121] regarded the experience of emotion (i.e., emotional feelings) as necessitating higher cortical areas that bring the operation of the machinery of emotional expression into conscious awareness. Echoing James (1890) [8], he regarded their involvement in the processing of the apperceived object necessary to integrating automatic motor, autonomic, and visceral processes with conscious awareness in order to “transform it from an object-simplyapprehended to an object-emotionally-felt” (in [121], p. 312). His elegant and prescient account of the dissociable neuroanatomies of emotional expression and experience foreshadowed subsequent mid-twentieth century descriptions of the limbic system. Papez (1937) [124], also building upon the works of James (1890) [8], Lange (1885) [48], Cannon (1927, 1931) [125, 126], Bard (1929, 1934) [127, 128], Penfield (1933) [129], and Ranson (1934) [130], reconceptualized the structures in Broca’s great limbic lobe as elements of a larger circuit constituting the neural substrate of emotion. He proposed that “the hypothalamus, the anterior thalamic nuclei, the gyrus cinguli, the hippocampus and their interconnections constitute a harmonious mechanism which may elaborate the functions of central emotion, as well as participate in emotional expression” (in [124], p. 743). His model included linked but distinct pathways subserving emotional expression and emotional experience (the Papez circuit; Figure 18.4). The former included the hippocampus, the anterior thalamic nucleus, and the hypothalamus in the “central production of the emotive process” (in [124], p. 734), and particularly their visceral, autonomic, and neuroendocrine components. At the level of the thalamus, Papez postulated that a set of concomitant impulses passing from the hippocampus via the mammillary bodies to the hypothalamus, a portion of which were communicated

277


Figure 18.4. The Papez circuit, as originally described by Papez in “A proposed mechanism of emotion” (Arch Neurol Psychiatry 1937;38:725–43).

via the ventral thalamus, served as the drivers of emotional expression. He suggested that upon arriving at the mammillary bodies a second pathway through the anterior thalamic nuclei to the gyrus cinguli represented “the stream of feeling” (in [124], p. 729). With this pathway, he identified the gyrus cinguli specifically as “the seat of dynamic vigilance by which environmental experiences are endowed with an emotional consciousness” (in [124], p. 737). Yakovlev (1948, 1968) [131, 132] applied an evolutionary perspective to the description of human brain organization, including the limbic system. He described three major zones of the brain: the median zone, the paramedian-limbic zone, and the supralimbic zone. The median zone includes the hypothalamic nuclei, medial thalamus, periventricular gray matter of the brainstem, and functionally related areas of the amygdala and insular cortex and related structures. The median zone mediates arousal (during wakefulness) and contributes to sleep regulation, and modulates energy metabolism, homeostasis, and visceral function. The paramedian-limbic zone includes the amygdala, orbitofrontal cortex, insula, hippocampus and parahippocampus, septum, ventral, anterior, and midline thalamic nuclei, habenula, and the basal ganglia. Consistent with the model developed by Papez (1937) [124], the paramedianlimbic zone mediates emotional expression and is necessary for the development of emotional feelings. The supralimbic zone includes the lateral thalamic nuclei and neocortical areas. The supralimbic zone mediates elementary sensorimotor functions as well as higher cortical (heteromodal association) functions. Unlike the paramedian-limbic zone, the functions of which are not strongly lateralized, the supralimbic zone demonstrates lateralization of function between

278

the cerebral hemispheres. This model suggests that the neurobiologies of basic emotions are preserved through evolution (i.e., “hard-wired”) to facilitate adaptation and fundamental everyday tasks [9, 61]. MacLean (1952, 1970, 1990) [133–135] also applied the principles of evolutionary neurobiology to the description of the limbic system and its function. Citing Ariëns Kappers (1928) [136] and Yakovlev (1948) [131], MacLean (1952) [133] asserted that the cortex of the limbic lobe is composed of archicortex (dentate gyrus, hippocampus) and the paleocortex of the olfactory area, as well as the transitional, or mesopallial, cortex adjacent to these areas. He also identified the structures of the limbic system as posterior orbital cortex and areas adjacent to it, the olfactory striae, the pyriform area, the hippocampal complex, the parasplenial, cingulate and subcallosal gyri, amygdala, anterior insula, temporal polar cortex, septal nuclei, hypothalamus, epithalamus, anterior thalamic nuclei, and parts of the basal ganglia [133]. He noted that “limbic” structures are strongly and reciprocally connected with multiple other brain areas and argued that the connections between limbic cortex and subcortical structures comprise a functionally integrated system. Adapting Broca’s (1878) [120] anatomic terminology, MacLean designated this functional unit “the limbic system” [133]. He hypothesized that it constituted a visceral brain for the “body viscus” that interprets and gives expression to incoming information in terms of feeling, “being incapable perhaps of getting at the meaning of things at the level of symbolic language” (in [133], quoting [137]). He also suggested that the frontotemporal portion of the limbic system contributes to the integration of memories and feelings related to the “oral” senses (i.e., information processed by the limbic system) and serves to tie limbic information to the workings of the brain as a whole. In subsequent works describing his triune brain model of the evolution of the vertebrate forebrain and behavior, MacLean (1970, 1990) [134, 135] suggested that the structures comprising the limbic system represent an evolutionarily preserved system supporting species-typical instinctual behaviors (e.g., “reptilian” functions of aggression, dominance, territoriality, ritualized displays) as well as feeding, reproductive behavior, parental behavior, emotion, and motivation (e.g., “paleomammalian” behaviors). This approach to describing the limbic system draws on Darwin’s (1890) [7] and Yakovlev’s (1948) [131] views of the

Chapter 18: Emotion

evolutionary cross-species preservation of mechanisms of emotional generation and expression, and parallels the contemporaneous suggestions of Ekman (1957, 1972, 1999) [9, 20, 59] that the distinctiveness and functional value of the basic emotions reflects their evolutionarily based neural “hard wiring.” Nauta (1958, 1969, 1973, 1979) [108, 138–140] regarded this hard wiring as extending beyond the telencephalic limbic “arch” (i.e., amygdaloid complex and hippocampal formation) to encompass a limbic system–midbrain circuit. The limbic “axis” of this circuit included, from rostral to caudal, the septal and preoptic regions, hypothalamus, and paramedian mesencephalic structures, including the mesencephalic central gray and the dorsal raphe nucleus (Nauta’s “limbic midbrain area”). Inputs to these structures derive from the amygdaloid complex and hippocampal formation as well as ascending visceralsensory pathways and humoral factors. He suggested that limbic axis regulates endocrine and visceral effector mechanisms – and thereby begins to offer a more complete account of the central representation (and control) of the visceral aspects of emotion and their influence on behavior. Mesulam (1985, 2000) [36, 141] argues that the shared behavioral specializations unifies the constituents of the limbic system: (1) perception of smell, taste, and pain; (2) linking autonomic, neuroendocrine, and neuroimmunological states with mental activity; (3) channeling of emotion and drives (e.g., hunger, thirst, libido) to extrapersonal events and mental content; (4) binding information from multiple distributed networks to recent events and experiences in a manner that supports explicit (i.e., declarative, episodic) memory; and (5) coordination of affiliative behaviors related to social cohesion. He identifies the limbic (allocortical and corticoid) and paralimbic cortices, paralimbic cortical belt, limbic striatum (olfactory tubercle, nucleus accumbens), limbic pallidum, ventral tegmental area, habenula, limbic and paralimbic thalamic nuclei (anterior dorsal, anterior ventral, anterior medial, laterodorsal, mediodorsal, medial pulvinar, and midline nuclei), and the hypothalamus as a set of tightly interconnected structures supporting these behavioral specializations, thereby justifying their aggregation into a unified system. Mesulam (2000) [36] also suggested that the limbic system is divisible into two general spheres of influence: amygdaloid and hippocampal. The amygdaloid sphere of influence encompasses the olfactocentric

paralimbic areas (echoing Broca’s (1878) [120] rhinencephalic formulation of the grand lobe limbique and MacLean’s (1952) [133] peri-olfactory anatomy of the limbic system). It is closely associated with autonomic–hormonal–immunologic function, emotion, motivation, and affiliative behavior. By contrast, the hippocampal sphere of influence includes the components of the Papez circuit, and tends to be most closely associated with cognition (e.g., explicit memory). This division of the limbic system provides a foundation for more recent descriptions of the dissociable anatomy of emotion (i.e., ex-movere phenomena) and emotional feelings [4, 25, 29, 33, 46], and echoes Wilson’s (1924) [121] and Papez’ (1937) [124] suggestions.

The greater limbic system Nieuwenhuys and colleagues (2008) [107], building on work by Nauta [108, 138–140] and Wilson [121], suggest that the rostrally situated components of the classical limbic system combine with their caudal extensions and adjuncts within the brainstem and cerebellum to form the “greater limbic system.” They suggest that the “central limbic continuum” does not end at the caudal diencephalic or mesencephalic levels and instead extends to a “core” region in the brainstem. This region includes the caudal aspects of the hypothalamic gray matter in continuity with the mesencephalic periaqueductal gray (PAG) and the pontine central gray, the parabrachial nuclei, and the dorsal vagal complex. Motor effector systems for emotional expression are integrated through a complex comprising the PAG, tegmentum, nucleus ambiguus, and nucleus retroambiguus (NRA) [42, 44]. As presaged by Wilson (1924) [121], the PAG-tegmentum component runs dorsally, and the PAG projects to the seventh cranial nerve, nucleus ambiguus (i.e., motor nuclei of the ninth, tenth, and eleventh cranial nerves), and the phrenic nerve. The NRA projects to the somatic motor neurons innervating the pharynx, soft palate, intercostal and abdominal muscles, and, possibly, the larynx. This complex receives inputs from the emotionalmotor pathway, which projects from posterolateral ventral frontal cortex and medial temporal (amygdaloid complex) and ventral striatopallidum to the PAG-tegmentum and medulla, generating automatic (i.e., involuntary) emotional expression. Modulatory efferents from motor and prefrontal cortices cerebellothalamo-fronto-pontine circuit as well as projections

279


from the elements of them provide mechanisms for the voluntary, albeit incomplete, control of these effectors of emotional expression [42, 44]. Nieuwuenhuys et al. (2008) [107] identify two adjuncts to these brainstem structures that further extend the caudal components of the limbic system. The first are the raphe nuclei, which extend through the brainstem and from which ascending and descending serotonergic efferents emanate. These nuclei are designated the “median paracore” of the greater limbic system. The second adjunct, designated the “lateral paracore,” includes a bilateral set of grisea (gray matter and fibers). These include the lateral part of the tegmental gray (at the midbrain level), the locus coeruleus (A6), nucleus subcoeruleus (A6sc), the Kölliker–Fuse nucleus (pontine respiratory group), the M region (pontine micturition center), L region (pontine continence region), nucleus reticularis parvocellularis, ventrolateral medulla, and the cytoarchitectonically illdefined A1, A2, A5, and A7 noradrenergic cell groups and C1, C2, and C5 adrenergic cell groups. Reciprocal cerebellohypothalamic projections also carry information between the cerebellum and the hypothalamus, and are coupled with indirect hypothalamocerebellar pathways related through brainstem nuclei. The function of cerebellar-limbic inputs is not defined fully, although disruption of cerebellar inputs into the greater limbic system is associated with disturbances in emotional control and, possibly, aberrant emotional generation [99, 142–144]. As summarized by Mesulam (1985, 2000) [36, 141], the limbic (allocortical and corticoid) cortices, paralimbic cortical belt (including the posterior and anterior cingulate cortices), ventral striatum, nucleus accumbens, olfactory tubercle, ventral pallidum, ventral tegmental area, habenula, limbic and paralimbic thalamic nuclei (anterior dorsal, anterior ventral, anterior medial, laterodorsal, mediodorsal, medial pulvinar, and midline nuclei), and the hypothalamus are the rostrally situated elements of the greater limbic system. These structures are connected to orbitofrontal, rostral (i.e., subgenual) cingulate, and dorsolateral prefrontal cortices, which extends the greater limbic system dorsally and establishes connections with areas capable of exerting control over the ventral and caudal aspects of the greater limbic system (see also Chapter 16). The components of the greater limbic system are usefully organized into several functional subsystems supporting emotional generation, expression,

280

experience, and control. These subsystems include the extended amygdala, the ventral striatopallidum, an arousal circuit, a motivational working memory circuit, a reward memory circuit, and the dorsal region [116, 119, 145–147].

Extended amygdala The extended amygdala includes the centromedial portion of the amygdala, the ventral portion of the substantia innominata, the stria terminalis, and the caudomedial portion of the “shell” of the nucleus accumbens [145]. Highly processed multimodal sensory information is projected to the extended amygdala from the secondary and heteromodal association areas, the hippocampal-posterior cingulate division of the limbic cortices, the anterior cingulatesubcortical and orbital-subcortical circuits (via their thalamic elements), visceral afferents ascending through the vagus nerve directly and indirectly via the hypothalamus, parabrachial nucleus, and sensory thalamus. Information is integrated in the extended amygdala in a manner that establishes a continuous, automatic, and – as suggested by MacLean (1949, 1952) [133, 137] – unconscious (or preconscious) awareness of the internal and external environment. The information processed in the extended amygdala appears to be assigned emotional valence and motivational significance prior to feeding-back into the rest of the greater limbic system [148]. Valence assignment may be predicated evolutionarily preserved (i.e., “hard-wired”) responses to specific types of humoral, interoceptive, and sensory stimuli as well as learned responses, including modifications of “hard-wired” responses based on prior experiences. The extended amygdala thereby facilitates associative (or conditioned) learning, develops a schema for automatic (e.g., pre- or unconscious) assignment of relative “survival values” (i.e., emotional and motivational significance) to incoming sensory information [145, 147]. The extended amygdala also contributes to the generation of automatic emotional expression. Outputs from the extended amygdala are communicated in parallel to: the locus coeruleus, facilitating arousal and attention; the medial portions of the hypothalamus, activating the hypothalamic-pituitary axis; the lateral hypothalamus, activating the sympathetic nervous system; the midbrain PAG, facilitating automatic motor responses and motoric “freezing;” the parabrachial nucleus, influencing respiration; and the

Chapter 18: Emotion

thalamus and the ventral striatopallidum, imparting influence on a broad range of brain and brainstem functions.

Ventral striatopallidum The ventral striatopallidum denotes the intersection of the ventral striatum (ventral caudate and putamen), ventral pallidum (ventral portion of the globus pallidum), the olfactory tubercle, and the nucleus accumbens [36]. The ventral striatum and nucleus accumbens receive input from limbic and paralimbic cortices, and often is described as the “limbic striatum” [107]. The ventral striatum projects to the ventral pallidum, which in turn projects to the lateral hypothalamic area, ventrolateral PAG, and mesencephalic locomotor region. The influence of the ventral striatopallidum on the mesencephalic locomotor region is emotional motor activity, including automatic emotional expression, oral behaviors, locomotion, respiration, and may modulate sleep–wake mechanisms. The ventral striatopallidum appears to be involved in the communication of information between the extended amygdala and the dorsal striatopallidum (i.e., the dorsal portions of the caudate, putamen, and globus pallidum involved in the frontal-subcortical circuits described in Chapter 5). The activity of the ventral striatopallidum is influenced strongly by dopaminergic projections from the ventral tegmental area (to the nucleus accumbens) and the substantia nigra (to the pallidum) [149], and plays a critical role in binding information from the extended amygdala into the selective distributed networks required for emotion and motivation. The extended amygdala and the ventral striatopallidum overlap anatomically and functionally, especially with respect to inclusion of the nucleus accumbens. The nucleus accumbens is an anatomically complex structure that, simplistically, can be regarded as influencing stimulus reward assignment and, hence, emotional and motivational significance. The nucleus accumbens is significantly influenced by dopamine received from the ventral tegmental area and substantia nigra pars compacta [149]. Dopaminergic neurons project from these brainstem areas into the nucleus accumbens, extended amygdala, and ventral striatopallidum and facilitate activity of these areas. The extended amygdala and ventral striatopallidum also exert descending influences on the brainstem dopaminergic nuclei, thereby influencing the extent and duration of activity in this system.

Arousal circuit This limbic subsystem includes the ventral pallidum, ventral tegmental area, and the cholinergic pedunculopontine nucleus. Reciprocal connections between these structures facilitate integration of autonomic activity and arousal status with prosencephalic structures subserving locomotion, emotion, and cognition [150, 151]. Afferents from the pedunculopontine nucleus project superiorly and inferiorly in a manner that increases action readiness. Activation of the pedunculopontine nucleus itself produces spontaneous fight or flight reactions, appetitive behavior, and stereotypic rhythmic displays.

Motivational working memory circuit This circuit includes the ventral tegmental area, nucleus accumbens, and ventral pallidum [146, 147], and is reciprocally connected with multiple caudal and rostral structures, including the arousal circuit, extended amygdala, ventral striatopallidum, hypothalamus, hippocampal complex, and prefrontal cortices. This circuit facilitates momentary “holding” of information from these sources and comparison of its emotional and motivational valence of that information with those of previously presented stimuli. In a manner analogous to an emotional and motivational rheostat, this circuit continuously adjusts behavioral response readiness. Two motivational working memory subcircuits – a limbic subcircuit and an emotional motor subcircuit – differentially influence behavioral responses to emotionally and motivationally significant stimuli [146, 147]. The threshold for activation of the limbic subcircuit is lower than that of the motor subcircuit. Stimuli with relatively modest emotional or motivational significance activate the limbic subcircuit easily. Through its connections to the arousal circuit, extended amygdala, ventral striatopallidum, and hypothalamus, activation of the limbic subcircuit increases arousal and autonomic activity. Stimuli of greater emotional or motivational significance activate the emotional motor subcircuit. By way of connections to the posterolateral ventral frontal cortex and medial temporal cortex (amygdaloid complex), ventral striatopallidum, hypothalamic, basal ganglia, and brainstem effector areas, the emotional motor subcircuit generates automatic and stereotypic motor responses – i.e., automatic, or involuntary, emotional expressions.

281


Reward circuit The core components of this circuit are the ventral tegmental area, the amygdala, and the nucleus accumbens [146, 147, 152], and their connections to orbitofrontal and anterior cingulate cortices [118, 153]. Connections among these areas are strengthened or weakened based on the outcomes of stimulusresponse pairings. Neurons of the nucleus accumbens appear to differentiate between rewarding stimuli by sorting into reinforcer type-specific distinct ensembles or networks that are “tuned” to particular associative behavioral contexts, and that couple response execution to reward delivery [152]. These networks are negatively coupled and mutually inhibitory in order to maintain accurate encoding of immediately experienced rewards as well as anticipated reward contingencies [152]. The orbitofrontal cortices (and the corticalsubcortical circuits to which they contribute) contribute to the reward circuit by facilitating evaluation of the emotional significance and valence of stimuli based on innate and learned social valuations [118]. In combination with the anterior cingulate cortex, these regions create a global workspace for and gateway to the conscious experience of transient positive and negative emotional states and overall hedonic tone [118, 153] (see also Chapter 16). The orbitofrontal and anterior cingulate components of this subsystem are necessary but not sufficient substrates for the subjective aspects of affect and mood (i.e., emotional feelings).

Dorsal region The dorsal region includes the hippocampus, posterior cingulate, previously described dorsolateral prefrontal-subcortical circuit (see Chapter 5) and related dorsal prefrontal heteromodal association cortices, as well as the cortical, subcortical, and diencephalic structures to which they are connected (see Chapter 16). Afferent and efferent connections from the prefrontal cortical origin of the dorsolateral prefrontal-subcortical circuit are made with the orbitofrontal and cingulate cortices, heteromodal parietal cortex, auditory and visual association cortices, retrosplenial cortex, parahippocampal gyrus, and presubiculum [154]. The dorsal caudate (the striatal portion of the circuit) receives afferents from parietal, temporal, and occipital cortices as well as the substantia nigra and mediodorsal thalamus. This region

282

contributes to processing information about the outside environment, the internal milieu, and emotional and motivational state, and is involved in developing action plans that are integrated with those developed in the motor-, oculomotor-, lateral orbitofrontal-, and anterior cingulate-subcortical circuits [154]. Ascending projections from the limbic, paralimbic, and caudally situated structures of the greater limbic system permit neocortical representations of exmovere phenomena (i.e., emotion) and development of the global workspace and conscious experience of reward and punishment [118, 153]. The integration of those phenomena with the conscious experience of reward and punishment as well as other sensory and cognitive information sets requires the dorsal prefrontal heteromodal association cortices. This integration permits conscious awareness of automatic reactive brain–body interactions (i.e., ex-movere, or emotional, processes) and the mental images with which they are (or will become) associated – and, therefore, provide a neurobiological basis for the development of emotional feelings [4, 46]. Descending corticolimbic projections permit modulation of activity within the greater limbic system, including activity within the classical limbic structures (i.e., amygdaloid complex, hippocampal formation, hypothalamus, thalamus, ventral striatopallidum), cerebellum, and brainstem [13, 29, 33, 155]. The control functions of the dorsolateral prefrontal cortex provide mechanisms for modulating and/or re-directing ex-movere phenomena (i.e., automatic emotional motor behaviors, visceral, autonomic, and neurohormonal responses) – i.e., they constitute neural mechanisms for emotional control.

Humoral, interoceptive, and sensory inputs to the greater limbic system Nieuwenhuys et al. (2008) [107] identify several general types of input into the greater limbic system. In addition to the aforementioned neocortical, extrapyramidal (i.e., ventrostriatopallidal), brainstem, and cerebellar inputs to the prosencephalic structures of the greater limbic system, humoral and interoceptive inputs provide a mechanism for introducing information on physiologic state and sensory data (actual, hallucinatory, or recalled) into the greater limbic system.

Chapter 18: Emotion

Humoral and interoceptive inputs Humoral inputs include sodium, glucose, free fatty acids, and other nutrient level monitoring by the hypothalamus, the trigger zones for blood and cerebrospinal fluid-borne substances in the circumventricular organs surrounding the third and fourth ventricles, as well as neurohormone (e.g., glucorticoid, mineralocorticoid, gonadal steroid receptors) receptors throughout limbic regions. Interoceptive inputs carrying information concerning the physiologic status of body tissues are carried by the vagus nerve to the nucleus of the solitary tract and, directly as well as indirectly, to classical limbic regions including the amygdala and, by extension, the anterior insular cortex. Additionally, interoceptive inputs are carried via spinal dorsal horn fibers that, following the trajectory of the lateral paracore bundle, terminate in the nucleus of the solitary tract, parabrachial nuclei, lateral pontine tegmentum, cuneiform nucleus, mesencephalic PAG, ventrolateral medulla, and the catecholaminergic A1-A7 and C1 cell groups. Efferents from this complex of structures ascend to the hypothalamus (supraoptic and paraventricular nuclei), dorsal septum, nucleus accumbens, hippocampus and retrosplenial cortex, and medial prefrontal cortex [156].

Sensory inputs Visual input reaches the suprachiasmatic nucleus of the hypothalamus directly via the retinohypothalamic tract, and projects from there to other limbic structures. This input is involved in light-cue entraining of circadian rhythms for sleep–wake cycling, feeding, drinking, and hormonal secretion. Olfactory input to the limbic system is provided by olfactory projections to the lateral hypothalamus, amygdala, and hippocampus [107], and influences feeding, mating, and other goal-oriented behaviors. Auditory inputs activate the limbic midbrain region [157], pedunculopontine nucleus [158], the amygdala and ventral striatum [159], hippocampus and cingulate [160], and, predominantly from secondary auditory association areas, the insular cortex [161]. Somatosensory input arising from the spinal cord and spinal trigeminal nucleus carry nociceptive input to the PAG and thermoreceptive and nociceptive inputs to the parabrachial complex; the latter subsequently projects to the hypothalamus and amygdala. The amygdala then sends projections to the anterior insula. Some neurons in lamina I of the spinal and medullary dorsal horn

as well as the central gray matter of the spinal cord project directly to the hypothalamus, amygdala, septum, nucleus accumbens, ventral pallidum, and orbital cortex, providing an additional set of somatosensory inputs to the greater limbic system. There is anatomical continuity between the insular cortex, orbital cortex, and medial limbic structures [162, 163]. In concert with the inputs to the medial limbic structures and orbital cortex, the insula contributes to processing of information concerning the internal and external environments. The insula, and especially the insular viscerosensory cortex, receives information regarding thoracic and abdominal viscera carried from the vagus nerve through the nucleus of the solitary tract, parabrachial complex, and ventral posteromedial thalamic nucleus (parvocellular portion).

Neurotransmitter modulation of the greater limbic system Multiple neurotransmitter systems are involved in emotional generation, expression, experience, and control, including glutamate, gamma-aminobutyric acid (GABA), dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters, respectively, in the central nervous system (CNS). Their functions at their target sites within the greater limbic system are modulated by the major ascending neurotransmitters, especially the catecholamines (dopamine and norepinephrine), serotonin, acetylcholine, and histamine. The function of these neurotransmitters is modified by colocalized neurohormones, neuroactive peptides, and the humoral factors described above [107]. As neurochemical anatomy is reviewed in Chapters 2, 5, and 16, its discussion here is limited to those aspects relevant to neurochemical modulation of the greater limbic system.

Serotonin As noted earlier, Nieuwenhuys et al. (2008) [107] identify the serotonergic raphe nuclei extending throughout the brainstem as the median paracore of the greater limbic system. Raphe system projections to the lower brainstem and spinal cord enhance motor signals and attenuate ascending sensory signals. Median raphe nucleus and nucleus raphe magnus efferents densely innervate the cerebellum. Efferents from the

283


dorsal raphe nucleus target the olfactory bulb, amygdala, entorhinal cortex, dentate gyrus, rectus gyrus (medial orbitofrontal cortex), inferior and superior temporal gyri, and striatum. The dorsal raphe nucleus receives projections from the heteromodal and paralimbic prefrontal cortices as well as limbic cortices [164]. Median raphe efferents target the hippocampus, basal forebrain, and septum, and receive modulatory inputs from limbic and paralimbic cortices [164, 165]. Efferents from the raphe nuclei also specifically target the substantia nigra, ventral tegmental area, locus coeruleus, pedunculopontine and laterodorsal tegmental nuclei (Chapters 5 and 6), resulting in an interconnected network between these modulatory neurotransmitter nuclei. Depending on the serotonin receptor type and its pre- or post-synaptic location, serotonergic modulation at any given neuron within the limbic system may be facilitory or inhibitory. Under non-pathological circumstances, serotonin appears to stabilize activity within the limbic and paralimbic belt, thereby modifying emotional generation and expression. These effects may reflect attenuation of amygdala activity and/or information processing at the level of the striatum, as well as serotonin-facilitated dopamine release by the ventral tegmental area. Serotonergic input also modulates activity within the prefrontal cortices, the striatum, and thalamus, and thereby modifies emotional experience and/or emotional control.

Dopamine Dopaminergic fibers from the ventral tegmental area and substantia nigra project to cortical, limbic and paralimbic, and striatal targets. Dorsal mesocortical dopaminergic projections arise from the ventral tegmental area. Ventral dopaminergic projections from the ventral tegmental area project to dorsal medial prefrontal areas and ventral aspects of the medial prefrontal cortices [166]. Dopaminergic fibers from the ventral tegmental area project into the nucleus accumbens, ventral striatum, orbitofrontal and cingulate cortices, and they modulate the function of the extended amygdala, ventral striatopallidum, arousal, motivational working memory, and reward circuits [164, 167, 168]. Dopaminergic inputs into these areas appear to alter reward value assignments, reward anticipation, and hedonic experience, and set overall hedonic tone [6, 118, 169, 170]. In these and other manners, dopamine affects emotional generation and expression.

284

Dopaminergic projections to prefrontal areas from the ventral tegmental area and into the dorsal striatum from the substantial nigra, retrorubral region, and ventral tegmental area modify the activity of heteromodal prefrontal cortices, the frontal-subcortical circuits to which they contribute, and the neocortical, limbic, and paralimbic areas to which they are connected. As reviewed in Chapter 16, the effects of dopamine on information processing systems vary with the types of receptors at which these neurotransmitters act and their locations, but generally serve the function of optimizing signal-to-noise ratio within information processing circuits. Such effects may modify attention to ex-movere phenomena and the experience of emotion. Prefrontal areas also project to dopaminergic cell groups; modification of the activity of these groups reciprocally influences dopaminergic tone in the more rostrally situated prosencephalic elements of the greater limbic system, which contributes to prefrontally mediated control of emotion.

Norepinephrine Noradrenergic fibers arise from the locus coeruleus and project to widespread areas of limbic and paralimbic cortices, hypothalamus, neocortex, brainstem, cerebellum and, along with fibers from the locus subcoeruleus, to the spinal cord. Neurons of the noradrenergic cell groups C1, C2, and C5 and adrenergic cell groups A1, A2, A5, and A7 are elements of the lateral paracore of the greater limbic system, and contribute to its role in response generation to interoceptive inputs. Neurons of the locus coeruleus are more responsive to the emotional and motivational relevance of a stimulus than to its sensorial properties [36]. Noradrenergic input to the extended amygdala increases arousal and attention, and facilitates the effect of emotional and motivational salience on new learning (especially fear memory) [171]. Norepinephrine inputs to the extended amygdala, including the bed nucleus of the stria terminalis, shell of the nucleus accumbens, and central nucleus of the amygdala, also modulate behavioral responses to environmental and internal stressors and contribute to the generation of anxiety [172]. In short, noradrenergic inputs to cortical and limbic systems adjust signal-tonoise ratio in emotion-related information processing circuits, thereby enhancing the specificity of responses to events, focusing attention, increasing resistance to distraction, and modulating novelty-seeking behaviors. Prefrontal cortical regions also project to the

Chapter 18: Emotion

locus coeruleus and modulate its activity, controlling its activity and reciprocally affecting the contribution of norepinephrine to emotional generation and expression [164].

Acetylcholine Cholinergic inputs to the greater limbic system include: Ch1 and Ch2, which project via the fornix to the hippocampus; Ch3, which projects via the olfactory tract to the olfactory bulb; Ch4 (nucleus basalis of Meynert), which projects to the amygdala via the ventral amygdalofugal stria terminalis, to the medial orbitofrontal, subcallosal area, cingulate and pericingulate gyri via the medial pathway (within the cingulum), to the insula via the perisylvian division of the lateral pathway, to the dorsal frontoparietal network, inferotemporal cortex, parahippocampal cortex, and possibly to the amygdala via the capsular division of the lateral pathway; Ch5–6 (pedunculopontine-laterodorsal tegmental complex), which projects to thalamus, cerebellum, globus pallidus, subthalamic nucleus, substantia nigra (pars compacta), the medullary reticular formation, and (to a lesser extent) the striatum; and the intrinsic cholinergic interneurons of the striatum. The cerebellum also contains cholinergic neurons that are localized predominantly in the vermis, flocculus, and tonsilla. Cholinergic inputs therefore contribute substantially to the function of the greater limbic system. The role of cholinergic tone in this system is complex, reflecting the large number of discrete cholinergic nuclei, their distinct and overlapping anatomic targets, and the wide range of receptors at which they act. In general, cholinergic activation increases arousal and facilitates information processing of many types, including emotion. However, the effects of acetylcholine are quadratic, with optimal function at the mid-range of acetylcholine concentrations and impaired function at lower or higher concentrations. Given its wide distribution to the greater limbic system, acetylcholine modulates emotional generation, expression, and experience. Cholinergic neurons, especially those in Ch4, also receive input from prefrontal regions, including the orbitofrontal cortices [164]. These inputs contribute to prefrontally mediated control over emotion by reciprocally affecting cholinergic tone in the greater limbic system.

Histamine Histamine neurons are located in the posterior hypothalamus, and project diffusely throughout the brain [173]. The histaminergic system modulates arousal, appetitive functions, sleep–wake cycling, memory, and emotion, and may modulate stress susceptibility [173]. Some fibers in the hypothalamocerebellar pathways are histaminergic, and (through their effects at metabotropic histamine type 1 and type 2 receptors), modulate cerebellar modulation of somatic motor and non-motor responses [174]. In light of the widespread direct effects of histamine on the function of neocortical, limbic, paralimbic, hypothalamic, and cerebellar areas, and the secondary influence of histaminergic hypothalamocerebellar inputs on cerebellar modulation of greater limbic system function, histamine also may contribute to emotional generation, expression, experience, and control.

Other systems Mu-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, amygdala, and inferior temporal cortex has been shown to regulate brain regions centrally implicated in emotional processing [44]. Sigma receptors, and their two subtypes, s-1 and s-2, exist mainly in the CNS, and regulate inositol 1,4,5-triphosphate receptors (IP3 receptors) and calcium signaling at the endoplasmic reticulum, modulation of neurotransmitter release and neuronal firing, and the modulation of potassium channels as a regulatory subunit. Sigma-1 agonists amplify signal transduction induced by glutamatergic, dopaminergic, IP3-related metabotropic, and nerve growth factor-related systems, and may contribute to the modulation of signal strength in the greater limbic system [44].

Networks for emotional generation, expression, experience, and control A network approach to information processing organizes the rostral and caudal components of the greater limbic system into two large-scale, selective distributed neural networks, or compartments, subserving emotional generation, expression, experience, and control: a ventral compartment and a dorsal compartment [17, 147, 175]. Analogous to the suggestions of Mega et al. (1997) [175], Phillips et al. (2003) [28], Seminowicz et al. (2004) [38], and Price et al. (2010) [29], these compartments may be organized usefully around

285


Figure 18.5. A schematic representation of many of the structures and circuits supporting emotional generation, expression, experience, and control and their functional relationships. Glutamatergic, presumed excitatory projections are shown in green, GABAergic projections are shown in orange, and modulatory projections in blue. In the model proposed here, dysfunction in the amygdala and/or the medial prefrontal network results in dysregulation of transmission throughout an extended brain circuit that stretches from the cortex to the brainstem, generating emotion and its expression through motoric, visceral, autonomic, endocrine, and neurochemical effectors. Intra-amygdaloid connections link the basal and lateral amygdaloid nuclei to the central and medial nuclei of the amygdala. Parallel and convergent efferent projections from the amygdala and the medial prefrontal network to the hypothalamus, periaqueductal gray, nucleus basalis, locus coeruleus, dorsal raphe, and medullary vagal nuclei organize neuroendocrine, autonomic, neurotransmitter and behavioral responses to stressors and emotional stimuli. Structures of the default system (or network) support emotional experience. The amygdala and medial prefrontal network interact with the cortico-striatal-pallidal-thalamic loop, through prominent connections both with the accumbens nucleus and medial caudate, and with the mediodorsal and paraventricular thalamic nuclei, to control and limit responses. Abbreviations: 5-HT – serotonin; ACh – acetylcholine; BNST – bed nucleus of the stria terminalis; Cort. – corticosteroid; CRH – corticotrophin releasing hormone; Ctx – cortex; NorAdr – norepinephrine; PAG – periaqueductal gray; PVH – paraventricular nucleus of the hypothalamus; PVZ – periventricular zone of hypothalamus; VTA – ventral tegmental area. Reprinted from Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology 2010;35(1):192–216, with permission. This figure is presented in color in the color plate section.

Mesulam’s (2000) [36] amygdaloid and hippocampal limbic spheres of influence. Each is subject to modulation by the humoral, interoceptive, sensory, and neurochemical inputs. Figure 18.5 identifies many of the key anatomic and neurochemical contributors to these networks and their putative functional relationships.

286

Ventral compartment The ventral compartment (amygdala-orbitofrontal division) integrates the structures included in the extended amygdala, ventral striatopallidum, arousal circuit, motivational working memory circuit, and reward memory circuit. This compartment receives

Chapter 18: Emotion

inputs from visceral, humoral, and sensory sources and integrates them with innate (i.e., “hard-wired”) stimulus appraisals, learned social cognitive information, and reward-related valuations. The products of these inputs and the integration of these processes are emotions – i.e., automatic responses mediated through the autonomic, visceral, neuroendocrine, and motor systems that modulate the individual’s internal milieu and move him into action through innate and learned behaviors in a manner that addresses physical and social needs (i.e., survival). The ventral compartment facilitates what might be described as the “unconscious” aspects of emotion, and generates much of the readily observable motor, visceral, autonomic, and neuroendocrine components of emotional expression [147].

Dorsal compartment The dorsal compartment (hippocampal-posterior cingulate division) includes the elements of the Papez circuit (i.e., hippocampal complex, fornix, mammillary bodies, anterior and ventral thalamus, anterior and posterior cingulate gyri, and hypothalamus), the dorsolateral prefrontal-subcortical circuit and related dorsal prefrontal heteromodal association cortices, and the cortical, subcortical, and diencephalic structures to which they are connected. Multimodal sensory inputs enter the hippocampus via the perforant pathway, from which the information flows in the fashion outlined by Papez (1937) [124] to anterior and posterior cingulate. The posterior cingulate is involved in the consolidation of declarative memory and in associative learning, reciprocally connected to the dorsolateral prefrontal cortex, and is a critical node within the “default network” of the brain [176–178]. In that context, it is regarded as a critical neural substrate for conscious awareness. In concert with and influenced by heteromodal dorsolateral prefrontal cortex, and via inputs to the posterior parahippocampal and perirhinal cortices, the posterior cingulate modulates the flow of information through the perforant pathway and into the hippocampus. Ascending projections from the ventral compartment permit neocortical representations and conscious awareness of ex-movere phenomena and their association with current and past percepts as well as other cognitive processes [4, 46]. Effective integration of information from the ventral compartment into the dorsal compartment is necessary for the transformation of objects apprehended into ones that are

felt emotionally. The structures comprising the dorsal compartment – especially those overlapping with the default network – integrate awareness, memory, and other cognitions into emotional processing, and (via reciprocal connections with the ventral compartment) bring “unconscious” or “preconscious” emotion into conscious awareness (i.e., create emotional feeling). The orbitofrontal cortex and rostral cingulate gyrus are critical nodes for the translation of information between the ventral and dorsal compartments [117, 175, 179–182]. The subgenual cingulate gyrus (Brodmann’s area 25), in particular, is a point of convergence for efferents and afferents from both compartments [117, 179–182], thereby integrating them into a distributed network subserving emotional generation, expression, and experience [147, 175]. Descending corticolimbic projections, corticobulbar projections, reciprocal cortico-limbic-subcorticothalamic-ponto-cerebellar circuits (and their influence on reciprocal cerebellohypothalamic projections) influence the function of the entire limbic continuum (i.e., prosencephalic, mesencephalic, and rhombencephalic components) [44, 107, 147, 175]. Through these dorsal-to-ventral pathways, the structures and systems involved in emotional generation and expression are modulated and a degree of emotional control is accomplished [13, 29, 33, 44, 121, 147, 155, 175, 183].

Lateralization of emotion and emotional feelings Yakovlev (1948, 1968) [131, 132] suggested that the functions of the paramedian-limbic zone (i.e., ventral compartment) are not strongly lateralized and that supralimbic zone (i.e., dorsal compartment) demonstrates hemispheric lateralization of function. It is not clear that the latter suggestion was intended to entail hemispheric lateralization of emotional functions, although many popular and scientific hypotheses regarding emotional lateralization in the human brain have been advanced subsequently. The most common of these hypotheses are the right-hemisphere hypothesis and the valence-specific hypothesis. The right-hemisphere hypothesis proposes that the right half of the brain is specialized for emotional processing, regardless of the valence of the emotion or emotional feeling being processed. The valence-specific hypothesis suggests that both hemispheres process emotion and emotional feelings, but the involvement

287


of each varies with the emotional valence of the information processed. There are two variations of the valence-specific hypothesis. One suggests that the left hemisphere is dominant for positively valenced emotions and the right hemisphere is dominant for negatively valenced emotions. The other suggests that lateralization of emotional functions is linked more strongly to approach (left) and avoidance (right) behaviors rather than emotional valence per se. Despite their conceptual differences, the only major point of disagreement between the valence-specific hypotheses is their hemispheric assignment of anger. Although colloquially regarded as a negative emotion, anger is often, even if sometimes maladaptively, associated with approach behaviors [63–65]. Several relatively recent research and clinical observations provide an opportunity to clarify which aspects of emotional generation, expression, experience, and control are represented asymmetrically in the human brain. Two meta-analyses assessed the functional magnetic resonance imaging (fMRI)-derived neuroanatomy and lateralization of emotion [31, 32]. These meta-analyses incorporated data acquired from 1600 healthy individuals across 105 fMRI studies performed between 1990 and 2008 in which the emotional faces paradigm (or its variants) were used to elicit brain activation. All emotional conditions, irrespective of stimulus valence, produced bilateral activations of limbic, temporoparietal, and prefrontal cortices, the putamen, and cerebellum areas as well as visual cortical pathways required for face stimulus processing. These structures included the amygdala, parahippocampal gyrus, posterior cingulate, middle temporal gyrus, inferior frontal and superior frontal gyri, fusiform gyrus, lingual gyrus, precuneus, and inferior and middle occipital gyrus. Happy, fearful, and sad faces activated the amygdala. Angry or disgusted faces did not activate the amygdala, but did activate insular cortex. Amygdala sensitivity was greater for fearful faces than for happy or sad faces, and insular sensitivity was greater for disgusted than for angry faces. Cerebellar activation was observed in all emotional conditions. A valence-specific lateralization to the left amygdala during processing of negative emotions was observed, as was a “left/approach” and “right/withdrawal” pattern of imaging activation related to prefrontal responses to emotional faces. These neuroimaging-based meta-analyses of emotional processing fail to support the right-hemisphere

288

hypothesis, at least as regards emotional activation associated with viewing human faces. Instead, it suggests that emotional processing in the human brain is a complex phenomenon that engages the ventral and dorsal compartments bilaterally and whose explanation may require both variations of the valence-specific hypothesis. Similarly, Damasio and colleagues (2000) [184], using positron emission tomography (PET), studied the neural correlates of happiness, sadness, fear, and anger using a personal life-episodes recall paradigm in 41 healthy individuals. There were individual variations in the specific brain regions activated during subjects’ experiences of these emotions. However, all subjects exhibited bilateral activation of limbic, paralimbic, somatosensory, prefrontal, brainstem, and cerebellar areas during these tasks. Their observations further suggest that healthy emotional processing usually involves bilateral activation of ventral and dorsal compartment structures. Additionally, models of the neurology of emotion and emotional regulation in healthy individuals and persons with idiopathic depressive disorders favor a ventral-dorsal dichotomy and do not support a strongly lateralized neuroanatomy of emotion [38, 185, 186]. Meta-analysis of the neuroimaging data used to construct these models reveals that the function of right and left BA9 (dorsolateral prefrontal cortex) is highly intercorrelated and their replacement by one another in these models produces similarly robust results [38]. Similarly, when deep brain stimulation of the subgenual cingulate gyrus is used to treat refractory depression, treatment effect does not differ as a function of the side stimulated [187]. Collectively, clinically derived models based on functional neuroimaging studies of healthy individuals and recent deep brain stimulation-related studies of persons with treatment refractory depression show that emotional generation, expression, and experience involve ventral and dorsal compartment structures bilaterally. By contrast, emotional control may be lateralized [13, 183]. Ochsner and Gross (2005) [13], based on an fMRI study examining brain activation patterns associated with emotional control [183], suggest that the specific ventral and dorsal compartment structures recruited during emotional control may vary as a function of the goal of control (Figure 18.6). The activation patterns observed are similar to those associated with executive function: task generation (or task setting) – in this context, increasing emotion – tends to

Chapter 18: Emotion

Figure 18.6. Results from a study examining the effects on brain activation and emotion of systematic variations in the goal and content of reappraisal strategies. A: Regardless of whether the goal is to increase or decrease emotion, lateral prefrontal and anterior cingulate cortices are activated. B: When the goal is to decrease emotion, right dorsolateral and ventrolateral prefrontal as well as right orbitofrontal cortex is more active than are left-hemispheric structures (left panel). By contrast, when the goal of control is to increase emotion, left lateral and dorsomedial prefrontal cortical regions are differentially recruited when imagining worsening experiences and outcomes (right panel). Abbreviations: LPFC, lateral prefrontal cortex; MPFC, medial prefrontal cortex; ACC, anterior cingulate cortex; OFC, orbitofrontal cortex. Adapted from Ochsner KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci. 2005;9(5):242–9, with permission. This figure is presented in color in the color plate section.

engage left lateral prefrontal cortex whereas performance monitoring [188], expectation re-setting [189], and/or response inhibition [190] – in this context, decreasing emotion – tend to engage right lateral prefrontal cortex.

Lateralized neurological processes and emotional disturbances The preceding review supports the view that emotional generation, expression, experience, and control are subserved by bilateral ventral and dorsal compartment structures. However, studies of persons with idiopathic psychiatric disorders or unilateral lesions suggest the possibility that lateralized abnormalities may produce specific types of emotional disturbances [17, 104, 191– 204]. Among the most commonly reported associations of these types are: depression and left anterior (i.e., lateral and/or polar prefrontal) and/or basal ganglia lesions; pathological crying and left hemispheric lesions or right hemispheric irritative (e.g., seizure) foci; mania and right ventrobasal lesions; and pathological laughing with right hemispheric lesions or left hemispheric irritative foci.

It has been suggested that the response of monoamine receptor systems to injury (e.g., stroke) or neurodegeneration may be lateralized such that right, but not left, hemisphere injuries are followed by robust upregulation or biogenic amine receptor densities [205, 206]. Lateralized relative biogenic amine deficits after left hemispheric injuries, it is argued, may constitute a vulnerability to conditions like depression or pathological crying. Conversely, right ventrobasal or dorsal prefrontal injuries might impair right hemisphere emotional control functions or “release” the generative left hemisphere emotional control systems, thereby leading to abnormal euphoric, dysphoric, irritable, or anxious states. Although common clinical experience suggests that there may be a relationship between emotional disturbances and lateralized brain injury or disease, emotional disturbances tend to be more common after bilateral injury [104]. Indeed, many of the neurological and idiopathic psychiatric conditions in which disturbances of emotion and emotional feelings develop affect bilateral ventral and dorsal compartment structures [203, 204]. Additional research is

289


needed to better establish the nature and frequency of relationships between hemispheric laterality and mood disorders and/or disorders of affect, and then to identify their neurobiological bases.

Neurobiological bases of mood and affect The neurological bases of emotional generation, expression, experience, and control suggest bilateral involvement of ventral and dorsal compartment structures for all emotional events. Neither activation patterns in these compartments nor the character (valence, intensity) of the emotions and emotional feelings predicated upon distinguish between mood and affect. For example, in a study employing fluorodeoxyglucose PET of a group of subjects with depression as well as healthy individuals engaged in a “transient induced sadness” task, Mayberg et al. (1997) [180] observed decreased dorsal compartment and increased ventral compartment activation during healthy sadness and depressive illness. After treatment of depression or cessation of transient sadness, metabolism in the ventral compartment normalized and was associated with co-occurring increases in dorsal compartment activity. The level of activation in the rostral anterior (i.e., subgenual) cingulate predicted these changes, concordant with its hypothesized role as a critical node for inter-compartment communication and functional integration. Given only crosssectional neuroimaging of activity in the ventral and dorsal compartments, however, neuroanatomic distinction between depression and transient healthy sadness is not possible. The neurobiological distinction between mood and affect does not rest on differences in the structures supporting their expressed and experienced components but on the durations over which those structures are activated. Under normal circumstances, transient stimuli and/or stressors engage the neural systems supporting emotional generation, expression, and experience resulting in brief emotions and emotional feelings – i.e., a change in the emotional weather, or affect. The emotional weather passes relatively quickly as a function of neurobiological allostasis, the process of achieving or re-establishing stability (i.e., homeostasis) through physiological or behavioral change [207]. This process permits transient changes in emotion and emotional feeling (affect) to remain transient (see Figure 18.1A). Provided that the frequency, intensity, and accompanying psychosocial context does not

290

overwhelm allostatic capacity, this process ensures that a return is made in relatively short order to a state of neurobiological and phenomenologic emotional homeostasis. The occurrence of frequent, prolonged, or excessive stressors that create allostatic overload and gradually compromise the function of the neural systems subserving emotional generation, expression, experience, and/or control [208]. Additionally, allostatic overload also may produce long-term changes in these neural systems. Alone or in combination with intrinsic neurobiological vulnerability factors, allostatic overload gradually alters (or creates a vulnerability to alteration of) homeostasis in the neural systems subserving emotion and emotional feeling [17, 87, 208, 209]. These alterations may include abnormalities of the hypothalamic-pituitary-adrenal axis [210], altered function of glutamate or GABA systems [211], monoaminergic neurotransmitter systems [87, 208], or neurotrophic factors [212–214], and/or disturbances of second messenger systems, cell turnover, gene transcriptions, and epigenetic mechanisms [17, 87, 208]. When the homeostatic “set point” of the emotional networks is altered by frequent, prolonged, or severe allostatic overload, that shift in homeostatic set point produces sustained and pervasive changes in emotion and emotional feeling – i.e., an emotional “climate shift,” or mood disorder (see Figure 18.1B). Although these ideas must be regarded as speculative, they represent an emerging view [17, 87, 208] of the neurobiological differences between transient and sustained disturbances of emotion and emotional feeling – i.e., disorders of affect and mood disorder, respectively. This view is heuristically valuable, and reconciles the neuroscience of emotion with the definitions of affect, mood, and mood disorders offered in the last several editions of the DSM [34, 35, 86] and descriptions of disorders of affect [17, 99, 121]. It also may explain commonly observed differences in the rapidity and/or differential treatment response of disorders of affect (e.g., pathological crying) and mood disorders (e.g., depression) to identical medications (e.g., selective serotonin reuptake inhibitors) [17, 43, 100]. When only affect is disturbed, agents with receptor-level effects may accelerate and/or support management of transient increases in allostatic load, thereby attenuating the frequency, intensity, and/or duration of disturbances in emotion and emotional feeling. Their provision also may preserve the long-term function of the neural systems subserving

Chapter 18: Emotion

emotion and emotional feeling, and maintain a normal homeostatic set point. By contrast, mood disorders respond very slowly, or not at all, to medications exerting receptor-level effects. Their slow, and often modest, alterations of stably abnormal emotional neurophysiology (i.e., mood disorders) may reflect the limitations of using medications with receptor-level effects to effect a shift in homeostatic set point created by persistent allostatic overload and translated into stable, albeit maladaptive, post-receptor processes.

Conclusion This chapter presented an account of the phenomenology and neurobiology of emotional generation, expression, experience, and control. Definitions of emotion, emotional feelings, mood, and affect were offered, anchoring the first two of these to the observable and experiential aspects of emotion and the latter ones to their durations. The clinical application of these terms was considered, including their use to guide clinical evaluation and to distinguish between mood disorders and disorders of affect. The putative structural and functional neuroanatomies of emotional generation, expression, experience, and control were considered, beginning with a review of the history of the concepts of the limbic lobe, limbic system, and greater limbic system. Modern views on the components of these systems and their relationship to emotional generation, expression, experience, and control were presented, which provided the background required for discussion of the distributed neural networks subserving emotion and emotional feeling. Hypotheses regarding the lateralization of emotional processes were discussed briefly, and the possibility of a relationship between lateralized neurological abnormalities and disturbances of emotion and emotional feeling was considered. Finally, an emerging view of the neurobiological differences between mood and affect was described in an effort to reconcile the temporally defined phenomenologic distinction between them with the nature and duration of the neurobiological processes upon which they are predicated. Although the breadth and depth of information in this chapter is not trivial, readers are encouraged to remain mindful of the necessary simplifications undertaken in the service of this synthesis. The science of emotion is advancing rapidly, and new findings may necessitate reconsideration of the material presented

here. In the meantime, it is hoped that the principles of the psychology of emotion and the structural and functional neuroanatomy of emotion offered in this chapter will guide usefully the practice of BN&NP.

References 1. Encyclopaedia Britannica Inc., University of Chicago, Hutchins RM. Great Books of the Western World. Founders’ edition. Chicago, IL: W. Benton; 1952. 2. Cornelius RR. The Science of Emotion: Research and Tradition in the Psychology of Emotions. Upper Saddle River, NJ: Prentice Hall; 1996. 3. Damasio AR, Tranel D, Damasio H. Somatic markers and the guidance of behaviour: theory and preliminary testing. In Levin HS, Eisenberg HM, Benton AL, editors. Frontal Lobe Function and Dysfunction. New York, NY: Oxford University Press; 1991, pp. 217–29. 4. Damasio AR. Descartes’ Error: Emotion, Reason, and the Human Brain. New York, NY: Putnam; 1994. 5. Dunn BD, Dalgleish T, Lawrence AD. The somatic marker hypothesis: a critical evaluation. Neurosci Biobehav Rev. 2006;30(2):239–71. 6. Kringelbach ML, Berridge KC. The functional neuroanatomy of pleasure and happiness. Discov Med. 2010;9(49):579–87. 7. Darwin C, Darwin F. The Expression of the Emotions in Man and Animals. 2nd edition. Mineola, NY: Dover Publications; 2007. 8. James W. The Principles of Psychology, Vol. 1. New York, NY: Henry Holt and Company; 1890. 9. Ekman P. Basic emotions. In Dalgleish T, Power MJ, editors. Handbook of Cognition and Emotion. Chichester: John Wiley and Sons; 1999, pp. 45–60. 10. Plutchik R, Kellerman H. Emotion, Theory, Research, and Experience. New York, NY: Academic Press; 1980. 11. LeDoux JE. Emotion and the brain. J NIH Res. 1991; 3:49–51. 12. Goleman D. Emotional Intelligence. New York, NY: Bantam Books; 1995. 13. Ochsner KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci. 2005;9(5):242–9. 14. Luppa M, Heinrich S, Angermeyer MC, Konig HH, Riedel-Heller SG. Cost-of-illness studies of depression: a systematic review. J Affect Disord. 2007;98(1–2): 29–43. 15. Young AH, Rigney U, Shaw S, Emmas C, Thompson JM. Annual cost of managing bipolar disorder to the UK healthcare system. J Affect Disord. 2011;133(3): 450–6. 16. Ferrari AJ, Baxter AJ, Whiteford HA. A systematic review of the global distribution and availability of

291


prevalence data for bipolar disorder. J Affect Disord. 2011;134(1–3):1–13. 17. Wortzel HS, Oster TJ, Anderson CA, Arciniegas DB. Pathological laughing and crying: epidemiology, pathophysiology and treatment. CNS Drugs 2008; 22(7):531–45. 18. Miller A, Pratt H, Schiffer RB. Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments. Expert Rev Neurother. 2011;11(7):1077–88. 19. Berking M, Wupperman P. Emotion regulation and mental health: recent findings, current challenges, and future directions. Curr Opin Psychiatry 2012;25(2): 128–34. 20. Ekman P. Universals and cultural differences in facial expressions of emotion. In Cole J, editor. Nebraska Symposium on Motivation. Lincoln, NE: University of Nebraska Press; 1972. 21. Plutchik R. Emotion, a Psychoevolutionary Synthesis. New York, NY: Harper & Row; 1980. 22. Plutchik R. Emotions: a general psychoevolutionary theory. In: Scherer KR, Ekman P, editors. Approaches to Emotion. Hillsdale, NJ: Lawrence Erlbaum Associates; 1984, pp. 197–219. 23. LeDoux JE. The Emotional Brain: The Mysterious Underpinnings of Emotional Life. New York, NY: Simon & Schuster; 1996. 24. Mackinnon DF, Pies R. Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders. Bipolar Disord. 2006;8(1):1–14. 25. Prinz JJ. Gut Reactions: A Perceptual Theory of Emotion. Oxford: Oxford University Press; 2004. 26. Phelps EA. Emotion and cognition: insights from studies of the human amygdala. Annu Rev Psychol. 2006;57:27–53. 27. Dolan RJ. Emotion, cognition, and behavior. Science 2002;298(5596):1191–4. 28. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry 2003;54(5):504–14. 29. Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology 2010;35(1): 192–216. 30. Mayberg HS. Defining the neural circuitry of depression: toward a new nosology with therapeutic implications. Biol Psychiatry 2007;61(6):729–30. 31. Fusar-Poli P, Placentino A, Carletti F et al. Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. J Psychiatry Neurosci. 2009;34(6): 418–32.

292

32. Fusar-Poli P, Placentino A, Carletti F et al. Laterality effect on emotional faces processing: ALE meta-analysis of evidence. Neurosci Lett. 2009;452(3): 262–7. 33. Pessoa L. On the relationship between emotion and cognition. Nat Rev Neurosci. 2008;9(2):148–58. 34. American Psychiatric Association. Work Group to Revise DSM–III. Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised: DSM–III–R. Washington, DC: American Psychiatric Association; 1987. 35. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision: DSM–IV–TR. Washington, DC: American Psychiatric Association; 2000. 36. Mesulam M-M. Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system, and hemispheric specializations. In Mesulam M-M, editor. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 1–120. 37. Anand A, Li Y, Wang Y et al. Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study. Biol Psychiatry 2005;57(10):1079–88. 38. Seminowicz DA, Mayberg HS, McIntosh AR et al. Limbic-frontal circuitry in major depression: a path modeling metaanalysis. Neuroimage 2004;22(1): 409–18. 39. Schmahmann JD. The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy. Neuropsychol Rev. 2010;20(3):236–60. 40. Schmahmann JD. Dysmetria of thought: clinical consequences of cerebellar dysfunction on cognition and affect. Trends Cogn Sci. 1998;2(9):362–71. 41. Arciniegas DB. A clinical overview of pseudobulbar affect. Am J Geriatr Pharmacother. 2005;3(Suppl. A): 4–8; quiz 16–7. 42. Arciniegas DB, Lauterbach EC, Anderson KE et al. The differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among disorders of mood and affect. Proceedings of a roundtable meeting. CNS Spectr. 2005;10(5):1–14; quiz 5–6. 43. Arciniegas DB, Topkoff J. The neuropsychiatry of pathologic affect: an approach to evaluation and treatment. Semin Clin Neuropsychiatry 2000;5(4): 290–306. 44. Rabins PV, Arciniegas DB. Pathophysiology of involuntary emotional expression disorder. CNS Spectr. 2007;12(4 Suppl. 5):17–22.

Chapter 18: Emotion

45. Arciniegas DB, Coffey CE, Cummings JL. Neurobiological basis of behavior. In Coffey CE, Cummings JL, editors. The American Psychiatric Publishing Textbook of Geriatric Neuropsychiatry. 3rd edition. Washington, DC: American Psychiatric Publishing; 2011, pp. 71–98. 46. Damasio AR. Looking for Spinoza: Joy, Sorrow, and the Feeling Brain. 1st edition. Orlando, FL: Harcourt; 2003. 47. Gregory RL. The Oxford Companion to the Mind. 2nd edition. Oxford: Oxford University Press; 2004. 48. Lange CG. Om sindsbevaegelser. Leipzig: T. Thomas; 1885. 49. Jackson M. Emotion and Psyche. Ropley, UK: John Hunt Publishing Ltd.; 2010. 50. Murphy ST, Zajonc RB. Affect, cognition, and awareness: affective priming with optimal and suboptimal stimulus exposures. J Pers Soc Psychol. 1993;64(5):723–39. 51. Zajonc RB. On the primacy of affect. Am Psychol. 1984;39(2):117–23. 52. Russell JA. Core affect and the psychological construction of emotion. Psychol Rev. 2003;110(1): 145–72. 53. Russell JA, Barrett LF. Core affect, prototypical emotional episodes, and other things called emotion: dissecting the elephant. J Pers Soc Psychol. 1999; 76(5):805–19. 54. Scherer KR. On the nature and function of emotion: a component process approach. In Scherer KR, Ekman P, editors. Approaches to Emotion. Hillsdale, NJ: Lawrence Erlbaum Associates; 1984, pp. 293–317. 55. Scherer KR. Feelings integrate the central representation of appraisal-driven response organization in emotion. In Manstead ASR, Frijda NH, Fischer A, editors. Feelings and Emotions: The Amsterdam Symposium. Cambridge: Cambridge University Press; 2004, pp. 136–57. 56. Scherer KR, Wranik T, Sangsue J, Tran V, Scherer U. Emotions in everyday life: probability of occurrence, risk factors, appraisal and reaction patterns. Soc Sci Inform. 2004;43(4):499–570. 57. Fontaine JR, Scherer KR, Roesch EB, Ellsworth PC. The world of emotions is not two-dimensional. Psychol Sci. 2007;18(12):1050–7. 58. Ortony A, Clore GL, Collins A. The Cognitive Structure of Emotions. Cambridge: Cambridge University Press; 1988. 59. Ekman P. A methodological discussion of nonverbal behavior. J Psychol. 1957;43:141–9. 60. Plutchik R, Kellerman H. Theories of Emotion. New York, NY: Academic Press; 1980.

61. Lench HC, Flores SA, Bench SW. Discrete emotions predict changes in cognition, judgment, experience, behavior, and physiology: a meta-analysis of experimental emotion elicitations. Psychol Bull. 2011;137(5):834–55. 62. Ekman P, Friesen WV. Unmasking the Face; A Guide to Recognizing Emotions from Facial Clues. Englewood Cliffs, NJ: Prentice-Hall; 1975. 63. Frijda NH. The Emotions. Cambridge: Cambridge University Press; Paris: Editions de la Maison des Sciences de l’Homme; 1986. 64. Averill JR, Nunley EP. Grief as an emotion and as a disease: a social-constructionist perspective. J Soc Issues 1988;44(3):79–95. 65. Bowlby J. Attachment and Loss. New York, NY: Basic Books; 1969. 66. Bachorowski JA, Braaten EB. Emotional intensity: measurement and theoretical implications. Pers Indiv Differ. 1994;17(2):191–9. 67. Larsen RJ, Diener E. Affect intensity as an individual difference characteristic: a review. J Res Pers. 1987; 21(1):1–39. 68. Goudbeek M, Scherer K. Beyond arousal: valence and potency/control cues in the vocal expression of emotion. J Acoust Soc Am. 2010;128(3):1322–36. 69. Pelissolo A, Rolland JP, Perez-Diaz F, Jouvent R, Allilaire JF. [Dimensional approach of emotion in psychiatry: validation of the Positive and Negative Emotionality scale (EPN-31)]. Encephale 2007; 33(3 Pt 1):256–63. 70. Woyshville MJ, Lackamp JM, Eisengart JA, Gilliland JA. On the meaning and measurement of affective instability: clues from chaos theory. Biol Psychiatry 1999;45(3):261–9. 71. Carver CS. Negative affects deriving from the behavioral approach system. Emotion 2004;4(1):3–22. 72. Bechara A, Damasio H, Tranel D, Damasio AR. Deciding advantageously before knowing the advantageous strategy. Science 1997;275(5304):1293–5. 73. Mouilso E, Glenberg AM, Havas DA, Lindeman LM. Differences in action tendencies distinguish anger and sadness after comprehension of emotional sentences. In McNamara DS, Trafton JG, editors. Proceedings of the 29th Annual Cognitive Science Society. Austin, TX: Cognitive Science Society; 2007, pp. 1325–30. 74. Hofer MA. Unexplained infant crying: an evolutionary perspective. Acta Paediatr. 2002;91(5):491–6. 75. Soltis J. The signal functions of early infant crying. Behav Brain Sci. 2004;27(4):443–58; discussion 459–90. 76. Cattell RB. Patterns of change: measurement in relation to state dimension, trait change, lability, and process concepts. In Cattell RB, editor. Handbook of

293


Multivariate Experimental Psychology. Chicago, IL: Rand McNally; 1966, pp. 355–402. 77. Mehrabian A. Pleasure-arousal-dominance: a general framework for describing and measuring individual differences in temperament. Curr Psychol. 1996;14(4): 261–92. 78. Morris BH, Bylsma LM, Rottenberg J. Does emotion predict the course of major depressive disorder? A review of prospective studies. Br J Clin Psychol. 2009; 48(Pt 3):255–73. 79. Rossi V, Pourtois G. Transient state-dependent fluctuations in anxiety measured using STAI, POMS, PANAS or VAS: a comparative review. Anxiety Stress Coping 2011 May 3. Epub ahead of print. 80. Gros DF, Antony MM, Simms LJ, McCabe RE. Psychometric properties of the State-Trait Inventory for Cognitive and Somatic Anxiety (STICSA): comparison to the State-Trait Anxiety Inventory (STAI). Psychol Assess. 2007;19(4):369–81. 81. Sasayama D, Hori H, Teraishi T et al. Difference in Temperament and Character Inventory scores between depressed patients with bipolar II and unipolar major depressive disorders. J Affect Disord. 2011;132(3): 319–24.

90. Green RL. Regulation of affect. Semin Clin Neuropsychiatry 1998;3(3):195–200. 91. Charcot JM. Lectures on the Diseases of the Nervous System: Delivered at La Salpêtr`ıere. London: The New Syndeham Society; 1881. 92. Fishman I, Benedict RH, Bakshi R, Priore R, Weinstock-Guttman B. Construct validity and frequency of euphoria sclerotica in multiple sclerosis. J Neuropsychiatry Clin Neurosci. 2004;16(3):350–6. 93. Minden SL. Mood disorders in multiple sclerosis: diagnosis and treatment. J Neurovirol. 2000; 6(Suppl. 2):S160–7. 94. Green RL, McAllister TW, Bernat JL. A study of crying in medically and surgically hospitalized patients. Am J Psychiatry 1987;144(4):442–7. 95. Mendez MF. Moria and Witzelsucht from frontotemporal dementia. J Neuropsychiatry Clin Neurosci. 2005;17(3):429–30. 96. Oppenheim H. Zur pathologie der grosshirngeschwülste. Arch Psychiatr Nervenkr. 1889;21:560–87.

82. Mian ND, Wainwright L, Briggs-Gowan MJ, Carter AS. An ecological risk model for early childhood anxiety: the importance of early child symptoms and temperament. J Abnorm Child Psychol. 2011;39(4): 501–12.

97. Henry C, Mitropoulou V, New AS et al. Affective instability and impulsivity in borderline personality and bipolar II disorders: similarities and differences. J Psychiatr Res. 2001;35(6):307–12.

83. Doyle F, McGee HM, Conroy RM, Delaney M. What predicts depression in cardiac patients: sociodemographic factors, disease severity or theoretical vulnerabilities? Psychol Health 2011; 26(5):619–34.

98. Beresford TP, Arciniegas D, Clapp L, Martin B, Alfers J. Reduction of affective lability and alcohol use following traumatic brain injury: a clinical pilot study of anti-convulsant medications. Brain Inj. 2005;19(4): 309–13.

84. de Winter RF, Wolterbeek R, Spinhoven P, Zitman FG, Goekoop JG. Character and temperament in major depressive disorder and a highly anxious-retarded subtype derived from melancholia. Compr Psychiatry 2007;48(5):426–35.

99. Olney NT, Goodkind MS, Lomen-Hoerth C et al. Behaviour, physiology and experience of pathological laughing and crying in amyotrophic lateral sclerosis. Brain 2011;134(Pt 12):3458–69.

85. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition: DSM–III. Washington, DC: American Psychiatric Association; 1980. 86. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: DSM–IV. Washington, DC: American Psychiatric Association; 1994. 87. Holtzheimer PE, Mayberg HS. Stuck in a rut: rethinking depression and its treatment. Trends Neurosci. 2011;34(1):1–9. 88. First MB. DSM-5 proposals for mood disorders: a cost-benefit analysis. Curr Opin Psychiatry 2011; 24(1):1–9.

294

89. Cummings JL, Arciniegas DB, Brooks BR et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr. 2006;11(6):1–7.

100. Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med. 1985;312(23):1480–2. 101. Panzer MJ, Mellow AM. Antidepressant treatment of pathologic laughing or crying in elderly stroke patients. J Geriatr Psychiatry Neurol. 1992;5(4):195–9. 102. Parmentier C, Etain B, Yon L et al. Clinical and dimensional characteristics of euthymic bipolar patients with or without suicidal behavior. Eur Psychiatry. 2011 Oct 4. Epub ahead of print. 103. Poeck K. Pathophysiology of emotional disorders associated with brain damage. Hand Clin Neurol. 1969;3:343–67. 104. Sackeim HA, Greenberg MS, Weiman AL et al. Hemispheric asymmetry in the expression of positive

Chapter 18: Emotion

and negative emotions. Neurologic evidence. Arch Neurol. 1982;39(4):210–18. 105. Chen RC, Forster FM. Cursive epilepsy and gelastic epilepsy. Neurology 1973;23(10):1019–29.

120. Broca P. Anatomie comparée des circonvolutions cerebrales: le grand lobe limbique et la scisure dans la serie des mammiferes. Rev Anthropol. (Paris) 1878; 2:285–498.

106. Sethi PK, Rao TS. Gelastic, quiritarian, and cursive epilepsy. A clinicopathological appraisal. J Neurol Neurosurg Psychiatry 1976;39(9):823–8.

121. Wilson SA. Some problems in neurology. II. Pathological laughing and crying. J Neurol Psychopathol. 1924;4(16):299–333.

107. Nieuwenhuys R, Voogd J, van Huijzen C. The Human Central Nervous System. 4th edition. New York, NY: Springer; 2008.

122. Sergi G. Principi di Psicologie: Dolore e Piacere; Storia Naturale Dei Sentimenti. Milano: Dumolard; 1894.

108. Nauta WJH. Hippocampal projections and related neural pathways to the midbrain in the cat. Brain 1958;81(3):319–40. 109. Nauta WJH. A proposed conceptual reorganization of the basal ganglia and telencephalon. Neuroscience 1979;4(12):1875–81. 110. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155–84. 111. Kotter R, Meyer N. The limbic system: a review of its empirical foundation. Behav Brain Res. 1992;52(2): 105–27. 112. Groenewegen HJ, Wright CI, Beijer AV. The nucleus accumbens: gateway for limbic structures to reach the motor system? Prog Brain Res. 1996;107: 485–511. 113. Blessing WW. Inadequate frameworks for understanding bodily homeostasis. Trends Neurosci. 1997;20(6):235–9.

123. Spencer W. The effect produced upon respiration by faradic excitation of the cerebrum in the monkey, dog, cat, and rabbit. Philos Trans R Soc Lond. B Biol. 1894; 185:609–57. 124. Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry. 1937;38:725–43. 125. Cannon WB. The James–Lange theory of emotion: a critical examination and an alternative theory. Am J Psychol. 1927;39:10–124. 126. Cannon WB. Thalamic theories of emotion. Psychol Rev. 1931;38:281–95. 127. Bard P. The central representation of the sympathetic nervous system as indicated by certain physiologic observations. Arch Neurol Psychiatry 1929;22:230–46. 128. Bard P. The neuro-humoral basis of emotional reactions. In Murchison CA, editor. A Handbook of General Experimental Psychology. Worcester, MA: Clark University Press; 1934, pp. 264–311.

114. Swanson LW. Limbic system. In Adelman G, editor. Encyclopedia of Neuroscience. Boston, MA: Birkhäeuser; 1987, pp. 589–91.

129. Penfield W, Wesley M. Carpenter Lecture: Influence of the diencephalon and hypophysis upon general autonomic function. Bull N Y Acad Med. 1933;9: 613–37.

115. Brodal A. Neurological Anatomy in Relation to Clinical Medicine. 3rd edition. New York, NY: Oxford University Press; 1981.

130. Ranson SW. The hypothalamus: its significance for visceral innervation and emotional expression. Tr Coll Physicians Philadelphia 1934;2:222–42.

116. Heimer L. The limbic system: a concept in perpetual search for a definition. In Heimer L, van Hoesen GW, Trimble M, Zahm DS, editors. Anatomy of Neuropsychiatry: The New Anatomy of the Basal Forebrain and its Implications for Neuropsychiatric Illness. Boston, MA and Amsterdam: Academic Press/Elsevier; 2008, pp. 1–14.

131. Yakovlev PI. Motility, behavior and the brain; stereodynamic organization and neural coordinates of behavior. J Nerv Ment Dis. 1948;107(4):313–35. 132. Yakovlev PI. Telencephalon “impar”, “semipar” and “totopar”. (Morphogenetic, tectogenetic and architectonic definitions). Int J Neurol. 1968;6(3–4): 245–65.

117. Mayberg HS, Liotti M, Brannan SK et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999;156(5):675–82.

133. MacLean PD. Some psychiatric implications of physiological studies on frontotemporal portion of limbic system (visceral brain). Electroencephalogr Clin Neurophysiol. 1952;4(4):407–18.

118. Kringelbach ML. The human orbitofrontal cortex: linking reward to hedonic experience. Nat Rev Neurosci. 2005;6(9):691–702.

134. MacLean PD. The triune brain, emotion and scientific basis. In Schmitt FO, editor. The Neurosciences: Second Study Program. New York, NY: Rockefeller University Press; 1970, pp. 336–49.

119. Heimer L. Anatomy of Neuropsychiatry: The New Anatomy of the Basal Forebrain and its Implications for Neuropsychiatric Illness. Boston, MA and Amsterdam: Academic Press/Elsevier; 2008.

135. MacLean PD. The Triune Brain in Evolution: Role in Paleocerebral Functions. New York, NY: Plenum Press; 1990.

295


136. Ariëns Kappers CU. The development of the cortex and the functions of its different layers. Acta Psychiatr Neurol. 1928;3:115–32. 137. MacLean PD. Psychosomatic disease and the “visceral brain.” Recent developments bearing on the Papez theory of emotion. Psychosom Med. 1949;11(6): 338–53. 138. Nauta WJH. Hypothalamic nuclei and fiber connections. In Haymaker W, Anderson E, Nauta WJH, editors. The Hypothalamus. Springfield, IL: Thomas; 1969, pp. 136–209. 139. Nauta WJH. Connections of the frontal lobe with the limbic system. In Laitinen LV, Livingston KE, editors. Surgical Approaches in Psychiatry. Baltimore, MD: University Park Press; 1973, pp. 303–14. 140. Nauta WJH. Expanding borders of the limbic system. In Rasmussen T, Marino R, editors. Functional Neurosurgery. New York, NY: Raven; 1979, pp. 7–24. 141. Mesulam M-M. Patterns in behavioral neuroanatomy: association areas, the limbic system, and hemispheric specialization. In Mesulam M-M, editor. Principles of Behavioral Neurology. Philadelphia, PA: F.A. Davis; 1985, pp. 1–70.

Descending modulation. Prog Brain Res. 2004;143: 283–90. 152. Deadwyler SA, Hayashizaki S, Cheer J, Hampson RE. Reward, memory and substance abuse: functional neuronal circuits in the nucleus accumbens. Neurosci Biobehav Rev. 2004;27(8):703–11. 153. Dehaene S, Kerszberg M, Changeux JP. A neuronal model of a global workspace in effortful cognitive tasks. Proc Natl Acad Sci USA 1998;95(24):14,529–34. 154. Cummings JL. Anatomic and behavioral aspects of frontal-subcortical circuits. Ann N Y Acad Sci. 1995;769:1–13. 155. Dumontheil I, Burgess PW, Blakemore SJ. Development of rostral prefrontal cortex and cognitive and behavioural disorders. Dev Med Child Neurol. 2008;50(3):168–81. 156. Zagon A, Totterdell S, Jones RS. Direct projections from the ventrolateral medulla oblongata to the limbic forebrain: anterograde and retrograde tract-tracing studies in the rat. J Comp Neurol. 1994;340(4):445–68. 157. Le Moal M, Olds ME. Peripheral auditory input to the midbrain limbic area and related structures. Brain Res. 1979;167(1):1–17.

142. Parvizi J, Joseph J, Press DZ, Schmahmann JD. Pathological laughter and crying in patients with multiple system atrophy-cerebellar type. Mov Disord. 2007;22(6):798–803.

158. Reese NB, Garcia-Rill E, Skinner RD. The pedunculopontine nucleus – auditory input, arousal and pathophysiology. Prog Neurobiol. 1995;47(2): 105–33.

143. Schmahmann JD, Caplan D. Cognition, emotion and the cerebellum. Brain 2006;129(Pt 2):290–2.

159. Poremba A, Saunders RC, Crane AM et al. Functional mapping of the primate auditory system. Science 2003;299(5606):568–72.

144. Schmahmann JD, Sherman JC. Cerebellar cognitive affective syndrome. Int Rev Neurobiol. 1997;41:433–40. 145. Heimer L. The Human Brain and Spinal Cord: Functional Neuroanatomy and Dissection Guide. 2nd edition. New York, NY: Springer-Verlag; 1995. 146. Duffy JD. The neural substrates of motivation. Psychiatr Ann. 1997;27:24–9. 147. Arciniegas DB. Emotion. In Arciniegas DB, Beresford TP, editors. Neuropsychiatry: An Introductory Approach. Cambridge: Cambridge University Press; 2001, pp. 75–91. 148. Liberzon I, Phan KL, Decker LR, Taylor SF. Extended amygdala and emotional salience: a PET activation study of positive and negative affect. Neuropsychopharmacology 2003;28(4):726–33. 149. Zahm DS, Trimble M. The dopaminergic projection system, basal forebrain macrosystems, and conditioned stimuli. CNS Spectr. 2008;13(1):32–40. 150. Tsang EW, Hamani C, Moro E et al. Involvement of the human pedunculopontine nucleus region in voluntary movements. Neurology 2010;75(11):950–9. 151. Garcia-Rill E, Homma Y, Skinner RD. Arousal mechanisms related to posture and locomotion: 1.

296

160. Laureys S, Faymonville ME, Degueldre C et al. Auditory processing in the vegetative state. Brain 2000;123(Pt 8):1589–601. 161. Lee CC, Winer JA. Connections of cat auditory cortex: III. Corticocortical system. J Comp Neurol. 2008; 507(6):1920–43. 162. Morgane PJ, Galler JR, Mokler DJ. A review of systems and networks of the limbic forebrain/limbic midbrain. Prog Neurobiol. 2005;75(2):143–60. 163. Morgane PJ, Mokler DJ. The limbic brain: continuing resolution. Neurosci Biobehav Rev. 2006;30(2): 119–25. 164. Arnsten AFT, Robbins TW. Neurochemical modulation of prefrontal cortical function in humans and animals. In Stuss DT, Knight RT, editors. Principles of Frontal Lobe Function. Oxford: Oxford University Press; 2002, pp. 51–84. 165. Mesulam M-M. Attentional networks, confusional states, and neglect syndromes. In Mesulam MM, editor. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 174–256.

Chapter 18: Emotion

166. Deutch AY. Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson’s disease. J Neural Transm Gen Sect. 1993;91(2–3): 197–221. 167. Pine A, Shiner T, Seymour B, Dolan RJ. Dopamine, time, and impulsivity in humans. J Neurosci. 2010; 30(26):8888–96. 168. St Onge JR, Floresco SB. Dopaminergic modulation of risk-based decision making. Neuropsychopharmacology 2009;34(3):681–97. 169. Berridge KC, Kringelbach ML. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology (Berlin) 2008;199(3):457–80. 170. Kringelbach ML, Berridge KC. Towards a functional neuroanatomy of pleasure and happiness. Trends Cogn Sci. 2009;13(11):479–87. 171. Tully K, Li Y, Tsvetkov E, Bolshakov VY. Norepinephrine enables the induction of associative long-term potentiation at thalamo-amygdala synapses. Proc Natl Acad Sci USA 2007;104(35):14,146–50. 172. Smith RJ, Aston-Jones G. Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence. Brain Struct Funct. 2008;213(1–2):43–61. 173. Yanai K, Tashiro M. The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies. Pharmacol Ther. 2007;113(1):1–15. 174. Zhu JN, Yung WH, Kwok-Chong Chow B, Chan YS, Wang JJ. The cerebellar-hypothalamic circuits: potential pathways underlying cerebellar involvement in somatic-visceral integration. Brain Res Rev. 2006; 52(1):93–106.

180. Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9(3):471–81. 181. Mayberg HS, Brannan SK, Mahurin RK et al. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 1997;8(4): 1057–61. 182. Mayberg HS, Lozano AM, Voon V et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45(5):651–60. 183. Ochsner KN, Ray RD, Cooper JC et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage 2004;23(2):483–99. 184. Damasio AR, Grabowky TJ, Bechara A et al. Subcortical and cortical brain activity during the feeling of self-generated emotions. Nat Neurosci. 2000;3:1049–56. 185. Mayberg HS. Positron emission tomography imaging in depression: a neural systems perspective. Neuroimaging Clin N Am. 2003;13(4): 805–15. 186. Lozano AM, Mayberg HS, Giacobbe P et al. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 2008; 64(6):461–7. 187. Hamani C, Mayberg H, Snyder B et al. Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting. J Neurosurg. 2009;111(6):1209–15. 188. Stuss DT, Alexander MP. Is there a dysexecutive syndrome? Philos Trans R Soc Lond B Biol Sci. 2007; 362(1481):901–15.

175. Mega MS, Cummings JL, Salloway S, Malloy P. The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci. 1997; 9(3):315–30.

189. Zandbelt BB, Bloemendaal M, Neggers SF, Kahn RS, Vink M. Expectations and violations: Delineating the neural network of proactive inhibitory control. Hum Brain Mapp. 2012 Feb 22. Epub ahead of print.

176. Raichle ME, MacLeod AM, Snyder AZ et al. A default mode of brain function. Proc Natl Acad Sci USA 2001; 98(2):676–82.

190. Vidal J, Mills T, Pang EW, Taylor MJ. Response inhibition in adults and teenagers: spatiotemporal differences in the prefrontal cortex. Brain Cogn. 2012;79(1):49–59.

177. Buckner RL, Vincent JL. Unrest at rest: default activity and spontaneous network correlations. Neuroimage 2007;37(4):1091–6; discussion 1097–9. 178. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008;1124: 1–38. 179. Holtzheimer PE, Kelley ME, Gross RE et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry 2012;69(2):150–8.

191. Jorge RE, Robinson RG, Moser D et al. Major depression following traumatic brain injury. Arch Gen Psychiatry 2004;61(1):42–50. 192. Jorge RE, Robinson RG, Starkstein SE, Arndt SV. Depression and anxiety following traumatic brain injury. J Neuropsychiatry Clin Neurosci. 1993;5(4): 369–74. 193. Jorge RE, Robinson RG, Starkstein SE et al. Secondary mania following traumatic brain injury. Am J Psychiatry 1993;150(6):916–21.

297


194. Fedoroff JP, Starkstein SE, Forrester AW et al. Depression in patients with acute traumatic brain injury. Am J Psychiatry 1992;149(7):918–23. 195. Starkstein SE, Mayberg HS, Berthier ML et al. Mania after brain injury: neuroradiological and metabolic findings. Ann Neurol. 1990;27(6):652–9. 196. Robinson RG, Boston JD, Starkstein SE, Price TR. Comparison of mania and depression after brain injury: causal factors. Am J Psychiatry 1988;145(2): 172–8. 197. Robinson RG. The Clinical Neuropsychiatry of Stroke. 2nd edition. Cambridge: Cambridge University Press; 2006. 198. Sackeim HA, Decina P, Malitz S. Functional brain asymmetry and affective disorders. Adolesc Psychiatry 1982;10:320–35. 199. Bhogal SK, Teasell R, Foley N, Speechley M. Lesion location and poststroke depression: systematic review of the methodological limitations in the literature. Stroke 2004;35(3):794–802. 200. Carson AJ, MacHale S, Allen K et al. Depression after stroke and lesion location: a systematic review. Lancet 2000;356(9224):122–6. 201. Oster TJ, Anderson CA, Filley CM, Wortzel HS, Arciniegas DB. Quetiapine for mania due to traumatic brain injury. CNS Spectr. 2007;12(10):764–9. 202. Arciniegas DB, Coffey CE, Cummings JL. In Coffey CE, Cummings JL, editors. Textbook of Geriatric Neuropsychiatry. 3rd edition. Washington, DC: American Psychiatric Publishing, Inc.; 2011, pp. 101–22.

205. Morris PL, Robinson RG, de Carvalho ML et al. Lesion characteristics and depressed mood in the stroke data bank study. J Neuropsychiatry Clin Neurosci. 1996;8(2):153–9. 206. Mayberg HS, Robinson RG, Wong DF et al. PET imaging of cortical S2 serotonin receptors after stroke: lateralized changes and relationship to depression. Am J Psychiatry 1988;145(8):937–43. 207. Sterling P, Eyer J. Allostasis: a new paradigm to explain arousal pathology. In Fisher S, Reason JT, editors. Handbook of Life Stress, Cognition, and Health. Chichester: John Wiley and Sons; 1988, pp. 629–249. 208. Beauchaine TP, Neuhaus E, Zalewski M, Crowell SE, Potapova N. The effects of allostatic load on neural systems subserving motivation, mood regulation, and social affiliation. Dev Psychopathol. 2011;23(4): 975–99. 209. Giacobbe P, Mayberg HS, Lozano AM. Treatment resistant depression as a failure of brain homeostatic mechanisms: implications for deep brain stimulation. Exp Neurol. 2009;219(1):44–52. 210. Musselman DL, Nemeroff CB. Depression and endocrine disorders: focus on the thyroid and adrenal system. Br J Psychiatry 1996;Suppl. (30):123–8. 211. Krystal JH, Sanacora G, Blumberg H et al. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 2002;7(Suppl. 1):S71–80. 212. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008;455(7215):894–902.

203. Bernstein HG, Klix M, Dobrowolny H et al. A postmortem assessment of mammillary body volume, neuronal number and densities, and fornix volume in subjects with mood disorders. Eur Arch Psychiatry Clin Neurosci. 2012 Feb 17. Epub ahead of print.

213. Hunsberger JG, Austin DR, Chen G, Manji HK. Cellular mechanisms underlying affective resiliency: the role of glucocorticoid receptor- and mitochondrially-mediated plasticity. Brain Res. 2009;1293:76–84.

204. Strakowski SM, Adler CM, DelBello MP. Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disord. 2002;4(2):80–8.

214. Li N, Lee B, Liu RJ et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;329(5994): 959–64.

298

Section I


Chapter

Personality

19

Sita Kedia and C. Robert Cloninger

Human personality is the collection of complex characteristics and traits that shape and distinguish an individual from a machine-like object. The study of these traits and differences among individuals can be dated back centuries to the ancient Greek and Roman physicians and philosophers. Hippocrates applied the concept of humors to medicine, and the writings of Galen elaborated this concept for centuries. The humoral theory held that four bodily fluids or humors – black bile, yellow bile, blood, and phlegm – corresponded to four temperaments. This simple description of human characteristics was an early step toward what has become an expansive field exploring the complexities of personality in the context of philosophy, psychiatry, and neurology, and ranging from the molecular and cellular levels to the individual organism. Personality is defined as the dynamic organization of the psychobiological systems by which a person shapes and adapts in a unique way to a changing internal and external environment [1]. In other words, personality describes the dynamic processes that occur within a person to allow behavior to shape and adapt to life experiences. The maturation and integration of human personality involves the development of habits and skills, learning facts and how to reason, and growing in self-awareness through experiences across a wide range of situations. Personality in adulthood is consistent and stable over time, allowing for the investigation of models that can classify personality types. Efforts to classify traits and characteristics over the last several decades have produced several models that mostly use a dimensional approach; however, establishing the biological associations of personality using these models has been difficult given the complexity of the concept. In

order to understand human behavior in a contemporary framework, a personality model that takes into account neurogenetic variables and psychosocial influences is crucial. The temperament and character comprehensive model of human personality provides a powerful tool for evaluating the role of both neurobiological and psychosocial influences of the development on mental health and mental illness. In brief, temperament refers to the emotional biases that are regulated by behavioral conditioning, whereas character refers to the higher cognitive processes by which human beings modify their behavior intentionally. This dimensional model of personality has, over several years, shown links to genetics, neurophysiology, and functional neuroanatomy. In this chapter, the complexity of personality will be illustrated by the exploration of its neurobiology, including neurochemistry, and neuroanatomy via the temperament and character dimensional model and its relationship to psychiatric and neurological disorders.

Temperament Temperament refers to the individual’s biases in the modulation of conditioned behavioral responses to prescriptive physical stimuli. Behavioral conditioning (i.e., procedural learning) involves pre-semantic sensations that elicit basic emotions, such as fear or anger, independent of conscious recognition, descriptive observation, reflection, or reasoning. Pioneering work by Thomas and Chess [2] conceptualized temperament as the stylistic component of behavior (how), as differentiated from the motivation (why) and content (what) of behavior.


299


Later work suggested that temperament refers to those aspects of personality that are heritable, based on primary emotions such as fear or anger, manifest in early childhood and stable across the lifespan, and are consistently found in cultures around the world [3]. Empirical studies did confirm that temperament traits are manifest in early life, remain moderately stable across the lifespan, and are found consistently irrespective of culture [4, 5]. A large meta-analysis of studies on the stability of temperament and personality traits showed that temperament is moderately stable in early childhood and increases in consistency over time with age. The estimated correlations in temperament over time were 0.35 for the age span 0–2.9 years, 0.52 for 3–5.9 years, and 0.45 for 6–11.9 years [6]. Consistent with the temporal stability and cultural universality of temperament, other work showed that all aspects of personality are equally heritable [7]. However, the four temperaments are now understood to be genetically independent dimensions that occur in all possible combinations within the same individual, rather than as mutually exclusive categories. Temperament mediates the automatic emotional response to experience, and is moderately heritable, observed first early in childhood and then relatively stable throughout life, and moderately predictive of adolescent and adult behavior. Temperamental differences tend to stabilize during the second and third year of life. Modern concepts of temperament emphasize its emotional, motivational, and adaptive aspects. Specifically, four major temperament traits have been identified and subjected to extensive neurobiological, psychosocial, and clinical investigation: harm avoidance, novelty seeking, reward dependence, and persistence. It is remarkable that this four-factor model of temperament can, in retrospect, be seen as a modern reformulation of the ancient humoral theory: individuals differ in the degree to which they are melancholic (harm avoidant), choleric (novelty seeking), sanguine (reward dependent), and phlegmatic (persistent). Table 19.1 details the traits associated with the extreme variants of the four individual temperament dimensions. The genetic components of temperament traits range from 40–60%. Neurobiologically, temperament appears to be closely related to the limbic system, and each of the temperament dimensions can be correlated with specific limbic regions.

300

Table 19.1. Descriptors of high and low scorers on four temperament dimensions.

Temperament

Descriptors of extreme variants

dimension

High

Low

Harm avoidance

Pessimistic Fearful Shy Fatigable

Optimistic Daring Outgoing Vigorous

Novelty seeking

Exploratory Impulsive Extravagant Irritable

Reserved Rigid Frugal Stoical

Reward dependence

Sentimental Open Warm Sympathetic

Critical Aloof Detached Independent

Persistence

Industrious Determined Ambitious Perfectionist

Apathetic Spoiled Underachiever Pragmatist

Description of temperament traits Harm avoidance This temperament involves a heritable bias in the inhibition of behavior in response to signals of punishment and frustrative non-reward. Simplistically, harm avoidance is a measure of the fear of uncertainty, shyness, social inhibition, passive avoidance of problems or danger, rapid fatigability, and pessimistic worry in anticipation of problems even in situations that do not worry other people. Adaptive advantages of high harm avoidance are cautiousness and careful planning when hazard is likely. The disadvantages occur when hazard is unlikely but still is anticipated, which leads to maladaptive inhibition and anxiety. People low in harm avoidance are carefree, courageous, energetic, outgoing, and optimistic even in situations that worry most people. The advantages of low harm avoidance are confidence in the face of danger and uncertainty, leading to optimistic and energetic efforts with little or no distress. The disadvantages are related to unresponsiveness to danger, or unrealistic optimism with potentially severe consequences when hazard is likely.

Novelty seeking This temperament reflects a heritable bias in the initiation or activation of appetitive approach in response to novelty, approach to signals of reward, active avoidance of conditioned signals of punishment, and escape

Chapter 19: Personality

from unconditioned punishment – all of which are hypothesized to co-vary as part of one heritable system of learning. Individuals high in novelty seeking are quick-tempered, curious, easily bored, impulsive, extravagant, and disorderly. Adaptive advantages of high novelty seeking are enthusiastic exploration of new and unfamiliar stimuli, potentially leading to originality, discoveries, and reward. The disadvantages are frequent and easy boredom, impulsivity, angry outbursts, potential fickleness in relationships, and impressionism in efforts. Persons low in novelty seeking are slow tempered, uninquiring, stoical, reflective, frugal, reserved, tolerant of monotony, and orderly. Their reflectiveness, resilience, systematic effort, and meticulous approach are clearly advantageous when these features are adaptively needed. The disadvantages reflect tolerance of monotony and lack of enthusiasm, potentially leading to mundane routinization of activities.

Reward dependence This temperament reflects a heritable bias in the maintenance of behavior in response to cues of social reward. Reward dependence is characterized as sentimentality, social sensitivity, attachment, and dependence on approval of others. Individuals high in reward dependence are tender-hearted, sensitive, dedicated, dependent, and sociable. One of the major adaptive advantages of high reward dependence is the sensitivity to social cues, which facilitates affectionate social relations and genuine care for others. The disadvantage is related to suggestibility and loss of objectivity frequently encountered with people who are excessively socially dependent. Individuals low in reward dependence are practical, tough-minded, cold, socially insensitive, irresolute, and indifferent if alone. The advantages of low reward dependence are personal independence and objectivity not corrupted by efforts to please others. Its adaptive disadvantage is related to social withdrawal, detachment, and coldness in social attitudes.

Persistence This temperament reflects a heritable bias in the maintenance of behavior despite frustration, fatigue, and intermittent reinforcement. It is observed as industriousness, determination, ambitiousness, and perfectionism. Highly persistent people are hard-working, perseverant, and ambitious overachievers who tend to

intensify their effort in response to anticipated reward and perceive frustration and fatigue as a personal challenge. High persistence is an adaptive behavioral strategy when rewards are intermittent but contingencies remain stable. When the contingencies change rapidly, perseveration becomes maladaptive. Individuals low in persistence are indolent, inactive, unstable, and erratic; they tend to give up easily when faced with frustration, rarely strive for higher accomplishments, and manifest a low level of perseverance even in response to intermittent reward. Accordingly, low persistence is an adaptive strategy when reward contingencies change rapidly and may be maladaptive when rewards are infrequent but occur in the long run. Each of these four temperament dimensions varies quantitatively between individuals with a roughly Gaussian distribution. The full range of possible temperament configurations occurs in both healthy and unhealthy people, but different configurations have different probabilities of poor adaptation on average [8]. As a result, temperament alone does not allow a reliable prediction of whether a person is healthy and mature. The adaptability of a particular temperament configuration is dependent on the person’s situational context, character, and degree of selfawareness [8].

Character Character refers to the individual differences in selfconcepts that reflect an individual’s personal goals and values, which in turn influence voluntary choices, intentions, and the meaning and salience of what is experienced in life. Simplistically, character is what we intentionally make ourselves; it is rational and volitional. Whereas temperament involves basic emotions such as fear and anger, character involves secondary emotions such as purposeful moderation, empathy, and patience. The three character dimensions can be regarded as a mental self-government, including the executive, legislative, and judicial branches. Character is influenced by socio-cultural learning and matures in progressive steps throughout life. Character can be measured in three dimensions: self-directedness, cooperativeness, and selftranscendence [9]. Character dimensions have genetic components that range from 10–15% and non-random environmental components that range from 30–35%. Table 19.2 details the traits associated with the extreme variants of these individual character dimensions.

301


Table 19.2. Descriptors of extreme high and low scorers on three character dimensions.

Character

Descriptors of extreme variants

dimension

High

Low

Self-directedness

Responsible Purposeful Resourceful Self-accepting Generative

Blaming Aimless Inept Vain Unproductive

Cooperativeness

Reasonable Empathic Helpful Compassionate Principled

Prejudiced Insensitive Hostile Revengeful Opportunistic

Self-transcendence

Judicious Insightful Intuitive Inventive Spiritual

Undiscerning Superficial Dualistic Unimaginative Materialistic

Description of character traits Self-directedness This character trait quantifies differences in the executive competence of individuals. A highly selfdirected person is self-sufficient, responsible, reliable, resourceful, goal-oriented, and self-accepted. The most advantageous summary feature of self-directed individuals is that they are realistic and effective, i.e., they are able to adapt their behavior in accord with individually chosen, voluntary goals. Individuals low in self-directedness are blaming, helpless, irresponsible, unreliable, reactive, and unable to define, set, and pursue meaningful internal goals. Such poor executive function, manifest as unrealistic behavior and lack of internal guidance, is rarely advantageous to the individual.

Cooperativeness This character trait quantifies differences in the legislative functions of individuals. Highly cooperative people conceptualize themselves as integral parts of human society, and are described as empathetic, tolerant, compassionate, supportive, and principled. These features are advantageous in teamwork and social groups, but not for individuals who must live in a solitary manner. People who are low in cooperativeness are self-absorbed, intolerant, critical, unhelpful, revengeful, and opportunistic. They primarily look out for themselves and tend to be inconsiderate of other peoples’ rights or feelings.

302

Self-transcendence This character trait quantifies individual differences in the judicial functions of people, and reflects the extent to which people conceptualize themselves as an integral part of the universe as a whole. Self-transcendent individuals are described as judicious, insightful, spiritual, unpretentious, and humble. These traits are adaptively advantageous when people are confronted with suffering, illness, or death, which is inevitable with advancing age. They may appear disadvantageous in most modern societies where idealism, modesty, and meditative search for meaning might interfere with the acquisition of wealth and power. People low in selftranscendence tend to be pragmatic, objective, materialistic, controlling, and pretentious. Such individuals appear to fit in well in most Western societies because of their rational objectivity and materialistic success. However, they consistently have difficulty accepting suffering, failures, personal and material losses, and death, which leads to lack of serenity and adjustment problems particularly with advancing age. The typical emotional responses to stress (i.e., frustration or negative reinforcement) are summarized for each of the temperament and character dimensions in Table 19.3. Both extremes of temperament dimensions are associated with some negative emotions. In contrast, low scorers in all the character dimensions are associated with negative emotions under both positive and negative reinforcement, whereas high scorers in character remain adaptive whether reinforcement is positive or negative. Regardless of age, all three character dimensions contribute to increasing well-being, as measured by presence of positive emotions, absence of negative emotions, life satisfaction, and virtuous conduct [8].

Neurobiology of temperament and character Temperament The neurobiology of temperament is complex because it involves adaptive responses to a variety of stimuli. A proposed model of stimulus-response characteristics for associative conditioning of temperament is summarized in Table 19.4. Empirical results have supported the model, as briefly summarized in Table 19.5. Illustrative results will be presented here, with more complete details described elsewhere [1, 10–12].


Table 19.3. Effects of positive and negative reinforcement on the emotional state of people scoring high and low on dimensions of temperament and character (adapted from Cloninger CR, Svrakic DM. Personality disorders. In Sadock BJ, Sadock VA, Ruiz P, Kaplan HI, editors. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009, p. 2 v. (lix, 4520, I–138)).

Effects on low scorers Personality dimension

Effects on high scorers

Trait

Positive reinforcement

Negative reinforcement

Positive reinforcement

Negative reinforcement

Temperament

Novelty seeking Harm avoidance Reward dependence Persistence

Placid Cheerful Aloof Unstable

Stoical Fearless Indifferent Discouraged

Euphoric Anxious Sympathetic Enthusiastic

Angry Depressed Disgusted Steadfast

Character

Cooperativeness Self-directedness Self-transcendence

Scornful Vain Greedy

Revengeful Shameful Miserable

Loving Hopeful Joyful

Forgiving Resourceful Peaceful

Table 19.4. Four dissociable brain systems influencing stimulus-response patterns underlying temperament. Abbreviations: GABA – gamma aminobutyric acid; CS – conditioned stimulus; UCS – unconditioned stimulus.

Brain system (related personality dimension)

Principal neuromodulators

Relevant stimuli

Behavioral response

Behavioral inhibition (harm avoidance)

GABA, serotonin (dorsal raphe)

Aversive conditioning (pairing CS and UCS); conditioned signals for punishment and frustrative non-reward

Formation of aversive CS; passive avoidance; extinction

Behavioral activation (novelty seeking)

Dopamine

Novelty CS of reward CS or UCS of relief of monotony or punishment

Exploratory pursuit; appetitive approach; active avoidance; escape

Social attachment (reward dependence)

Norepinephrine, serotonin (median raphe)

Reward conditioning (pairing CS and UCS)

Formation of appetitive CS

Partial reinforcement (persistence)

Glutamate, serotonin (dorsal raphe)

Intermittent (partial) reinforcement

Resistance to extinction

Table 19.5. Neurobiological and clinical correlates of temperaments: harm avoidance, novelty seeking, reward dependence, persistence. Abbreviation: GABA – gamma aminobutyric acid. Reprinted from Cloninger CR. Functional neuroanatomy and brain imaging of personality and its disorders. In D’Haenen HAH, Boer JAd, Willner P, editors. Biological Psychiatry. 2002, pp. 1377–85, with the permission of John Wiley and Sons, Inc.

Principal neuromodulators

Associated genes

Neuroanatomical paths in limbic system

Clinical disorders

Harm avoidance

Serotonin, GABA

Serotonin transporter, tryptophan hydroxylase

Serotonin pathways, septal subdivision

Depression, anxiety disorders, anxious personality disorders

Novelty seeking

Dopamine

Dopamine transporter, dopamine receptors (types 2 and 4)

Dopamine pathways, amygdaloid subdivision

Parkinson’s disease, attention-deficit hyperactivity disorder, substance abuse, impulsive personality disorders

Reward dependence

Norepinephrine

Norepinephrine transporter

Noradrenergic pathways, thalamo-cingulate subdivision

Melancholia, pathological gambling, aloof personality disorders

Persistence

Glutamate, serotonin

Serotonin receptor type 2c

Striato-frontal pathway

Anorexia, perseveration, obsessive personality disorders

303


Temperament dimensions quantify the regulation of primary emotional drives in four subdivisions of the limbic system, which are integrated centrally by the hypothalamus. Novelty seeking involves a tonic opposition of craving and desire for thrilling or novel stimuli and avoidance of fear-inducing stimuli. For example, when hunger or hunting urges are unsatisfied, there is irritability and impulsive aggressive behavior, which activates the amygdaloid subdivision of the limbic system and dopaminergic projections from the ventral tegmental area to the striatocortical system [12]. To test the proposed importance of the striatum in novelty seeking, and in particular the role of dopamine as its principal neuromodulator, studies of personality and dopamine function have been carried out in patients with Parkinson’s disease (PD) [13–16]. Patients with PD have premorbid characteristics that are described uniformly as industrious, rigidly moral, stoic, serious, and non-impulsive. This premorbid personality was found to be low in novelty seeking and to have an associated deficit in dopaminergic activity in the striatum, supporting the original model [14]. Subsequent work has confirmed that dopamine D2 receptor availability in the connections of the dorsal striatum and insular cortex is strongly negatively correlated with novelty-seeking scores (r = −0.7) in patients with PD [13]. High novelty seeking is a strong moderator of overeating [16] and susceptibility to alcoholism and other forms of substance dependence [17, 18]. The dopamine transporter density is also moderately correlated (r = +0.5) with novelty seeking [19]. The importance of dopaminergic corticostriatal function in novelty seeking has also been confirmed in healthy subjects [8]. Large-scale meta-analysis has confirmed that the dopamine DRD4 gene accounts for about 3% of the variance in novelty seeking in the general population [20]. Dopamine function as measured by growth hormone and prolactin levels after bromocriptine administration (a specific D2 receptor agonist) found a significant association with novelty-seeking scores [21]. Harm avoidance quantifies behavioral inhibition in response to conditioned aversive stimuli, generally modulating the response to fear-inducing stimuli. For example, when compared with the magnitude of the eye-blink startle to a loud noise while the subject is viewing a neutral foreground stimulus, high harm avoidance potentiates startle while viewing

304

an unpleasant stimulus whereas low harm avoidance reduces startle while viewing a pleasant stimulus [22, 23]. A variable number tandem repeat polymorphism of the upstream transcription regulator for the serotonin transporter (short allele of 5-HTTPLR) is associated with harm avoidance scores [24, 25] and was found to have a dose effect on harm avoidance in the elderly [26]. Furthermore, fibromyalgia patients with this particular allele of 5-HTTPLR have been shown to display harm avoidance and higher levels of depression [27]. Individuals carrying the short allele also have an increased reactivity of the amygdala to fear [28, 29], and increased risk of depression compared with others [30]. Harm avoidance scores account for 30% of the variance in the functional connectivity between the amygdala and perigenual cingulate cortex, which are involved in the perceptual processing of fear-inducing stimuli. The cingulate cortex serves as a cross-road between the emotional brain (i.e., limbic system) and the rational brain; essentially, fear hijacks control of behavior in the sense that people stop being reasonable and act automatically according to the emotional drives. Reward dependence quantifies the drive for social approval and attachment. In animals, stimulation of the noradrenergic locus coeruleus or its dorsal bundle, or direct application of norepinephrine, decreases the firing rate of terminal neurons and increases their sensitivity to other afferents, so that targeted stimuli can stand out from non-targeted stimuli. In humans, short-term reduction of norepinephrine release by acute infusion of the alpha-2 presynaptic agonist clonidine selectively impairs paired-associate learning, particularly the acquisition of novel associations [1]. Individuals who are high in reward dependence were confirmed to have facilitated acquisition of condition signals of reward compared with those low in reward dependence [31]. Norepinephrine metabolites in urine have been found to be elevated in individuals high in reward dependence [32, 33]. A functional polymorphism in the norepinephrine transporter has been associated with temperament [34], but the effects are weak and inconsistent because of other genetic and environmental influences. For example, the so-called “love” hormone oxytocin is released into blood after nursing or sexual orgasm regardless of gender and is moderately correlated with reward dependence (r = 0.5) but not cooperativeness (r = 0.1) [35]. Persistence quantifies the resistance to distinction in response to intermittent reinforcement, serving as


Table 19.6. Distinctive patterns of activation and deactivation of brain regions associated with increasing scores on the three character dimensions in single photon emission computed tomography of 20 normal men.

Character dimensions

Region of activation

Region of deactivation

Self-directedness

Left frontal lobe

Right precentral gyrus, right inferior temporal gyrus, left temporal lobe

Cooperativeness

Bilateral frontal lobes, left temporal lobe, right striatum

Bilateral parietal lobes, central regions, and occipital lobes

Self-transcendence

Left occipital lobe, optic radiation

Right temporal lobe, right parietal lobe

a self-report measure of the partial reinforcement extinction effect [36]. Individual differences in persistence were strongly correlated (r = 0.8) with responses measured by functional magnetic resonance imaging (fMRI) in a circuit involving the ventral striatum, orbitofrontal cortex and rostral insula, and dorsal anterior cingulate cortex, in Brodmann’s area (BA) 32. Subjects low in persistence exhibited relative decreases in activity within this circuit, whereas those high in persistence exhibited relative increases. Persistence scores also correlated with apparent selection bias, such that subjects with high scores made relatively more pleasant judgments at the expense of neutral judgments when viewing pictures from the International Affective Picture System [37]. In summary, temperament reflects heritable individual differences in the stimulus-response characteristics of subdivisions of the limbic system or emotional brain. Activation of temperament dimensions in response to primary drive stimuli such as sex, hunger, and social approval influence communication of the emotional brain with the human neocortex.

Character Character traits are hypothesized to involve higher cortical functions allowing primates, particularly human beings, to perform abstraction and symbolic activities. Thus, character has been proposed to involve more recently evolved brain regions, particularly the neocortex [12]. Functional brain-imaging studies now confirm that each character trait is associated with distinct patterns of activation and deactivation of the neocortex [38]. Results of this work are summarized briefly in Table 19.6, omitting details about specific gyri and Tailairach coordinates. Cooperativeness exhibited the largest cluster (in the frontal cortex) and the largest number of clusters, nearly all of which were bilateral.

Self-directedness has also been strongly positively correlated (r = 0.8) with individual differences in the activation of the medial prefrontal cortex (BA 9/10) while carrying out a simple executive function task [8, 39, 40]. This is the same brain region that is activated when a person evaluates internal cues, such as whether a picture is judged to be pleasant or not [39]. Self-transcendence has shown a strong negative correlation with individual differences in the density of serotonin 1a receptors in the frontal cortex, cerebellum, and dorsal raphe [41]. High self-transcendence is also associated with the preservation of temporoparietal gray matter in the elderly [42]. Self-transcendence has also been correlated with genetic polymorphisms involving dopamine function, namely dopamine DRD4 [43] and vesicular monoamine transporter 2 (VMAT2) [44]. However, the variance explained by such specific polymorphisms is small and inconsistent.

The complexity of personality Personality dimensions involve complex adaptive systems of multiple genetic and environmental variables. Both gene–gene and gene–environment interactions are expected for understanding quantitative developmental phenomena, and these have been abundantly confirmed for personality [8]. For example, novelty seeking depends on a three-way interaction of DRD4 with catechol-O-methyl transferase (COMT) and the serotonin transporter locus promoter’s regulatory region (5-HTTLPR). In the absence of the short 5-HTTLPR allele and in the presence of the high activity COMT Val/Val genotype, novelty-seeking scores are higher in the presence of the DRD4 seven-repeat allele than in its absence [45]. Within families, siblings who shared identical genotype groups for all three polymorphisms had significantly correlated novelty seeking (r = 0.4), whereas siblings with any different genotypes at these three loci showed no significant

305


Table 19.7. Heritability of seven dimensions of temperament and character in 4572 Australian twins.

Personality dimension

% Total heritability

% Unique heritability

Harm avoidance

42

70

Novelty seeking

39

82

Reward dependence

35

57

Persistence

30

76

Self-directedness

34

74

Cooperativeness

27

59

Self-transcendence

45

57

correlation. This interaction was confirmed in unrelated individuals and in a study by independent investigators in another country [46]. Gene–environment interaction has also been demonstrated for novelty seeking and for harm avoidance in prospective population-based studies. For example, particular variants of DRD4 are associated with high novelty seeking in adulthood, but only if the carriers were subject to social coldness and harsh physical discipline by their mothers during childhood [47]. Both the genotype and provocative childhood experiences were essential for the development of novelty seeking, which involves a predisposition to violent behavior emulating the childhood experience of social coldness and harsh physical discipline.

Inheritance of personality Twin studies show that human personality traits are roughly equally influenced by genetic and by environmental influences. Twin studies of temperament and character have confirmed heritabilities of all seven temperament and character dimensions to be around 50% when the reliability of the scales is taken into account [7, 48, 49]. Table 19.7 summarizes the heritability of all seven dimensions, presenting results conservatively without any correction for the reliability of the short form used in the large-scale Australian twin study [7]. Notably, each of the seven personality dimensions is heritable, with unique genetic antecedents unrelated to any of the other dimensions. These findings show that both temperament and character are heritable. Personality therefore develops through the interaction of hereditary dispositions and environmental

306

influences. The notion of genetic canalization (or “epigenetic landscape”) has been revised to include reciprocal interactions among genetic endowment, environmental stimulation, and changes in self-awareness across the lifespan [8]. Genetic differences account for about half of the variance in differences between people. Of the remaining 50% of the variance in differences between people, 30–35% is explained by nonshared environmental effects (i.e., influences unique to each individual) and 10–15% by measurement error [7]. Contrary to common belief, environmental influences that are shared by siblings (such as having the same parents, living in the same neighborhood, going to the same schools, and so forth) are modest influences on the differences between people. Of note, adoption studies suggest somewhat lower heritability of about 30% for personality traits. The higher heritability estimates from twins are most likely the result of non-additive genetic influences (e.g., higher-order interaction among alleles at each locus or among loci), which is the same for monozygotic twins but contributes little to the resemblance of other relatives [8]. Character matures with increasing age (i.e., increases in both adaptiveness and also integration over time), particularly from adolescence to age 30 years [5, 9]. The maturation of character with age differs prominently from the effect of time on temperament, and occurs regardless of the comparable degrees of heritability of temperament and character. Heritability estimates refer only to genetic influences on the differences between people at one point in time. People are able to change from one time to another as a result of growth in self-awareness in ways that are only partly constrained by their past genetic expression. For example, intelligence (IQ) is highly heritable, but there has been an increase of about 3.3 IQ points per decade that requires frequent re-standardization of IQ tests. This increase in IQ scores in successive birth cohorts is called the Flynn effect [50]. The IQ increase is attributable to skill in problem-solving on the spot (fluid intelligence), such as recognition of similarities, rather than skills dependent on past individual education, such as vocabulary size (crystallized intelligence). Likewise, the differences between people in self-transcendence at one point in time is 49% heritable, but the prevalence of self-transcendent experiences increased from 48% in 1987 to 76% in 2000 among people in England


[51]. These rapid changes in fluid intelligence and selftranscendence cannot be explained by genetic evolution. Character and fluid intelligence can develop rapidly within individuals in response to cultural developments that influence human society as a whole.

Conclusion Human personality is the collection of complex characteristics and traits that shape and distinguish an individual from a machine-like object. It is defined as the dynamic organization of the psychobiological systems by which a person shapes and adapts in a unique way to a changing internal and external environment. Maturation and integration of human personality involves the development of habits and skills, learning facts and how to reason, and growing in self-awareness through experiences across a wide range of situations. Once established, personality in adulthood is consistent and stable over time. This chapter reviewed a contemporary model of personality that takes into account neurogenetic variables as well as psychosocial influences. This model facilitates investigation of neurobiological and psychosocial influences of the development on mental health and mental illness, and includes temperament and character. Temperament refers to the emotional biases that are regulated by behavioral conditioning whereas character refers to the higher cognitive processes by which human beings modify their behavior intentionally. The findings presented in this chapter illustrate the neurobiological complexities of personality, and support the perspective that further research using the temperament and character dimensional model will inform usefully on our understanding of human personality and its relationships to psychiatric and neurological disorders.

References 1. Cloninger CR, Svrakic DM. Personality disorders. In Sadock BJ, Sadock VA, Ruiz P, Kaplan HI, editors. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009. 2. Thomas A, Chess S. Genesis and evolution of behavioral disorders: from infancy to early adult life. Am J Psychiatry 1984;141(1):1–9. 3. Goldsmith HH, Buss AH, Plomin R et al. Roundtable: what is temperament? Four approaches. Child Dev. 1987;58(2):505–29.

4. Sigvardsson S, Bohman M, Cloninger CR. Structure and stability of childhood personality: prediction of later social adjustment. J Child Psychol Psychiatry 1987;28(6):929–46. 5. Cloninger CR. Completing the psychobiological architecture of human personality development: Temperament. In Staudinger UM, Lindenberger U, editors. Understanding Human Development: Dialogues with Lifespan Psychology. Boston, MA: Kluwer Academic Publishers; 2003, pp. 159–82. 6. Roberts BW, DelVecchio WF. The rank-order consistency of personality traits from childhood to old age: a quantitative review of longitudinal studies. Psychol Bull. 2000;126(1):3–25. 7. Gillespie NA, Cloninger CR, Heath AC, Martin NG. The genetic and environmental relationship between Cloninger’s dimensions of temperament and character. Pers Indiv Differ. 2003;35(8):1931–46. 8. Cloninger CR. Feeling Good: The Science of Well-being. Oxford: Oxford University Press; 2004. 9. Cloninger CR, Svrakic DM, Przybeck TR. A psychobiological model of temperament and character. Arch Gen Psychiatry 1993;50(12): 975–90. 10. Burns DD. Feeling Good: The New Mood Therapy. 1st edition. New York, NY: Morrow; 1980. 11. Cloninger CR. Biology of personality dimensions. Curr Opin Psychiatry 2000;13(6):611–16. 12. Cloninger CR. Functional neuroanatomy and brain imaging of personality and its disorders. In D’Haenen HAH, Boer JAD, Willner P, editors. Biological Psychiatry. Chichester: John Wiley and Sons; 2002, pp. 1377–85. 13. Kaasinen V, Aalto S, Nagren K, Rinne JO. Insular dopamine D2 receptors and novelty seeking personality in Parkinson’s disease. Mov Disord. 2004;19(11):1348–51. 14. Menza MA, Golbe LI, Cody RA, Forman NE. Dopamine-related personality traits in Parkinson’s disease. Neurology 1993;43(3 Pt 1):505–8. 15. Tomer R, Aharon-Peretz J. Novelty seeking and harm avoidance in Parkinson’s disease: effects of asymmetric dopamine deficiency. J Neurol Neurosurg Psychiatry 2004;75(7):972–5. 16. Sullivan S, Cloninger CR, Przybeck TR, Klein S. Personality characteristics in obesity and relationship with successful weight loss. Int J Obes. (Lond) 2007;31(4):669–74. 17. Howard MO, Kivlahan D, Walker RD. Cloninger’s tridimensional theory of personality and psychopathology: applications to substance use disorders. J Stud Alcohol. 1997;58(1):48–66.

307


18. Grucza RA, Robert Cloninger C, Bucholz KK et al. Novelty seeking as a moderator of familial risk for alcohol dependence. Alcohol Clin Exp Res. 2006;30(7):1176–83.

32. Curtin F, Walker JP, Peyrin L et al. Reward dependence is positively related to urinary monoamines in normal men. Biol Psychiatry 1997;42(4):275–81.

19. Laine TP, Ahonen A, Rasanen P, Tiihonen J. Dopamine transporter density and novelty seeking among alcoholics. J Addict Dis. 2001;20(4):91–6.

33. Garvey MJ, Noyes R, Jr., Cook B, Blum N. Preliminary confirmation of the proposed link between reward-dependence traits and norepinephrine. Psychiatry Res. 1996;65(1):61–4.

20. Munafo MR, Yalcin B, Willis-Owen SA, Flint J. Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biol Psychiatry 2008;63(2):197–206. 21. Gerra G, Zaimovic A, Timpano M et al. Neuroendocrine correlates of temperamental traits in humans. Psychoneuroendocrinology 2000;25(5):479–96. 22. Corr PJ, Kumari V, Wilson GD, Checkley S, Gray JA. Harm avoidance and affective modulation of the startle reflex: a replication. Pers Indiv Diff. 1997;22(4):591–3. 23. Corr PJ, Wilson GD, Fotiadou M et al. Personality and affective modulation of the startle reflex. Pers Indiv Diff. 1995;19(4):543–53. 24. Van Gestel S, Forsgren T, Claes S et al. Epistatic effect of genes from the dopamine and serotonin systems on the temperament traits of Novelty Seeking and Harm Avoidance. Mol Psychiatry 2002;7(5):448–50. 25. Lesch KP, Bengel D, Heils A et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274(5292):1527–31. 26. Ricketts MH, Hamer RM, Sage JI et al. Association of a serotonin transporter gene promoter polymorphism with harm avoidance behaviour in an elderly population. Psychiatric Genet. 1998;8(2):41–4. 27. Offenbaecher M, Bondy B, de Jonge S et al. Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region. Arthritis Rheum. 1999;42(11):2482–8. 28. Hariri AR, Mattay VS, Tessitore A et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002;297(5580):400–3. 29. Hariri AR, Drabant EM, Munoz KE et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry 2005;62(2):146–52. 30. Pezawas L, Meyer-Lindenberg A, Drabant EM et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neuroscience 2005;8(6):828–34. 31. Corr PJ, Pickering AD, Gray JA. Personality and reinforcement in associative and instrumental learning. Pers Indiv Diff. 1995;19(1):47–71.

308

34. Ham BJ, Choi MJ, Lee HJ, Kang RH, Lee MS. Reward dependence is related to norepinephrine transporter T-182C gene polymorphism in a Korean population. Psychiatric Genet. 2005;15(2):145–7. 35. Bell CJ, Nicholson H, Mulder RT, Luty SE, Joyce PR. Plasma oxytocin levels in depression and their correlation with the temperament dimension of reward dependence. J Psychopharmacol. 2006;20(5): 656–60. 36. Gusnard DA, Ollinger JM, Shulman GL et al. Persistence and brain circuitry. Proc Natl Acad Sci USA 2003;100(6):3479–84. 37. Lang PJ, Bradley MM, Cuthbert BN. International Affective Picture System (IAPS): Affective Ratings of Pictures and Instruction Manual. Gainesville, FL: University of Florida; 2008. 38. Turner RM, Hudson IL, Butler PH, Joyce PR. Brain function and personality in normal males: a SPECT study using statistical parametric mapping. Neuroimage 2003;19(3):1145–62. 39. Gusnard DA, Akbudak E, Shulman GL, Raichle ME. Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function. Proc Natl Acad Sci USA 2001;98(7):4259–64. 40. Gusnard DA, Ollinger JM, Shulman GL, Cloninger CR, Raichle ME. Personality differences in functional brain imaging. Soc Neurosci Abstr. 2001;27(80):11. 41. Borg J, Andree B, Soderstrom H, Farde L. The serotonin system and spiritual experiences. Am J Psychiatry 2003;160(11):1965–9. 42. Kaasinen V, Maguire RP, Kurki T, Bruck A, Rinne JO. Mapping brain structure and personality in late adulthood. Neuroimage 2005;24(2):315–22. 43. Comings DE, Gonzales N, Saucier G, Johnson JP, MacMurray JP. The DRD4 gene and the spiritual transcendence scale of the character temperament index. Psychiatric Genet. 2000;10(4):185–9. 44. Hamer DH. The God Gene: How Faith is Hardwired into our Genes. 1st edition. New York, NY: Doubleday; 2004. 45. Benjamin J, Osher Y, Kotler M et al. Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter


promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT). Mol Psychiatry 2000;5(1):96–100. 46. Strobel A, Lesch KP, Jatzke S, Paetzold F, Brocke B. Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR, and COMT val/met variants. Mol Psychiatry 2003;8(4):371–2. 47. Keltikangas-Jarvinen L, Raikkonen K, Ekelund J, Peltonen L. Nature and nurture in novelty seeking. Mol Psychiatry 2004;9(3):308–11. 48. Heath AC, Cloninger CR, Martin NG. Testing a model for the genetic structure of personality: a comparison

of the personality systems of Cloninger and Eysenck. J Pers Soc Psychol. 1994;66(4):762–75. 49. Stallings MC, Hewitt JK, Cloninger CR, Heath AC, Eaves LJ. Genetic and environmental structure of the Tridimensional Personality Questionnaire: three or four temperament dimensions? J Pers Soc Psychol. 1996;70(1):127–40. 50. Flynn JR. What is Intelligence? Beyond the Flynn Effect. Cambridge: Cambridge University Press; 2007. 51. Hay D. Something There: The Biology of the Human Spirit. West Conshohocken, PA: Templeton Foundation Press; 2006.

309

Section II

Neurobehavioral and Neuropsychiatric Assessment

Chapter

Neuropsychiatric evaluation

20

Fred Ovsiew

The old adage has it that the neurological diagnosis is gained from the history, the localization from the examination. In Behavioral Neurology & Neuropsychiatry (BN&NP), the history contributes to disease diagnosis (along with examination, laboratory tests, imaging, and so on) but also provides information about impairment, disability, the patient’s experience of illness, and the psychological and social forces that facilitate or hamper treatment and recovery that cannot be gathered in any other fashion. This chapter provides an outline of what can be learned from the history, but only an outline, because the substance of history-taking forms the topic of the rest of this volume. The emphasis is on neuropsychiatric evaluation, and this chapter serves as complementary to other chapters devoted to examination procedures most relevant to BN&NP.

Understanding history-taking in BN&NP Chapters about how to take a history customarily appear toward the beginning of medical textbooks, but perhaps they belong at the end. Most of us have overheard a student or resident taking a history from a patient with cardiac disease. “Have you had shortness of breath, or swelling of your ankles, or anything like that?” the clinician inquires. “Anything like what?” the patient may well wonder. To see the common thread among disparate symptoms requires knowledge of the pathophysiology of heart failure, knowledge only the doctor can be expected to possess. To take a complete history (as this author was taught at the beginning of medical school) requires knowledge of all of medicine. This is why senior physicians take more

effective histories than junior trainees [1]. Moreover, subspecialists in BN&NP ask about phenomena that do not appear in many manuals of psychopathology. Personality change in limbic epilepsy provides good examples: hypergraphia and humorless sobriety do not appear in any diagnostic criteria of any version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) used over the last 60 years [2]. Only a firm grasp of the disease-oriented material in this book can provide the clinician with the capacity to take a neuropsychiatric history; this chapter can do no more than sketch out the matrix into which more specific questions fit. These comments about the expertise that underlies history-taking imply that the historian in the clinical encounter is the clinician, not the patient. The patient is a witness to his or her symptoms and is not responsible for knowing what is relevant to the diagnostic process and certainly not responsible for creating a narrative framework that makes sense of events. Those tasks, the historical enterprise, fall to the clinician. It follows that the often-heard excuse “The patient is a poor historian” has no place in BN&NP. “If the history is non-informative, changing, or contradictory, the patient usually has a confusional state, a cognitive problem or a psychiatric disorder, not bad intentions” ([3], p. 296). Thus for the subspecialist in BN&NP, the patient as “poor historian” is a clinical finding to be explained, not an excuse for an incomplete or incoherent narrative. Hearing the patient’s account is only the beginning of putting together the history. The shortcomings of human communication under stressful circumstances mandate skill and care in pursuing the historical inquiry with the patient. Misunderstandings, imprecision, and the frailty of


310

Chapter 20: Neuropsychiatric evaluation

memory facilitate error in history-taking even in patients without cognitive impairment [4, 5]. Because cerebral disease deranges narrative capacity, in almost every BN&NP evaluation, information must be sought from collateral sources. A particularly important source of collateral information is the medical record. Whenever possible, the history as obtained from the patient and family should be supplemented and corrected by reference to medical records. Patients whose symptoms are not explained by structural disease in particular give incomplete and inaccurate accounts of those symptoms with dramatic inconsistency in reporting from one assessment to the next [6]. Only by checking the patient’s report of past medical diagnoses and treatments against the medical record can an adequate degree of accuracy be attained [7]. Further, the patient may be unaware of or ill equipped to report medical details of importance: results of neuroimaging studies, electroencephalographic (EEG) findings, specific doses of medicines, and so on. Unfortunately, it may be difficult to obtain medical records from other institutions (and, sometimes, even at one’s own institution) in a fashion timely enough to assist the diagnostic enterprise. Patients sometimes arrive for a consultation having deliberately failed to provide medical records on the grounds that they want a fresh opinion. This is misguided; as the saying goes, one is entitled to one’s own opinions but not one’s own facts. Sometimes a non-informative or contradictory account from the patient, signals deliberate deception or concealment. Especially in a forensic context the examiner must listen with a certain skepticism, and indeed the exaggeration or concoction of symptoms may be much more common than clinicians assume [8, 9]. In most contexts, however, clinicians should follow one of Fisher’s rules: “The patient is always doing the best he can” ([10], p. 390). Good history-taking requires more from the clinician than a thorough knowledge of the phenomenology of disease. An open-minded approach and genuine curiosity help avoid the related errors of influencing the patient by suggestion and reaching premature closure in diagnostic thinking. As Jaspers [11] advised, even if the patient is reporting delusions, the examiner should “listen attentively and . . . go along with the patient a little in his ideas and judgments.” Knowing what additional material is relevant to the presenting complaint, knowing what to survey even if no

relevance is immediately apparent, keeping an eye open for a surprise, and knowing how to weigh what one hears mark the expert. The appraisal of the patient’s account, as it occurs in the clinician’s mind, is the subject of Richard Asher’s joke about medical diagnosis. Asher, the British physician and essayist, posed the following riddle: “What runs around farm yards, flaps its wings, lays eggs and barks like a dog?” The answer, of course, is “a hen,” the bit about the barking having been thrown in to confuse the diagnostician. “Few patients oblige with the symptoms it is their duty to have and not many refrain from complaining of those they ought not to have,” commented Asher ([12], p. 64). To separate history-taking from examination and treatment is to some degree artificial. From the beginning of the encounter with the patient and the family, the clinician observes the patient’s behavior and mode of thought (as well as the patient’s station and gait, movements, spontaneous emotional expression, and other motor phenomena) and the family’s attitude and interactions. Further, the clinician’s demeanor, interest, focus, and comments form part of the psychological environment of treatment. The ability of the clinician to elicit certain features of the history – for example, matters the patient finds embarrassing or “crazy” – depends to a considerable extent on the clinician’s skill in creating a suitably supportive ambiance. In the following section, the chapter takes up neuropsychiatric aspects of the family, developmental, social, and general medical history as the background to the history of the present illness and then provides comments on a few standard elements of neuropsychiatric phenomenology.

Family history The genetic contribution to many neuropsychiatric disorders can be disclosed by obtaining a family history. The accuracy of family history information varies considerably depending on disease and method [13– 16]. In general, the closer the degree of relatedness, the more accurate the report. Affected family members may be more aware of similar illnesses in the family than unaffected ones are. The clinician can improve accuracy by taking the family history from several family informants. Obtaining the history relative-byrelative, rather than disease-by-disease, should be routine practice. Thus the examiner – rather than asking, for example, “Is there anybody in the family

311

Section II: Neurobehavioral and Neuropsychiatric Assessment

with Alzheimer’s disease?” – explores the pedigree and inquires about the health of each family member. Of course, both pathways can be pursued in the interview. Drawing a family tree facilitates the relativeby-relative inquiry and may help in recording the information [17]. Unfortunately, the advent of the electronic medical record has made the freehand familytree diagram impossible to maintain in some settings. The present author often tacks on, at the end of the structured inquiry, the questions “Is there anyone in the family with an unusual illness, or are there any illnesses that run in the family?” but cannot recall yet being rewarded by a mention of acute intermittent porphyria.

Developmental history Birth history and developmental milestones Investigating the possible role of cerebral dysfunction in mental disorders, information about the patient’s gestation, birth, and development provides an oftenneglected perspective on the contribution of early brain injury to adult cognitive and motor function as well as to behavioral disorders generally considered idiopathic [18–21]. The most obvious consequences, such as cerebral palsy and mental retardation, need not be present for early injury to be relevant, as the ample literature on the relevance of obstetric complications to schizophrenia shows [22]. Patients or, better, their mothers should be asked about the course of the pregnancy (such as bleeding, infection, and indicators of intrauterine growth retardation), labor (such as indicators of hypoxia), and delivery (including whether at term and birth weight). If available, Apgar scores provide standardized information about the state of the baby’s brain at birth. Inquiring about serious illness in early childhood also may be productive. Parental recall for early milestones is imperfect [23], but asking about age of first steps can yield useful information. Often parents can compare the patient with a “control” sibling in regard to developmental trajectory. Given the inaccuracy in recall and the wide range of normal development, inference from information gathered in adulthood should be cautious. Nonetheless, accumulating data suggest that this information may be relevant to an understanding of adult function and psychopathology [24, 25].

312

Handedness and motor skills Handedness is a multidimensional construct and falls on a continuum from fully dextral through various degrees and patterns of mixed-handedness to highly sinistral [26]. Although the writing hand is strongly correlated with hand preference, the clinician can additionally inquire as to the preferred hand for using a toothbrush or scissors, throwing a ball, and so on. Establishment of the patient’s handedness should be routine, as handedness is a variable relevant to the cerebral contribution to a wide variety of conditions [27, 28]. For most clinical purposes, classifying patients as either dextral or not fully dextral is adequate. Clumsiness, or developmental coordination disorder, is a non-specific marker of cerebral dysfunction [21, 29]. Inquiring as to a childhood history of clumsiness that interferes with daily life – not just incapacity to excel at sports – gives an idea of this aspect of brain development, and may be an interesting comparator for the physical examination for soft signs.

Academic and intellectual performance Achievement in school is the simplest and most accessible index of general intelligence. The answer “I graduated from high school” may need to be supplemented by the question “Were you in regular or special classes?” Low intelligence points to a cerebral factor in the pathogenesis of idiopathic mental disorders [30, 31], and its recognition leads to consideration of its etiology, a diagnostic evaluation that often is not performed [32]. Patients also can report whether they showed an anomalous pattern of academic strengths and weaknesses. Dyslexia and attentional disorders are well known; the features of non-verbal learning disability – trouble with visuospatial perception, impaired recognition of facial expression and tone of voice, low mathematics achievement, clumsiness – can also be ascertained [33]. Congenital disorders of face recognition are common, have interesting genetics, and may be associated with disturbances of social and emotional processing [34, 35].

Psychological trauma Patients with dissociative and conversion disorders (i.e., pseudo-neurological, mental or somatic symptoms) often present to subspecialists in BN&NP. These


disorders are commonly thought to have their origins in childhood traumatic experience, particularly sexual and physical abuse, although the connection between them remains under investigation [36, 37]. Disorganized attachment in childhood and adult psychiatric disorder may be mediating variables in the development of such conditions. It therefore is important to inquire about adverse experiences in childhood, including loss of important attachment figures, sexual abuse, and physical abuse. This inquiry requires delicacy, as the memories being sought may be enormously painful and conveying skepticism is sure to poison the atmosphere; the clinician must understand that appalling things are done to children and many patients will be exquisitely sensitive to the implied or expressed moral judgments by the clinician. Yet the deficiencies of retrospective accounts – i.e., history-taking – are all too evident in the psychological literature about childhood trauma. Prospective data based on medical records may fail to confirm clinical impressions based on retrospective patient accounts [38]. Iatrogenesis in the forms of suggestion and/or “false memories” must be avoided [39, 40]. The following cases are offered as examples.

Case 1 A young female psychiatric social worker presented for neuropsychiatric consultation regarding spells that had previously been diagnosed as epileptic but that she was now convinced were pseudoseizures. In her first visit, she reported that she had attended a seminar in which the relationship between childhood sexual abuse and pseudoseizures was emphasized, after which she “remembered” that she had been abused in childhood by her mother. On a second visit, after old records had been requested and an EEG ordered, she reported having additionally “remembered” that her father had abused her, too. Later, she “recalled” that her brother had engaged in sexual abuse of her as well. Her apparently reliable sister believed no abuse had occurred. The question of pseudoseizures was adequately settled when she had a generalized convulsion witnessed in her medical work-place. Over a period of years she developed a clear schizophrenic illness, with florid persecutory and misidentification delusions; however, she continued to believe that she had only pseudoseizures, had multiple personality disorder, and had been hypnotized by the present author (a delusional memory).

Case 2 A middle-aged woman presented for a second opinion regarding pseudoseizures after a period of psychotherapy had been unproductive. Her mother-inlaw accompanied her. Previous video-EEG monitoring demonstrated pseudoseizures, and her account of the progression from non-physiological pain to nonphysiological spells left little doubt about the diagnosis. Asked if she had any idea why she was having such spells, she hesitantly indicated that it related to events in her childhood. Thinking that she was reluctant to talk about experiences of abuse in front of her motherin-law, the examiner offered to see her privately. She did not wish to have her mother-in-law leave, however, and she proceeded to recount having been abducted by space aliens in her pre-teen years [41]. Further discussion revealed that this “memory” had “returned” to her during her psychotherapeutic treatment by guided imagery.

Social history Many elements of the traditional social history gathered by psychiatrists and other clinicians are helpful to subspecialists in BN&NP. For example, it is helpful to learn about the patient’s household make-up, vocational background, financial status, and other relevant psychosocial information. Of specific import in patients with brain disease is the impact of the brain disease on the family and social network and the capacity of those involved with the patient to provide psychological and practical support. Clinical experience leaves no doubt that those closest to the brain-injured patient suffer along with the patient, and sometimes seemingly more than the insightless patient. Living with the characterologically altered brain-injured patient [42] commonly has distressing consequences for spouses, children, and others who provide care. Previous clinicians may not have recognized these consequences, and knowledgeable sensitivity on the part of a new examiner often is met with relief and gratitude by the patient’s family members. While the need for physical care of a family member with brain disease is potentially burdensome, personality change has the greater impact on family relationships [43]. Caregivers become socially isolated and face the difficulty of grieving for the lost person even while that person, in an altered condition, is still present. Even adult children of patients with brain disease experience complex and often intense reactions

313


to the altered personality and responsiveness of the patient, but minor children living with their ill parent have particularly painful, consequential, and poignant reactions [44]. A changed sexual relationship between the patient with a brain injury and his or her spouse also deserves frank recognition [45].

General medical history In addition to cerebral symptoms, inquiry about general health and systemic illnesses also is essential to the evaluation in BN&NP. A thorough review of the general medical history should focus on brainrelated disease and potentially psychotoxic treatments. Some clinicians may be unfamiliar with the sorts of details necessary: not just a stroke, but a righthemisphere stroke of embolic origin with occlusion of the inferior division of the middle cerebral artery, and so on. Risk factors for cardiovascular disease are often relevant: obesity, smoking, dyslipidemia, hypertension, and diabetes. The review of systems should routinely include questions about organ systems in which disease can produce the neuropsychiatric symptoms reported by the patient. For example, along with inquiry about a known history of thyroid disease and replacement therapy, the depressed patient should be asked about constipation, heat and cold intolerance, and changes in menses. An acutely psychotic patient in whom rheumatic disease might be under consideration should be asked about a history of miscarriages or thrombocytopenia, rash, joint swelling or pain, dry eyes or mouth, and oral or genital ulcers.

Neuropsychiatric phenomenology Progress in neuroimaging, neurogenetics, and neurophysiology notwithstanding, BN&NP remains a bastion of bedside medicine in an increasingly technological medical world. Virtually alone in medicine (excluding psychoanalysis), the field honors the old tradition of the individual case study, even having a journal devoted to these efforts (Neurocase). As Caplan [10] points out, the detailed phenomenological study at the bedside of already-diagnosed cases pays dividends for the clinician when similar phenomena appear in another case in which making a diagnosis proves difficult. The exploration of personal experience in the history-taking will never be replaced by neuroimaging, and the clinician who takes no interest in this aspect of clinical work is well advised to seek a different specialty

314

area. In fact, the cerebral substrate of subjective experience of emotion or deficit may differ surprisingly from the substrate of their non-conscious behavioral manifestations [46, 47]. Further, the clinician uses history-taking not only to reveal pathophysiology and diagnosis but also to understand the patient’s predicament, which is fundamentally a social fact. The examiner needs to learn how the illness has affected the patient’s life: family relationships, job performance, prospects for the future, and so on. Understanding the impact of the illness – impairment, disability, and handicap – also constitutes a domain in which the patient and clinician may proceed collaboratively, even when the patient is otherwise reluctant. “What kinds of things can’t you do any longer?” is the sort of question that a patient may well respond to cooperatively even when the details of the symptom-picture are hard to elicit, thus affording a tactful way of furthering the inquiry and leading on to harder-to-access matters. There are distinctive obstacles in elucidating the phenomena of illness in the practice of BN&NP. As Glick notes, “In problems involving the brain, the disease processes that can distort the history form a sort of pathologic insulation, obstructing the perception and flow of information within the patient’s mind and from the patient to you, the interviewer” ([48], p. 6). Symptoms may be the product of disordered brain function and outside the ordinary categories of thought and language. As a simple example, the olfactory aura of a limbic seizure is sometimes indescribable (in five of 14 patients in one study) [49], presumably because it represents a pathological event not corresponding to any real-world sensation. Other symptoms may be dreamlike or bizarre, not the sort of thing one ordinarily talks about to a doctor, or to anyone, or even formulates clearly to oneself. The patient may be amnestic for the symptoms, or anosognosic, or aphasic. Describing the process of interviewing patients for the broad range of problems with which they present to BN&NP subspecialists for evaluation is beyond the scope of the present work; however, the clinical phenomenology and presentations of persons with such problems are described at length in many of the chapters included in Part I of this volume. Here, additional brief discussion is offered about the key elements of history-taking in the context of a few more of the most common and/or challenging clinical problems encountered by clinicians working in this field.


Box 20.1. Sample reports by patients about dissociative experiences; from the DES-II and Somatoform Dissociation Questionnaire [50–52]. Finding yourself in a place and can’t remember how you got there Finding yourself dressed in clothes you can’t remember buying, can’t remember putting on Having no memory for important events in your life Feeling your body does not belong to you Being unsure if something really happened or was part of a dream Finding evidence of having done things you don’t remember doing Body or part of it insensitive to pain Cannot see (hear, move) for a while as if blind (deaf, paralyzed) Cannot sleep for nights on end but still active during day Dislike smells, tastes that you usually like

Dissociative symptoms When a dissociative or conversion disorder diagnosis is under consideration, the clinician should screen for other symptoms in this domain. The Dissociative Experiences Scale (DES-II), the most commonly used instrument, and the Somatoform Dissociation Questionnaire provide a useful inventory of questions (Box 20.1) [50–52]. The clinician should remember that the term somatization is insufficiently broad: somatizing patients report not just somatic but also mental symptoms of diseases they do not have, mimicking cognitive or psychiatric as well as sensorimotor disorders [53, 54].

Sleep and sleep-related phenomena Clinicians should routinely ask about nocturnal sleep timing and duration, sleep quality, and excessive daytime sleepiness [55]. If the patient’s sleep–wake cycle is unusual, for example because of shift work, then particular care needs to be taken to gain clarity about the patient’s schedule. In addition, alterations of behavior during sleep should be ascertained. This includes routine questioning about snoring, as a simple indicator of a common disorder – obstructive sleep apnea – that has significant cognitive, affective, and general medical consequences [56–58]. Reports of other disturbed sleep-related behavior, the parasomnias, should be elicited. These latter concerns often require

information from a bed partner or other observer of the patient’s sleep. This subject is discussed at length in Chapter 7.

Traumatic brain injury Traumatic brain injury (TBI) is common and associated with various adverse cognitive and behavioral consequences. Many patients presenting with psychiatric symptoms have a remote history of TBI, and a screening question about TBI should be routine in the psychiatric evaluation. The history focuses on key indicators of suggesting: circumstances and mechanism of injury; occurrence of a TBI (i.e., application of biomechanical force that immediately disrupts brain function, as evidenced by loss of consciousness, posttraumatic amnesia [PTA], alteration of consciousness [being made “dazed and confused”], or focal neurologic deficits); if an injury occurred, then also its severity (i.e., length of coma, length of PTA, length of retrograde amnesia); presence of skull fracture, other head or neck injury, and other physical injuries; any substances (e.g., alcohol, illicit drugs, medications) used in the immediate pre-injury period and/or intoxication at the time of injury; details of immediate post-injury evaluation (or lack thereof); the need for and details of neurosurgical intervention, if any; interventions provided in the immediate post-injury period (i.e., opiate analgesics, sedatives, intubation, anticonvulsants, etc.); length of hospitalization (if any); early and late rehabilitation interventions; and residual sensorimotor, cognitive, emotional, and behavioral disturbances.

Mild cognitive impairment Patients with many cerebral diseases – including incipient degenerative disease, cerebrovascular disease, multiple sclerosis, and past mild TBI – experience cognitive problems that are distressing and noticeable to others but not of a severity sufficient to warrant a diagnosis of dementia. Identifying subtle cognitive impairment in older patients who present with depression or psychosis, particularly by discovering memory failures (e.g., getting lost, forgetting people and not just their names, forgetting information that does not come to mind later unbidden), shifts the diagnostic priorities substantially: families of patients with such problems need to be asked about progressive changes in cognitive function. The cognitive profile and symptoms depend on the disease anatomy

315


and tempo, but some cognitive features of mild cerebral dysfunction are frequent independent of cause. Lezak [59] summarized the distinctive deficits as “perplexity, distractibility, and fatigue.” Patients perform more poorly in circumstances demanding focused or divided attention, and their performance declines precipitously with fatigue. Fatigue itself is common with brain disease and interacts with depression and cognitive impairment but is not reducible to them [60].

Case 3 A middle-aged man suffered meningitis due to spillage of the contents of a craniopharyngioma. He was a business executive accustomed to multi-tasking, the sort of person who carries on a phone conversation with one ear while listening to a subordinate with the other, all while attending to paperwork on his desk. After a period of recuperation at home, he felt well enough to return to outside activities. He went with his family to a fast-food restaurant but became overwhelmed by the choices listed on the menu above the counter and the noisy setting. He ultimately was able to return to creative professional work, but he still noted that he could do only one thing at a time.

Personality change Patients with brain diseases often undergo changes in their characteristic ways of handling emotion and personal relationships, i.e., changes in personality. Cognitive deficits may be subtle or even absent, certainly on routine bedside testing and even on elaborate assessment in the neuropsychological laboratory [61, 62]. Often observed changes are interpreted as an exaggeration of pre-morbid traits, but scant evidence supports this perspective [63]. Lishman ([62], p. 188) noted that “frontal lobe personality change bears a definitive stamp that in large measure cuts across differences in pre-morbid personality.” Nonetheless, the clinician should explore pre-morbid personality, if only to know what is genuinely new, as illustrated in the following case.

Case 4 A young woman suffered depressive states and a conflictual relationship with her family in the aftermath of a large stroke. Her behavior was described as selfcentered, demanding, and “entitled.” Review of the history revealed that she had always had a conflictual

316

relationship with her family, and they considered her personality not to have changed. Emotional states may be superficial and blunted, with irritability, anxiety, and petulance. Reactions to trivial events may be extreme; reactions to important matters apathetic. Concern about obviously abnormal behavior may be reduced or minimal. Social behavior may be crude or inappropriate. The sense of humor may be coarsened or lost. Initiative, spontaneity, and energy may be reduced; or impulses to act may be poorly controlled, with sexual misconduct, episodes of aggressive behavior, or other forms of comportmental disturbance. Inventories of these symptoms can provide standardized information about “frontal” behavioral symptoms, including the identification of frontotemporal dementia [64, 65].

Conclusion Taking the neuropsychiatric history depends on both an expert knowledge of the psychological and behavioral manifestations of brain disease and patient, openminded, and thoughtful listening. Acquiring and using this knowledge and skill results in better diagnostic results and a fuller understanding of the patient and their illness, whose need for this expertise is great.

References 1. Chimowitz MI, Logigian EL, Caplan LR. The accuracy of bedside neurological diagnoses. Ann Neurol. 1990;28(1):78–85. 2. Houts AC. Fifty years of psychiatric nomenclature: reflections on the 1943 War Department Technical Bulletin, Medical 203. J Clin Psychol. 2000;56(7): 935–67. 3. Michel P, Bogousslavsky J. Ever missed a diagnosis? Then take another history! Pract Neurol. 2004;4:294–7. 4. Redelmeier DA, Schull MJ, Hux JE, Tu JV, Ferris LE. Problems for clinical judgment: 1. Eliciting an insightful history of present illness. Can Med Assoc J. 2001;164(5):647–51. 5. Redelmeier DA, Tu JV, Schull MJ, Ferris LE, Hux JE. Problems for clinical judgment: 2. Obtaining a reliable past medical history. Can Med Assoc J. 2001;164(6): 809–13. 6. Simon GE, Gureje O. Stability of somatization disorder and somatization symptoms among primary care patients. Arch Gen Psychiatry 1999;56(1):90–5. 7. Schrag A, Brown RJ, Trimble MR. Reliability of self-reported diagnoses in patients with neurologically


unexplained symptoms. J Neurol Neurosurg Psychiatry 2004;75(4):608–11. 8. Malleson A. Whiplash and Other Useful Illnesses. Montreal: McGill-Queen’s University Press; 2002. 9. Halligan PW, Bass C, Oakley DA. Willful deception as illness behaviour. In Halligan PW, Bass CM, Oakley DA, editors. Malingering and Illness Deception. New York, NY: Oxford University Press; 2003. 10. Caplan LR. Fisher’s rules. Arch Neurol. 1982;39(7): 389–90. 11. Jaspers K. General Psychopathology. Baltimore, MD: Johns Hopkins University Press; 1997. 12. Asher R. A Sense of Asher: A New Miscellany, Selected and Introduced by Ruth Holland. Holland R, editor. London: Keynes Press, British Medical Association; 1983. 13. Bromberg JE, Rinkel GJ, Algra A et al. Validation of family history in subarachnoid hemorrhage. Stroke 1996;27(4):630–2. 14. Louis ED, Ford B, Wendt KJ, Ottman R. Validity of family history data on essential tremor. Mov Disord. 1999;14(3):456–61. 15. Marder K, Levy G, Louis ED et al. Accuracy of family history data on Parkinson’s disease. Neurology 2003;61(1):18–23. 16. Hardt J, Franke P. Validity, reliability and objectivity of the family history method in psychiatry: a meta analysis. Eur Psychiatry 2007;22(1):49–58. 17. Razvi SSM, Bone I. Draw a pedigree during the neurological consultation. Pract Neurol. 2005;5:38–45. 18. Cheung YB. Early origins and adult correlates of psychosomatic distress. Soc Sci Med. 2002;55(6): 937–48. 19. Verdoux H, Sutter AL. Perinatal risk factors for schizophrenia: diagnostic specificity and relationships with maternal psychopathology. Am J Med Genet. 2002;114(8):898–905. 20. Martinussen M, Fischl B, Larsson HB et al. Cerebral cortex thickness in 15-year-old adolescents with low birth weight measured by an automated MRI-based method. Brain 2005;128(Pt 11):2588–96. 21. Whitaker AH, Feldman JF, Lorenz JM et al. Motor and cognitive outcomes in nondisabled low-birth-weight adolescents: early determinants. Arch Pediatr Adolesc Med. 2006;160(10):1040–6. 22. Clarke MC, Harley M, Cannon M. The role of obstetric events in schizophrenia. Schizophr Bull. 2006;32(1): 3–8. 23. Majnemer A, Rosenblatt B. Reliability of parental recall of developmental milestones. Pediatr Neurol. 1994;10(4):304–8.

24. Murray GK, Jones PB, Moilanen K et al. Infant motor development and adult cognitive functions in schizophrenia. Schizophr Res. 2006;81(1):65–74. 25. Murray GK, Veijola J, Moilanen K et al. Infant motor development is associated with adult cognitive categorisation in a longitudinal birth cohort study. J Child Psychol Psychiatry 2006;47(1):25–9. 26. Corey DM, Hurley MM, Foundas AL. Right and left handedness defined: a multivariate approach using hand preference and hand performance measures. Neuropsychiatry Neuropsychol Behav Neurol. 2001;14(3):144–52. 27. Lipsanen T, Lauerma H, Peltola P, Kallio S. Associations among dissociative experiences, handedness, and demographic variables in a nonclinical population. J Nerv Ment Dis. 2000;188(7):422–7. 28. Martin J, Do Vale S, Trinca A, Saldanha C, Martins ESJ. Personality, manual preference and neuroendocrine reactivity in hirsute subjects. Physiol Behav. 2004;82(4):741–9. 29. Gibbs J, Appleton J, Appleton R. Dyspraxia or developmental coordination disorder? Unravelling the enigma. Arch Dis Child. 2007;92(6):534–9. 30. David AS, Malmberg A, Brandt L, Allebeck P, Lewis G. IQ and risk for schizophrenia: a population-based cohort study. Psychol Med. 1997;27(6):1311–23. 31. Koenen KC, Moffitt TE, Poulton R, Martin J, Caspi A. Early childhood factors associated with the development of post-traumatic stress disorder: results from a longitudinal birth cohort. Psychol Med. 2007;37(2):181–92. 32. Bodensteiner JB, Schaefer GB. Evaluation of the patient with idiopathic mental retardation. J Neuropsychiatry Clin Neurosci. 1995;7(3): 361–70. 33. Sundheim ST, Voeller KK. Psychiatric implications of language disorders and learning disabilities: risks and management. J Child Neurol. 2004;19(10): 814–26. 34. Kennerknecht I, Grueter T, Welling B et al. First report of prevalence of non-syndromic hereditary prosopagnosia (HPA). Am J Med Genet A. 2006;140(15):1617–22. 35. Barton JJ, Hefter RL, Cherkasova MV, Manoach DS. Investigations of face expertise in the social developmental disorders. Neurology 2007;69(9):860–70. 36. Ovsiew F. Hysteria in neurological practice: the somatoform and dissociative disorders. In Jeste DV, Friedman JH, editors. Psychiatry for Neurologists. Boston, MA: Humana Press; 2006, pp. 67–79.

317


37. Ovsiew F. An overview of the psychiatric approach to conversion disorder. In Hallett M, Cloninger CR, editors. Psychogenic Movement Disorders: Neurology and Neuropsychiatry. Philadelphia, PA: Lippincott Williams & Wilkins; 2006, pp. 115–21.

52. Nijenhuis ER, Spinhoven P, van Dyck R, van der Hart O, Vanderlinden J. The development of the somatoform dissociation questionnaire (SDQ-5) as a screening instrument for dissociative disorders. Acta Psychiatr Scand. 1997;96(5):311–18.

38. Raphael KG, Widom CS, Lange G. Childhood victimization and pain in adulthood: a prospective investigation. Pain 2001;92(1–2):283–93.

53. Lenze EJ, Miller AR, Munir ZB, Pornnoppadol C, North CS. Psychiatric symptoms endorsed by somatization disorder patients in a psychiatric clinic. Ann Clin Psychiatry 1999;11(2):73–9.

39. Brenneis CB. Recovered Memories of Trauma: Transferring the Present to the Past. Madison, CO: International Universities Press; 1996. 40. Conway MA. Recovered Memories and False Memories. Oxford: Oxford University Press; 1997.

54. Bruce AS, Ray WJ, Bruce JM, Arnett PA, Carlson RA. The relationship between executive functioning and dissociation. J Clin Exp Neuropsychol. 2007;29(6): 626–33.

41. Clancy SA. Abducted: How People Come to Believe they were Kidnapped by Aliens. Cambridge, MA: Harvard University Press; 2005.

55. Stores G. Clinical diagnosis and misdiagnosis of sleep disorders. J Neurol Neurosurg Psychiatry 2007;78(12): 1293–7.

42. Lezak MD. Living with the characterologically altered brain injured patient. J Clin Psychiatry 1978;39(7): 592–8.

56. Ovsiew F. Seeking reversibility and treatability in dementia. Semin Clin Neuropsychiatry 2003;8(1):3–11.

43. Marsh NV, Kersel DA, Havill JA, Sleigh JW. Caregiver burden during the year following severe traumatic brain injury. J Clin Exp Neuropsychol. 2002;24(4): 434–47. 44. Butera-Prinzi F, Perlesz A. Through children’s eyes: children’s experience of living with a parent with an acquired brain injury. Brain Inj. 2004;18(1):83–101. 45. Oddy M. Sexual relationships following brain injury. Sex Relation Ther. 2001;16(3):247–59. 46. Ghika-Schmid F, van Melle G, Guex P, Bogousslavsky J. Subjective experience and behavior in acute stroke: the Lausanne Emotion in Acute Stroke Study. Neurology 1999;52(1):22–8. 47. Dolan RJ. Emotion, cognition, and behavior. Science 2002;298(5596):1191–4. 48. Glick TH. Neurologic Skills: Examination and Diagnosis. Boston, MA: Blackwell Scientific Publications; 1993. 49. Acharya V, Acharya J, Luders H. Olfactory epileptic auras. Neurology 1998;51(1):56–61. 50. Carlson EB, Putnam FW. An update on the Dissociative Experiences Scale. Dissociation 1993;6(1):16–27. 51. Nijenhuis ER, Spinhoven P, Van Dyck R, Van der Hart O, Vanderlinden J. The development and psychometric characteristics of the Somatoform Dissociation Questionnaire (SDQ-20). J Nerv Ment Dis. 1996; 184(11):688–94.

318

57. El-Ad B, Lavie P. Effect of sleep apnea on cognition and mood. Int Rev Psychiatry 2005;17(4):277–82. 58. Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-related breathing disorder and depression. Arch Intern Med. 2006;166(16):1709–15. 59. Lezak MD. Subtle sequelae of brain damage. Perplexity, distractibility, and fatigue. Am J Phys Med. 1978;57(1):9–15. 60. Friedman JH, Chou KL. Sleep and fatigue in Parkinson’s disease. Parkinsonism Relat Disord. 2004;10(Suppl. 1):S27–35. 61. Eslinger PJ, Damasio AR. Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology 1985;35(12):1731–41. 62. Lishman WA. Organic Psychiatry: The Psychological Consequences of Cerebral Disorder. 3rd edition. Oxford: Blackwell Science; 1998. 63. Tate RL. Impact of pre-injury factors on outcome after severe traumatic brain injury: does post-traumatic personality change represent an exacerbation of premorbid traits? Neuropsychol Rehabil. 2003;13(1–2):43–64. 64. Kertesz A, Davidson W, Fox H. Frontal behavioral inventory: diagnostic criteria for frontal lobe dementia. Can J Neurol Sci. 1997;24(1):29–36. 65. Malloy P, Grace J. A review of rating scales for measuring behavior change due to frontal systems damage. Cogn Behav Neurol. 2005;18(1):18–27.

Section II


Chapter

Neurological examination

21

Stuart A. Schneck

The neurological examination is a foundational element of the clinical skill set in Behavioral Neurology & Neuropsychiatry (BN&NP), and its adept performance is a core competency of subspecialists in this field [1]. When so performed and interpreted, and in combination with findings from a thorough mental status examination, the constellations of cognitive, emotional, behavioral, and sensorimotor impairments revealed by the neurological examinations facilitate construction of a neuroanatomy of illness. They then may be used to corroborate a diagnosis suggested by clinical history, identify a neurological diagnosis (or refine the differential diagnosis) when history alone is inconclusive or unavailable, and define the severity of a neurobehavioral disorder. Information provided by the neurological examination also informs on neurobehavioral treatment needs, including medical and neurorehabilitative interventions directed at the neurological condition underlying neurobehavioral disturbances as well as its functional consequences. Finally, neurological examination findings may be used to gauge treatment response, whether beneficial or adverse, and to monitor disease progression. The neurological examination therefore is not merely a “screening” examination in BN&NP, but instead is a necessary component of a comprehensive subspecialty evaluation – regardless of whether one is evaluating a patient with neuropsychiatric manifestations of a neurological condition or a primary psychiatric disorder. The commonly performed components of the neurological examination in BN&NP are presented in Table 21.1. Importantly, it is not necessary to perform all of these examination items on all patients. The specifics of any individual history and clinical

presentation usually suggest the components of the examination most likely to yield clinical useful findings, thereby making the construction and administration of each patient’s neurological examination a matter of clinical judgment [2]. However, the major sections of the examination should all be systematically surveyed in some fashion so that unsuspected findings are not overlooked. Standardized neurological examinations are used commonly in neurobehavioral research and are emerging as standards of care in clinical settings as well (e.g., acute stroke and neurotrauma evaluations, pre-surgical evaluation of patients with Parkinson’s disease, concussion assessment, baseline evaluation before maintenance antipsychotic prescription). Similarly, examination for subtle neurological signs (e.g., paratonia, primitive reflexes, complex motor sequencing, integrative sensory functions) is relatively common in neuropsychiatric research and, in some contexts, may be clinically valuable [3–12] (see Chapter 22). Familiarity with standardized neurological examinations such as those presented in Tables 21.2 [13–25] and 21.3 [4, 26–31] is expected of subspecialists in BN&NP [1], and incorporating such scales and/or specific items from them into one’s clinical examination repertoire can be very useful. As with the conventional clinical neurological examination, it is not necessary to administer and score standardized neurological examinations on all patients evaluated in BN&NP subspecialty settings. Further, it is not always necessary to administer standardized scales in their entirety; in some clinical settings, performing clinically relevant portions of a standardized scale may address a specific clinical question


319


Table 21.1. Outline of the neurological examination in Behavioral Neurology & Neuropsychiatry.

Examination section

Elements of the examination

General physical

Vital signs, including heart rate, respiratory rate, blood pressure, height, and weight Evaluation for developmental anomalies, trauma, physical signs of substance abuse or withdrawal, and other signs of medical illness or injury Auscultation of carotid arteries and cardiac examination Additional system-specific examinations relevant to the neuropsychiatric presentation (e.g., abdominal examination in a patient with alcohol dependence, thyroid examination in a patient with suspected dementia)

Neurological

Cranial nerves I – olfaction, use items such as coffee, mint, vanilla, cinnamon II – visual fields, visual acuity, and pupillary responses, and funduscopy III, IV, VI – pupillary responses to light and accommodation, and extraocular movements (up, down, lateral, and convergent gaze) V – facial sensation and masseter strength VII – facial motor function VIII – hearing and vestibular function IX, X – palatal elevation (deviates to intact side), gag reflex (when clinically indicated; test on each side of the posterior pharynx) XI – sternocleidomastoid and trapezius strength XII – tongue protrusion (deviates to affected side) Motor Resistance to passive manipulation, including assessment of intrinsic tone and assessment for paratonia (see also Table 21.5) Bulk Observation for abnormal involuntary movements Strength testing, including assessment for pronator drift Sensory Pain (pin prick), temperature Vibration, proprioception (including finger-to-nose with eyes closed and Romberg test) Light touch Coordination Finger-nose-finger, fine finger movements, finger-thumb opposition Rapid repetitive movement, rapid alternating movement Heel-to-shin movement Gait Posture, station Walking, including initiation, stride length, arm swing, turning, toe walking, and heel walking Tandem gait Reflexes Stretch reflexes, including those at biceps, triceps, brachioradialis, patellar, and Achilles tendons; when clinically appropriate, other stretch and cutaneous reflexes Assessment for primitive reflexes (see Table 21.4) Corticospinal signs Response to plantar stimulation (assessment for Babinski sign) and related maneuvers Assessment for Hoffman’s sign

adequately (e.g., monitoring response to treatment of a specific neurological symptom). For trainees and practitioners well practiced in the performance of the neurological examination, some of the information provided in this chapter may be elementary. In our experience, however, even the most skilled examiners can benefit from a review of this examination’s components and administration techniques – and particularly the art of the neurological examination borne of many decades of clinical practice.

320

Toward that end, this chapter presents a practical clinical approach to the neurological examination in BN&NP. In the text, the examination is presented in the manner in which it is most usefully administered rather than the way in which it often is taught (e.g., Table 21.1). This difference in organization serves well the BN&NP subspecialist’s goal of performing a time-efficient examination that thoroughly assesses neurological function. For convenience, only one gender will be used to refer to examiners and patients.

Chapter 21: Neurological examination

Table 21.2. Standardized assessments of elementary neurological function and their typical applications in clinical research and practice. See references [13–25].

Table 21.3. Examinations for subtle neurological signs. See references [4, 26–31]. Neurological Evaluation Scale (NES)

Buchanan and Heinrichs (1989) [4]

Condensed Neurological Examination (CNE)

Rossi et al. (1990) [26]

General, multiple sclerosis

National Institutes of Health Stroke Scale (NIHSS)

Stroke (acute, rehabilitation)

Quantified Neurological Scale

Convit et al. (1988) [31]

Heidelberg Scale

Schroder et al. (1991) [27]

Glasgow Coma Scale (GCS)

Neurotrauma, coma/ consciousness

Cambridge Neurological Inventory

Chen et al. (1995) [28]

Unified Parkinson’s Disease Rating Scale (UPDRS)

Parkinson’s disease, parkinsonism

Woods Scale

Woods et al. (1986) [29]

Hoehn and Yahr Scale

Parkinson’s disease

Brief Motor Scale

Jahn et al. (2006) [30]

Unified Huntington’s Disease Rating Scale (UHDRS)

Huntington’s disease

Abnormal Involuntary Movement Scale (AIMS)

Drug-induced movement disorders

Barnes Akathisia Scale

Drug-induced akathisia

Multiple Sclerosis Functional Composite Scale

Multiple sclerosis

Expanded Disability Status Scale (EDSS)

Multiple sclerosis

Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS)

Amyotrophic lateral sclerosis

Berg Balance Scale

Balance, fall risk, elderly individuals

Balance Error Scoring System (BESS)

Concussion assessment

Standardized neurological examinations

Typical applications

Neurological Rating Scale (NRS)

Speaking to the patient Give directions in a clear and simple manner. Use simple words when directing the patient. If a patient is asked to “clench” the teeth rather than “bite hard,” some may not understand the request. Similarly, rather than asking a patient “Can you do this?” when demonstrating rapid alternating hand movements, say instead “Please do this” when demonstrating a task. These communication approaches accomplish several things. They ensure that requests of the patient are made concisely and courteously, using language that almost everyone can understand. Additionally, this approach puts patients at ease and decreases the likelihood that anxiety or stress will confound other aspects of the examination’s administration and interpretation (e.g., reflexes and muscle tone). Anticipate that some patients may attempt to minimize their deficits, some may not be aware of their deficits, and others may have motivations for

responding inaccurately during the examination. Such issues are most evident during sensory testing. For example, when asking the patient to indicate whether he felt cotton touching his face, or whether he saw a finger move during visual field testing, it can be difficult to ascertain whether or not his negative responses reflect true neurological deficits. Where possible, examining neurological functions whose evaluation relies entirely on a patient’s subjective responses should include several different maneuvers that assess the function that appears to be impaired and/or by adding objective assessments (e.g., neurodiagnostic assessments such as evoked potentials).

Listening for bruits The upper body examination during a complete physical usually ends with auscultation of the heart and lungs. At this point, the neurological examination can begin with auscultation of the great vessels to the brain. For the anterior circulation, the stethoscope’s bell or small diaphragm is placed just behind the angle of the jaw for a few seconds on each side. The common carotid artery bifurcates into the internal and external carotid arteries approximately at this point. Listening lower in the neck, over the common carotid artery, may miss bruits arising higher, as from a distal internal carotid artery stenosis. To assess the posterior circulation to the brain, listen over the midpoint of the clavicle on each side, where the pulse of the subclavian artery can be felt. The vertebral artery is the first branch of the subclavian artery, at about that location. In patients over 50 years of age, one has almost as much chance of hearing a bruit here as over the carotids.

321


Cranial nerves Olfactory nerve (cranial nerve I) Cloves are a commonly used test substance, since their odor lasts relatively unchanged for decades. If there has been recent head trauma, check the nostrils to be sure they are not packed with blood. Instruct the patient to “Please close your eyes” to avoid any chance of cheating. The examiner should gently close one nostril to be certain that it is closed, and ask the patient to “Please tell me what you smell.” The test is then repeated on the other side. Assessment of the olfactory nerves is especially important in the evaluation of persons with traumatic brain injury as well as neurodegenerative disorders involving medial temporal structures and/or cholinergic dysfunction. In addition to compromising the sense of smell, injury to the olfactory nerves also affects the sense of taste. Since loss of smell and taste in other medical conditions usually occurs as a late feature of illness, cranial nerve I function is not of primary diagnostic value and hence may be omitted in a screening examination.

Optic nerve (cranial nerve II) Funduscopic examination, testing of visual fields, and visual acuity testing are used to assess the optic nerves. Funduscopic examination is performed using an ophthalmoscope, with the examiner using his left eye to examine the patient’s left eye and right eye to examine the patient’s right eye. The room lights should be lowered in order to facilitate (without pharmacologic intervention) dilation of the pupils, and both the examiner and the patient should remove any eyeglasses worn. The patient is instructed to fix his gaze on a relatively distant object in the room. Pupillary responses to light (which rely on cranial nerves II and III) are assessed in each eye; light is shown into each eye, and the ipsilateral (direct) and contralateral (consensual) pupillary responses are evaluated. Standing slightly lateral (temporal) to the patient’s direction of gaze, light is directed through the pupil in order to visualize the red reflex. The ophthalmoscope is then moved toward the patient’s eye and directed medially (nasally). The examiner identifies large vessels and follows them temporally to the optic disc, assessing the retina, retinal blood vessels, optic nerve head (disc), and subjacent choroid (to a limited degree).

322

After inspecting these structures, the patient is asked to look at the light; when he does so, the macula may be appreciated in the moment before pupilloconstriction of involuntary eye movement removes it from view. This procedure is then repeated with the other eye. The first instruction for visual field testing, without any hand movements by the examiner, is “Please cover your right eye with your right hand.” This instruction serves as a brief mental status test, requiring that the patient quickly determine right and left, eye and hand, and accurately carries out the maneuver. Standing an arm’s length away from the patient, the examiner closes his left eye opposite the patient’s covered right eye. One now assumes that the visual fields of the open eyes are roughly equal. The examiner places his raised right hand halfway between himself and the patient, and at the periphery of his visual field, which can be assumed to be the periphery of the patient’s visual field. The goal is to quickly establish that the patient has four usable quadrants of vision. The examiner then asks, “Please tell me quickly when my finger moves.” A fingertip is then flicked slightly in each visual quadrant. The patient should respond each time this is done. The finger movement to each quadrant should be done irregularly, so as not to get the patient into a rhythm of saying “Yes, yes, etc.” The test is repeated for the other eye. If the examiner cannot voluntarily close one eye, it can be held closed with one hand. Visual acuity (centrally) is assessed using a Snellen (far) chart and/or a Rosenbaum (near) card. If the patient wears glasses, the examiner may permit the patient to wear them during the examination; if this is done, it is important to document findings as “corrected visual acuity” in the medical record. Each eye is assessed independently, with the patient reading each line on the chart and/or card at the appropriate distance (usually specified on the chart or card) to the point of failure. Visual acuity is reported accordingly using the last (smallest) line of print on the chart and/or card at which the patient correctly read all stimuli present.

Oculomotor, trochlear, and abducens nerves (cranial nerves III, IV and VI) The first request is “Please hold your head still.” Unless so instructed, many patients will move their head and not just their eyes. The examiner measures an arm’s


length from the patient’s chin, and holds the finger to be followed at this distance. The next request is “Please follow my finger with your eyes.” The finger is moved horizontally at a speed sufficient to move the patient’s eyes quickly, but not so rapidly that the examiner’s eyes cannot detect any eye movement abnormality. The finger is moved vertically in a similar fashion, and can be moved obliquely, if desired, at the same speed to test oblique muscle functions. Patients who move their head with their eyes even after being instructed not to do so demonstrate synkinesis, a subtle neurological sign that is common among many patients with neuropsychiatric disorders. The finger is then moved slowly towards the patient’s nose to test convergence of the eyes and pupillary accommodation. It is often very difficult to observe miosis in very dark brown eyes. In such instances, the examiner can place his head up close and lateral to the patient’s head to visualize the miosis, while moving his finger in towards the nose.

Trigeminal nerve (cranial nerve V) This cranial nerve has both a motor and a sensory component. Don’t ask, “Do you feel this” when the facial skin is tested, since there is no way of validating this subjective response. The most sensitive part of fifth nerve sensation is the corneal reflex, which is usually affected first whenever the fifth nerve is damaged. Hence, if the corneal reflex is intact, other facial sensory testing can be skipped in this screening examination. Be aware that the corneal reflex is the first of four tests that, if done improperly, might hurt and anger the patient. Cotton, either from a cotton-tip applicator or a cotton ball, is the best test stimulus, although very soft paper tissue can also be used. The cotton or tissue is made into a wick, held in the examiner’s hand. The patient is instructed to look at the examiner’s finger on the other hand in a direction opposite to the hand holding the cotton. The wick, coming from a lateral direction, is then quickly and gently touched to the cornea. This produces an obvious blink and head movement of the patient. The wick is quickly switched to the examiner’s other hand, and the procedure is reversed. If approached from the front, the patient likely will involuntarily back away, and may develop blepharospasm. Performed correctly, the test will surprise but not hurt the patient. Be sure to touch the

cornea, and not the sclera, lids, or lashes. In addition, do not blow in the eye. If the patient has worn contact lenses for some time, the cornea becomes hypalgesic, invalidating the corneal reflex test. A good substitute is nasal tickle, which also tests the first division of the trigeminal nerve, and is almost as sensitive as the corneal reflex. The cotton wick is quickly twirled just inside the orifice of one nostril. This produces a quick jerk of the patient’s head. The other nostril is immediately tested for the same response. The motor portion of the V nerve innervates three muscle groups. Two fingers of the examiner’s hands are gently and simultaneously placed over each temporal muscle. The request made is “Please bite hard.” A good contraction of these muscles should be felt. Next, two fingers are placed over both masseter muscles, and the same request is made. They too should be felt to contract bilaterally. Lastly, the examiner’s fingers are placed under the patient’s chin, and the request is “Please open your jaw hard.” The strength of the pterygoid muscles, which open the jaw, should easily be felt.

Facial nerve (cranial nerve VII) The patient’s face is examined in three parts. For the upper face, the patient is asked, “Please wrinkle your forehead up and down.” For the middle face, the request is “Please close your eyes tightly and don’t let me open them,” while the examiner gently attempts to open the closed eyes. Lastly, the patient is asked to “Please show me your teeth.”

Vestibulocochlear (acoustic) nerve (cranial nerve VIII) Rather than asking “Do you hear this” or “Please tell me on which side you hear me rub my fingers together,” the bedside assessment of hearing is made somewhat more objective with a simple maneuver: gently push on the tragus of one ear, thus blocking that ear completely; while very softly whispering a double number into the un-occluded ear, ask the patient to repeat the whispered number. The test is repeated on the other side. Additional bedside evaluation of hearing impairments can be assessed without the use of a tuning fork by simply asking the patient to hum. In the presence of

323


a conductive hearing defect (e.g., cerumen in the ear, damage to the tympanic membrane or ossicles), the hum is heard more loudly on the side of that defect. For example, when a finger is used to occlude the ear canal of a person with normal hearing, that person’s own hum is heard more loudly on the side of the occlusion. When a sensorineural deficit is present and the ears are unoccluded, the hum is heard more loudly on the unaffected side.

Glossopharyngeal and vagus nerves (cranial nerves IX and X) These nerves are tested together. Testing is performed without using a tongue blade because testing the gag reflex with this implement is almost always uncomfortable. Break the test request in two. The first part is “Please open your mouth widely.” This allows the examiner to be certain that there are no involuntary movements of the pharynx, soft palate, and uvula. In many people, the back of the tongue may block the view of the pharynx. The next request is “Please say Ah.” The pharynx immediately contracts, and the soft palate and uvula are raised in the midline, with no deviation in one direction or another. This procedure is an equivalent of the gag reflex performed without a tongue blade. Also listen to the patient’s voice for thickened or slurred speech.

Spinal accessory nerve (cranial nerve XI) This nerve innervates both the trapezius and sternomastoid muscles. To test the former, first ask the patient to “Please shrug your shoulders up.” Sometimes one can recognize the presence of a mild hemiparesis by observation better than during strength testing. In this instance, the affected side may rise up less quickly and not as high as the intact side. It also is important to test the strength of the shrug by bearing down on each elevated shoulder with the examiner’s arms. Test the sternocleidomastoid by having the patient fully turn his head in a direction opposite to the muscle being tested. The examiner’s hand is placed on the lateral aspect of the patient’s chin, and an attempt is made to turn the chin back to the midline while the patient resists. Placing the examiner’s hand on the medial aspect of the patient’s chin may block the view of the sternomastoid, which should visibly bulge out

324

during testing. The test is then reversed for the opposite sternomastoid.

Hypoglossal nerve (cranial nerve XII) Fasciculations and atrophy of the tongue are best observed when it rests on the floor of the mouth. Thus, inspect the tongue as it sits quietly when the pharynx is being visualized. To actively test the tongue, the patient is asked to “Please put out your tongue and move it from side to side.”

The upper extremities Since the position of the patient and examiner has not changed, it is now easy to examine the arms. The examiner looks for muscle fasciculations and atrophy throughout the examination. Tone, reflexes, strength, sensation, and coordination in the arms must also be examined. The order in which these are listed is important. If one were to test muscle strength before tone or reflexes, doing this will heighten activity in the nervous system, and therefore tone and reflexes will no longer be at baseline. Similarly, since position sense (proprioception) is important for good coordination, this modality is tested before coordination.

Tone (resistance to passive manipulation) Tone is defined as resistance to passive movement. Stand in front of the patient and gently grasp the patient’s hands. One hand and forearm is rapidly rotated several times to the right and left. The same movement is then performed with the other forearm. In this way, tone is assessed in one forearm, and then immediately compared with the other. What is most important is whether tone is symmetrical, rather than whether it is increased or decreased. The upper arms now are assessed, first on one side and then on the other, by a rapid upward and outward underhanded lifting motion of either hand. Then the forearms, first one and then the other, are quickly flexed and extended while being shaken to see how loosely the hands flap about. Again, what is being ascertained is whether the two sides have symmetrical responses to passive manipulation. If abnormalities are identified, then the examiner will need to distinguish disturbances of intrinsic tone from paratonia. The former include rigidity, spasticity, and cogwheeling (tremor during movement) and the latter include mitgehen and gegenhalten (Table 21.4).


Table 21.4. Description of the examination for paratonia. When present, these findings are suggestive of frontal-subcortical dysfunction. They appear to be similar to dyspraxia (i.e., inability to integrate the command given regarding limb movement with the execution of the task). Mitgehen is more common than gegenhalten, which is most commonly associated with advanced or severe neurological conditions.

Paratonia

Examination maneuver

Normal response

Abnormal response

Comment

Mitgehen

Examiner passively manipulates patient’s extremities

Patient relaxes and does not resist manipulation

Patient is unable to permit full passive manipulation by the examiner and instead moves with the examiner – almost as if unable to resist “helping” the examiner move the patient’s limb

Roughly translates from German as “go with” or “match”

Gegenhalten

Examiner passively manipulates patient’s extremities

Patient relaxes and does not resist manipulation

Patient is unable to permit passive manipulation and offers a “counterpull” and increasing resistance to continued manipulation

Roughly translates from German as “go against”

Reflexes

Table 21.5. Grades assigned to reflex responses.

The examiner stands in front of the patient to test one reflex, and then immediately test its mate in the other arm. Testing three or four reflexes in one arm and then walking around to test the other arm reflexes may not allow for an accurate comparison of any abnormal reflex. There are four reflexes in each arm to be tested. Each is a monosynaptic stretch reflex, and thus is a useful clinical marker for four cervical spinal cord segments. The biceps reflex involves C5, the brachioradialis reflex C6, the triceps reflex C7, and the finger jerk C8. Use of a hammer designed specifically for the assessment of reflexes (e.g., Queen’s square, Babinski, Buck, Trömner, Berliner, Tookey) is recommended over the much lighter Taylor percussion hammer. If a Taylor percussion (tomahawk) hammer is used, this instrument should be held at the end of its metal shaft so that the head may be forcefully arced to strike the tendon. It is important not to grip the upper end of the handle or place an index finger atop the shaft, since then the hammer can only be pushed and not arced forcefully. The two proximal reflexes, biceps and triceps, are best obtained with the point, while the two distal reflexes, brachioradialis and finger jerk, are best elicited with the flat part of the head. The response is graded on a scale of zero (absent) to four (pathological), as described in Table 21.5.

Response grade

Biceps reflex Right-handed examiners should put the left thumb on the right biceps tendon of the patient, and strongly tap

Description

4+

Very brisk response, with spread to other muscle groups and clonus

3+

Brisk response, often with spread to other muscle groups

2+

Active response

1+

Diminished response; elicitation may require re-enforcement

0

Absent

the thumb with the hammer just above the nail bed. A reflex jerk, ranging from barely perceptible to strong, should be elicited. The left thumb is then immediately placed on the left biceps tendon, and the tap repeated. Left-handers should do the reverse. As with tone, the most important observation is whether the reflexes are symmetrical.

Brachioradialis reflex The brachioradialis reflex presents two problems. First, because one must strike the tendon hard as it sits directly above the bone periosteum, this is the only tendon reflex that may hurt the patient when it is examined. Second, the examiner, while looking at the forearm near the elbow to see whether the brachioradialis muscle contracts, may miss the simultaneous finger flexion that might occur in hyperreflexia. To mitigate these problems, the examiner lifts the hand

325


to be examined from underneath, while flexing and supporting the forearm. The tendon is struck transversely with the flat part of the hammer just above the radial side of the wrist, while the brachioradialis muscle is observed for any contraction. Often, this contraction is quite slight. At the same time, flexion of the patient’s fingers can be felt by the examiner, and viewed again with repeated testing. The same procedure is then repeated with the other forearm.

Triceps reflex From the patient’s front, the examiner lifts an arm so that it is parallel to the floor, and then briskly taps the triceps tendon with the hammer’s point about an inch above the elbow. This procedure is then repeated for the other arm.

Finger jerk The second to fourth fingers of the examiner’s free hand are placed at right angles across the volar surface of the gently flexed four fingers of the patient’s hand. The flat of the reflex hammer is then used to strike the examiner’s fingers, producing a quick flexion of the patient’s fingers. The process is then repeated with the other hand.

Primitive reflexes This group of developmentally normal reflexes is present in neonates, and the reflexes in this group usually are increasingly inhibited as the central nervous system (CNS) matures [8, 32]. When the neuroanatomy supporting that inhibition is compromised by CNS injury or disease, or when maturation of the inhibitory systems is incomplete, these reflexes are disinhibited and may be elicited by the examination maneuvers described in Table 21.6. Although sometimes described as “frontal release signs,” these reflexes are predicated on several largescale distributed neural networks involving frontalsubcortical circuits (especially those in which the motor association and supplementary motor areas participate), and the pontocerebellar circuits modifying their function [32]. While these are commonly present among persons with neurological and neuropsychiatric disorders in which frontal function is disrupted, description of these reflexes as “frontal release signs” is too neuroanatomically specific to be correct and may be misleading with respect to their interpretation when present. As such, referring to them as primitive reflexes is encouraged.

326

Strength testing Testing six muscles or muscle groups in each arm is the minimum number needed to define every pattern of human weakness. The method described allows these tests to be done safely, and gives mechanical advantage to the examiner. The examiner should always exert maximum strength. Muscle strength may be graded on a scale from zero (no muscle movement) to five (normal strength) or using the brief descriptions presented in Table 21.7.

Arm abductors After instructing the patient to “Please hold your arms out strongly on each side,” the examiner holds onto the midpoint of the raised arms, and pulls straight down while partially squatting. This maneuver allows use of all of the examiner’s body weight, while at the same time back muscles are tightened to avoid injury.

Triceps (forearm extensor) To avoid being struck in the chest by a quick, powerful thrust of this extremely strong muscle, the examiner now moves from the patient’s front. Right-handed examiners move to the right side of the patient, and vice versa. The examiner’s left hand is placed on the patient’s right scapula region, while the examiner’s right hand is placed on the flexed forearm of the patient. When the patient is asked to “Please push out,” by pulling in with his left hand and pushing in with his dominant hand to keep the triceps flexed, the examiner tries to block the movement. If, as is often the case, the triceps is simply too strong to be overcome, it will move harmlessly by the examiner. To test the other arm, the examiner keeps the position of the left hand unchanged, and simply reaches across the patient’s body to test the other flexed triceps muscle in the same way.

Forearm flexors The left hand of the examiner is placed on the patient’s chest under the flexed right forearm, while the right hand grasps the forearm. The request is “Please pull up hard.” With the left hand, the examiner tries to push the patient away, while the right hand attempts to pull the grasped forearm down. The other side is tested in the same way by reaching across the patient.


Table 21.6. Description of the examination for primitive reflexes.

Primitive reflexes

Examination maneuver

Normal response

Abnormal response

Comment

Glabellar

Tapping ten times on the glabella (area just above and between eyebrows)

No blinking

Partial or full blinking in response to each tap

If response extinguishes within three taps, response should be noted but not necessarily considered abnormal when it occurs in the absence of other pathological responses

Snout

Light tap on patient’s lips; alternatively, and to determine the presence of any asymmetry of response, tap above the upper lip just lateral to the filtrum on each side

No movement

Lips pucker

May be normally present in 30% of persons 60 years or older

Suck

Gloved knuckle is placed between patient’s lips; alternatively, a cotton tip applicator is placed across the patient’s tongue and lower lip simultaneously

No movement

Sucking motion

The alternate stimulation maneuver described here appears to evoke this response as well as the traditional one, and decreases the risk of examiner injury

Rooting

Stroke patient’s cheek

No movement

Head turns toward side being stroked

Unusual even among persons with severe neurological disorders; may be state dependent (hunger)

Palmomental

Stroke palm from lateral aspect of hypothenar eminence to thenar eminence

No movement

Ipsilateral mentalis (chin) muscle contracts

May be normally present in 20% of persons 30 years or older and in 50% of persons older than 50 years

Grasp

Place two fingers in patient’s hand and stroke across palm or along fingers

No grasp

Patient grasps fingers

An alternative abnormal response is for the patient to reflexively extend the wrists and fingers – this is referred to as an avoidance response

Self-grasp

Examiner uses patient’s hand to stroke patient’s contralateral ulnar surface

Strokes ulnar surface

Grasps forearm

Less common than grasp response; tends to be elicited in persons with more severe or advanced neurological conditions

Foot grasp

Examiner places his or her hand on the plantar surface of the distal part of the patient’s foot and toes

No response

Plantar flexion and adduction of the toes

Analogous to grasp reflex in the hand

Wrist extensors Table 21.7. Grading of muscle strength.

Grade

Description

5

Normal strength

4

Full range of movement against resistance, but less than normal strength

3

Movement against gravity, but not against added resistance

2

Full range of motion with gravity eliminated, but not against gravity

1

Palpable or visible muscle contraction only

0

No muscle movement

The examiner moves his left hand under the fully extended wrist of the patient to act as a fulcrum. After the request “Please keep your wrist bent up,” the examiner, using the lateral edge of his right hand, attempts to push the extended wrist down. The test is repeated for the other hand.

Finger extensors The fulcrum moves to the patient’s metacarpophalangeal joints where the examiner’s left hand presses up from the patient’s palmar side, while the right hand attempts to push the extended fingers down. The test is repeated on the other side.

327


Finger abductors The patient is asked to “Please spread your fingers.” The examiner’s dominant hand attempts to squeeze them closed, first on one side and then on the other.

Sensation Testing touch and pin prick perception (pain) in the absence of any history suggesting impairment of these sensory modalities seems unnecessary. Similarly, impaired vibration sensibility in the hands occurs late in the course of most neuropathies so that it too is not worth early screening. Hence, only position sense (proprioception) needs to be tested if a simple screening examination is performed. After the patient is asked to close his eyes, an index finger is grasped at its base by two of the examiner’s fingers and lifted up. The raised finger is then grasped on either side of the distal phalanx. Make the smallest movements of the distal phalanx, up or down, while asking the patient to report the direction of each movement. The test is then repeated using the opposite index finger. Alternatively, light touch (which relies on both the spinothalamic and dorsal column systems) at the distal extremities may be used to test sensation in a screening examination.

Coordination The examiner grasps the patient’s index finger, carries it fully extended to touch his index finger tip, and then turns it around to touch the patient’s nose, while saying “Please touch my finger tip with yours, turn it around, and then touch your nose.” The patient should fully extend his arm during this test. After each repetition, the examiner moves his target finger slightly laterally or vertically to increase the test’s difficulty. The test is repeated using the other hand and arm. Rapid movement on one side and then on the other is tested next, using the thigh, palm, or tabletop. The examiner demonstrates rapid hand tapping, and the patient is asked to “Please do this.” Each test is done unilaterally, inasmuch as the brain’s capacity for mirror movements makes it easier to perform rapid bilateral movements than unilateral ones. Rapid alternating movements are tested next, first on one side and then on the other. Demonstrate this by rapidly alternately tapping the palm and then the dorsum of the hand on a surface. The patient is asked to

328

“Please do this.” The palm should be lifted with each movement, and the edge of the hand should not be used as a fulcrum. The best single test for ataxia in the upper extremity is the Fisher Test. The patient is asked to follow the examiner’s movements. An arm is held up parallel to the floor while the forearm and hand extend straight up. The next request is to flex the forward facing wrist 90◦ . The index finger then rapidly taps the first joint of the thumb. This test requires that the elbow and arm remain fixed in position and also tests rate, range, direction, and force in the tapping finger. Normally, the tapping rate is smooth, the range of movement of the index finger is the same each time, and the finger hits exactly the same spot on the thumb each time with the same amount of force. Minimal ataxia is readily seen when the tapping finger strikes the thumb at different places along its length. The wrist should remain flexed, despite a tendency for it rise to a vertical position in which it is easier to perform the maneuvers. After several taps, the test is repeated with the other hand.

The lower extremities The neurological examination of the lower half of the body may be conveniently performed while the patient is in the recumbent position required during a general medical examination. If the examination is performed in this position, the patient’s arms should either be at his sides or crossed gently across the abdomen. If the neurological examination of the lower extremities is performed with the patient in a seated position, then it will be important to ensure that the patient’s lower extremities are able to be elevated (or suspended) off the floor in order to provide for relatively free movement. The same five phenomena are examined in the legs as in the arms, and in the same order. If the examiner is right handed, he should stand on the patient’s right, and vice versa.

Tone (resistance to passive manipulation) Placing both hands gently on the patient’s right thigh, the examiner rapidly shakes the leg back and forth while observing the foot. With normal tone, the foot usually flops back and forth rapidly, unlike its movement in spastic or rigid limbs when it moves in concert with the entire limb. The test is repeated on the other


side. The examiner then places his left hand beneath the right knee of the patient, holds the leg with his right hand, and gently flexes the hip and knee up and down, while feeling for any significant resistance to this passive movement. The test is repeated on the other side. In elderly or arthritic patients, do not fully flex the hip since this may cause pain. If the patient is female and wearing a short hospital gown, flexing the hip maximally is likely to cause the gown to move up and expose the patient. As with the examination of the upper extremities, the examiner will need to distinguish between abnormalities of intrinsic tone and paratonia (Table 21.4) when increased resistance to passive manipulation is encountered.

Reflexes The two monosynaptic stretch reflexes are the knee jerk, involving L4, and the ankle jerk, involving S1. To obtain the knee jerk, the knee should be slightly flexed when the patellar tendon is struck forcefully, either with the hammer’s point or flat. This test is repeated by reaching across the body so the other knee can be slightly lifted. For the ankle jerk, the examiner externally rotates the right leg, and with his left hand dorsiflexes the right foot. This exposes the Achilles tendon, which can now be struck in the same tomahawk chop manner as the other reflexes. In patients without hip difficulty, the left leg can then be crossed over the right, and the foot dorsiflexed with the left hand, again exposing the Achilles tendon for the downward strike. If this movement might cause pain, the examiner should walk around the patient and perform the first maneuver again. The remaining pathological reflex for which to assess is the Babinski reflex (or sign), the quintessential sign of corticospinal tract dysfunction. A dull implement, such as a key, is used to elicit this reflex; a sharp object, such as a pin, should not be used. The examiner dorsiflexes the patient’s left foot with his left hand, while his left thumb straightens the big toe slightly. The implement used should be traced up the lateral aspect of the sole very gently and then across the sole at the ball of the foot. The big toe is observed for the slightest movement, up or down. If no movement is seen, the test can be repeated with a little more force. If the examiner presses too hard initially, this may cause pain or even tickle, resulting in a rapid withdrawal of the foot. The test is then repeated on the other side.

Strength testing The examiner continues to stand on the patient’s right. Only three muscle groups need be tested to define clear patterns of motor impairment, and muscle strength is graded using the numeric scale or strength descriptors presented in Table 21.7.

Hip flexors The examiner turns his body to face the patient’s head. This position allows him to test these very powerful muscles using not only his arm, which is placed midway on the upper thigh, but also his entire upper body. The request is “Please lift up your whole leg,” and the examiner attempts to force it down. To test the other leg, the examiner reaches across the patient’s body to perform the same maneuver.

Leg extensors The examiner places his left forearm under the knee of the closest leg, and holds on to the other knee with his left hand. The patient is asked to “Please keep your leg straight and don’t let me bend it.” The examiner then forcefully tries to bend the extended knee over his arm. For the other leg, the examiner’s left hand is placed under the knee while lifting the leg and the same maneuver is repeated.

Foot dorsiflexors The patient is first asked to “Please bend each foot up hard.” The examiner then attempts to force the dorsiflexors down on each side.

Sensation Position sense (proprioception) is tested in each great toe by slightly moving it up or down while the patient’s eyes are closed. Inasmuch as many peripheral neuropathies begin with vibratory impairment in the feet, this modality of sensation should be tested also. The tines of the fork are struck, and the base is placed either on the medial malleolus or the base of the big toe. The patient is asked to describe what is felt. Usually the answer is a buzzing or vibration. In a screening exam, it is not necessary to count the seconds during which the vibration is felt.

Coordination The heel-knee-shin test is the most common assessment of coordination in the lower extremities. When

329


giving the instruction, it is helpful to tap each part of the patient’s leg that will be involved. “Please put this heel (tapped several times) on this knee (the opposite knee is tapped several times) and run it down the leg (the examiner runs his hand down that leg).” If the patient is wearing a skirt or hospital gown, the examiner should stand near the patient’s head so as not to raise any question of impropriety when the leg is raised. The test is then repeated on the other side. All of the coordination tests done so far are ones that predominately involve the cerebellar hemispheres. The remaining components of the examination allow for testing the midline (vermis) of the cerebellum.

Parkinson’s disease or related conditions, then the pull test may also be useful to perform. With the patient still standing, the examiner stands behind him, places both hands on the patient’s shoulders, and states “I’m going to pull you. Please keep your balance.” A brief and moderately forceful pull backwards is performed. Patients with intact postural (righting) reflexes will either not move when pulled backwards or will step backwards while maintaining their balance. Patients with impaired postural reflexes will be set into a backward fall by this maneuver; accordingly, the examiner should be prepared to immediately support the patient and prevent falling in the face of impaired postural reflexes.

Stance, balance, and gait Stance (station)

Gait

Ask the patient to fold his arms across his chest and then stand up. This maneuver provides a brief assessment of stance, as well as lower extremity strength and motor initiation. If the patient is unable to arise with arms folded across his chest, then he should be permitted to attempt to do so using his arms. If he is unable to accomplish this task, then the examiner may assist the patient with rising – but only with safe support of the patient in order to prevent the patient and the examiner from injury [33]. If the patient is able to stand, the patient’s posture is assessed.

Ordinary walking is first assessed. One watches the feet to assess equality of stride, veering, or dragging of a foot. The axis of the patient is observed to determine whether the head is situated reasonably centrally over the spine. Finally, one watches the associated arm movements, which are normally used for balance in brisk walking. In some disorders, such as Parkinson’s disease, these movements are lost early, either unilaterally or bilaterally. The patient is then asked to “Please turn quickly.” One looks to see if this is accomplished in one or two steps (normal), in many more (as in Parkinson’s disease), or not at all (as in an ataxic patient). One should do this test in a corridor as most clinical examination and hospital rooms are too small. As a complementary assessment of distal lower extremity strength as well as balance, it is also useful to ask the patient to walk on his toes and then on his heels. Walking on the lateral edges of the feet also may be useful as an assessment for motor overflow such as occurs in movement disorders such as Huntington’s disease; this maneuver elicits dystonic posturing of the upper extremities in a manner that parallels eversion of the foot.

The Romberg test Next, the Romberg test is begun by asking the patient to stand erect with his feet together, eyes open, and arms down. Usually this is accomplished without any problem, due to input into the vermis from visual, vestibular, and proprioceptive receptors. Next, the patient is asked to “Please close your eyes.” Most patients respond to this loss of visual input by slight swaying, but not by falling. The Romberg test is positive if the patient demonstrates marked swaying or loses his or her balance when his eyes are closed. If the patient is able to maintain his balance with eyes closed, the examiner states “I’m going to bump you. Please keep your balance.” The patient is then bumped to one side to the other. If the patient is displaced by these maneuvers, then he also may be regarded as having a positive Romberg test.

The Pull test If the patient does not have a positive Romberg test, and when there is concern regarding a condition like

330

Tandem (heel-to-toe) walking Walking in this manner (a good assessment of the cerebellar vermis) first is demonstrated by the examiner. It is useful to identify a line between floor tiles, or a seam in a carpet, or another feature of the floor to which the walking is anchored. While demonstrating tandem walking, the examiner states “I’d like you to walk in a straight line placing one foot in front of the other, like this; walk as if you are walking along a tightrope.” If


the patient is frail, elderly, or exhibiting motor or balance impairments, the examiner should walk closely enough to provide the support needed to prevent a fall.

6. Molloy DW, Clarnette RM, McIlroy WE et al. Clinical significance of primitive reflexes in Alzheimer’s disease. J Am Geriatr Soc. 1991;39(12):1160–3.

Conclusion

7. Vreeling FW, Houx PJ, Jolles J, Verhey FR. Primitive reflexes in Alzheimer’s disease and vascular dementia. J Geriatr Psychiatry Neurol. 1995;8(2):111–17.

Proficiency in the administration and interpretation of the neurological examination is a core competency of subspecialists in BN&NP. Regardless of the clinical condition for which a patient is being evaluated, performing a neurological examination is an essential component of a comprehensive neuropsychiatric assessment. This chapter describes our approach to the neurological examination used in BN&NP, presented as it is most usefully administered rather than as it is often taught. When performed in combination with findings from a history and thorough mental status examination, the neurological examination contributes usefully to the construction of a neuroanatomy of illness, clinical diagnosis, and treatment planning and monitoring. Using the information provided in the narrative and tables offered in this chapter, BN&NP trainees and practitioners will share a common set of neurological examination techniques to incorporate into their practices and research – and advance their skills in the art of neurological examination.

References 1. Arciniegas DB, Kaufer DI, Joint Advisory Committee on subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13. 2. Montgomery K. How Doctors Think: Clinical Judgment and the Practice of Medicine. Oxford: Oxford University Press; 2006. 3. Sanders RD, Keshavan MS. The neurologic examination in adult psychiatry: from soft signs to hard science. J Neuropsychiatry Clin Neurosci. 1998;10(4):395–404. 4. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res. 1989;27(3):335–50. 5. Wortzel HS, Frey KL, Anderson CA, Arciniegas DB. Subtle neurological signs predict the severity of subacute cognitive and functional impairments after traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2009;21(4):463–6.

8. Damasceno A, Delicio AM, Mazo DF et al. Primitive reflexes and cognitive function. Arq Neuropsiquiatr. 2005;63(3A):577–82. 9. Diehl-Schmid J, Schulte-Overberg J, Hartmann J et al. Extrapyramidal signs, primitive reflexes and incontinence in fronto-temporal dementia. Eur J Neurol. 2007;14(8):860–4. 10. Links KA, Merims D, Binns MA, Freedman M, Chow TW. Prevalence of primitive reflexes and Parkinsonian signs in dementia. Can J Neurol Sci. 2010;37(5):601–7. 11. Sjogren M, Wallin A, Edman A. Symptomatological characteristics distinguish between frontotemporal dementia and vascular dementia with a dominant frontal lobe syndrome. Int J Geriatr Psychiatry 1997;12(6):656–61. 12. Gregory CA, Orrell M, Sahakian B, Hodges JR. Can frontotemporal dementia and Alzheimer’s disease be differentiated using a brief battery of tests? Int J Geriatr Psychiatry 1997;12(3):375–83. 13. Sipe JC, Knobler RL, Braheny SL et al. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology 1984;34(10):1368–72. 14. Brott T, Adams HP, Jr., Olinger CP et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20(7):864–70. 15. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2(7872):81–4. 16. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17(5): 427–42. 17. Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord. 1996;11(2):136–42. 18. Guy W, National Institute of Mental Health. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976. 19. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672–6. 20. Cutter GR, Baier ML, Rudick RA et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999;122(5):871–82.

331


21. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444–52.

27. Schroder J, Niethammer R, Geider FJ et al. Neurological soft signs in schizophrenia. Schizophr Res. 1991;6(1):25–30.

22. The ALS CNTF treatment study (ACTS) phase I–II Study Group. The Amyotrophic Lateral Sclerosis Functional Rating Scale. Assessment of activities of daily living in patients with amyotrophic lateral sclerosis. Arch Neurol. 1996;53(2):141–7.

28. Chen EY, Shapleske J, Luque R et al. The Cambridge Neurological Inventory: a clinical instrument for assessment of soft neurological signs in psychiatric patients. Psychiatry Res. 1995;56(2):183–204.

23. Berg KO, Wood-Dauphinee SL, Williams JI, Maki B. Measuring balance in the elderly: validation of an instrument. Can J Public Health 1992;83(Suppl. 2): S7–11.

29. Woods BT, Kinney DK, Yurgelun-Todd D. Neurologic abnormalities in schizophrenic patients and their families. I. Comparison of schizophrenic, bipolar, and substance abuse patients and normal controls. Arch Gen Psychiatry 1986;43(7):657–63.

24. Riemann BL, Guskiewicz KM. Effects of mild head injury on postural stability as measured through clinical balance testing. J Athl Train. 2000;35(1): 19–25.

30. Jahn T, Cohen R, Hubmann W et al. The Brief Motor Scale (BMS) for the assessment of motor soft signs in schizophrenic psychoses and other psychiatric disorders. Psychiatry Res. 2006;142(2–3):177–89.

25. Fahn S, Elton RL, UPDRS Program Members. Unified Parkinson’s Disease Rating Scale. In Fahn S, Marsden CD, Calne DB, Goldstein M, editors. Recent Developments in Parkinson’s Disease. Florham Park, NJ: Macmillan Health Care Information; 1987. pp. 153–63.

31. Convit A, Jaeger J, Lin SP et al. Prediction of violence in psychiatric inpatients. In Moffitt TE, Mednick S, editors. Biological Contributions to Crime Causation. Amsterdam: Martinus Nijhof; 1988.

26. Rossi A, De Cataldo S, Di Michele V et al. Neurological soft signs in schizophrenia. Br J Psychiatry 1990;157:735–9.

33. Timby BK. Fundamental Nursing Skills and Concepts. 8th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

332

32. Walterfang M, Velakoulis D. Cortical release signs in psychiatry. Aust N Z J Psychiatry 2005;39(5):317–27.

Section II


Chapter

Assessment for subtle neurological signs

22

Igor Bombin, Celso Arango, and Robert W. Buchanan

Most psychiatric disorders are characterized by alterations of brain function and/or structure. The causes of such alterations range from changes in physiology secondary to environmental, genetic, or interactive conditions, as well as to structural alterations, which are related to developmental or acquired factors, and may produce persistent chemical and functional disorders. Over the last 50 years, there have been an increasing number of neuroanatomical, neuroimaging, neurophysiological, and neuropsychological studies investigating the structural, functional and cognitive correlates of brain insult(s), which could ultimately lead to a better understanding of the complex etiopathophysiology of neuropsychiatric disorders. This has been especially so for the most severe forms of psychiatric disorders, such as schizophrenia and other psychoses, for which changes in brain structure and function have been demonstrated through different research approaches. A direct, easily administered, and inexpensive way of investigating brain dysfunction is the study of subtle neurological signs (SNS; see Table 22.1). Neurological abnormalities include both “hard” signs and “subtle” (or “soft” signs). Hard signs refer to impairments in basic motor, sensory, and reflex behaviors. Hard signs are often indicative of a specific abnormality in the central nervous system. In contrast, SNS are described as non-localizing neurological abnormalities that cannot be related to impairment of a specific brain region, or are not believed to be part of a well-defined neurological syndrome [1]. This distinction may be artificial, and reflects the state of our understanding of the brain–behavior relationships that underlie the presence of SNS [1]. Moreover, SNS are frequently clustered in categories according to their putative neuroanatomical localization (see Table 22.1). These

distinctions between hard and soft neurological signs led to the hard signs inclusion in the routine neurological examination, with soft signs reserved for the examination of cognitive and behavioral problems. Assessment of neurological soft signs is relevant to a broad range of neuropsychiatric conditions, including Alzheimer’s disease [2–4], frontotemporal dementia [5–8], Parkinson and Lewy body diseases [6, 9], cerebrovascular disease [4, 9, 10], multiple sclerosis [11], and traumatic brain injury [12], among others. Subtle neurological signs also have been investigated in the context of healthy aging [2, 13, 14] and as potential aids to the differential diagnosis of dementia [6, 15, 16]. They are most studied in the context of schizophrenia, and the literature in this area is anchored most usefully to the 1988 review by Heinrichs and Buchanan [1] describing the significance of SNS in schizophrenia. In 2005, we updated the review with additional evidence for the utility of SNS investigations in schizophrenia and related disorders [17]. Accordingly, this chapter will focus on subtle neurological signs in schizophrenia and use this focus to illustrate the principles of their assessment and interpretation among persons with neuropsychiatric disorders more generally.

Assessment of subtle neurological signs Growing appreciation of the role of SNS has led to the development of multiple, structured instruments to assess neurological impairment. These instruments differ markedly in the specific neurological signs assessed and in their psychometric properties. The most commonly employed neurological scales and


333


Table 22.1. Frequently assessed subtle neurological signs grouped according to category of neurological function and putative neuroanatomical localization.

Category of neurological sign

Putative localization

Abnormal finding

Integrative sensory function

Parietal lobe

Extinction to double simultaneous stimulation Impaired audiovisual integration Agraphesthesia Astereognosis Right-left confusion Impaired habituation

Motor coordination and inhibition

Frontal lobe Cerebellum

Intention tremor Imbalance Gait abnormality Impaired hopping Abnormal finger-thumb opposition Dysdiadochokinesis Dysmetria on fingerto-nose test Mirror movements Synkinesis Convergence Motor (including gaze) impersistence

Sequencing of complex motor acts

Prefrontal region

Impaired performance on: Fist-edge-palm test Fist-ring test Ozeretski test Go/no-go test Rhythm tapping (foot or hand)

Primitive reflexes

Frontal lobe

Glabellar sign Exaggerated jaw jerk Palmomental sign Corneomandibular reflex Snout reflex Sucking reflex Grasp reflex Instinctive grasp reaction (forced groping, forced grasping)

their characteristics are described briefly in the following sections.

The Woods Scale The Woods Scale [18] is a 79-item scale, with items rated on a four-point scale: absent = 0, mild = 1, moderate = 2, and severe = 3. The scale was originally developed and validated in persons with schizophrenia, bipolar disorder, substance abuse, as well as controls. The scale provides an interesting innovation,

334

in which the “probable etiology” of the neurological signs is classified into one of three categories: (1) probably due to medication; (2) the result of a known or identifiable neurological or medical disorder; and (3) etiology of signs unknown. Pairwise interrater reliability among the three raters, analyzed with Kendall’s w, were 0.86, 0.87, and 0.87 for the total score, and 0.68, 0.67, and 0.79 for the items categorized as “etiology of signs unknown.” Strengths of the Woods Scale include the wide scope of coverage, established interrater reliability, potential etiologic assignment, information about sociodemographic (i.e., age and gender) and clinical characteristics (i.e., diagnosis, age of onset, duration of illness) of the validation sample, and data from multiple diagnostic groups. Limitations of this scale include the lack of standardized scoring, the lack of test–retest reliability data to assess internal reliability, and the lack of clustering or factor analysis.

The Rossi Scale The Rossi Scale [19] consists of 26 items, seven of which are assessed bilaterally. There is not a single scoring method for items in the scale; some items are rated as present or absent, whereas others are rated from 0–6. Moreover, administration and scoring instructions are not sufficiently operationalized (e.g., complex motor acts, two-object test). Strengths of the Rossi Scale are established interrater reliability, information about sociodemographic (i.e., age, gender, and education level), and clinical characteristics (i.e., diagnosis, medication status and dosage, duration of illness) for the validation sample, and three comparison groups used to document validity. The limitations of the scale are the lack of test–retest reliability data to assess internal reliability, lack of clustering or factor analysis, differential weight of specific SNS due to the scoring system, and the absence of standardized instructions.

The Heidelberger Scale The Heidelberger Scale (HS) [20] is comprised of 17 SNS items that are rated on a 0–3 scale: absent = 0, slight = 1, present = 2, and marked = 3. All items, with the exception of station and gait, tandem walking, right/left orientation, speech articulation, primitive reflexes and Ozeretski’s test, are rated separately on the right and left side. Interrater reliability was 0.88. The authors also performed a factor analysis that identified five factors (motor coordination, integrative functions, complex motor tasks, right/left and spatial

Chapter 22: Assessment for subtle neurological signs

orientation, and hard signs). The strengths of the scale are the established interrater and internal reliability, information about sociodemographic (i.e., age) and clinical characteristics (i.e., diagnosis, medication status, clinical status) of the validation sample, clustering of items supported by a factor analysis, and test–retest reliability data. Sociodemographic and clinical characteristics of the validation sample, such as gender, medication dosage, and handedness are not available.

The Modified Quantified Neurological Scale The final version of the Modified Quantified Neurological Scale (QNS) [21] comprises 96 items that assess 48 SNS. The items were scored as normal or abnormal for the published study, though in the appendix, some items are to be rated as: normal = 0, suggestive = 1, or abnormal = 2. The scale groups the items according to the probable localization of the SNS: overall neurological abnormalities; frontal soft signs; and cerebellar function. Interrater reliability, assessed by Kappa values for individual items, ranged from 0.69 to 1.0, with 96% of items having a kappa of 0.75 or greater. The strengths of the scale are the operational instructions to rate items, interrater reliability data, external validity data, clustering of items in subscales. Its limitations include the lack of test–retest reliability data, lack of SNS severity measures, lack of factor analysis that support the a-priori clusters, and interrater reliability only applied to the presence–absence of the SNS, whereas some items are to be rated according to a 3-point scale; moreover, the clinical and sociodemographic data refer to the total study sample and it is not clear whether the sample used to assess interrater reliability is taken from the study sample or if it is a completely different sample.

The Cambridge Neurological Inventory The Cambridge Neurological Inventory (CNI) [22] includes not only items that assess SNS, but also items that assess extrapyramidal symptoms, tardive dyskinesia, and catatonia, resulting in an 87-item scale. Items are rated as: normal response = 0, equivocal response = 0.5, abnormal response = 1, and grossly abnormal response = 2. Interrater reliability was assessed with Kendall’s w statistics, but only for 14 items, and the Kendall’s w ranged from 0.82 to 1.0. In subsequent studies, Chen and colleagues have reported additional interrater reliability data for the CNI: ICC = 0.94 for total score; and consistency over time ICC = 0.85 for

total score, and 0.45–0.91 for the individual subscales [23]. The CNI provides operational instructions to rate items, a wide scope of coverage, information regarding interrater reliability, analysis of the clustering of items, information about sociodemographic (i.e., age, gender, handedness) and clinical characteristics (i.e., diagnosis, medication status and dosage) of the validation sample. Similar to other assessment tools, there is a lack of test–retest reliability data, lack of information regarding interrater reliability for the final version, and no information about the factor analysis that supported the given clusters.

The Neurological Evaluation Scale The Neurological Evaluation Scale (NES) [24] is among the most widely used SNS scales in schizophrenia research. The NES is comprised of 26 discrete items, of which 14 are rated separately on the right and left. The items are clustered into three a-priori subscales that are based on conceptual considerations of neuroanatomy and function. These subscales are: sensory integration subscale (SI), motor coordination subscale (MC), and sequencing of complex motor acts (SQ). The remaining items are lumped together under the rubric of “others.” Administration and scoring instructions are provided in an operationalized fashion to ensure standardized and reliable rating (specific instructions appear in the appendix). Each item is scored on a 3-point scale: no abnormality = 0, mild but definite impairment = 1, and marked impairment = 2, except for the snout and suck reflexes which are assigned either 0 (absent) or 2 (present). Interrater reliability values are: 0.95 for the total score, 0.99 for the SI subscale, 0.71 for the MC subscale, and 0.89 for the SQ subscale. Interrater reliability for 14 individual items is ≥ 0.90. The authors also assessed whether raters other than the authors could be trained on the NES, and found interrater reliability values for total and subscale scores ranging from 0.72 to 0.98. The strengths of the NES include the availability of data describing the sociodemographic (i.e., age, gender, and race) and clinical characteristics (i.e., diagnosis, medication status, duration of illness) of the validation sample and the control group; operationalized instructions to score items; information regarding interrater reliability; information regarding external validity; a large validation sample; control for potentially confounding variables; and demonstration of ability to train others to administer and score this examination reliably.

335


Its weaknesses include the lack of test–retest reliability data; and the fact that factor analyses by different authors have only partially supported the clustering of neurological signs as provided by the NES subscales [25–27].

Additional considerations on subtle neurological sign examinations While the choice of the right assessment tool is crucial, other methodological issues are to be considered when assessing SNS in neuropsychiatric populations. First, behavioral problems may interfere with SNS assessment by compromising the ability to complete the evaluation and, hence, giving the impression of increased neurological impairment. It is therefore strongly recommended to conduct the assessment during periods of clinical stability. Second, although SNS are mainly independent of sociodemographic variables, such as gender, age, education level, and socioeconomic status (for a review see [17]), it is recommended to register these variables and to test for their effects on data derived from such examinations – especially since neurological impairment has been shown to be increased in aging populations, and to be moderately related to ethnicity [24, 28–30]. Finally, antipsychotic motor side effects, such as extrapyramidal symptoms (EPS) and tardive dyskinesia (TD), may be erroneously rated as neurological signs, although investigations of the relationships between antipsychotic treatment and SNS have produced negative results [19, 22, 28, 31–41]. On the other hand, the search of associations between SNS with EPS and TD has produced both positive [33, 42–44] and negative results [20, 40, 45, 46]. Although it is clear that SNS are not secondary to antipsychotic medication – SNS have repeatedly been found to be present in antipsychoticna¨ıve patients [20, 43, 47–51] – longitudinal SNS assessment with test–retest measures and a drug washout period is the gold standard for the evaluation of this matter and is undertaken rarely. Additionally, when short-term longitudinal assessments have been conducted in subacute patients, both stability [52] and improvement [53] of SNS have been reported.

Clinical significance of subtle neurological signs An increased prevalence of SNS has been reported in schizophrenia, bipolar disorder, and other forms of

336

psychosis, although the presence of SNS has been also documented in patients with obsessive-compulsive disorders (OCD), substance dependence, depression, attention-deficit hyperactivity disorder (ADHD), and in samples of patients with mixed psychiatric disorders [17, 54–57]. Their higher prevalence has also been documented in borderline personality disorder patients [58], and has been associated with higher schizotypal features in normal populations [59, 60]. Subtle neurological signs also are observed among persons with Alzheimer’s disease [2–4], frontotemporal dementia [5–8], Parkinson and Lewy body diseases [6, 9], cerebrovascular disease [4, 9, 10], multiple sclerosis [11], and traumatic brain injury [12], and among persons infected with human immunodeficiency virus (HIV) [61]. As noted earlier in this chapter, however, research in this area focuses mainly on the potential role of SNS as a biological marker of schizophrenia (discussed further in the next section of this chapter) as well as the search for associations of SNS with schizophreniarelated symptoms. In regard to the latter issue, the most relevant findings are summarized below. In light of the association between brain dysfunction and cognitive impairments, the corollary hypothesis is that there should be a relationship between neurological abnormalities and one or more domains of cognitive impairment. Such a hypothesis has received consistent support: SNS are associated with attention [34, 40, 62, 63], visual-spatial memory [34, 64], visuo-spatial processing [34, 42, 63–67], and visuoconstructive abilities [34, 64]. Impairments in executive functions, which are associated with prefrontal cortex dysfunction, are associated with SNS as well [21, 34, 40, 63–65, 67] and with overall neurological functioning [40, 64, 65, 67]. In addition, results consistently support the notion that higher rates of SNS are associated with more severe cognitive impairment, and specific signs (clustered according to their putative localization) seem to predict specific cognitive domain impairments [64]. Neuroanatomical and brain functional disturbances have been largely documented in schizophrenia and other psychoses. However, few studies have examined the relationship between neurological impairment and brain structural measures. Most of the studies addressing this issue have found some structural abnormalities associated with the presence of SNS. Ventricular brain ratio and third ventricular enlargement have been associated with overall neurological functioning [20, 40, 68],


motor coordination signs [20], and sensory integration signs [69]. Other structures that have been associated with SNS include cerebral cortex [70] frontal and hemispheric measures [71, 72], basal ganglia [70], sulcal volume, interhemispheric fissure [40] brain length, width of left Sylvian fissure [48], temporal, lingual, and cingulate gyri [70, 71], and hippocampal [69] and cerebellar volume [69, 73]. In these studies, the numbers and severities of SNS were associated with greater structural abnormalities or brain volume reductions. However, these findings are non-specific and do not inform on SNS localization, since only associations between neurological impairment and nonspecific structural measures have been reported. The associations observed could be explained solely on the basis that both phenomena occur more frequently in chronic or poor prognosis patients. Functional imaging studies may be more useful in SNS localization, but the potential relationships of neurological status and functional neuroimaging variables have not been adequately assessed in the studies performed to date. These studies generally compare non-specific variables (i.e., overall neurological impairment with overall brain activation) with SNS. A noteworthy exception is the study of Schroder and colleagues [74], which reports an association between motor SNS in schizophrenia and hypoactivity of sensorimotor cortex and supplementary motor area. Schizophrenia and other psychoses are characterized by the presence of psychotic symptoms, which are frequently divided into positive symptoms (i.e., hallucinations, delusions, bizarre and disorganized thinking and behavior) and negative symptoms (i.e., social withdrawal, anhedonia, alogia, avolition, blunted affect). The former are usually state dependent – their presence varies with the severity of illness – whereas the latter represent a trait feature of the illness and are more consistently associated with cognitive impairment, neuroanatomical abnormalities, and overall poorer outcome [75, 76]. As a consequence of such a distinction, it is reasonable to expect that SNS would more likely be associated with enduring negative symptoms than with positive symptoms. Concordant with this expectation, most studies do not report associations between SNS and positive symptoms [31, 33, 34, 40, 42, 44, 48, 49, 65, 77, 78]. When such associations are reported, there also are significant associations between SNS and negative symptoms [40, 78] and also global psychopathology

[78], reflecting a selection bias towards a highly symptomatic subgroup of persons with schizophrenia. When positive symptoms are divided into hallucinations–delusions versus symptoms of behavioral and cognitive disorganization (i.e., inappropriate affect, bizarre behavior, and positive formal thought disorder), the former remained unrelated to SNS whereas the latter are consistently associated with neurological dysfunction [20, 28, 40, 68, 79]. Most studies report associations between higher rates of SNS and more severe negative (enduring) symptoms [34, 45, 51–53, 63, 66, 67, 80–83]. Interestingly, negative and deficit (enduring negative) symptoms are associated with prefrontal (motor function) and parietal (sensory integration) SNS in a higher proportion than with other SNS, suggesting a shared neural substrate. All the above findings suggest that higher frequencies and severities of SNS are associated with more severe forms of the illness: i.e., those in which there is a higher degree of cognitive impairment and neuroanatomical abnormalities, more severe negative symptoms, and more severe conceptual and behavioral disorganization. In the light of these findings, some studies investigated the association between SNS and functional and clinical outcome. The ability of SNS to predict antipsychotic treatment response has had mixed results. Buchanan and colleagues failed to find a relationship between baseline NES total or subscale scores and change in positive or negative symptoms in either clozapine- or haloperidol-treated patients [33], and other similar negative results have been reported [84, 85]. In contrast, other authors reported that higher rates of SNS predicted [21, 46] or have been associated with poorer treatment response [40, 81]. In a study examining the relationship of SNS to nonantipsychotic drug response, higher rates of visuospatial SNS were found to be associated with poorer response to selective serotonin reuptake inhibitors in OCD patients [86]. In studies of outcome measures, five studies found significant correlations between severity of neurological impairment and poor current social function [53, 56, 63, 83, 87], whereas three studies failed to find correlations with current [30] or premorbid social adjustment [80, 88]. Cross-sectional studies have also reported both the presence [42, 89] and absence [40, 43] of associations of number of previous hospitalizations with neurological impairment. Among persons with recent traumatic brain injury undergoing inpatient rehabilitation, SNS also predict functional

337


status proximate to the time of their assessment and at rehabilitation discharge [12]. In summary, the majority of studies support the hypothesis of an association between SNS and poorer functional outcome.

Implications for research Relationships among neurological signs, psychotic symptoms, cognitive impairments, neuroanatomical abnormalities, and clinical and functional outcome make SNS a good, easy-to-assess candidate for a biological marker of a broad range of neurological and neuropsychiatric conditions. As part of the efforts to test the suitability of SNS as a biological marker of schizophrenia more specifically, several studies have assessed the power of SNS to discriminate between patients with schizophrenia and healthy subjects, and between the former and patients with other psychiatric disorders. Among studies that included a healthy control group, most of them have reported increased neurological impairment in patients with schizophrenia (for a review see [1, 17]). This supports strongly the proposition that neurological signs significantly differentiate patients with schizophrenia from healthy control subjects. As to the comparison with other psychiatric disorders, patients with schizophrenia have shown more SNS than patients with obsessivecompulsive disorder [90], alcohol dependence [40], substance abuse, bipolar disorder [91], non-bipolar mood disorders [92], and patients with mixed psychiatric diagnoses [93]. However, the specificity of neurological impairment to schizophrenia versus other forms of psychoses is not supported consistently [83]. The potential validity of SNS as a biological marker also depends on the stability of SNS across the course of illness. Multiple studies of persons with schizophrenia that assessed the presence of SNS in first-episode patients documented the presence of neurological signs [20, 30, 36, 43, 47–49, 77, 89, 93, 94]. When first-episode patients are compared with healthy controls, SNS are more prevalent in patients than controls [30, 95, 96]. In light of the fact that SNS are already present by the time of positive psychotic symptom onset, the question then becomes whether neurological impairment follows a progressive deterioration or remains stable across the illness course. Most crosssectional studies do not report significant correlations between neurological impairment and illness duration [27, 31, 35, 38–40, 43, 97–100]. Additionally, when

338

SNS prevalence is compared among groups of patients who are at different stages of illness, no differences are reported [49, 57]. Longitudinal studies reported increasing [23, 93], stabilizing [47, 100, 101], and decreasing [83, 94] severity of SNS. In short, the appearance of SNS in persons with schizophrenia usually pre-dates the appearance of positive symptoms, coincides with the premorbid occurrence of negative symptoms and cognitive impairment, and remains moderately stable throughout the course of illness, notwithstanding variations related to symptom exacerbations or medication side effects. There are limited data regarding the relationship between SNS and the genetics of any given neuropsychiatric condition, but some instructive observations derive from studies of persons with schizophrenia. The search for genes associated with an increased risk for developing schizophrenia is a major element of research in this area. However, psychosis and schizophrenia both are syndromes that encompass an array of biological, emotional, and behavioral phenomena. Moreover, these conditions are the result of a multitude of complex interactions between genes and environmental factors, and multiple genes are probably involved. In addition, an operative definition of schizophrenia and its core symptoms remains controversial, so a consensus phenotype to study is lacking. An alternative strategy to solve these methodological difficulties is to study a well-defined intermediate phenotype, whose measurement has acceptable reliability, in whose expression there are fewer genes implicated, and for which the effect of environmental factors is less prominent. These more accessible phenotypes are called endophenotypes, and ideally must satisfy a series of conditions [102]. As discussed above, SNS associated consistently with schizophrenia are stateindependent (a trait feature). The remaining conditions for classification of SNS as an endophenotype are: (a) trait heritability; (b) co-segregation with the associated illness within families; and (c) presence in the unaffected family members at a higher rate than in the general population. In order to test their suitability as endophenotypes, several studies have assessed the prevalence of neurological signs among unaffected relatives of patients with schizophrenia. Most of the studies assessing neurological signs in healthy relatives of patients with schizophrenia report that the level of neurological impairment in clinically unaffected relatives is intermediate between patients and healthy controls


[29, 35, 37, 44, 91, 103–110]. Interestingly, in the study by Ismail and colleagues [105] comparing patients, siblings, and normal controls, there were significant positive correlations between patients and their own siblings in the scores for total neurological abnormality, soft signs, and motor functions; these findings suggest that the degree of neurological abnormality in these families may be genetically mediated. Studies of monozygotic twins discordant for schizophrenia report similar findings, with SNS prevalence rate in the healthy discordant monozygotic twin in between the rate of the affected twins and the rate observed in healthy comparison twins [111]. Niethammer and colleagues [112] reported higher rates of SNS in patients with schizophrenia than in their unaffected monozygotic twins, as well as a higher prevalence of SNS in both groups than in a sample of 17 pairs of healthy monozygotic twins. In summary, SNS meet the proposed conditions for an endophenotype in schizophrenia. However, we are not aware of any genetic study that has examined possible SNS–single nucleotide polymorphism associations.

Finally, neurological signs may represent a valid endophenotype, which could help focus genetic research on the etiopathogenesis of schizophrenia and other cognitive and behavioral conditions. In order to be adopted as a valid biological marker for genetic research, the genetic mediation of neurological signs or specific clusters of neurological signs needs to be demonstrated. Family studies have consistently found a significantly higher presence of neurological signs in the relatives of patients with schizophrenia. However, the possibility that specific neurological signs may be due to pre- or perinatal complications, or secondary to the early development of the schizophrenic brain has not been excluded. Full delineation of the significance of SNS in neuropsychiatric diseases would benefit from continued methodological improvements, including the development of standardized, broadly accepted assessment tools with acceptable sensitivity and specificity. Toward that end, the investigation of SNS among persons with schizophrenia serves usefully as a model for understanding and investigating SNS in other neurological and neuropsychiatric conditions.

Conclusion

References

Research on neurological signs provides strong evidence supporting the conceptualization of neurological signs as a trait feature of schizophrenia, with similar findings in other cognitive and behavioral disturbances. Neurological signs seem to be more prominent in patients with schizophrenia than in healthy controls and in patients with other psychiatric disorders. Relationships among neurological signs, symptoms, cognitive impairments, and other schizophrenia phenomena confer to the former the category of an easy-to-assess biological marker. The study of potential relationships with symptomatology has shown negative and disorganized symptoms to potentially be significantly related to neurological impairment, especially pre-frontal/frontal and parietal signs, whereas positive symptoms appear to be unrelated to SNS. In light of the higher prevalence of SNS in patients with schizophrenia than in patients with other psychiatric illnesses, SNS may be used to identify subjects at high risk for developing schizophrenia (e.g., psychotic firstepisode patients, relatives of patients with schizophrenia). As with other risk factors for schizophrenia, the low predictive value of SNS recommends their use in combination with other risk factors.

1. Heinrichs DW, Buchanan RW. Significance and meaning of neurological signs in schizophrenia. Am J Psychiatry 1988;145(1):11–18. 2. Damasceno A, Delicio AM, Mazo DF et al. Primitive reflexes and cognitive function. Arq Neuropsiquiatr. 2005;63(3A):577–82. 3. Molloy DW, Clarnette RM, McIlroy WE et al. Clinical significance of primitive reflexes in Alzheimer’s disease. J Am Geriatr Soc. 1991;39(12):1160–3. 4. Vreeling FW, Houx PJ, Jolles J, Verhey FR. Primitive reflexes in Alzheimer’s disease and vascular dementia. J Geriatr Psychiatry Neurol. 1995;8(2):111–17. 5. Diehl-Schmid J, Schulte-Overberg J, Hartmann J et al. Extrapyramidal signs, primitive reflexes and incontinence in fronto-temporal dementia. Eur J Neurol. 2007;14(8):860–4. 6. Links KA, Merims D, Binns MA, Freedman M, Chow TW. Prevalence of primitive reflexes and Parkinsonian signs in dementia. Can J Neurol Sci. 2010;37(5): 601–7. 7. Sjogren M, Wallin A, Edman A. Symptomatological characteristics distinguish between frontotemporal dementia and vascular dementia with a dominant frontal lobe syndrome. Int J Geriatr Psychiatry 1997;12(6):656–61.

339


8. Gregory CA, Orrell M, Sahakian B, Hodges JR. Can frontotemporal dementia and Alzheimer’s disease be differentiated using a brief battery of tests? Int J Geriatr Psychiatry 1997;12(3):375–83.

22. Chen EY, Shapleske J, Luque R et al. The Cambridge Neurological Inventory: a clinical instrument for assessment of soft neurological signs in psychiatric patients. Psychiatry Res. 1995;56(2):183–204.

9. Okuda B, Kawabata K, Tachibana H, Kamogawa K, Okamoto K. Primitive reflexes distinguish vascular parkinsonism from Parkinson’s disease. Clin Neurol Neurosurg. 2008;110(6):562–5.

23. Chen EY, Kwok CL, Au JW, Chen RY, Lau BS. Progressive deterioration of soft neurological signs in chronic schizophrenic patients. Acta Psychiatr Scand. 2000;102(5):342–9.

10. Di Legge S, Di Piero V, Altieri M et al. Usefulness of primitive reflexes in demented and non-demented cerebrovascular patients in daily clinical practice. Eur Neurol. 2001;45(2):104–10.

24. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res. 1989;27(3):335–50.

11. Franklin GM, Nelson LM, Filley CM, Heaton RK. Cognitive loss in multiple sclerosis. Case reports and review of the literature. Arch Neurol. 1989;46(2): 162–7.

25. Compton MT, Bercu Z, Bollini A, Walker EF. Factor structure of the Neurological Evaluation Scale in a predominantly African American sample of patients with schizophrenia, unaffected relatives, and non-psychiatric controls. Schizophr Res. 2006;84(2–3): 365–77.

12. Wortzel HS, Frey KL, Anderson CA, Arciniegas DB. Subtle neurological signs predict the severity of subacute cognitive and functional impairments after traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2009;21(4):463–6. 13. van Boxtel MP, Bosma H, Jolles J, Vreeling FW. Prevalence of primitive reflexes and the relationship with cognitive change in healthy adults: a report from the Maastricht Aging Study. J Neurol. 2006;253(7): 935–41.

27. Sanders RD, Keshavan MS, Forman SD et al. Factor structure of neurologic examination abnormalities in unmedicated schizophrenia. Psychiatry Res. 2000; 95(3):237–43.

14. Hogan DB, Ebly EM. Primitive reflexes and dementia: results from the Canadian Study of Health and Aging. Age Ageing 1995;24(5):375–81.

28. Arango C, Kirkpatrick B, Buchanan RW. Neurological signs and the heterogeneity of schizophrenia. Am J Psychiatry 2000;157(4):560–5.

15. Brodsky H, Dat Vuong K, Thomas M, Jankovic J. Glabellar and palmomental reflexes in Parkinsonian disorders. Neurology 2004;63(6):1096–8.

29. Egan MF, Hyde TM, Bonomo JB et al. Relative risk of neurological signs in siblings of patients with schizophrenia. Am J Psychiatry 2001;158(11):1827–34.

16. Thomas RJ. Blinking and the release reflexes: are they clinically useful? J Am Geriatr Soc. 1994;42(6):609–13.

30. Sanders RD, Keshavan MS, Schooler NR. Neurological examination abnormalities in neuroleptic-naive patients with first-break schizophrenia: preliminary results. Am J Psychiatry 1994;151(8):1231–3.

17. Bombin I, Arango C, Buchanan RW. Significance and meaning of neurological signs in schizophrenia: two decades later. Schizophr Bull. 2005;31(4):962–77. 18. Woods BT, Kinney DK, Yurgelun-Todd D. Neurologic abnormalities in schizophrenic patients and their families. I. Comparison of schizophrenic, bipolar, and substance abuse patients and normal controls. Arch Gen Psychiatry 1986;43(7):657–63. 19. Rossi A, De Cataldo S, Di Michele V et al. Neurological soft signs in schizophrenia. Br J Psychiatry 1990;157:735–9. 20. Schroder J, Niethammer R, Geider FJ et al. Neurological soft signs in schizophrenia. Schizophr Res. 1991;6(1):25–30. 21. Convit A, Volavka J, Czobor P, de Asis J, Evangelista C. Effect of subtle neurological dysfunction on response to haloperidol treatment in schizophrenia. Am J Psychiatry 1994;151(1):49–56.

340

26. Malla AK, Norman RM, Aguilar O, Cortese L. Relationship between neurological ‘soft signs’ and syndromes of schizophrenia. Acta Psychiatr Scand. 1997;96(4):274–80.

31. Bartko G, Zador G, Horvath S, Herczeg I. Neurological soft signs in chronic schizophrenic patients: clinical correlates. Biol Psychiatry 1988;24(4):458–60. 32. Bersani G, Gherardelli S, Clemente R et al. Neurologic soft signs in schizophrenic patients treated with conventional and atypical antipsychotics. J Clin Psychopharmacol. 2005;25(4):372–5. 33. Buchanan RW, Koeppl P, Breier A. Stability of neurological signs with clozapine treatment. Biol Psychiatry 1994;36(3):198–200. 34. Cuesta MJ, Peralta V, de Leon J. Neurological frontal signs and neuropsychological deficits in schizophrenic patients. Schizophr Res. 1996;20(1–2):15–20. 35. Chen YL, Chen YH, Mak FL. Soft neurological signs in schizophrenic patients and their nonpsychotic siblings. J Nerv Ment Dis. 2000;188(2):84–9.


36. Flyckt L, Sydow O, Bjerkenstedt L et al. Neurological signs and psychomotor performance in patients with schizophrenia, their relatives and healthy controls. Psychiatry Res. 1999;86(2):113–29.

49. Shibre T, Kebede D, Alem A et al. Neurological soft signs (NSS) in 200 treatment-naive cases with schizophrenia: a community-based study in a rural setting. Nord J Psychiatry 2002;56(6):425–31.

37. Griffiths TD, Sigmundsson T, Takei N, Rowe D, Murray RM. Neurological abnormalities in familial and sporadic schizophrenia. Brain 1998;121(Pt 2): 191–203.

50. Torrey EF. Studies of individuals with schizophrenia never treated with antipsychotic medications: a review. Schizophr Res. 2002;58(2–3):101–15.

38. Ismail BT, Cantor-Graae E, Cardenal S, McNeil TF. Neurological abnormalities in schizophrenia: clinical, etiological and demographic correlates. Schizophr Res. 1998;30(3):229–38.

51. Varambally S, Venkatasubramanian G, Thirthalli J, Janakiramaiah N, Gangadhar BN. Cerebellar and other neurological soft signs in antipsychotic-naive schizophrenia. Acta Psychiatr Scand. 2006;114(5): 352–6.

39. Lane A, Colgan K, Moynihan F et al. Schizophrenia and neurological soft signs: gender differences in clinical correlates and antecedent factors. Psychiatry Res. 1996;64(2):105–14.

52. Sevincok L, Topaloglu B. Neurological soft signs and positive treatment response to olanzapine in chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2006;30(1):141–3.

40. Mohr F, Hubmann W, Cohen R et al. Neurological soft signs in schizophrenia: assessment and correlates. Eur Arch Psychiatry Clin Neurosci. 1996;246(5): 240–8.

53. Jahn T, Hubmann W, Karr M et al. Motoric neurological soft signs and psychopathological symptoms in schizophrenic psychoses. Psychiatry Res. 2006;142(2–3):191–9.

41. Arciniegas DB, Rojas DC, Kleman MR, Asherin R, Reite ML. Neurological signs and cognitive performance distinguish between adolescents with and without psychosis. J Neuropsychiatry Clin Neurosci. 2007;19(3):266–73.

54. Anderson KE, Savage CR. Cognitive and neurobiological findings in obsessive-compulsive disorder. Psychiatr Clin North Am. 2004;27(1):37–47, viii.

42. Flashman LA, Flaum M, Gupta S, Andreasen NC. Soft signs and neuropsychological performance in schizophrenia. Am J Psych. 1996;153(4):526–32.

55. Dickstein DP, Garvey M, Pradella AG et al. Neurologic examination abnormalities in children with bipolar disorder or attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;58(7):517–24.

43. Gupta S, Andreasen NC, Arndt S et al. Neurological soft signs in neuroleptic-naive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. Am J Psychiatry 1995;152(2):191–6.

56. Goswami U, Sharma A, Khastigir U et al. Neuropsychological dysfunction, soft neurological signs and social disability in euthymic patients with bipolar disorder. Br J Psychiatry 2006;188:366–73.

44. Yazici AH, Demir B, Yazici KM, Gogus A. Neurological soft signs in schizophrenic patients and their nonpsychotic siblings. Schizophr Res. 2002; 58(2–3):241–6.

57. Poyurovsky M, Faragian S, Pashinian A et al. Neurological soft signs in schizophrenia patients with obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 2007;19(2):145–50.

45. Merriam AE, Kay SR, Opler LA, Kushner SF, van Praag HM. Neurological signs and the positivenegative dimension in schizophrenia. Biol Psychiatry 1990;28(3):181–92.

58. De la Fuente JM, Bobes J, Vizuete C et al. Neurologic soft signs in borderline personality disorder. J Clin Psychiatry 2006;67(4):541–6.

46. Smith RC, Kadewari RP. Neurological soft signs and response to risperidone in chronic schizophrenia. Biol Psychiatry 1996;40(10):1056–9. 47. Chen EY, Hui CL, Chan RC et al. A 3-year prospective study of neurological soft signs in first-episode schizophrenia. Schizophr Res. 2005;75(1):45–54. 48. Rubin P, Vorstrup S, Hemmingsen R et al. Neurological abnormalities in patients with schizophrenia or schizophreniform disorder at first admission to hospital: correlations with computerized tomography and regional cerebral blood flow findings. Acta Psychiatr Scand. 1994;90(5):385–90.

59. Barkus E, Stirling J, Hopkins R, Lewis S. The presence of neurological soft signs along the psychosis proneness continuum. Schizophr Bull. 2006;32(3): 573–7. 60. Bollini AM, Compton MT, Esterberg ML et al. Associations between schizotypal features and indicators of neurological and morphological abnormalities. Schizophr Res. 2007;92(1–3): 32–40. 61. Lopez OL, Becker JT, Banks G et al. Development of subtle neurological signs after systemic illness in HIV-infected individuals. Eur Neurol. 1996;36(2): 71–5.

341


62. Chen EY, Lam LC, Chen RY et al. Neurological signs and sustained attention impairment in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2001;251(1):1–5. 63. Wong AH, Voruganti LN, Heslegrave RJ, Awad AG. Neurocognitive deficits and neurological signs in schizophrenia. Schizophr Res. 1997;23(2):139–46. 64. Arango C, Bartko JJ, Gold JM, Buchanan RW. Prediction of neuropsychological performance by neurological signs in schizophrenia. Am J Psychiatry 1999;156(9):1349–57. 65. Braun CM, Lapierre D, Hodgins S et al. Neurological soft signs in schizophrenia: are they related to negative or positive symptoms, neuropsychological performance, and violence? Arch Clin Neuropsychol. 1995;10(6):489–509. 66. Cimmer C, Szendi I, Csifcsak G et al. Abnormal neurological signs, visual contrast sensitivity, and the deficit syndrome of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2006;30(7): 1225–30. 67. Smith RC, Kadewari RP, Rosenberger JR, Bhattacharyya A. Nonresponding schizophrenia: differentiation by neurological soft signs and neuropsychological tests. Schizophr Bull. 1999; 25(4):813–25. 68. Schroder J, Buchsbaum MS, Siegel BV, Geider FJ, Niethammer R. Structural and functional correlates of subsyndromes in chronic schizophrenia. Psychopathology 1995;28(1):38–45. 69. Bersani G, Paolemili M, Quartini A et al. Neurological soft signs and cerebral measurements investigated by means of MRI in schizophrenic patients. Neurosci Lett. 2007;413(1):82–7. 70. Dazzan P, Morgan KD, Orr KG et al. The structural brain correlates of neurological soft signs in AESOP first-episode psychoses study. Brain 2004;127(Pt 1): 143–53. 71. Dazzan P, Morgan KD, Chitnis X et al. The structural brain correlates of neurological soft signs in healthy individuals. Cereb Cortex 2006;16(8):1225–31. 72. DeMyer MK, Gilmor RL, Hendrie HC et al. Magnetic resonance brain images in schizophrenic and normal subjects: influence of diagnosis and education. Schizophr Bull. 1988;14(1):21–37. 73. Bottmer C, Bachmann S, Pantel J et al. Reduced cerebellar volume and neurological soft signs in first-episode schizophrenia. Psychiatry Res. 2005;140(3):239–50. 74. Schroder J, Wenz F, Schad LR, Baudendistel K, Knopp MV. Sensorimotor cortex and supplementary motor area changes in schizophrenia. A study with functional magnetic resonance imaging. Br J Psychiatry 1995; 167(2):197–201.

342

75. Arango C, Buchanan RW, Kirkpatrick B, Carpenter WT. The deficit syndrome in schizophrenia: implications for the treatment of negative symptoms. Eur Psychiatry 2004;19(1):21–6. 76. Carpenter WT, Jr., Arango C, Buchanan RW, Kirkpatrick B. Deficit psychopathology and a paradigm shift in schizophrenia research. Biol Psychiatry 1999;46(3):352–60. 77. Browne S, Clarke M, Gervin M et al. Determinants of neurological dysfunction in first episode schizophrenia. Psychol Med. 2000;30(6):1433–41. 78. King DJ, Wilson A, Cooper SJ, Waddington JL. The clinical correlates of neurological soft signs in chronic schizophrenia. Br J Psychiatry 1991;158:770–5. 79. Schroder J, Tittel A, Stockert A, Karr M. Memory deficits in subsyndromes of chronic schizophrenia. Schizophr Res. 1996;21(1):19–26. 80. Buchanan RW, Kirkpatrick B, Heinrichs DW, Carpenter WT, Jr. Clinical correlates of the deficit syndrome of schizophrenia. Am J Psychiatry 1990;147(3):290–4. 81. Prikryl R, Ceskova E, Kasparek T, Kucerova H. Neurological soft signs, clinical symptoms and treatment reactivity in patients suffering from first episode schizophrenia. J Psychiatr Res. 2006;40(2): 141–6. 82. Tosato S, Dazzan P. The psychopathology of schizophrenia and the presence of neurological soft signs: a review. Curr Opin Psychiatry 2005;18(3): 285–8. 83. Whitty P, Clarke M, McTigue O et al. Diagnostic specificity and predictors of neurological soft signs in schizophrenia, bipolar disorder and other psychoses over the first 4 years of illness. Schizophr Res. 2006;86(1–3):110–17. 84. Bartko G, Frecska E, Horvath S, Zador G, Arato M. Predicting neuroleptic response from a combination of multilevel variables in acute schizophrenic patients. Acta Psychiatr Scand. 1990;82(6):408–12. 85. Ceskova E, Drybcak P, Lorenc M. Biological markers and possibilities for predicting therapeutic results in schizophrenia: a methodological contribution. Prog Neuropsychopharmacol Biol Psychiatry 2002;26(4):683–91. 86. Hollander E, Kaplan A, Schmeidler J et al. Neurological soft signs as predictors of treatment response to selective serotonin reuptake inhibitors in obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 2005;17(4):472–7. 87. Galderisi S, Bucci P, Mucci A et al. ‘Simple schizophrenia’: a controlled MRI and clinical/ neuropsychological study. Psychiatry Res. 1999;91(3):175–84.


88. Gupta S, Rajaprabhakaran R, Arndt S, Flaum M, Andreasen NC. Premorbid adjustment as a predictor of phenomenological and neurobiological indices in schizophrenia. Schizophr Res. 1995;16(3):189–97. 89. Johnstone EC, Macmillan JF, Frith CD, Benn DK, Crow TJ. Further investigation of the predictors of outcome following first schizophrenic episodes. Br J Psychiatry 1990;157:182–9. 90. Bolton D, Gibb W, Lees A et al. Neurological soft signs in obsessive compulsive disorder: standardised assessment and comparison with schizophrenia. Behav Neurol. 1998;11(4):197–204.

hospitalized schizophrenic patients. J Neuropsychiatry Clin Neurosci. 1999;11(1):91–6. 101. Boks MP, Selten JP, Leask S, Van den Bosch RJ. The 2-year stability of neurological soft signs after a first episode of non-affective psychosis. Eur Psychiatry 2006;21(5):288–90. 102. Gottesman, II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003;160(4):636–45. 103. Appels MC, Sitskoorn MM, de Boo M et al. Neurological signs in parents of schizophrenic patients. Neuroreport 2002;13(5):575–9.

91. Kinney DK, Yurgelun-Todd DA, Woods BT. Neurologic signs of cerebellar and cortical sensory dysfunction in schizophrenics and their relatives. Schizophr Res. 1999;35(2):99–104.

104. Gourion D, Goldberger C, Olie JP, Loo H, Krebs MO. Neurological and morphological anomalies and the genetic liability to schizophrenia: a composite phenotype. Schizophr Res. 2004;67(1):23–31.

92. Krebs MO, Gut-Fayand A, Bourdel M, Dischamp J, Olie J. Validation and factorial structure of a standardized neurological examination assessing neurological soft signs in schizophrenia. Schizophr Res. 2000;45(3):245–60.

105. Ismail B, Cantor-Graae E, McNeil TF. Neurological abnormalities in schizophrenic patients and their siblings. Am J Psychiatry 1998;155(1):84–9.

93. Madsen AL, Vorstrup S, Rubin P, Larsen JK, Hemmingsen R. Neurological abnormalities in schizophrenic patients: a prospective follow-up study 5 years after first admission. Acta Psychiatr Scand. 1999;100(2):119–25. 94. Bachmann S, Bottmer C, Schroder J. Neurological soft signs in first-episode schizophrenia: a follow-up study. Am J Psychiatry 2005;162(12):2337–43. 95. Dazzan P, Murray RM. Neurological soft signs in first-episode psychosis: a systematic review. Br J Psychiatry Suppl. 2002;43:s50–7.

106. Kelly BD, Cotter D, Denihan C et al. Neurological soft signs and dermatoglyphic anomalies in twins with schizophrenia. Eur Psychiatry 2004;19(3):159–63. 107. Kinney DK, Yurgelun-Todd DA, Woods BT. Hard neurologic signs and psychopathology in relatives of schizophrenic patients. Psychiatry Res. 1991;39(1): 45–53. 108. Lawrie SM, Byrne M, Miller P et al. Neurodevelopmental indices and the development of psychotic symptoms in subjects at high risk of schizophrenia. Br J Psychiatry 2001;178:524–30.

96. Zabala A, Robles O, Parellada M et al. Neurological soft signs in adolescents with first episode psychosis. Eur Psychiatry 2006;21(5):283–7.

109. Niemi LT, Suvisaari JM, Haukka JK, Lonnqvist JK. Childhood predictors of future psychiatric morbidity in offspring of mothers with psychotic disorder: results from the Helsinki High-Risk Study. Br J Psychiatry 2005;186:108–14.

97. Goswami U, Gulrajani C, Varma A et al. Soft neurological signs do not increase with age in euthymic bipolar subjects. J Affect Disord. 2007;103(1–3):99–103.

110. Schubert EW, McNeil TF. Prospective study of neurological abnormalities in offspring of women with psychosis: birth to adulthood. Am J Psychiatry 2004;161(6):1030–7.

98. Gureje O. Neurological soft signs in Nigerian schizophrenics: a controlled study. Acta Psychiatr Scand. 1988;78(4):505–9.

111. Cantor-Graae E, McNeil TF, Rickler KC et al. Are neurological abnormalities in well discordant monozygotic co-twins of schizophrenic subjects the result of perinatal trauma? Am J Psychiatry 1994;151(8):1194–9.

99. Martin P, Tewesmeier M, Albers M, Schmid GB, Scharfetter C. Towards an understanding of sensory soft signs of schizophrenia. Psychopathology 1995;28(6):281–4. 100. Smith RC, Hussain MI, Chowdhury SA, Stearns A. Stability of neurological soft signs in chronically

112. Niethammer R, Weisbrod M, Schiesser S et al. Genetic influence on laterality in schizophrenia? A twin study of neurological soft signs. Am J Psychiatry 2000; 157(2):272–4.

343

Section II


Chapter

Mental status examination

23

David B. Arciniegas

The mental status examination is a systematic assessment of cognition, emotion, and behavior that draws upon a hierarchically organized set of observations, questions, and tasks in order to develop a detailed cross-sectional description of an individual’s state of mind [1–7]. Information derived from this examination is integrated into a comprehensive assessment with history, general physical and neurological examinations, and relevant neurodiagnostic assessments. In conjunction with information obtained by all these means, the mental status examination informs on the anatomy of illness, permits construction of the differential diagnosis, directs additional examinations, investigations, and consultations, and establishes a baseline against which the course of illness and the effects of treatment are compared. In an era in which advanced neurodiagnostic assessments are available, one might ask whether the mental status examination remains as relevant and important to the practice of Behavioral Neurology & Neuropsychiatry (BN&NP) as in decades past. On this point, the words of Norman Geschwind (1977) [8] – progenitor of the modern era of behavioral neurology [9] and the teacher to whom the editors of this volume trace their neurobehavioral training – merit repeating here:

We should remember, however, that the real measure of a physician’s usefulness lies in his capacity to make critical decisions when he is alone with the patient in the small hours of the night. Furthermore, unless he can screen patients effectively, he will fail to refer intelligently to others. Finally, if the ultimate decisions lie in his hands, he will fail to use adequately the opinions of his consultants unless he has a basic understanding of all aspects of his patient’s problems. ([8], p. viii)

Although offered as a response to the proposal that physicians defer performance of the mental status examination to other clinicians, Geschwind’s comments are equally apropos of suggestions that the mental status examination be supplanted by other, including technology-based, neurodiagnostic assessments [10]. Structural and functional neuroimaging, electrophysiologic assessments, neuropsychological testing, and laboratory studies can inform diagnosis and treatment planning. However, there are circumstances in which it is impractical, unsafe, or simply impossible to perform these types of neurodiagnostic assessments: in under-resourced practice environments, while oncall “in the small hours of the night,” when evaluating patients with severe and physically dangerous behaviors, and in many high-security (e.g., forensic) settings, among others. By contrast, the mental status examination can be performed in all of these settings. When administered skillfully and interpreted thoughtfully, its findings guide initial clinical decisionmaking about diagnosis, consultation and other necessary assessments, and treatment. The mental status examination therefore is, and will remain, an essential skill for clinicians of all professional disciplines working with persons affected by brain disorders, including subspecialists in BN&NP [11]. There is no single, best, or universally accepted approach to the mental status examination [1–4, 12]. Regardless of its specific content and methods, however, the mental status examination generally addresses the areas described in Table 23.1. It also commonly employs several techniques: observation, interviewing with indirect (i.e., open-ended) and direct (i.e., “yes or no”) questions, and cognitive testing. The relative contributions of these techniques vary with the


344

Chapter 23: Mental status examination

Table 23.1. Outline of the mental status examination.

Section

Elements

Appearance and behavior

Arousal Apparent age Body habitus and other physical characteristics Position and posture Attire and grooming Personal hygiene Voluntary and involuntary motor activity Eye contact Comportment and motivation Engagement with examiner

Emotion and emotional feeling

Mood Affect

Communication

Voice Speech Language Prosody and kinesics

Thought process

Style (flow) Structure (organization)

Thought content

Perception Ideas and concerns Themes Lethality

Cognition

Arousal Attention Processing speed Working memory Recognition Language and prosody Declarative memory Praxis Visuospatial function Calculation Executive function

Insight

Awareness of self and personal circumstances Inferences about the environment and the minds of others

Judgment

Ability to reason soundly and draw conclusions rationally

circumstances under which the examination is performed as well as the mental state of the patient being assessed. Several limitations of the mental status examination require acknowledgment before its contents and methods are discussed further. A single mental status examination provides a cross-sectional view of a patient’s thoughts, emotion, and behavior; however, that view is not always an accurate one. Although mental status examination findings generally reflect the effects of the condition for which a patient is being

evaluated, other factors also affect mental state at the moment of its examination. These factors include the circumstances of the evaluation (e.g., elective outpatient versus medical or psychiatric emergency versus court-ordered forensic settings), the environment in which the examination is performed, the patient’s prior clinical experiences (including previous mental status examinations), and the interpersonal styles, methods, experiences, and clinico-theoretical perspectives of the examiner, among others. Ignoring these influences on mental status examination findings risks drawing erroneous conclusions about a patient’s mental state and its causes. Clinical impressions based on a single mental status examination therefore cannot be taken too absolutely. Serial examinations, structured clinical interviews of patients and knowledgeable informants, and standardized cognitive assessments may improve confidence in mental status examination findings. Given the cross-sectional nature and relatively limited scope of most mental status examinations, supplementation with (and reinterpretation following) additional history, examinations, and neurodiagnostic assessments are also often required to confirm “bedside” findings and to test the diagnostic hypotheses they generate. Bearing these issues in mind, this chapter presents an overview of the mental status examination, its core elements (Table 23.1), and its most commonly used methods. The mental status examination focuses on cognitive, emotional, behavioral, and related sensorimotor functions (referred to collectively in this chapter as “neuropsychiatric” phenomena) and their disturbances – i.e., neuropsychiatric symptoms, signs, and syndromes. The role of observation and interview in their identification is discussed next. In light of the complementary, and often intermingled, tasks of history-taking and mental status examination, standardized neuropsychiatric assessments are described briefly as well. Thereafter, the elements and methods of mental status examination, including cognitive testing, are reviewed.

Neuropsychiatric phenomenology Symptoms and signs Through observation, interview, and testing, the mental status examination identifies the symptoms and signs of structural and/or functional disturbances of

345


the brain. A “symptom” is an abnormality in somatic or mental function that is noticed as such by the patient (i.e., subjectively experienced), and a “sign” is an abnormality in a patient’s somatic or mental function that is observable by others (i.e., objectively identifiable) [13]. It is the perspective from which somatic or mental abnormalities are viewed, and not necessarily their nature, that distinguishes symptoms from signs. Nonetheless, the nature of some of these phenomena precludes their apprehension by any means other than direct experience. For example, color perception, auditory hallucinations, feeling sad or fearful, or other qualia are accessible only to the individual experiencing them; these, necessarily, are neuropsychiatric symptoms. Corresponding signs do not always, but often enough do, accompany such symptoms, and their presence sometimes may be inferred from response patterns on perceptual, cognitive, emotional, or behavioral tests. Observing these signs provides clues as to the presence, nature, and severity of patients’ symptoms even when they are unable or unwilling to discuss them. For example, frequent sudden head turning, eye version, changes in facial expression or posture, and angry verbal outbursts directed at targets not visible to the examiner made by a person refusing, or too distracted, to engage with the examiner suggest that individual may be experiencing hallucinations. Neuropsychiatric signs also may be experienced concurrently as symptoms. For example, word-finding difficulties, impaired sustained attention (“concentration”) or working memory, problems retrieving previously learned information, and task disorganization may be subjectively experienced and reported by patients and easily observed by others. Some signs always occur in the absence of a corresponding subjective experience (e.g., hemispatial neglect, hemiplegic anosognosia, unawareness of choreoathetosis in Huntington’s disease); the converse of qualia, these are phenomena about which, by definition, patients are unaware and therefore are signs. Variability in the relationship between neuropsychiatric symptoms and signs leads some authors to refer to any abnormality in somatic or mental function as a symptom, regardless of whether that evidence is drawn from the patient’s perspective or the observations of others [2]. For example, the Diagnostic and Statistical Manual of Mental Disorders (DSM) [14–16] uses “symptom” to describe clinical features

346

deriving not only from patient reports but also from others’ observations. The use of symptom in this manner extends to phenomena about which patients may have no, or extremely limited, awareness. For example, the DSM–IV–TR [14] uses symptoms to refer to: “grand mal” seizures of alcohol withdrawal; pupillary dilation, elevated or lowered blood pressure, cardiac arrhythmias, and seizures of amphetamine intoxication; “disturbance of consciousness” and “change in cognition” of substance intoxication delirium; and hyperactive–impulsive behaviors among relatively young children with attention-deficit hyperactivity disorder. Describing such problems as symptoms, on its face, is nosologically imprecise and risks fostering the incorrect impression that psychiatric diagnoses are entirely subjective. Elsewhere in this manual [14], use of the terms signs and symptoms is abandoned in favor of describing psychiatric phenomena as “disturbances.” Maintaining the traditional distinction between symptoms and signs in subspecialty BN&NP evaluations is recommended. The extent to which a patient subjectively experiences abnormalities of somatic and mental function, is able to describe them, and is cognizant of the relationships (or lack of such) between signs and symptoms informs on the differential diagnosis and neuroanatomy of illness. Assiduous assessment for traditionally defined signs and symptoms, as well as evaluation of the correspondence between the patient’s subjective experience and the examiner’s observation of those phenomena, therefore is an important characteristic of the mental status examination in BN&NP.

Positive and negative neuropsychiatric signs and symptoms Neuropsychiatric symptoms and signs are sometimes categorized as positive (productive) or negative (deficit) [12, 15, 17, 18]. Although these terms are used most often to describe the clinical features of schizophrenia and other psychotic disorders, they can be used to describe any excess or distortion of normal function (positive symptom or sign, Box 23.1) or reduction or loss of a normal function (negative symptom or sign, Box 23.2) [2, 12]. The heuristic value of these purely phenomenological descriptions is debatable. If positive and negative clinical phenomena are predicated on comparable neurobiological excesses/distortions or reductions/


Box 23.1. Examples of positive neuropsychiatric symptoms and signs.

Box 23.2. Examples of negative neuropsychiatric symptoms and signs.

Illusions Hallucinations Palinopsia Tinnitus Synesthesia Rumination Obsession Confabulation Delusions Flight of ideas Clang associations Flashbacks

Inattention Bradyphrenia Agnosia Amnesia Aphemia Alogia Aphasia Alexia Aprosodia Apraxia Acalculia Anosognosia

Nightmares Persistent excessive sadness Exaggerated startle response Panic attacks Affective lability Compulsions Agitation Aggression Suicidality Homicidality

losses, respectively, then categorizing symptoms and signs identified by the mental status examination in this manner might usefully direct differential diagnostic and etiologic considerations. For example, auditory verbal hallucinations are traditionally regarded as positive symptoms and may reflect abnormal activation of language-related cortices in a manner that generates the external stimulusindependent experience of language-related auditory events [19]. However, investigations of this positive symptom suggest that it may be related to aberrant activation of language-related cortex, impaired recognition of inner speech and its subsequent mislabeling of its origin as non-self, and aberrant activation and/or failed inhibition of declarative memories [19, 20]. Recent investigations of the neurobiology of other positive symptoms, including delusions [21–25], thought disorder [26–29], obsessions [30–32], impulsivity/disinhibition [33, 34], aggression [35–38], and pathological crying [39–41] also reveal their bases in complex combinations of structural and functional neurobiological excesses and deficits. There tends to be a more consistent relationship between negative symptoms and signs and deficits in brain structure and/or function, although these relationships are not without exceptions [42]. The inconsistent correspondence between positive and negative neuropsychiatric phenomena and neurobiological excesses and deficits, respectively, does not require clinicians to eschew these clinical terms. However, one must remain circumspect about the neurobiological meaningfulness of describing signs and symptoms neuropsychiatric as positive or negative.

Unilateral neglect Loss of insight Anhedonia Affective flattening Inanition Avolition Apathy Abulia Akinetic mutism Bradykinesia

Syndromes A syndrome is a complex of symptoms and signs resulting from a single cause or occurring together so commonly as to suggest a single disease or inherited abnormality [43–45]. Linkage between co-occurring signs and symptoms as well as coupling of their resolution is central to the concept of a syndrome (from Greek, syn “together” + dromos “course”). Although the features of a specific syndrome may vary between affected individuals, the onset of symptoms and signs in any particular patient are linked in a manner that is generally consistent with the course and (where known) the neurobiology and/or neurogenetics of that condition. When a patient experiences a transient or episodic syndrome (e.g., delirium, major depressive episode, manic episode), spontaneous and/or treatment-induced remission of symptoms and signs as a group is expected, although the rate and, occasionally, the extent to which individual components of that syndrome resolve may vary. Distinguishing between neuropsychiatric symptoms, signs, and syndromes is critical to the interpretation of mental status examination findings. Coherence between the symptoms reported by a patient and the signs observed by the examiner informs the differential diagnosis. When symptoms and signs characteristic of a specific syndrome are identified, those findings move the examination toward other assessments that either support that diagnosis or suggest alternative ones. Marked discrepancies between neuropsychiatric symptoms and signs suggest the need to reconsider the content and process of the examination: Were the observations accurate? Were the appropriate questions asked? Is the patient capable of accurate self-report?

347


Do collateral sources of information explain discrepancies between self-report and objective assessment? Are there factors influencing patient effort or the validity of the assessments performed? Secondary neuropsychiatric syndromes (i.e., those resulting from a primary neurological disorder such as stroke, traumatic brain injury, epilepsy) often do not conform fully to the prototypic primary psychiatric disorders for which they are named. In many cases, their symptoms and signs cross conventional diagnostic boundaries. For example, the cardinal symptom of depression is persistent excessive sadness and/or anhedonia. Among adults with secondary depressive syndromes, however, the clinical presentation often is dominated by persistent excessive irritability. Although persistent excessive irritability is more typical of hypomania, mania, or mixed mood episodes, its occurrence amidst a set of symptoms and signs that otherwise suggests depression then supports that diagnosis. Economy of explanation should be sought where possible – i.e., diagnosing variants of typical syndromes in most patients rather than presuming modest differences bespeak entirely different syndromes. Many patients present to subspecialists in BN&NP with highly complex and/or very unusual constellations of signs and symptoms. Atypical clinical presentations sometimes are neurological condition-specific variants of typical neuropsychiatric syndromes. In other cases, atypicality reflects polyetiology. Before labeling atypical presentations as a “syndrome” per se, it is essential to assess the relationships between cooccurring symptoms and signs, including the degree to which their onset is linked and the extent to which their course is coupled. These assessments will determine whether their co-occurrence is characterized correctly as syndromal. This approach minimizes the risk of misdiagnosis and subsequent therapeutic misadventures.

Observation and interview The observational components of the mental status examination are undertaken at the first moment of any form of contact with a patient and continue throughout the entire clinical encounter. Although the etymology of observe (from Latin, ob “over” + servare “to attend, look at”) [46] might seem to constrain obser-

348

vation to the act of seeing the patient, the astute examiner observes using all of his or her senses. Often, observations about a patient’s mental state are made well in advance of the clinical encounter. For example, the verbal outbursts, unsanitary odors, and bedraggled surroundings of a psychotic and agitated patient will sometimes be easily and fully appreciated from the hallway outside that patient’s hospital room. Similarly, observing a patient’s effects on the emotions, behaviors, and interactions between other healthcare providers (and, sometimes, on other patients) with whom that patient has interacted also can provide useful clues about mental state. There also are circumstances in which face-to-face interview and examination are not possible (e.g., telephone calls). Although the information derived from such encounters is necessarily limited (i.e., excludes not only data derived from visual observation but also general physical and neurological examinations), non-visual observations and structured clinical interview permit valid and reliable assessment of mental state [47–51], including many aspects of cognition [52–54]. Experienced clinicians also recognize that a patient’s environment – including the characteristics of the physical plant, the people therein, and their behaviors – affects mental state and therefore is an important focus of the mental status examination [55–57] (see Chapters 33 and 37). In short, maintaining a broad notion of observation is fundamental to the mental status examination in BN&NP. Observation continues throughout the clinical interview, during which the examiner attends to the patient’s appearance, behavior, statements (or lack thereof), manner of communicating, interpersonal interactions with examiner, and changes in any of these. The examiner also monitors his or her own feelings and reactions throughout the interview [2, 58]; the examiner’s responses to the patient serve as potentially important sources of information about the patient’s mental state and the examiner’s influence on it. Effective self-reflection by the examiner also prompts expressions of empathy and support in the midst of examination, facilitates the development of rapport with the patient, and reduces the likelihood of reacting to the patient in a clinically counterproductive and unprofessional manner. Using all of these sources of information, hypotheses regarding the patient’s mental state and its causes are developed. Tests of those hypotheses are integrated


seamlessly into the clinical interview and, to the greatest extent possible, matched to the patient’s needs, abilities, and style. Patients capable of engaging in the encounter effectively and reporting reliably on their mental state may be interviewed in a less structured, although entirely clinical, manner. This type of interview encourages anamnesis – the complete history recalled and recounted by the patient – and is unobtrusively guided by the clinician to address critical areas of the clinical history and to reveal relevant symptoms and signs [2]. This approach is typical of clinical interviewing in many clinical disciplines, especially general psychiatry. This approach may be useful in the practice of BN&NP, but many patients seen in this context may lack the cognitive, emotional, and/or behavioral resources needed to communicate effectively, reliably, and/or independently. Engaging such patients in the mental status examination can generate anxiety, agitation, aggression, and other forms of emotional and behavioral dyscontrol, especially when they have limited or no understanding of the reason for the encounter or the purpose of performing a seemingly arcane set of tasks. Encouraging unstructured anamnesis among patients with severe cognitive, emotional, and/or behavioral disturbances also can be countertherapeutic. In such circumstances it is more useful to guide the interview of such patients to important topics using simple direct questions that are within their abilities to answer. The examination of patients with such limitations also tends to focus more directly on cognitive assessment, which is best undertaken relatively early in the encounter. When examining patients with severe neuropsychiatric impairments or disturbances, the examiner must remain vigilant for interview- and/or examination-induced emotional and behavioral disturbances (e.g., paranoid, anxious, irritable, agitated, or aggressive responses to questions or cognitive failures). When such disturbances develop, modifying the clinical approach used or terminating the encounter altogether is appropriate. The safety of the examiner is an important consideration. Interviewing knowledgeable and reliable informants about a patient’s mental state is important and is an essential element of the examination of patients with severe cognitive, emotional, and behavioral disturbances. In general, individuals whose contact with

the patient is sufficiently frequent and intimate to afford them the opportunity to observe all behaviors are the most useful informants (e.g., spouses, family members, and other daily caregivers). In institutional settings, nursing staff, patient care technicians, and individuals involved in the scheduling and coordination of the clinical encounter also can be useful informants on a patient’s mental state. Additionally, verbal and written reports about a patient, including those offered spontaneously by other patients, also may be highly informative. Contextually appropriate selection and administration of self-report, clinician-administered, and/or informant-based instruments also can enhance history-taking and mental status examination. These instruments are designed to facilitate identification of clinically important neuropsychiatric symptoms and signs and, in some cases, the syndromes with which they are associated. Their incorporation into the clinical interview can help direct the interview and mental status examination to particularly important issues and guide the examiner’s observations, questions, and testing. The use of structured tools, assessment, and tests creates a context and focus for patient and caregiver education about neuropsychiatric problems and develops a shared language and frame of reference for their discussion. The quantitative and qualitative data they yield is easily communicated to patients, caregivers, clinicians, and other parties. Their results also establish baselines against which illness progression and treatment response can be objectively compared. Examples of assessment instruments used with patients are presented in Table 23.2 [17, 59–67] and Table 23.3 [68–87]. The Neuropsychiatric Inventory (NPI) [88] is an informant-based assessment for neuropsychiatric disturbances associated with neurological conditions [89–97], and its several versions are presented in Table 23.4 [88, 98–100]. Comprehensive compilations of other assessments of these types are presented in Burns et al. [101] and Tate [102]. In light of the preceding discussion of observation and interview in the mental status examination, and based on review of the contents of structured assessments of symptoms and signs presented in Tables 23.3 and 23.4, the foundation for the traditional practice of dividing this examination into cognitive and non-cognitive sections [1–7, 12] is not entirely sound. The mental status examination consists

349


Table 23.2. Clinician-administered and self-report measures that broadly assess neuropsychiatric symptoms, signs, and syndromes. These symptom- and syndrome-focused measures offer complementary information sets. The former provide information about the types and severities of symptoms experienced by a patient but, in general, are not used to make categorical psychiatric diagnoses. By contrast, the latter (especially the SCID-CV and MINI) yield categorical diagnoses but do not quantify the severities of symptoms and signs.

Measure

Target

Method(s)

Comments

Schedules for Clinical Assessment in Neuropsychiatry

Symptoms

Semi-structured clinical interview and observation

A set of instruments and manuals assessing neuropsychiatric symptoms, as well as the syndromes with which they are commonly associated, within the framework described by the World Health Organization

Neurobehavioral Rating Scale-Revised

Symptoms

Structured clinical interview and observation

Originally developed for use among persons with traumatic brain injury, this instrument assesses a broad range of disturbances in cognition, emotion, behavior, and motor function

Brief Psychiatric Rating Scale

Symptoms


One of the most commonly used multidimensional psychiatric rating scales in clinical research

Positive and Negative Syndrome Scale

Symptoms


Assesses a broad range of positive, negative, and general psychopathological symptoms; organizes subsets of these into the positive and negative syndromes of schizophrenia

Neurobehavioral Functioning Inventory

Symptoms

Self-report and/or family report

Symptoms assessed are organized into scales describing depression, somatic concerns, memory/attention problems, communication difficulties, aggression, and motor disturbances

Symptom Checklist-90-Revised

Symptoms

Self-report

Identifies somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, phobic anxiety, hostility, paranoid ideation, and psychoticism; also yields symptom severity and distress indices

Minnesota Multiphasic Personality Inventory-2

Symptoms

Self-report

Identifies a broad range of psychopathological symptoms and characterizes personality structure

Structured Clinical Interview for DSM Disorders-Clinician Version (SCID-CV)

Syndromes


Identifies psychiatric syndromes defined by DSM–IV–TR criteria; adapted from the research measure of the same name

Mini-International Neuropsychiatric Inventory (MINI)

Syndromes


Identifies psychiatric syndromes defined by DSM–IV–TR criteria; high reliability with the SCID and less time-consuming to administer

Millon Clinical Multiaxial Inventory-III

Syndromes

Self-report

Identifies clinical syndromes, including personality disorders, as defined by DSM–IV

principally of observations made under different conditions (i.e., baseline, spontaneous statements, emotions, and behaviors, during specific questions about non-cognitive mental functions, and during structured cognitive testing), and the observations made differ more by context than kind. The close relationship between cognitive and non-cognitive processes (especially the influence of the latter on the former) [103–106] also undermines the strict separation of these elements of the mental status examination. Understanding any type of mental process requires understanding others with which it co-occurs and the manner(s) in which they interact. Nonetheless, the performance and documentation of the cognitive portions of the mental status

350

examination are commonly separated from those focused on non-cognitive processes. For convenience, then, the cognitive examination is addressed in a distinct section of this chapter as well.

Appearance and behavior In this section of the examination, level of arousal (wakefulness), physical characteristics, comportment, and interactions with the examiner and environment are assessed and described. Arousal denotes a patient’s level of consciousness or state of wakefulness. Patients with normal levels of consciousness are either described as such or by using the term “alert.”


Table 23.3. Examples of self-report and clinician-administered instruments used to assess relatively narrow categories of neuropsychiatric symptoms and/or signs.

Measure

Method(s)

Comments

Cognitive Failures Questionnaire

Self-report

Asks questions about subjectively experienced failures in perception, memory, and motor function; although cognitively focused, responses to these questions tend to correlate highly with self-ratings of depression and other psychiatric symptoms

Multiple Abilities Self-Report Questionnaire

Self-report

Asks questions about experiences of cognitive performance in five domains: attention, verbal memory, visuospatial memory, visual perception, and language

Behavioral Rating Inventory of Executive Function-Adult Version

Self-report, informant report

Asks questions about executive function and self-regulation, responses to which comprise behavioral regulation, metacognition, and global executive composite indices

Hamilton Depression Rating Scale


Depression-focused, with questions about anxiety, general somatic symptoms, insight, depersonalization, paranoia, and obsessional thinking

Beck Depression Inventory – II

Self-report

Asks questions about depressive symptoms described in DSM–IV

Young Mania Rating Scale


Assesses classically defined manic symptoms; a version based on interview of others (e.g., parents) is also available

Hamilton Anxiety Rating Scale


Assesses psychological symptoms of anxiety and physical complaints related to anxiety

Beck Anxiety Inventory

Self-report

Asks questions about current anxiety symptoms

State-Trait Anxiety Inventory

Self-report

Asks questions about current anxiety (state) as well as the propensity to be anxious (trait)

PTSD Checklist (PCL)

Self-report

Asks questions about symptoms of post-traumatic stress disorder (PTSD) as defined in DSM–IV; includes military (PCL-M), civilian (PCL-C), and event-specific (PCL-S) versions

Yale–Brown Obsessive-Compulsive Scale

Semi-structured clinical interview or self-report

Assesses the types and severities of obsessions and compulsions; the clinician-administered and self-report versions yield comparable data

Pathological Laughing and Crying Scale (PLACS)

Structured clinical interview

Identifies the characteristics of pathological laughing and crying (PLC); affords a more thorough evaluation than the CNS-LS

Center for Neurologic Study-Lability Scale (CNS-LS)

Self-report

Asks a brief set of questions about symptoms of PLC

Agitated Behavior Scale

Clinical observation

Provides anchored ratings for agitation, including disinhibition, aggression, and affective lability

Overt Aggression Scale

Clinical observation

Provides anchored ratings for verbal aggression, aggressive behaviors towards objects or other people, and self-directed aggression

Apathy Evaluation Scale

Semi-structured clinical interview and observation, or informant interview, or self-report

Three versions of this scale are available, the choice of which depends on a patient’s ability to accurately self-report and/or the availability of a knowledgeable informant; each assesses cognitive, emotional, behavioral, and other manifestations of disorders of diminished motivation

Awareness Questionnaire

Semi-structured clinical interview and observation, or informant interview, and self-report

Assesses self-awareness of deficits through comparisons of clinician ratings, informant ratings, and patient self-ratings of cognitive, behavioral, motor, and functional abilities

MacArthur Competence Assessment Tool for Treatment


Provides a systematic assessment of a patient’s capacity to make treatment decisions independently; related measures derived from this tool assess capacity to consent to research and competence to stand trial (adjudicative competency)

Personal and Social Performance Scale


Assesses multiple aspects of self-care (including grooming and hygiene), comportment, and interpersonal conduct

351


Table 23.4. Versions of the Neuropsychiatric Inventory (NPI) used to obtain informant-based assessment of non-cognitive neuropsychiatric disturbances among persons with neurological disorders. Ten- and 12-item forms of each version of the NPI are available. Items assessed include hallucinations, delusions, agitation/aggression, dysphoria/depression, anxiety, irritability, disinhibition, euphoria, apathy, aberrant motor behavior (mannerisms, stereotypies, perseverative behaviors), sleep and nighttime behaviors (12-item form only), and appetite and eating behaviors (12-item form only). The NPI-Q is most useful after first interviewing and educating caregivers with one of the interview-based versions of this instrument.

Measure

Method

Timescale

Output

Neuropsychiatric Inventory (NPI)

Structured clinical interview of informant

Prior 4 weeks

Frequency, severity, neuropsychiatric domain-specific (frequency × severity) and total (sum of domain) scores Caregiver distress score

Neuropsychiatric Inventory – Questionnaire (NPI-Q)

Self-report of observations made by informant

Prior 4 weeks

Severity of specific and total neuropsychiatric disturbances Caregiver distress score

Neuropsychiatric Inventory – Clinician (NPI-C)

Structured clinical interview of informant and structured clinical interview and observations of patient

Prior 4 weeks

Frequency, severity, neuropsychiatric domain-specific (frequency × severity) and total (sum of domain) scores Caregiver distress score Neuropsychiatric domain-specific and total (sum of domain) frequency score based on patient interview Neuropsychiatric domain-specific and total (sum of domain) severity score based on clinician impression from all available data

Neuropsychiatric Inventory – Nursing Home Version (NPI-NH)

Structured clinical interview of informant

Prior week

Frequency, severity, neuropsychiatric domain-specific (frequency × severity) and total (sum of domain) scores Occupational disruption on informant score

Heightened states of arousal are most often described as hyperarousal or hypervigilance (although the latter is more strictly a manifestation of the former). Diminished arousal is often described using terms such as somnolent, lethargic, obtunded, stuporous, semi-comatose, and comatose. Although there may be distinct referents for each of these terms, there is considerable overlap in how they are used clinically [107]. The use of any qualitative term to describe impaired arousal is best accompanied by a brief description of: (1) the type and intensity of stimulus necessary to arouse the patient; (2) the patient’s behavioral response to that stimulus; and (3) the duration of that response. For example, a patient might be described in this manner as “somnolent: appeared nearly asleep initially, but aroused easily to verbal stimulation, remained alert during the exam, and quickly fell asleep upon its conclusion” or “stuporous: eyes closed and restless initially, required vigorous physical stimulation to arouse, opened eyes for a few seconds, and then resumed his initial appearance.” Descriptions of appearance made during the mental status examination include the patient’s

352

apparent age (i.e., consistent with chronological age or appearing much older or younger), body habitus (size and shape), and other noteworthy physical characteristics (e.g., craniotomy scars, dysmorphic features, missing body parts, tattoos, piercings). The patient’s body position during the examination (e.g., standing, seated, lying down) and posture (including unusual posturing) are described as well. Attire, grooming, and hygiene are observed and are important to document in general and especially when they inform on a patient’s ability, or willingness, to attend to self-care and conform to social norms (or reflect conformity to culture- or subculture-specific norms). In particular, disheveled and/or dirty clothing, unilateral hemispatial inattention, highly unusual styles of dress (e.g., multiple clothing layers, aluminum foil skull cap, outlandish or costume-like garb, subculture-specific clothing), marked deficits or asymmetries in personal hygiene, or, conversely, rigidly meticulous attention to appearance may provide potentially useful information about a patient’s mental state. Motor behaviors (Boxes 23.3 and 23.4), including excesses and/or deficits in voluntary motor function as well as involuntary movements, are observed


Box 23.3. Examples of voluntary and involuntary motor disturbances.

Box 23.4. Examples of voluntary and involuntary complex motor acts.

Difficulty initiating movement Bradykinesia Akinesia Paresis Focal or multi-focal Hemibody Paraparesis Quadriparesis Contracture Cataplexy Restlessness Fidgeting Akathisia

Gestures Exaggerated Childish or playful Flirtatious Bizarre Obscene Mannerisms Habits Rituals Stereotypies Automatisms

Simple or complex tics Vocal Motor Dyskinesia Dystonia Catalepsy Rigidity Tremor Chorea Athetosis Ballismus Myoclonus Exaggerated startle response

throughout the clinical encounter. These include gestures and movements made, or the lack of such, as the patient communicates (discussed further in the Communication section of this chapter). The extent to which a patient without obvious motor impairments does or does not volitionally move during the examination may provide information about the patient’s emotional and/or motivational states as well as his ability and willingness to engage with the examiner. When deficits in voluntary motor function and/or involuntary movements are observed, their types, locations, and severities help establish the neuroanatomy of the disorder and its cognitive, emotional, and behavioral accompaniments. For example, a flat expression, slightly stooped posture, and little spontaneous movement save a 3–5 Hz resting tremor of the face and hands suggests parkinsonism, and hence the need to emphasize assessment of cognitive, emotional, and behavioral manifestations of frontal-subcortical circuit dysfunction during the mental status examination. Observing motor disturbances during the interview and mental status examination also guides and focuses the neurological examination. Eye contact is an important element of non-verbal communication [108] that merits attention during the mental status examination. The manner and extent to which an individual makes eye contact with others provides important information about his emotional state, interpersonal intentions, and, in some cases, social comfort or competence [108, 109]. Eye contact also tends to evoke automatic reactions and changes in interpersonal behavior from others, including

Perseverative behaviors Compulsions Disinhibition Verbal Non-aggressive physical Sexual Aggression Externally directed Self-directed

examiners [110]. It is important to be aware that the customs and meaning of eye contact differ between cultures [111]. In many Western cultures, for example, a premium is placed on direct eye contact at the beginning of and frequently during conversation. In other cultures, lowering gaze or minimizing eye contact is a sign of respect. The patient’s background and culture require consideration before interpreting eye contact and related eye movements. Comportment refers to the manner in which the patient conducts himself, and in this context includes demeanor, propriety, attitude, and interpersonal interactions with the examiner. Demeanor describes the way in which a person behaves toward other people, and propriety refers more specifically to adherence to conventional expectations regarding social conduct. Attitude describes the dispositions, opinions, feelings, and beliefs that underlie these behaviors. In the context of the mental status examination, demeanor (including the capacity to adhere to social norms) and attitude strongly influence the manner in which the patient interacts with the examiner. A patient may appear uncooperative (demeanor) during the encounter, but may be so out of suspicion, resentment, or hostility (attitudes) towards the examiner or the fact that he is being evaluated. Conversely, a patient may be overly cooperative and solicitous (demeanor) due to disinhibition, a pathological need to please the examiner, or fear of reprisal based on prior experiences with authority figures (attitudes). Comportment or its loss thus carry important diagnostic implications (see also Chapter 17) and inform on the quality and reliability of the information obtained from the clinical encounter.

353


Motivation, which refers in this context to the extent to which the patient has goal-directed thoughts, feelings, and behaviors, contributes to comportment and influences the patient’s conduct throughout the entire clinical encounter. Disorders of diminished motivation (i.e., apathy and related conditions) produce and exaggerate deficits in cognition, emotion, and behavior identified elsewhere in the examination. These problems require identification as such in order to interpret the patient’s presentation accurately – that is, to ascribe these impairments to a loss of the capacity for motivated behaviors rather than volitional avoidance, passivity, or passive aggressive behavior. It is useful to synthesize into a summary statement (to oneself and for the record) observations about the patient’s capacity to engage effectively with the examiner. In many respects, observations made over the course of the clinical encounter bear upon the examiner’s conclusions about a patient’s comportment and motivation. Although Table 23.1 places these elements of the mental status examination in the section on Appearance and Behavior, placement there belies the importance of completing the entire clinical encounter before drawing conclusions or documenting comments about comportment, motivation, and the quality and consistency of the patient’s engagement with the examiner.

Emotion and emotional feeling Despite the conflated meanings and synonymous use of the terms “emotion” and “feeling” in common parlance, their psychophysiologic referents are distinct. Emotion (from Latin ex “out” + movere “move”) describes a neural impulse that moves an organism to action, prompting automatic reactive behaviors adapted through evolution and experience as mechanisms to meet survival needs [103, 112–115]. Damasio [103, 112] describes emotion more specifically as a coordinated constellation of brain–body interactions, comprising facial expressions, vocalizations, gestures, body posture, behaviors, autonomic activity, visceral activity, neurohormonal, and neurotransmitter processes that occur automatically as reactions to specific types of external or internal, including imagined, stimuli. Feeling (from Old English felan “to touch, perceive”) describes a broad class of subjective psychological phenomena (qualia) of which emotional feelings are a subset [103, 112–115].

354

For example, sadness, happiness, anger, fear, surprise, and disgust are emotional feelings. By contrast, “hot,” “tired,” and “pain” are feelings but they are not emotional feelings. Although individuals may develop emotional feelings in response to nonemotional feelings (e.g., “I get irritable when I am very tired”), there is neither a strict nor logically necessary relationship between emotional feelings and other qualia. Emotional feelings represent the juxtaposition of conscious awareness of automatic reactive brain– body interactions (i.e., literally ex-movere processes) with the mental images with which they are (or subsequently become) associated. These associations are labeled using descriptors specific to this class of subjective experiences (happy, sad, angry) [103, 112]. Emotions are necessary for the development of emotional feelings [103], but emotions can (and often do) occur outside of conscious awareness – that is, in the absence of a corresponding emotional feeling. The assessment of emotions and emotional feelings is organized around two temporally defined categories, mood and affect. Since the reclassification of depression, dysthymia, bipolar disorder, and cyclothymia as mood (rather than affective) disorders in DSM–III–R [16], this diagnostic system has defined mood as pervasive and sustained emotions and feelings (the “emotional climate”). Affect refers to emotions and feelings that are variable and fluctuate from moment-tomoment (the “emotional weather”) [6, 14–16, 41, 116]. Given the temporal distinction between mood and affect, both are understood as entailing subjective (experienced) and objective (expressed) components, yielding the heuristic for understanding and assessing mood and affect presented in Table 23.5. Consistent with the meteorological analogy for mood and affect, the emotional weather of the moment occurs in the context of, and may be constrained or amplified by, the emotional climate. Characterizing a patient’s mood requires the clinician to answer two key questions: (1) How does the patient feel most of the time? (2) How does the patient appear to feel most of the time? Affect is characterized by the answers to several questions: (1) How does the patient feel presently? (2) How does the patient appear to feel presently? (3) What variability, if any, is there in how the patient feels or appears to feel from moment-to-moment? The answers to these questions provide information that allows


Table 23.5. A heuristic for the evaluation of mood and affect. Mood refers to pervasive and slowly changing emotions and emotional feelings (the “emotional climate”). Affect refers to relatively brief emotions and emotional feelings (the “emotional weather”). The expressed (literally ex-movere, or emotion) elements of the both “climate” and the “weather” are assessed by interview and/or observation. Assessment of emotional feelings depends on patient self-report.

Emotion (expression)

Emotional feeling (experience)

Mood

Facial expressions, vocalizations, gestures, body posture, behaviors, autonomic activity, visceral activity, neurohormonal, and neurochemical processes that are present most of the day, nearly every day, over a period of days to weeks

Emotion-related sensorimotor phenomena and associated cognitions that are present most of the day, nearly every day, over a period of days to weeks

Affect

Transient facial expressions, vocalizations, gestures, body posture, behaviors, autonomic activity, visceral activity, neurohormonal, and neurochemical processes superimposed on background mood

Transient emotion-related sensorimotor phenomena and associated cognitions

clinicians to discriminate more accurately between mood disorders (e.g., depression, dysthymia, mania, cyclothymia) and disorders of affect (e.g., pathological crying, laughing, or both) and to direct treatments accordingly. In general, it is useful to begin the discussion of emotions and emotional feelings with questions about affect. Begin by asking the patient to describe how he feels presently. If the answers to this question are minimally informative (“fine,” “pretty good”), or if they describe physical feelings (e.g., “tired,” “in pain,” “restless”) or beliefs (i.e., “alone,” “like a failure”), provide the patient with a definition of emotional feelings, ensure that the patient understands that definition, and re-ask the patient to describe his present emotional feelings (e.g., sad, happy, irritable, angry, anxious, fearful, surprised, disgusted). Repeat, paraphrase, and/or reflect the patient’s response to him in order to ensure that it has been understood correctly. Concurrently, observe the patient’s emotion in the moments during which these questions are asked, including his facial expressions, vocalizations, gestures, body posture, and related behaviors. It sometimes is useful to ask the patient to describe (or for the clinician to measure) his heart rate, respiratory rate, and other physical sensations, especially among patients who appear anxious or angry. Discrepancies between the patient’s stated feelings and apparent emotion merit exploration; however, the patient’s ability to engage in and/or tolerate that exploration will influence its timing and depth. Questions then focus on characterizing mood. Ask the patient to describe how he feels “most of the day, nearly every day” or “most of the day, on more days than not” over a period of at least one week preceding the clinical encounter. For example, the examiner

might ask: “You’ve told me how you are feeling now; how have you felt most of the time over the last week?” Responses that describe emotional feelings are solicited and repeated, paraphrased, and/or reflected back to the patient: “So, you have been feeling [sad, anxious, irritable, euphoric, etc.] most of the day, nearly every day for the last week?” A patient whose responses pertain to transient feelings rather than sustained and pervasive ones often will reject such restatements. In such circumstances, clarifying the intended referent of the question – how he feels most of the time – and restating it often improves the patient’s ability to characterize clearly his emotional climate. Then ask the patient his own and others’ observations of his emotional appearance. Responses to this question are explored in the same manner used to clarify the patient’s statements about feelings, with the emphasis placed on the way the patient appears emotionally most of the time. An empathic and observant interviewer also is able, in most cases, to discern the emotional background (mood) that the patient brings to the interview. Developing the ability to attend to the emotional climate is an important and useful clinical skill in general, and is especially important to deploy in the evaluation of patients whose capacity for accurate self-report is compromised by neurological or neuropsychiatric conditions. For example, a patient who appears consistently doleful, with a minimally reactive facial expression, downcast eyes, head held in partial flexion and body in kyphotic posture, frequently sighs, and is mildly bradyphrenic and bradykinetic throughout the clinical encounter and whose persistent tendency, without encouragement to do otherwise, is to speak in a soft and monotonic voice would appropriately be suspected of suffering from depression [117,

355


118] – even if that patient does not report or actively denies the feelings of sadness typically associated with that condition [117]. Similarly, a patient who appears euthymic or emotionally neutral most of the time but has occasional paroxysms of uncontrollable crying, including lacrimation, sad facial expression, and corresponding respiratory, postural, head, limb, and body movements, regardless of the intensity or valence of feelings during those paroxysms, would not be suspected of suffering from a depressive disorder but instead a disorder of affect (e.g., pathological crying). Among patients capable of engaging in a discussion about the observed emotional climate, the examiner communicates these observations and asks how well they correspond to the way he or she feels “most of the time.” This discussion is especially important when the examiner’s observations about the emotional climate are discordant with the patient’s reported experience. In such circumstances, a structured assessment of mood (see Tables 23.2 and 23.3 for examples) may help resolve such discrepancies. An interview lasting more than a few moments also provides opportunities to observe transient (i.e., moment-to-moment) changes in emotion and feeling, even among patients with mood disorders. When the examiner observes a change in the emotional weather, it is useful to pause the interview, comment on that observation, and ask the patient to describe his feeling at that moment. For example, observing a slight smile in a patient who otherwise appears depressed prompts the examiner to ask: “You mentioned that you’ve been feeling sad most of the time during the last several weeks. Just now, you smiled a bit and appeared more relaxed for a moment – did you notice that? How did that feel?” When patients are able to recognize momentary changes in emotion and feeling (affect), discussing those changes presents an opportunity to help the patient learn to distinguish mood from affect. It also yields information that clarifies the differential diagnosis and may direct treatment. For example, patients able to experience moments of happiness in the midst of a major depressive episode may benefit from cognitive–behavioral psychotherapies that help the patient recognize their occurrence and precipitants and gradually develop control over their intensity and duration. Occasionally, patients cannot be engaged effectively in a discussion of mood and affect. This occurs most often among those with severe cognitive, communication, or behavioral impairments that preclude

356

reliable self-report. Individuals with alexithymia (from Greek, “without words for feelings”), a personality trait, also are unable to identify feelings accurately, distinguishing emotional feelings from other bodily sensations, and/or describing their feelings to others [119–121]. Combined direct patient observation and interview of reliable informants, augmented with structured assessments (Tables 23.2–23.4), is often needed to assess mood and affect accurately in these types of patients.

Communication Communication refers to the conveyance of meaningful information between individuals by verbal and/or non-verbal means. Speaking and writing are critically important methods of communication, and their assessment during the mental status examination is essential. At the same time, it is important for clinicians to remain mindful that body language and tone of voice communicate as much or more information than words during any given exchange [58, 122, 123]. The communicative aspects (and timing) of a patient’s position and posture, gestures, eye contact and gaze, demeanor and facial expression, attitude, interpersonal distance, and touch (e.g., handshake, hug) offer important information about his mental state. Non-verbal communication also includes paralinguistic cues such as voice quality and prosody (rhythm, intonation, affective import, and stress) as well as the style, spacing, and non-alphanumeric symbols used when writing. The non-verbal behaviors used by a patient to communicate with the examiner and others therefore are essential to observe and document in the mental status examination. Many of these are documented most appropriately in the sections of the mental status examination to which they closely pertain (e.g., Appearance and Behavior, Emotion and Feeling, Thought Process). Comments on voice and speech, as well as initial observations of language, prosody and kinesics, are documented specifically in this section of the examination. Voice is a product of the laryngeal function of phonation, i.e., the production of sounds by the vocal folds through quasi-periodic vibration [124]. The ability to produce vocal sounds may be compromised by disease or injury to the larynx, its innervation, the vocal folds, and/or the respiratory mechanisms needed to produce air movements of sufficient force


to generate vocal sounds. Such disturbances may diminish vocal volume, produce hoarseness, or eliminate entirely the capacity for voicing. Cerebral disturbances, including diminished function of the frontalsubcortical systems required to sustain automatic, effortless vocal activation, also may produce hypophonia [125]. Observations about the volume and quality of the patient’s voice are made and documented; when reasons for voice impairments are obvious (e.g., intubation, open tracheostomy stoma, laryngectomy), these are appropriately noted in this section of the mental status examination as well. Speech refers specifically to the use of tongue, lips, jaw, and other oropharyngeal muscles to articulate words. It is distinct from language, which is the use of symbols (including spoken words, among others) to communicate, as well as from voice. Disturbances of speech observed commonly among persons with neurological disorders include dysarthria (from Greek dys “mis-, accidental” + arthrosis “articulation”) and speech apraxia. The former refers to a speech disorder resulting from a weakness, paralysis, or incoordination of the musculature required for speech whereas the latter reflects impairment of the cerebral motor programming systems required to produce speech despite preservation of the non-speech motor outputs to and intrinsic function of the articulatory musculature [126]. Stuttering is also sometimes observed among persons with acquired neurological conditions or as a congenital condition. Although commonly discussed as disturbance of speech, it is a complex centrally mediated disturbance of both speech and voice [127]. Observations of any type of speech disturbance are recorded in this section of the mental status examination. If present, sensorimotor function of the cranial nerves involved in speech production is then examined (see Chapter 21). This includes assessment of movements of the lips, mouth, tongue, palate, and other orofacial musculature. If any of these are impaired, then dysarthria may be the sole, or a substantial, contributor to speech impairment. If there is no weakness or sensory impairment to explain impaired speech production, then the patient’s ability to produce several sets of phonemes is assessed using verbal movements (“puh-puh-puh,” “tih-tih-tih,” “kuh-kuh-kuh,” “puh-tih-kuh, puh-tih-kuh, puh-tih-kuh”) and nonverbal mouth movements. Impairments of phoneme (or full word) articulation and non-verbal mouth movements despite normal elementary sensorimotor

function suggest oral apraxia. Selective impairment of the production of phonemes and/or words suggests speech apraxia. Language is a systematic means of communicating that uses conventionalized symbols (i.e., signs, sounds, gestures, or marks) with specific meanings to convey information. Speaking and writing are the most common forms of linguistic communication; however, among patients with congenital or acquired impairments in voice, speech, hearing, writing, and/or reading, linguistic communication may be accomplished through the use of signing, Braille, or other (sometimes idiosyncratic) methods. Bearing in mind that language refers to symbolic communication by any means and not simply to verbal (or written) communication reduces the likelihood of mistaking disturbances of speech and/or written language for disturbances of language (i.e., aphasias). In most patients, however, the mental status examination involves observing spoken and written language. Word-finding difficulties during conversational speech may reflect retrieval deficits (i.e., impaired executive control of language), difficulties with language fluency, or anomia (inability to name). Observing word-finding difficulties, reduced phrase length, agrammatisms, paraphasic errors (i.e., phoneme or word substitutions), difficulty understanding the examiner questions or instructions, and difficulty reading and/or writing indicates a need for specific examination of language (see Cognitive section of this chapter). Suspicions for such problems should be especially high among persons with left hemisphere injuries and other disorders affecting perisylvian language areas, subcortical structures, or white matter within language areas or their connections to other parts of the brain. Prosody and kinesics are paralinguistic functions that are used to augment or modify linguistic communication (see Chapter 13). Prosodic communication is used to convey linguistic, affective (attitudinal and emotional), dialectical, and idiosyncratic information through modification of the pitch, intonation (variation of pitch over time), melody, cadence, loudness, timbre (voice quality), stress, and pauses used during verbal communication. Kinesics refers to facial, limb, and body movements associated with language communication. Observations are made of the effective use of prosody and kinesics by the patient, and his ability to understand the prosodic and kinesic components of the examiner’s language also are assessed. Among

357


patients with right hemisphere injuries or other disorders affecting the right hemisphere homologs of left hemispheric language areas, suspicion for disturbances of prosody and kinesics should be high. As with language, observed impairments in these paralinguistic functions necessitate further examination of prosody and kinesics (see Cognitive section of this chapter).

Thought process In most Western cultures, a premium is placed on “analytic” thought involving formal logic, emphasis on object of thought over context, and the avoidance of contradiction [128–130]. Thought is expected to be logical and goal-directed, with exchanges between patient and examiner focused directly on the object or topic of conversation. Abnormalities of thought process are characterized by departures from this form (Figure 23.1) as well as markedly unusual styles of thought (Table 23.6). The assessment of thought process is performed throughout the clinical encounter. Responses to openended questions that prompt the examiner to use very direct and concrete questions may signal problems with the organization and/or style of a patient’s thoughts (i.e., higher perceived need by the examiner to structure the encounter suggests a more severe disorganization of the patient’s thoughts). Patients able to reflect on and describe the structure and style of their thinking should be asked to do so. Among patients unwilling or unable to engage effectively with the examiner, observing spontaneous communications, affects, and behaviors may provide insight into their mental state, especially when patients are unaware of being observed (e.g., from the hallway outside a hospital room, in the waiting room of a clinic, on a video monitoring of a seclusion room). In all cases, inferences about a patient’s thought process derive from observations about the organization and style of his communication, affective responses, and behaviors, including his ability to pursue and attain contextually relevant cognitive, emotional, or behavioral goals. Some non-Western cultures organize thought in manners quite different from those stemming from an “analytic” tradition [128–130]. Thought may be less discretely object- or topic-focused and instead may emphasize context, relationships, and experiencebased knowledge. “Holistic” thinking of this type also fosters a higher tolerance of contradiction (as

358

Figure 23.1. A diagram illustrating thought processes demonstrated commonly by patients presenting for neuropsychiatric evaluation. Each white circle represents a specific thought; these are contained within the gray circle, which represents all of a patient’s actual or possible thoughts. The arrows depict thought processes that are identified through observing a patient’s spoken and/or written output. A: logical and goal-directed thoughts, coherent associations; B: circumferential thought, characterized by addressing a topic via a circuitous or indirect route; C: tangential thought, characterized by shifting to a logically related but distinct topic and failing thereafter to return to the original topic; D: circumstantial thought, which, like circumstantial evidence, indirectly addresses a topic by speaking on a closely related one from which the observer may be able to draw inferences about the intended target of thought or conversation; E: incoherent thought, which reflects a lack of organization and logical association between ideas, often manifested by speech that consists of real and/or imaginary words lacking meaning (i.e., word salad) – from the listener’s perspective, it is as if the patient is speaking about many ideas simultaneously; F: loose association, in which the logical connection between thoughts (or the patient’s response to the examiner) is not apparent; G: thought blocking, in which a thought is interrupted suddenly, often manifested by speech that stops in mid-sentence and may be so severe that return to the interrupted idea is precluded.

viewed from a Western perspective) and tends to deemphasize the need for and value of formal logic. This style and organization of thought may be difficult for some Western observers to understand, and may lead to mistakenly identifying culturally normal styles and organizations of thought as psychopathological. It therefore is important to consider the influence of culture on the patient’s thought process as well as the cultural values and biases brought to the encounter by the examiner to the task of examining thought process.

Thought content Perceptions, ideas and concerns, themes, and other cognitive experiences comprise thought content. Where thought process describes “how” a patient thinks, thought content describes “what” he thinks about. As with the rest of the mental status


Table 23.6. Examples of commonly observed thought process disturbances.

Abnormality

Description

Flight of ideas

A sequence of tangential thoughts and/or loose associations that at its most extreme may result in incoherent thought and/or speech; often co-occurs with racing or pressured thoughts

Racing thoughts

Increase in the speed of thought that is often, but not always, apparent in speech and/or behavior

Pressure

A driven quality to thought or speech that often is difficult to interrupt

Clanging

Associations based on rhyming or alliteration rather than logical relationships

Derailment

A sequence of unrelated or only remotely related ideas; conceptually similar to tangentiality and loose associations

Perseveration

Persistence and/or repetition of a thought when it is no longer useful or relevant; sometimes used to describe the persistent repetition of word elements, words, or ideas (which may be more accurately described by palilalia or logoclonia)

Rumination

Repetitively focusing on symptoms of distress, their possible causes, and their feared consequences

Obsession

Preoccupation with a persistent, idea, image, desire, or concern; also used to describe a specific idea, image, desire, or concern (i.e., thought content)

Illogicality

Conclusions are reached based on non sequiturs and/or faulty inferences

Bradyphrenia

Slowness of thought

Poverty of thought

Severely diminished thought process and content

examination, thought content is evaluated using the information provided spontaneously by the patient, especially during unstructured moments of the clinical encounter, as well as responses to open-ended and direct questions about perceptual experiences, ideas, or concerns. In general, beginning the interview portion of the encounter with a non-specific open-ended inquiry and allowing the patient several minutes to respond without interruption may reveal the ideas, concerns, and themes that are most important to the patient. For example, after introducing oneself, an appropriate opening question can be as simple as “How are you?”, “Tell me about yourself ”, “What’s on your mind?”, “What can I do for you today?” The last question, in which the patient is asked about his goals for the clinical encounter, is important to ask relatively early in the encounter and improves the likelihood of identifying issues of greatest concern to the patient [131]. It is important not to adopt a highly structured and directive style or to interrupt the patient’s spontaneous response unless it is clear that the interview will not otherwise proceed usefully. Premature and/or inappropriate use of these styles risks frustrating patients’ communication attempts and missing clinically important information [2, 131–133]. However, when these questions are met with confusion or begin causing a patient to become disorganized, the examiner may need to adopt a more structured

interview style and to more quickly direct the conversation to subjects relevant to the problem (or suspected problem) for which the patient is being evaluated. The Brief Psychiatric Rating Scale [60], Neurobehavioral Rating Scale–Revised [67, 134], and the Positive and Negative Syndrome Scale [17] are particularly useful measures with which to assess thought content among such patients. The patient’s responses guide the examiner’s follow-up questions, including requests for clarification and elaboration. Although these responses and the specific circumstances under which a patient presents for evaluation may direct attention to specific elements of thought content, general screening questions for unusual or abnormal thought content also are included in the mental status examination. Such questions are directed at the identification of perceptual disturbances (Table 23.7), delusions (Tables 23.8 and 23.9), preoccupations, obsessions (Table 23.10), specific phobias (Table 23.11), and dangerousness to self (i.e., suicidal ideation) or others (homicidal ideation). Affirmative responses to questions about these types of disturbances of thought content are often useful to explore more fully using the symptomspecific assessment instruments described in Tables 23.2 and 23.3. It is neither clinically feasible nor appropriate to screen all patients for disturbances in all of these areas of thought content. However, developing the skills

359


Table 23.7. Disturbances of perception and experience. Some of these phenomena are reported by healthy individuals; their occurrence is not necessarily pathological, especially if they occur infrequently, are not associated with other disturbances of cognition, emotion, and/or behavior, and do not compromise personal, social, or occupational function.

Phenomenon

Description

Illusion

Misperception of a sensory stimulus; described according to the sensory domain in which it occurs (i.e., visual, auditory, tactile, olfactory, gustatory, nociceptive, thermoceptive, proprioceptive, equilibrioceptive)

Hallucination

Sensory perception in the absence of a stimulus; described according to the sensory domain in which it occurs (i.e., visual, auditory, tactile, olfactory, gustatory, nociceptive, thermoceptive, proprioceptive, equilibrioceptive); may be formed (i.e., persons, objects, voices making comments or commands) or unformed (non-specific sensory perceptions within a sensory domain)

Palinopsia

Persistent perception of a visual stimulus after that stimulus is no longer present (i.e., an afterimage)

Synesthesia

Perception of a stimulus outside the sensory modality in which that stimulus is presented (i.e., hearing colors, tasting sounds) or that adds perceptual features not normally perceived within a sensory modality (e.g., black numbers or letters evoking the perception of color)

Cortical sensory loss

Impaired perception due to injury or degeneration of primary sensory cortex

Apperceptive agnosia

Impaired recognition of a stimulus in a single sensory domain resulting from failure to integrate individual elements of that stimulus into a simultaneously perceived group; distinguished from associative agnosia in which the individual elements are perceived and integrated but are not recognized as a result of impaired association of that integrated perception with previously learned percepts of identical or like kind

Dissociation

Segregation of a group of mental processes from the usually integrated functions of perception, memory, awareness, and/or sensory and motor behaviors

Derealization

Experiencing the external world as unreal

Depersonalization

Experiencing oneself as detached from (as if an outside observer of) one’s mental processes or body

Autoscopy

Seeing one’s body from a position outside the body (out-of-body experience); an extreme form of depersonalization

Déjà vu

Experiencing a novel image or scene as one previously witnessed or experienced, even when the exact circumstance of the previous experience is uncertain or imagined

Déjà entendu

Experiencing a novel sound as one previously witnessed or experienced, even when the exact circumstance of the previous experience is uncertain or imagined

Jamais vu

Experiencing a familiar image or scene as unfamiliar

Jamais entendu

Experiencing a familiar sound as unfamiliar

needed to ask about unusual or abnormal thoughts in a tactful and productive manner is essential. Administering structured clinical assessments into BN&NP training affords trainees and their teachers with opportunities to evaluate through clinical application the various methods by which thought content may be assessed. Questions taken verbatim or adapted from formal assessments of thought content then may be integrated easily into everyday clinical practice and the formal assessments themselves, when needed, can be deployed with skill and relative ease. Routinely asking about lethal thought content (i.e., dangerousness to self and others) is recommended. Questions about suicidal ideation begin with assessment of the presence of such thoughts (e.g., “Have you thought that life is not worth living?” “Have you had thoughts about wanting to die or wishing you were

360

dead?”). If present, then the frequency and quality of these thoughts require clarification. The latter occur along a continuum from passive thoughts of death to the active desire to end one’s life. If active suicidal thoughts are reported, then the patient’s intent to act on those thoughts and specific plans for doing so should be identified. The realism of those plans (i.e., could the act described be carried out by the patient), the patient’s ability to carry out such plans (e.g., access to weapons, physical abilities/limitations, environment), and the intensity/quality of supervision as it alters the risk for and/or likelihood of attempting to act on those plans are all assessed. Inquiries also are made about past suicide attempts, the means by which they were attempted, and the consequences of those attempts. Current and past homicidal and/or other-directed violent thoughts, plans, and acts are

Table 23.8. Examples of delusions observed among persons with neuropsychiatric disorders. Delusions are fixed false beliefs. They are false in that they reflect incorrect conclusions about reality (external to and/or about oneself) and fixed in that they are maintained despite the presentation of evidence contradicting them. Ordinary delusions derive from misinterpretation of real phenomena. Bizarre delusions involve phenomena that are physically impossible or that most people in that person’s culture would regard as entirely implausible. Beliefs pertaining to culturally specific or religious ideas are delusional only when they are not ordinarily accepted by other members of the person’s culture or subculture. When the belief involves a value judgment, it is delusional only when the judgment made defies credibility. Delusions are contrasted with overvalued ideas, which are unreasonable but unfixed beliefs that occur in persons with otherwise normal cognitive abilities. Delusion also is distinguished from confabulation, which refers to the automatic and non-deceitful fabrication of information, usually of an autobiographical nature, by a patient with declarative memory impairments and deficits in error detection (i.e., executive dysfunction); the fabricated information may be firmly believed in the moment that it is offered but is usually soon forgotten and, in that sense, is a false but not a fixed belief.

Delusion

Description

Persecutory

Fixed false belief that one is being harmed or that such harm is impending and that the perpetrators of that harm are causing it intentionally; common examples include the belief that one is being followed, tricked, spied on, poisoned or drugged, tormented, ridiculed, cheated, conspired against, or that one’s goals are being obstructed

Grandiose

Insightless and unshakable conviction that one possesses special powers, talents, knowledge, and/or abilities, is famous (or a famous person or character) or holds a special relationship to a famous person or deity

Religious

Any delusion with religious content, especially beliefs that one is God, an angel or devil, the son or daughter of God, a saint, or otherwise deific (subtypes of grandiose delusions)

Referential

Fixed false belief that remarks, objects, events, or other phenomena are directed at or are about oneself

Thought control

Fixed false belief that one’s thoughts, feelings, or behaviors are being controlled by an external force, person, or group

Thought insertion

Delusion that thoughts are being inserted into one’s mind (“thoughts are not my own”)

Thought withdrawal

Delusion that an outside force, person, or group is removing or extracting one’s thoughts

Thought broadcasting

Delusion that one’s thoughts are being broadcast to others and/or can be heard aloud by others

Mind being read

Delusion that one’s mind can be or is being read by another person or group; does not entail “broadcasting” one’s thoughts or that one’s thoughts can be heard aloud by others, and may be a subtype of persecutory (paranoid) delusions

Jealousy

Fixed false belief that a spouse or lover is unfaithful; also referred to as delusion of infidelity

Erotomania

Delusion that one is loved by another person (usually one of higher status)

Theft

Fixed false belief that one’s valuables are being stolen, often by an unseen thief; tends to develop in the context of declarative memory impairments (e.g., Alzheimer’s disease)

Phantom intruder

Delusion that a stranger, usually unwanted, is in one’s home

Somatic

A delusion that pertains to the appearance (including smell) or functioning of one’s body, usually involving the fixed false belief that one’s body is abnormal, diseased, or changed in some manner

Parasitosis

Fixed false belief that one is infested with insects, bacteria, mites, lice, fleas, spiders, worms, or other organisms

Nihilistic

Delusion that one does not exist or is dead; also described as delusion of negation

Table 23.9. Examples of delusional misidentification and other delusions involving a belief that the identity of a person, object, or place has been changed or replaced.

Delusion

Description

Capgras

Fixed false belief that an identical-looking impostor has replaced a close relative or spouse

Clonal pluralization of the self

Delusion that there are multiple, physically and psychologically identical, copies of oneself

Delusional companions

Fixed false belief that non-living objects (e.g., toys, appliances, cars) are sentient beings

Fregoli

Fixed false belief that different individuals are one person in disguise

Intermetamorphosis

Fixed false belief people in the environment swap identities while maintaining their original appearance

Mirrored self-misidentification

Delusion that one’s reflection in a mirror is someone else

Reduplicative paramnesia

Delusion that a familiar person, place, or object has been duplicated

Subjective doubles

Delusion that there is a double of oneself (doppelgänger) carrying out independent actions; also known as the subjective Capgras delusion

Cotard

Fixed false belief that one or more of one’s organs or body parts are missing or no longer exist


Table 23.10. Categories of obsessions (anxiety-provoking and/or subjectively distressing ideas, thoughts, impulses, or images that are persistent and experienced as intrusive and inappropriate) experienced by persons with neuropsychiatric disorders, including obsessive-compulsive disorder.

Obsession

Description

Aggressive

Recurrent ideas of harming oneself or others Recurrent violent or horrific images Excessive concerns about blurting out obscenities or insults or of doing something embarrassing, about acting on unwanted impulses (e.g., stealing, fire setting), or about harming others as a result of carelessness (e.g., hit-and-run car accident)

Contamination

Excessive concerns about or disgust with bodily waste or secretions, environmental contaminants (e.g., dirt, germs), household items, animals, sticky substances, or residues Excessive concern about being made ill by a contaminant or contaminating others

Sexual

Recurrent sexual thoughts, images, or impulses that are regarded as forbidden or perverse

Hoarding

Excessive concerns about losing items or not having an item that may be needed in the future Exaggerated beliefs, preoccupation with, and attachment to specific kinds or types of objects

Religious

Excessive concern about right and wrong, moral correctness, sacrilege, blasphemy, and the proper performance of religious tasks or rituals; also referred to as scrupulosity

Symmetry or exactness

Excessive concern about the arrangement, symmetry, and/or shape of objects Fear of harm befalling self or others as a result of things not being symmetric, properly shaped, or in some form of perceived disarray (magical thinking)

Somatic

Excessive concern with illness, disease, body part, or appearance (e.g., dysmorphophobia)

Miscellaneous

Excessive concern about remembering or knowing information, saying or not saying things, or specific environmental sounds or noises Excessive preoccupation with colors of special significance, lucky or unlucky numbers, or superstitions Recurrent intrusive images (non-violent, non-sexual), nonsense sounds, words, or music Excessive concern about losing one’s personality or other special qualities

Table 23.11. Common types of phobias.

Phobia type

Fear cue

Animal

Animals or insects

Natural environment

Objects in the natural environment (e.g., storms, heights, water)

Blood-injection-injury

Seeing blood or injury, receiving an injection or other invasive procedure

Situational

Being in specific situations or locations such as public transportation, tunnels, bridges, elevators, flying, driving, or enclosed spaces

Other

Choking, vomiting, contracting an illness, “space” (i.e., being away from a wall or physical support needed to prevent falling), loud sounds, costumed characters

assessed in the same manner as suicidal thoughts. Among patients with disinhibition or other conditions that compromise impulse control, the risk for impulsive intentional and non-intentional self-harm and harm to others also requires consideration during the assessment of dangerousness. Among patients unable or unwilling to engage in a discussion of thought content, careful observation of behavior may allow inferences to be drawn about it (e.g., eye and head movements that suggest perceptions of internal stimuli; demeanor and body posture that suggests paranoid concerns about the examiner;

362

supine and motionless position in bed under the covers with arms folded across the chest and eyes closed suggesting nihilistic delusions). In such circumstances, the Brief Psychiatric Rating Scale [60] or Neurobehavioral Rating Scale–Revised [67, 134] may help the clinician organize the assessment of thought content in an uncooperative or non-communicative patient. Interview of reliable informants about the patient’s behaviors using the NPI [88, 98–100], and especially NPI–Clinician version, also may provide useful information about the apparent contents of a patient’s thoughts.


Cognition The major domains of cognition routinely assessed during the mental status examination include arousal, attention, processing speed, working memory, recognition, language and prosody, declarative memory, praxis, visuospatial function, calculation, and executive function. Other cognitive domains (e.g., nondeclarative memory) or subcategories of cognition may be tested when the history or general mental status examination suggest the need to do so or when an extended examination is called for contextually (e.g., forensic examination). Some authors recommend organizing the cognitive assessment hierarchically, beginning with the most basic function (e.g., arousal) and proceeding in a stepwise manner to tests of complex cognition (i.e., executive function) [1]. With practice, a subspecialist in BN&NP is generally able to perform this type of assessment relatively quickly – often less than 30 minutes [1]. Alternatively, cognitive screening may employ a test whose performance requires relatively intact function across multiple cognitive domains. Errorless performance may obviate additional cognitive testing, and impaired performance indicates a need to examine cognition further [12]. For example, clock drawing assesses multiple cognitive domains, including selective and sustained attention, auditory comprehension, verbal working memory, numerical knowledge, visual memory and reconstruction, visuospatial abilities, ondemand motor execution (praxis), and executive function, among others [135–138]. This breadth makes clock drawing well suited as a screening test of cognition [135]. Adding a brief assessment of declarative memory to a clock drawing test creates a brief and broadly useful cognitive screening assessment [139]. This approach requires that examiners set the bar for “normal” performance very high. Any, even minor, performance problems on this type of screening assessment must be evaluated further with tests capable of clarifying the domain(s) and degree(s) of cognitive dysfunction contributing to them. Another approach to cognitive screening – one recommended by the American Neuropsychiatric Association Committee on Research (ANPA CoR) [140] and used routinely by the editors of this volume – employs a brief battery comprised by several standardized tests [140]. For example, we (the Colorado Group) routinely administer the Mini-Mental State Examination (MMSE) [141] or the Montreal Cognitive

Assessment (MoCA) [142], a clock drawing test [5, 135, 143], and the Frontal Assessment Battery (FAB) [144] to all patients evaluated in the outpatient and inpatient neurological, psychiatric, and neurorehabilitation settings in which we practice. This approach addresses the need to screen broadly for cognitive impairments, while at the same time reducing the length, complexity, and time requirements of the assessment. This approach also yields data amenable to both qualitative and quantitative interpretation. These and many other measures may be used to screen for cognitive impairments as well as to perform more comprehensive and/or cognitivedomain-specific assessment (Table 23.12) [135, 136, 141, 142, 144–161]. The appropriate use, administration, scoring, interpretation, and documentation of standardized cognitive tests requires training and experience with these measures and familiarity with the populations and clinical settings to which they are best suited. Normative data are available for many of these and other bedside assessment measures. Readers are referred to the compendium developed by Strauss et al. (2006) [162] as a useful resource and guide to selection, administration, and interpretation of cognitive tests. There also is a well-established and productive tradition in BN&P of performing “bedside” cognitive examinations using relatively simple and, putatively, domain-specific tests. These tests may be aggregated into an informal bedside cognitive test battery or used as screening tests that, when they reveal impairments, are supplemented with or complemented by standardized cognitive assessments. The following subsections of this chapter describe domain-specific cognitive assessments and examples of bedside cognitive tests used commonly in the practice of BN&NP.

Arousal Arousal denotes a patient’s level of consciousness or state of wakefulness. As described earlier in this chapter (see Appearance and Behavior), the assessment of arousal is based on four observations: (1) whether or not the patient is awake and alert; (2) if the patient is not awake and alert, then the type and intensity of stimulus necessary to arouse the patient; (3) the patient’s behavioral response to that stimulus (or stimuli) used to provoke arousal; and (4) the duration of response during and/or after stimulation is discontinued.

363


Table 23.12. Examples of commonly used standardized cognitive assessments.

364

Measure

Comments

Mini-Mental State Examination (MMSE)

Most commonly used measure of general cognitive function; although commonly used as a screening test, the American Neuropsychiatric Association Committee on Research recommend that its use be supplemented with other cognitive measures, including measures of spatial function, delayed memory, and executive function; interpretation using raw scores is inadvisable; population-based normative data across the entire range of adult ages and multiple education levels are available

Modified Mini-Mental State (3MS) Examination

Incorporates additional memory, naming, language, items and adds test of abstraction to the MMSE; normative data are available

Montreal Cognitive Assessment (MoCA)

Includes items that assess attention, memory, orientation, language, construction, and executive function (including abstraction); it was designed as a screening assessment for cognitive dysfunction among older adults; factor analysis suggests unidimensionality (i.e., the MoCA is an assessment of general cognition); as with the MMSE, interpretation using raw scores is inadvisable; population-based normative data for a broad range of adult ages and education levels are available

Mini-Cog

A very brief screening measure for cognitive impairment among older adults; includes a three-word memory task and a clock drawing test, administered as learning trial, followed by clock drawing, followed by word recall

Saint Louis University Mental Status (SLUMS) Examination

An alternative to the MMSE as a screening measure for mild cognitive impairment or dementia

Neurobehavioral Cognitive Status Examination (NCSE)

Includes assessments of arousal (level of consciousness), attention, memory, orientation, language, calculation, and constructions; it requires more time to administer than many other screening measures (approximately 45 minutes) but provides a more comprehensive screening assessment; also available as a web-based assessment (CogniStat)

Coma Recovery Scale–Revised (CRS–R)

A structured assessment of disorders of consciousness; recommended for use by the American Congress of Rehabilitation Medicine

Symbol Cancellation Test

Provides a brief assessment of selective and sustained attention, screens for hemi-spatial neglect, and organizational process; although often interpreted qualitatively, normative data are available

Delirium Rating Scale–Revised–98 (DRS–R–98)

A relatively brief assessment of attention, memory (including orientation), and other neuropsychiatric disturbances exhibited during delirium

Galveston Orientation and Amnesia Test (GOAT)

Among the best developed and most commonly used assessments of post-traumatic amnesia; although commonly used to assess recovery of declarative memory in other rehabilitation populations, the validity and reliability of its use for such purposes is not well established

Orientation Log (O-Log)

This measure was designed and validated as an assessment of post-traumatic amnesia; unlike the GOAT, it assesses both spontaneous and cued recall

Three Words Three Shapes (3W3S) Test

A bedside assessment of verbal and visual memory that is easily administered at the bedside; assesses the rate and accuracy of new learning through stimuli copying and recall (writing and drawing) immediately and after 5-, 15-, and 30-minute delays

Mississippi Aphasia Screening Test (MAST)

A standardized language examination that structures and extends the bedside assessment of language

Florida Apraxia Battery–Extended and Revised Sydney (FABERS)

A structured assessment of pantomime reception, verbal semantics, action semantics, transitive and intransitive pantomime expression, and meaningless imitation; provides a pantomime expression qualitative scoring system

The Executive Clock Drawing Task (CLOX)

A structured clock drawing task designed specifically to elicit executive impairments and to discriminate between executive and non-executive constructional failure

Executive Interview (EXIT-25)

A useful and more comprehensive extended screening examination of executive function

Frontal Assessment Battery (FAB)

This brief assessment of executive function includes tests of similarities, lexical fluency, complex motor sequencing, sensitivity to interference, inhibitory control (go no-go), and environmental autonomy; normative data are available to guide FAB interpretation

Behavioral Dyscontrol Scale–2 (BDS–2)

Assesses nine areas of frontally mediated cognition; these items comprise three factors: motor programming, environmental autonomy, and fluid intelligence (the capacity to think logically and solve problems in novel situations independent of previously acquired knowledge)


Table 23.13. Qualitative terms with which to describe reduced levels of consciousness.

Term

Description

Clouding of consciousness

Mildly reduced wakefulness or awareness

Obtundation

Mildly to moderately reduced attention, with lessened interest in the environment, drowsiness while awake, and increased sleep

Stupor

Deep sleep or a similarly unresponsive state from which the patient can be aroused only with vigorous and repeated stimulation

Coma

Unarousable unresponsiveness

Patients who are awake and alert are simply described as such. If a more complex descriptor is preferred, then such patients may be described as having a normal level of consciousness. When a patient does not have a normal level of consciousness, then describing the series of observations made above is recommended. If a qualitative description of decreased level of consciousness is used, then the term used should be anchored to definitions that are generally accepted within BN&NP (Table 23.13) [12, 163]. When evaluating patients with disorders of consciousness (i.e., coma, vegetative states, minimally conscious state), structured assessment is encouraged. Based on a systematic review of the content validity, reliability, diagnostic validity, and prognostic value of the scales used most commonly to assess disorders of consciousness, the American Congress of Rehabilitation Medicine [148] recommends using the Coma Recovery Scale–Revised [149] for this purpose.

Attention and processing speed Attention refers to the ability to select and sustain information processing on an internal or external stimulus and, with executive control of attention, to alternate between information processing targets. Spatial attention is a related concept that refers to processing information about the location of an internal stimulus (including self- or body parts) or external stimulus (i.e., one in the environment). Processing speed denotes the rate at which an individual processes and reacts to stimuli or information, and is manifested clinically as reaction time or response latency. Impaired attention and processing speed often co-occur. Observations are made about the patient’s ability to select targets of attention and to sustain attention to those targets (also referred to as concentration or vigilance). Observations also are made of the patient’s ability to sustain attention despite the presence of

potential distractors, regardless of whether those are internal (e.g., physical sensations, emotional feelings, hallucinations) or external (environmental stimuli). If sustained attention appears to be impaired (i.e., the patient appears distractible), then interview and/or observation are used to identify the types of distractor(s) that interfere with sustained attention. The ability to attend to targets on both sides of the body and in both visual hemi-fields is also assessed (discussed further below). Speed of processing is assessed with attention. Judgments about the normalcy of processing speed are necessarily subjective in the absence of quantitative testing. However, if processing speed appears unusually slow or rapid or clearly interferes with conversation, task completion, or other important functions, then concern about a disturbance in this cognitive function is warranted. These observations are often sufficient qualitative assessments of attention or processing speed among patients with severe disturbances in these cognitive domains. However, they tend to be less revealing for mild or moderate attention and processing speed impairments, especially in the quiet, non-distracting, and controlled environments in which cognitive examinations often are performed. When a bedside assessment of attention is needed, some clinicians may turn to the items on the MMSE identified as “attention and calculation” tests. These items include either serial seven subtractions from 100 or, when this task cannot be performed, spelling “world” backwards. Although performance of these tasks requires sustained attention, they also require working memory, language (for both tasks), calculation (for serial seven subtractions), and executive function [162]. Additionally, the domain of cognitive function, or dysfunction, that their performance reflects varies with the clinical population to which these items are administered [162]. The “attention and calculation” tests on the MMSE therefore should not

365


be relied upon or interpreted strictly as tests of either of these cognitive domains. Verbal letter or digit vigilance tests are relatively more straightforward tests of selective and sustained attention, although their performance also relies upon language and working memory and may be intruded upon by executive deficits. In these tests, the patient is instructed to signal (by word or a motor act) when he hears a specific letter (e.g., “A,” “7”) in a list read aloud by the examiner. The list is read at a pace of approximately one stimulus per second and may be continued for up to 60 seconds. Individuals with normal selective and sustained attention are able to complete this task without errors. Failing to respond to the target stimulus (i.e., error of omission) suggests impaired selective attention; responding to nontargets (i.e., errors of commission) may reflect impaired working memory (e.g., the patient is unable to remember the correct target), impulsivity (e.g., failed inhibition of responses to non-targets), perseveration (e.g., repeated responding to non-targets or all targets), or some combination of these problems. Waning engagement in the test prior to its termination by the examiner suggests impaired sustained attention. Inability to respond despite the modest pace of stimulus presentation suggests decreased processing speed. There are several written versions of this task, many of which are timed and therefore provide measures of processing speed as well (see Strauss et al., 2006 [162] for review and norms). The verbal trail-making test (vTMT) [164] is a two-part verbal analog of the written neuropsychological test by the same name. In Part A (vTMT-Part A), the patient is asked to count from 1 to 25 (i.e., “I would like you to count from 1 to 25 as quickly as you can. 1, 2, 3, 4, and so on. Ready? Begin”). Although languagedependent, this is a relatively straightforward test of simple sustained attention. In Part B (vTMT-Part B), the patient is asked to alternate between numbers and letters progressively up to 13-M (i.e., “Now, I would like you to count again, but this time you are to switch between numbers and letters when you count. 1-A, 2-B, 3-C, and so on until you reach the number 13. Ready? Begin”). If the patient makes an error on either task, he is directed back to the last correct item and asked to continue the task from that point. The vTMTPart B is a test of sustained attention and processing speed, but its performance also requires relatively intact working memory (i.e., keeping the last number or letter spoken in mind while alternating between

366

sets) and executive function (e.g., executive control of attention for alternating between sets). The examiner records the times to perform each part of this task and records errors of omission and/or commission. Qualitative interpretation of vTMT is based on the patient’s ability to sustain attention to these tasks as well as the accuracy and speed of task performance. Among patients with impaired working memory and/or deficits in executive control of attention, errors of commission on vTMT-Part B are common. These may include difficulty maintaining “in mind” the last item stated in one set after alternating to the other, failure to alternate between sets entirely, and/or repetition of a specific number or letter within a set (perseveration). The latter error type sometimes occurs despite that patient’s continued switching between sets (e.g., “ . . . 3-C, 4-C, 5-C, 6-C . . . ”). Based on data reported by Ruchinskas (2003) [165], approximately 98% of healthy younger patients are able to complete Part A in less than 11 seconds and Part B in less than 64 seconds. Among older patients, including patients with medical illnesses, the reliability of this task is less robust [162, 165]. Performance failures are predicted by lower MMSE scores and lower education, suggesting that it may not be necessary or productive to use this task among persons with these characteristics. When used at all, comparison of performance to normative data for the written TMT is encouraged and is made by multiplying vTMT-Part B score (in seconds) by 2.44 [166]. Mesulam’s letter, number, and symbol cancellation tasks [155] are useful assessments of selective, sustained, and spatial attention. These are paper-andpencil tasks with a sheet containing an array of letters, numbers, or symbols on which the patient is instructed to strike through every instance of a pre-specified target. One of these, the random symbol cancellation test, is presented in Figure 23.2 [156]. The examiner points to the open, diagonally bisected circle with six spokes on its outer circumference and instructs the patient to draw a line through each instance of that shape on the page. There are 60 of these targets (15 in each quadrant) embedded in a background of 300 distractors. In addition to selective, sustained, and spatial attention, performance of this task also requires working memory (i.e., keeping the target of attention “in mind”) and executive function (i.e., developing an effective search strategy, or novel problem solving). Qualitative assessments of the random symbol cancellation test include: accuracy and completeness of


Figure 23.3. Example of relatively normal line bisection task performed by a healthy 44-year-old right-handed man. The black lines are the targets, and the gray lines are the patient’s line bisections.

Figure 23.2. The random version of the symbol cancellation test. Reproduced from Lowery N, Ragland JD, Gur RC, Gur RE, Moberg PJ. Normative data for the symbol cancellation test in young healthy adults. Appl Neuropsychol. 2004;11(4):218–21, with permission of C 2004 Taylor & Francis Taylor & Francis Informa UK Ltd – Journals. Informa UK Ltd.

target stimuli identification (selective attention); persistence with the task (sustained attention), including the ability to keep the target in mind without reminders from the examiner (working memory); identification of targets in all quadrants (spatial attention); the time required to complete the task (processing speed); and the planning and organization of task performance (executive function). Normative data for the random symbol cancellation task [156] reveal a mean time to completion of approximately one minute. Approximately 98% of healthy adults are able to complete this task in less than 90 seconds and errors of omission in healthy adults are infrequent (no more than two per hemi-field) [156]. Weintraub (2000) [167] suggests that most older adults are able to complete this task in less than three minutes and omit no more than two targets per hemi-field. Most adults develop a systematic strategy with which to complete this task, usually consisting of searching left-to-right in horizontal rows or vertical columns despite the random nature of the symbol array.

Visual spatial attention also can be assessed by the line bisection task. The patient is given a sheet of paper on which a number of lines in a variety of orientation are drawn. The patient is asked to draw a line through the middle of each of the pre-drawn lines. In general, healthy adults are able to perform this test without error (Figure 23.3). If spatial attention is impaired, then the patient may strike through the lines off-center (usually with a rightward bias) or neglect lines on a portion of the page (usually the left). A complementary assessment of hemi-spatial inattention is simultaneous bilateral somatosensory stimulation. The patient is instructed to close his eyes and to identify where on the body he feels the examiner’s touch. The patient is first touched unilaterally in order to ensure that elementary somatosensation is intact. Thereafter, the examiner quickly and gently touches the tops of both hands. Patients with normal bilateral somatosensory attention will identify bilateral simultaneous stimulation whereas patients with hemispatial inattention will fail to attend to the stimulus on the unattended (usually left) side and report only experiencing the stimulus on the normally attended side of the body.

Working memory Working memory refers to the process of holding information in mind, or “on-line,” for a brief period immediately after its presentation. As such, working

367


memory overlaps and extends the process of sustained attention. Bedside assessment of working memory may be informed by performance on the tests of attention and processing described above. Although the three-word registration task on the MMSE requires working memory, the amount of information and time required to hold it in mind are so small as to make this an unrevealing test of this cognitive function for all but the most severely impaired (and, usually, markedly inattentive) patients. Performing serial seven subtractions and spelling “world” backwards also may inform on working memory but, as discussed above, performance of these tasks is influenced by so many cognitive functions that they cannot be relied upon as tests of working memory. However, impaired performance on all of these tasks in the setting of relatively preserved selective and sustained attention may together suggest and support an impression of impaired working memory. When working memory impairments are suspected, the digit span (digit repetition) task is a useful test of attention and freedom from distractibility. The patient is first asked to repeat single digits as spoken by the examiner; this procedure increases confidence that the patient can hear and repeat numbers effectively. The examiner then presents a string of two digits, and the patient is asked to repeat them in the order they were presented. Digits are presented by the examiner at the rate of one per second, and with as little inflection as possible. With each successful repetition, the examiner offers a new string of digits that is one digit longer than the last. It is best for the examiner to read from a set of numbers written ahead of time in order to avoid repeating all or part of a previously presented string and/or patterning the digit string (e.g., odd or even strings, fixed numeric intervals, telephone-style number groups). Reading from a pre-written script also minimizes the risk of scoring errors resulting from the examiner’s working memory limitations. This procedure is repeated until the patient fails to correctly repeat the string of presented digits. The longest string that the patient is able to repeat successfully defines forward digit span (a measure of simple working memory), which for most adults is 7 ± 2. After defining forward digit span, the procedure is then repeated with a change in rules: the patient is instructed to repeat the digits spoken by the examiner in reverse order (i.e., “If I say 1–2–3, then you say 3–2–1”). The longest string that the patient is able to

368

repeat successfully defines backward digit span, which for most adults is 5 ± 1. This is a complex working memory task whose performance requires both simple working memory and executive control of working memory (i.e., digit reversal) [1, 168]. Since the backward digit span task relies on more than simple working memory, impaired performance on this task should not be taken as incontrovertible evidence of impairment of this cognitive function.

Recognition (gnosis) Sensory domain-specific recognition may be assessed during the cognitive examination, although many examiners do not do so routinely. The evaluation for recognition impairments (i.e., agnosia) is important to perform when there are concerns about the patient’s ability to recognize stimuli in a specific sensory modality (e.g., vision, hearing, somatosensation, olfaction) and/or the history or examination suggests a condition in which agnosia is relatively common (e.g., Alzheimer’s disease, frontotemporal dementia, Lewy body dementia, Parkinson’s disease with dementia). When the patient has naming impairments on language (discussed later in this chapter), distinguishing between impaired object recognition and anomia also should be performed. Establishing that the elementary sensory function in the domain being assessed is intact (i.e., the patient is not blind, deaf, or anosmic, and does not have a dense hemi-sensory loss or peripheral neuropathy) is a prerequisite to the assessment for agnosia. Once intact sensation is established, stimuli are presented in the sensory domain in which agnosia is suspected. Since agnosia is sensory domain-specific, the stimuli used to test for agnosia must be easily recognizable in more than one sensory modality. For example, the patient is asked to close his eyes and place his dominant hand on his lap with palm up. An object (e.g., a key, paperclip, rubber ball, whistle, coin, button) is placed in the hand; the patient is instructed to feel the object with his fingers and name it. If the patient is unable to do so, then the examiner instructs him to open his eyes and identify it by sight and/or to demonstrate how the object is used (i.e., to demonstrate recognition by appropriate use of the object). Conversely, objects presented to a patient with visual agnosia may be able to name the objects when presented tactilely or auditorily. The inability to identify the object by active touch despite the ability to recognize it by sight (or


Table 23.14. Disturbances of language, including aphasic and non-aphasic types.

Abnormality

Description

Phonemic paraphasia

Mispronunciation of the intended word as a result of phonemic substitution or transposition

Semantic paraphasia

A type of verbal paraphasia involving the substitution of a semantically related word for the intended word

Remote paraphasia

A type of verbal paraphasia involving the substitution of a semantically unrelated word for the intended word

Neologistic paraphasia (neologism)

Construction of a novel, often meaningless, word

Word approximations

Partial words or novel constructions used that are semantically meaningful, thereby distinguishing them from neologisms; used commonly by children learning to speak

Circumlocution

Literally “talking around” the intended word, often by describing it (akin to a dictionary definition) or, if an object, its use

Parapraxis

An error in speech in which the intended word is substituted with another that reveals a repressed feeling, belief, or motive

Echolalia

Immediate, often involuntary, and frequently meaningless repetition of another person’s spoken words and/or phrases

Palilalia

Repetition or echoing of one’s own spoken words (or terminal parts of one’s words)

Clanging

Production of words based on rhyming or alliteration rather than logical relationships

Assonance

The repetition of similar or identical vowel sounds or diphthongs in non-rhyming stressed syllables

another sensory domain) and/or by its appropriate use defines somatosensory agnosia (astereognosia). Some patients with agnosia may be able to match stimuli that they do not recognize with ones that are identical or of like kind, to describe the elementary sensory characteristics of the unrecognized stimulus, or be able to use it functionally (all of these preserved abilities vary with the type of agnosia). By contrast, the inability to name the object regardless of the sensory domain in which it is presented suggests anomia (i.e., impaired language) rather than agnosia. The most common types of recognition impairments included in the cognitive portion of the mental status examination are asterognosia, agraphesthesia (inability to recognize letters or numbers drawn on the finger tip or hand), simultanagnosia (inability to recognize a whole image/scene despite recognition of its constituents), pure word deafness (inability to recognize words when spoken despite preserved reading), non-aphasic alexia (inability to recognize words by writing despite their auditory recognition), visual agnosia (inability to recognize objects by sight despite preserved recognition in other modalities), finger agnosia (inability to recognize fingers on the hand, and an element of the Gerstmann syndrome), and olfactory agnosia (inability to recognize smells despite intact olfactory sensation). Methods of assessment for these and other types of perception and recognition

impairments are described in Chapters 10 and 15 of this volume.

Language and prosody Language is the verbal or written representation of thought that permits symbolic communication with other individuals. As noted in the Communication section of this chapter, language is distinct from voice (the production of sounds by the vocal folds through quasi-periodic vibration) and speech (the use of tongue, lips, jaw, and other oropharyngeal muscles to articulate words). The elements of language include naming, fluency (verbal and written), repetition, and comprehension (verbal and written). These are complemented by the paralinguistic functions of prosody and kinesics. Impaired naming is a common characteristic of the aphasias and therefore is the first element assessed during the language examination. The evaluation begins with the examiner presenting objects (e.g., pen, watch) and asking the patient to name them and their parts (e.g., tip of the pen, clip of the pen, face or hands of the watch, watchband, crystal, stem). Difficulties with confrontation naming may manifest as word-finding failures, paraphasias, circumlocutions, neologisms, or word approximations (Table 23.14). These abnormalities of language vary with the type of aphasia

369


with which they are most closely associated (e.g., semantic paraphasias and neologisms are associated with disturbances in the more posterior sectors of the language network whereas phonemic paraphasias are more often associated with disturbances of the anterior portions of those networks) and must be distinguished from other disturbances of speech content (e.g., parapraxis, palilalia, assonance, clanging). Anomic (or dysnomic) patients often demonstrate more difficulty naming parts of objects than the object itself. They also may demonstrate more difficulty naming objects from one category than from another (i.e., tools/implements vs. non-action objects). As noted earlier, the examination must distinguish between anomia and apparent naming failures resulting from agnosia (see the section on assessment of Recognition, above). Fluency denotes the formulation of language output without undue word-finding pauses, word-finding failures, agrammatisms, or abnormally reduced phrase lengths. Non-fluent language is characterized by consistent generation of phrases that, on average, are of five or fewer words and marked by word-finding pauses and agrammatisms. The production of phrases that, on average, contain six to eight words, fewer word-findings pauses, and modest (if any) agrammatisms are at the border between non-fluent and fluent language output (i.e., dysfluent). Fluency is assessed throughout the interview and examination by observing the patient’s spoken language. Written language also is assessed; the sentence-writing task on the MMSE is used commonly for this purpose. Among patients with suspected non-fluent language disturbances, the patient is asked to write a brief narrative and the examiner evaluates it with respect to the characteristics of fluency described above. Although word-list generation tasks are sometimes discussed as tests of fluency, they are more accurately understood as tests of the executive control of language [166]. These tasks are discussed in the Executive Function section of this chapter. Repetition is assessed by asking the patient to repeat exactly the examiner’s spoken (or written) words and sentences. The material to be repeated is presented in order of increasing complexity, beginning with monosyllabic words (i.e., “yes,” “no,” “true,” “false”) and simple sentences (i.e., “It is sunny,” “You are here”). If the patient is successful, the complexity of the material to be repeated is gradually increased (i.e., “Today is a sunny day in Denver,” “The quick brown fox jumped over the lazy dog,” “My grandfather is very

370

old and wears a long black coat when it is cold outside”). Finally, the patient is asked to repeat the agrammatical (or irregular) phrase “no ifs ands or buts.” Repetition of this idiom tends to be difficult for persons with aphasia in light of the fact that its correct content cannot be deduced from its intended meaning. This phrase is included on the MMSE and serves as a useful screen for repetition failures (if normal, other repetition difficulties are unlikely) and central dysarthria. However, performance on this and other repetition tasks may result from impairments of attention and working memory as well as social, cultural, and native language factors. These issues require consideration before attributing impaired repetition to aphasia. Comprehension refers to the ability to understand spoken (or written) language. It generally is assessed verbally. However, the common co-occurrence of comprehension and verbal fluency impairments necessitates assessing comprehension by asking the patient to provide responses non-verbally as well. The assessment of comprehension begins during the interview and continues throughout the examination. Formal assessment of comprehension, like that of repetition, presents test material in order of increasing complexity. The patient first is asked to point to objects in the room, singly and then in groups of two and three (NB: the objects to which the patient points during this assessment may be used later to test visual and spatial memory). The patient is then asked a series of “yes/no” questions; these are easy at first (e.g., “Is your name [patient name]?” and “Are the lights on?”) and then made more difficult (e.g., “Do you put your shoes on before your socks” and “Does the sun rise in the evening?”). The assessment also may include asking the patient to respond to a series of “true/false” questions. For example, the examiner might say: “True or false: fish swim in the ocean. [Patient answers.] Cows live in pastures. [Patient answers.] Cows live on the moon. [Patient answers].” Higher-level comprehension is asking the patient to respond to a scenariobased question: “It is a dark night in the jungle. A lion and a tiger fight. The lion is killed. Which one is alive?” The ability to comprehend written language is also assessed. This is accomplished most simply by the written command on the MMSE, “Close your eyes.” Among patients with hearing impairments, the tests of comprehension described here may be presented in writing. Performance on tests of comprehension are dependent on attention, working memory, praxis, and executive function, as well as non-cognitive


Table 23.15. The classic aphasias. The minus symbol (−) denotes impairment, whereas the plus symbol (+) denotes intact or relatively preserved function.

Aphasia type

Naming

Fluency

Repetition

Comprehension

Anomic

−

+

+

+

Broca’s

−

−

−

+

Transcortical motor

−

−

+

+

Conduction

−

+

−

+

Wernicke’s

−

+

−

−

Transcortical sensory

−

+

+

−

Mixed transcortical

−

−

+

−

Global

−

−

−

−

factors (e.g., motivation, comportment). Interpreting performance on these tasks requires consideration of these and other non-language factors. Since the three-step command used on the MMSE (“Take a paper in your right hand, fold it in half, and put it on the floor”) [141] is presented in the “Language” section of that measure and sometimes is used by clinicians as a test of comprehension, a brief comment on this task is warranted. Although normal performance of this task suggests relatively normal language comprehension, the task more directly assesses praxis. It is constructed like a test of ideational praxis (i.e., the ability to carry out a complex activity requiring a sequence of movements with real objects), although it is performed without first establishing that the patient is able to perform each step in that sequence (ideomotor praxis). Poor performance of this threestep command cannot be attributed prima facie to impaired comprehension; a detailed examination of comprehension and praxis is needed to understand the contributor(s) to that performance. The pattern of impairments on naming, fluency, repetition, and comprehension define the classic aphasias (Table 23.15). These and related problems are discussed in detail in Chapter 12 of this volume. When a structured bedside assessment of language is needed by subspecialists in BN&NP, the Mississippi Aphasia Screening Test [147] may be particularly useful. Concurrent with language, the paralinguistic functions of prosody and kinesics are assessed. The procedure for their assessment is similar to that used to assess language fluency, repetition, and comprehension. The examiner observes the degree, quality, and communicative effectiveness of spontaneous affective

prosody and gesturing (analogous to language fluency). The patient is asked to repeat sentences and imitate the manner in which they are stated by the examiner. A simple approach is to modify a single statement with several affects and inflections; for example, “He’s going to sing?” (surprise) versus “He’s going to sing?!” (anger, irritation) versus “He’s going to sing!” (happiness, excitement). These same sentences may be used to assess comprehension of affective prosody, in which the patient identifies both the affect and the meaning communicated by the manner in which each of these sentences is presented. Finally, the examiner assesses comprehension of gestures by miming an emotion using only the face and limbs (i.e., silently); the patient is asked to identify the mimed emotion. Disturbances of prosody and kinesics (i.e., aprosodias) are classified in a manner analogous to the aphasias. The aprosodias include motor, transcortical motor, conduction, sensory, transcortical sensory, mixed transcortical, and global types, as well as agesic aprosodia (defined by isolated impairment of gestural comprehension). The aprosodias and their assessment are discussed in additional detail in Chapter 13 of this volume.

Declarative memory Declarative memory is a multifaceted construct that includes verbal and visual new learning and recall, as well as episodic memory (memory for events) and autobiographic memory (memory of personal information). Provided that the patient is alert, attentive, and able to communicate effectively, verbal and visual memory may be assessed.

371


The three-word registration (working memory to new learning) and recall (short-term memory) task on the MMSE is among the most commonly used bedside assessments of verbal memory. Since the normative data for this measure [169] were developed using the original version of the MMSE [141], the administration instructions described in that version must be followed if results are to be interpreted with those norms. The examiner asks the patient if he may test the patient’s memory. Then the examiner says the names of three unrelated objects, clearly and slowly, at a pace of about one object per second; “apple,” “table,” and “penny” are commonly used as the test items. After the examiner says all three words, then the patient is asked to repeat them. The patient’s first repetition determines his score on the registration item of the MMSE (one point per word repeated correctly). If that score is less than three, this procedure is repeated up to six times in order to provide the patient with opportunities to repeat all three words (as a set) successfully. If the patient is unable to correctly repeat all three words despite six trials, then their delayed recall cannot be tested meaningfully. Impaired performance of this task suggests impairments of arousal, attention, and/or working memory and should prompt their assessment. If the patient is able to repeat the set of three words, then delayed memory is assessed a few minutes later. Consistent with the original administration instructions for this measure [141], the patient is not told that he will be asked to recall these items or provided with any other cue to rehearse the registered word. This approach tests incidental memory, rather than intentional (i.e., rehearsal-cued) memory, optimizing its effectiveness as a bedside screen for subtle memory impairments [170]. Delayed recall is tested after first completing a non-memory task. The purpose of undertaking a nonmemory task between the registration and recall portions is to ensure that the latter does not simply test working memory but instead assesses delayed recall (in clinical parlance, “short-term memory”). Performing a non-memory task also interferes with covert rehearsal of the memory stimuli, increasing the likelihood that it remains a test of incidental memory. Serial seven subtractions and/or spelling “world” backwards are the tasks used for this purpose on the MMSE. After their completion, the patient is asked to recall the three words presented earlier (i.e., “A few minutes ago I asked you to repeat three words. Please say them for

372

me.”). One point is given on the MMSE for each item recalled spontaneously. If the patient is unable to recall one or more of the words spontaneously, then a semantic cue is provided for those not recalled (i.e., “something you eat,” “something in a dining room,” “a type of coin”). If the patient is unable to recall one or more items in response to a semantic cue, then recognition cues are provided (i.e., “banana, apple, orange,” “cabinet, table, dish,” “nickel, penny, dime”). No points are given on the MMSE for semantic or recognition cue-facilitated recall. However, the process of evaluating the benefits, or the lack of such, of recall cues facilitates distinguishing between impaired new learning and impaired retrieval (Figure 23.4). It also can be informative to repeat the assessment of recall after additional delays (e.g., 5 or 10 minutes) and the performance of other cognitive tests. Similar procedures are used to assess visual memory and spatial memory. Spatial memory begins with an object location registration task, accomplished most simply by asking the patient to point to three objects in his immediate environment (this may have been done during the assessment of comprehension). After a several minute delay and one or more tests not involving pointing or object identification, the patient is asked to point to those three objects. Directional cues may be provided to facilitate recall of the objects. If the patient does not point to them in the order of initial presentation, then he should be asked to do so. Difficulty recalling the order of their presentation may reflect impaired temporal coding and inform on similar impairments for everyday events [171–173]. Visual memory is assessed most easily at the bedside by asking the patient to copy three relatively simple figures. After a several minute delay and completion of an intervening task, the patient is asked to draw those shapes from memory. Verbal and visual memory can be assessed concurrently at the bedside using the Three Words Three Shapes test [154, 155]. This test assesses the rate and accuracy of new learning through stimuli copying and recall (writing and drawing) immediately and after 5-, 15-, and 30-minute delays. The assessment of memory also includes orientation to place, time, and situation. Orientation to place is assessed by asking the patient to identify the building, floor of that building, city, county, and state in which the examination takes place; on the MMSE, current county location may be substituted for county of


Figure 23.4. Declarative memory evaluation flow chart.

residence. Temporal orientation is assessed by asking the patient to identify the current day, date, month, year, and season. The ability to learn new information may be reflected in his “orientation to situation;” that is, memory for the reasons (even if not agreed to) for the clinical encounter, events leading to it, recent events in the family or subject areas of personal interest (e.g. politics, sports, entertainment, weather), and other details about current circumstances. The typical pattern of impairments among persons with memory disorders involves inability to recall the most recent and/or quickly changing information (i.e., building, floor, city, day, date) and relative preservation of information learned more remotely. Isolated loss of memory for past information (i.e., retrograde amnesia without anterograde amnesia), especially loss of memory for name or personal identity, is very unusual and concerning for dissociative amnesia and dissociative fugue [14]. Remote memory (i.e., fund of knowledge) is assessed by asking the patient to recall personal (i.e., autobiographical) information as well as historical information and events (e.g., past political leaders, celebrities, dates of historical events). Meaningful assessment of autobiographical memory requires that the answers provided by the patient are verifiable by a reliable source (e.g., spouse or other family member, written records). Similarly, questions about historical

information and events need to be aligned with the patient’s neurodevelopmental, sociocultural, and educational backgrounds (i.e., about information that is common knowledge among demographically similar individuals).

Praxis Praxis is the process by which a skill is enacted. Although this term has other meanings in other fields, its use in medicine is generally limited to its negative forms, apraxia (without praxis) or dyspraxia (poor praxis), and describes impaired ability to perform skilled purposeful movements that is not attributable to sensory, motor, or language deficits (see Chapter 14). Apraxia may involve axial, limb, and/or whole-body movements and includes three major subtypes: limb-kinetic (or melokinetic), ideomotor, and ideational. Melokinetic, or limb-kinetic, apraxia refers to the inability to execute fine movement on demand. This form of apraxia is typically tested with instructions to pantomime finely graded finger movements, such as buttoning a shirt or performing pincer or tapping movements. Clumsiness of fine movements is often apparent not only while performing these movements but also during many other motor tasks, including one requiring ideomotor praxis [167]. This impairment

373


appears to reflect elementary motor impairment and therefore is not universally regarded as an apraxia [1]. Regardless, observations for impaired movements of these types are made throughout the clinical encounter. Ideomotor apraxia refers to the inability to perform gestural (pantomime) movements to verbal command despite preservation of the same movement in a naturalistic setting. This apraxia may affect not only pantomime-command but also spontaneous, environmentally relevant movements. Ideomotor apraxia frequently involves both axial and limb movements. Ideomotor apraxia is assessed by asking the patient to pantomime various axial, limb, and whole body movements. Common examples of pantomime tasks used to assess ideomotor praxis include brushing teeth, blowing out a match, striking a match, dealing cards, using scissors, hammering a nail, sawing wood, throwing a ball, and opening the lid of a jar. In general, pantomime is a more complex function of praxis than imitation, and therefore is more revealing of subtle impairments than imitation of the examiner or actual task performance. Performance on command is more complex than spontaneous performance (i.e., performance dictated by environmental or contextual demands). Assessing the patient’s ability to perform ideomotor tasks by pantomime, imitation, and actual objects use is informative, as are observations of the patient’s task performance in response to request by the examiner as well as spontaneous acts in his environment. Ideational apraxia refers to the inability to carry out a complex sequence of movements despite preserved ability to correctly execute the individual components of that sequence. Ideational praxis is assessed by observing the patient’s ability to perform multistep tasks, including pantomime, imitation, and actual object use in response to requests by the examiner and spontaneously in his environment. A commonly used task is asking the patient to pantomime putting a letter in an envelope, sealing and addressing the envelope, and placing a stamp on its face. Another useful task requires the patient to “touch your right hand to your left ear after you point to the ceiling.” This task assesses ideomotor praxis, includes a temporal qualifier, and screens for right-left confusion. As noted earlier, the three-step command on the MMSE is constructed as a test of ideational praxis, and involves actual object use. It therefore may be somewhat less revealing of ideational apraxia than multi-step pantomime or

374

imitation tasks. When poor performance on any of these tasks is observed, assessment of the patient’s ability to perform each of its steps, other tasks of ideomotor praxis, and to comprehend language comprehension are required. Among the bedside tests of praxis, the Florida Apraxia Battery–Extended and Revised Sydney (FABERS) [153] is among the most useful. This battery comprises structured assessments of pantomime reception, verbal semantics, action semantics, transitive and intransitive pantomime expression, and meaningless imitation. It also offers a quantitative scoring system for pantomime expression. Among patients with functionally significant apraxia identified by bedside examination, performing the FABERS clarifies the types and severity of apraxia and yields information that facilitates development of compensatory strategies for patients and/or their caregivers.

Visuospatial function Visuospatial function denotes a set of complex visual processing abilities that include spatial awareness and attention, awareness of self-other and self-object spatial relationships, visuospatial memory, and the ability to interpret and navigate the extrapersonal space (see Chapter 15). The evaluation for visuospatial dysfunction requires careful assessment of sensory and motor function as well as memory, language, recognition, praxis, and executive function. Deficits in any of these cognitive domains may produce performance impairments on tasks that are commonly regarded as tests of visuospatial function. Several easily administered bedside tests of visuospatial function were addressed earlier in this chapter, including letter, number, or symbol cancellation tasks, line bisection tests, and test for extinction to double simultaneous stimulation as assessments of spatial awareness and attention (and, conversely, screening tests for hemi-spatial neglect) and the object location registration and recall test for spatial memory. Additionally, reading tasks, dressing tasks, and personal hygiene may reveal visuospatial dysfunction (i.e., hemi-spatial inattention or neglect) when the patient consistently demonstrates lateralized inattention to one side of the body and/or extrapersonal space. Observing the patient dressing may reveal either neglect or difficulty aligning the body axis with the axis of the garment; although the latter is


Box 23.5. Administration instructions for a clock drawing test. Step 1. Hand the patient a blank sheet of paper and a pencil. Say to the patient: “Please draw a large circle on this piece of paper and fill it in with numbers so that it looks like the face of a clock. Make it large enough so that even a child could read it.” Watch the patient carefully as he or she performs this task and make note of how he or she goes about executing it. If the patient is demonstrating difficulty completing the task independently, then provide only repetition of the cues contained in the original instruction (i.e., repeat “draw a large circle” and/or “fill it in with numbers so that it looks like the face of a clock”). If the patient attempts to place hands on the clock during this step, ask him to wait until instructed to do so. Step 2. After the patient has drawn a circle with numbers in it, then say to the patient: “Place the hands on the clock so that it reads 10 after 11.”

sometimes described as “dressing apraxia,” it is more usefully understood as a manifestation of visuospatial dysfunction [174]. Construction tasks such as two-dimensional figure drawing or copying (e.g., interlocking pentagons on the MMSE), or three-dimensional figure copying or drawing (e.g., cube) and clock drawing tests also are used commonly to assess visuospatial function. On the MMSE, the patient is asked to copy two interlocking pentagons provided by the examiner. A single point is given on this test, each polygon has five sides, five angles, and only one angle from each overlaps with the other. Responses may be graded qualitatively as excellent (exact copy), good (mild distortion of size, shape, lengths of sides of each pentagon and one angle from each overlaps with the other), fair (moderate distortion of figures, may be missing sides and/or angles, overlap contains more than two angles), or poor (unrecognizable). A more complex constructional task incorporates a three-dimensional element to the design such as a cube. Performance on this task is also rated as qualitatively excellent (correctly proportioned and angled three-dimensional cube), good (mild distortions), fair (moderate distortion and/or loss of three-dimensionality), or poor (unrecognizable). There are multiple administration and scoring systems for clock drawing [138]. A system that the editors of this volume find useful follows

Figure 23.5. Examples of drawing demonstrating left hemi-spatial inattention (neglect). A: clock drawing demonstrating inattention to the left hemi-field. B: face drawing made by a man with left hemi-neglect associated with a right parietal neoplasm. C: drawing of a flower by a man with left hemi-neglect after a right hemisphere stroke. Examples B and C courtesy of Jody Newman, MA, CCC-SLP, Neurobehavioral Disorders Program, Department of Psychiatry, University of Colorado School of Medicine.

the administration instructions described in Box 23.5. Clocks drawn in response to these instructions are usefully scored using Mendez’ Clock Drawing Interpretation Scale [137] or other similar systems [138]. All of these constructional tasks also can reveal hemi-spatial inattention (Figure 23.5). However, care must be exercised when interpreting abnormalities other than hemi-spatial inattention on constructional tasks. As noted earlier in this chapter, performance on these tasks (especially clock drawing tests) is dependent upon multiple cognitive functions, including selective and sustained attention, auditory comprehension, verbal working memory, numerical knowledge, visual memory and reconstruction, visuospatial abilities, on-demand motor execution (i.e., praxis), and executive function, among others [135–138]. In our experience, figure and clock drawing that is poorly organized, demonstrates uneven spacing, or contains disorganized content more often reflects impaired executive function than visuospatial dysfunction. Moreover, clock drawings in which the hands are placed on the numbers stated by the examiner (i.e., 10 and 11) rather than those intended by the instructions (i.e., hour hand pointing towards the 11, minute hand pointing at the 2) reflects stimulus-bound responding (i.e., executive dysfunction) rather than impaired visuospatial function.

Calculation Calculation requires the ability to manipulate mathematical knowledge. This ability requires multiple cognitive functions, and may be impaired as a result of

375


acquired brain injury (e.g., stroke, tumor, neurodegenerative disease), neurodevelopmental problems, or learning disorders. It therefore is commonly assessed at least briefly in the cognitive examination of persons with such conditions. The patient is asked to perform simple verbal and written arithmetic, including addition, subtraction, and the operations of “borrowing” and “carrying” [167]. Monetary calculation (e.g., “How many quarters are there in $1.75” or “How many nickels in $1.15”) is often used as an initial assessment of calculation ability since it is a familiar daily operation for most people and does not provoke performance anxiety as readily as asking the patient to solve “math problems.” Impaired ability to calculate (i.e., dyscalculia or, when severe, acalculia) may occur as an isolated disorder or as an element of the Gerstmann syndrome. The latter is associated with discrete left angular gyrus lesions, and consists of dyscalculia (or acalculia), dysgraphia (or agraphia), finger agnosia, and left–right disorientation. Lesions in this location frequently produce impairments that extend beyond the classic tetrad of the Gerstmann syndrome to include anomia, alexia with dysgraphia (or agraphia), and constructional disturbances [12]. When such lesions produce fluent aphasia, impaired calculation may reflect problems with reading, writing, comprehending spoken language, and/or paraphasic errors. In this context, problems calculating may be regarded as either a feature of fluent aphasia or as impossible to assess meaningfully due to fluent aphasia. Patients with right hemispheric lesions resulting in visuospatial dysfunction may have difficulty with written calculations; this also may not be usefully understood as acalculia but instead regarded as interference of visuospatial dysfunction on written calculation.

Executive function Executive function refers to cognitive processes that manage and control “basic” aspects of cognition (i.e., executive control functions) as well as intrinsically complex cognitive skills such as information retrieval and generation, set shifting, inhibitory control, environmental autonomy, planning and organization, pattern recognition, problem solving, and abstraction. Executive dysfunction is common among persons with psychiatric and/or neurological conditions and may arise as a result of damage to or dysfunction of either systems supporting executive function or the basic

376

Figure 23.6. Examples of stimuli used in written alternating sequence tasks. A: cursive m and n in a linked repeating pattern. B: partial squares and triangles in a linked repeating pattern.

cognitive functions [162]. This assessment also is one of the most challenging elements of the cognitive examination to perform and interpret, but its inclusion in the cognitive examination is essential in light of the substantial influence of executive function on functional status [175, 176]. Many of the tests presented earlier in this chapter rely upon executive function, and some pair assessment of a relatively basic cognitive function with a test of executive control functions. Examples of tests of the latter include vTMT-Part B, digit span backward, cancellation tasks (search strategy component), retrieval of remotely learned information, complex ideational praxis tasks, and clock drawing tests. There are many other tests of executive function that may be performed at the bedside (see [162] for review). Several relatively brief and clinically useful sets of these tests include the Frontal Assessment Battery (FAB) [144], Behavioral Dyscontrol Scale-2 [159, 160], and the Executive Interview [177]. Clinicians may find these or similar measures [140, 175] useful approaches to the assessment of executive function and are encouraged to consider using them in clinical practice. Several items from these tests as well as a few others that may be useful are presented as examples of tests of executive function.

Set shifting Set shifting integrates executive control of attention and working memory as well as inhibitory control. The assessment of set shifting is embedded in the vTMTPart B, and also may be assessed using written alternating sequence tasks. In these tasks, the examiner presents the patient with a piece of paper on which a half-line pattern of alternating letters or symbols is written (Figure 23.6). The patient is instructed to copy the pattern in the space below that line and continue the pattern across the full width of the page. Healthy adults are able to complete this written alternating sequences pattern without difficulty. Patients


with executive dysfunction may have difficulty replicating the pattern correctly, fail to generate more than a copy of the half-line stimulus, perseverate on one element in the pattern (e.g., m or n, square- or trianglelike shape), or persistently repeat the pattern even after reaching the edge of the page. The FAB [144] includes a sensitivity to interference and an inhibitory control task, each of which assesses set shifting (among other capacities). The sensitivity to interference task requires the patient to learn a set of conflicting instructions (i.e., “Tap twice when I tap once,” “Tap once when I tap twice”) and to perform a task in which they are used. Immediately after completing this task, inhibitory control is assessed using a go no-go task (i.e., “Tap once when I tap once,” “Do not tap when I tap twice”). Performance of these tasks requires the patient to hold two instruction sets in mind and to switch between them in order to respond appropriately to the tapping stimuli presented by the examiner. Poor performances on these tasks may reflect impaired working memory, inability to shift between response sets effectively, or stimulus-bound behavior (i.e., echopraxia). Closely pairing these tasks creates a second-level set shifting assessment on which patients with executive dysfunction often perform poorly – they fail to shift, or are unable to sustain the shift of, their responses to those associated with the conflicting instructions task and instead continue using the stimulus-response rules of the sensitivity to interference task.

Executive control of language Lexical fluency tasks, also known as verbal fluency tasks, also are included commonly in the cognitive examination. Although these tests can be used to assess fluency as a part of the language examination [12], they are tests of executive control of language [162]. Lexical fluency is assessed most commonly by testing the patient’s ability to generate a list of words based on a specific letter (phonemic fluency) or category (semantic fluency). A modified version of the Controlled Oral Word Association Test [162], sometimes referred to as the “F-A-S” test (the letter stimuli used to prompt word-list generation), is included on the FAB [144]. The test begins with the examiner instructing the patient to “Say as many words as you can beginning with the letter ‘S’ . . . any words except surnames or proper nouns.” The meaning of surnames and proper nouns is explained, if needed. If the patient gives no response during the first five seconds, say “for instance,

snake.” If the patient pauses 10 seconds, stimulate him or her by saying “any word beginning with the letter S.” The patient is allowed 60 seconds to complete this task. As per the test instructions, surnames and proper nouns are not counted as correct responses. Additionally, only the first instance of a word that is repeated or offered in several variations (e.g., shoe, shoes, shoemaker; sun, sunny, sunspot) is counted in the word-list total. The procedure is repeated using the letters F and A as prompts for word list generation. Although the average adult is able to produce a list of more than nine words per minute for each of these letters, age and education strongly influence test performance; it therefore is prudent to use normative data to interpret results of word-list generation tasks [162]. Another version of this test asks the patient to list aloud as many animals (or foods or articles of clothing) as he or she can. The examiner allows one minute for each word-list generation. The majority of healthy adults are able to produce more than 12 words in each category. As with tests of phonemic fluency, age and education influence semantic fluency test performance; using normative data to interpret performance on such tests therefore is encouraged [162].

Executive control of visuospatial function The Executive Clock Drawing Test (CLOX) [136] is a brief constructional task assessing executive control functions, especially executive control of spatial attention, working memory, and visuospatial function. Alternatively, Mendez’ Clock Drawing Interpretation Scale [137] provides a method for scoring clock drawing tests undertaken in routine clinical practice using the instructions described in Box 23.5. Like the CLOX, this method of scoring clock drawing performance focuses the clinician’s attention on executive function. These and other assessments of executive control of visuospatial function [162] are useful to include in the cognitive examination.

Pattern recognition Pattern recognition requires the ability to identify ordered and predictable relationships between stimuli, objects, or events. Although pattern recognition occurs at a basic sensory level (i.e., object recognition), discerning patterns in more complex information sets requires executive function. This type of pattern recognition does not necessarily entail additional abstraction and may be assessed using verbal, graphic, or motor stimuli. For example, the examiner instructs

377


Figure 23.7. Luria’s fist-edge-palm series. The ability to perform a skilled movement involving three consecutive components is assessed by observing the patient’s ability to alternate between the positions demonstrated in either row A (Luria’s original sequence) or row B (an alternate used by the Colorado Group). This pattern is repeated up to 15 times, during which the examiner observes for transition hesitations, position errors, or breakdown in the performance of this sequence of movements.

the patient to provide answers to a set of verbal math problems: “1 + 1 =” (2), “2 + 2 =” (4), “4 + 3 =” (7), “7 + 4 =” (11), “11 + 5 =” (16), “16 + 6 =” (22), “22 + 7 =” (29). At the end of this sequence, the patient is asked, “What is the next problem?” (NB: the next problem is 29 + 8 = 37). The patient then is asked, “What was the pattern in this series of problems?” (NB: each new problem is created by adding the integer representing the place of the problem in this sequence (i.e., 1, 2, 3, 4, 5, 6, 7, 8) to the sum of the preceding problem). Some patients, especially those with mild executive dysfunction, recognize the pattern implicitly and state the next problem correctly but are unable to describe the pattern. When patients are unable to state the next problem or describe the pattern, the set of problems is presented visually in order to see if this facilitates pattern recognition. This is a challenging test, and its performance is easily compromised by attention, working memory, language, and calculation impairments and/or limited educational background. Poor performance on this task suggests executive dysfunction when these other factors are noncontributory. A behavioral version of this task begins with the examiner holding both hands palms up in front of the patient, in one of which a paper clip is held. The examiner asks the patient to point to the hand containing the paper clip. The examiner then closes both hands, places them behind his or her back, and brings them out again with both hands closed. The patient is asked

378

Figure 23.8. The Ozeretskii test. Reciprocal coordination of bilateral hand movements is assessed by asking the patient to alternate smoothly between the hand positions presented in panels A and B. This pattern is repeated up to 15 times, during which the examiner observes for transition hesitations, position errors, or breakdown in the performance of this sequence of movements.

to guess which hand holds the paper clip. After the patient makes a guess, both hands are opened, revealing the location of the paper clip. The patient is told that this procedure will be repeated several times and is asked to indicate the hand in which he believes the paper clip is held before the examiner reveals it. The examiner changes the hand in which the paperclip is held in a pre-determined pattern (for example, rightright-left). After several repetitions of the entire pattern, the examiner observes whether the patient learns the pattern, responds with an incorrect pattern or randomly, or perseveratively identifies one hand as containing the paper clip. When a patient appears to recognize the pattern, he is asked to describe it.

Complex motor sequencing Executive control of motor programming is assessed with tests requiring the dynamic organization of motor acts, and most commonly include the Luria’s fist-edge-palm series [178] (Figure 23.7) and the Ozeretskii test [179] (Figure 23.8). In these and the other complex motor sequencing tasks of Luria [178], the patient is instructed to smoothly perform a series comprising relatively simple individual movements organized into specific sequences. Although Luria originally described using both verbal and visual instructions for these tasks, the version of the fistedge-palm series included on the FAB [144] directs the examiner to demonstrate three repetitions of the sequence to the patient, engage the patient in an imitation of three repetitions of the sequence, and then to ask the patient to continue performing it independently. This approach precludes the opportunity for the patient to use verbal cues to support task performance. In the experience of the Colorado Group,


this is a useful approach to the administration of all of these tasks and tends to reveal impaired executive control of motor programming more readily than does administration employing verbal task instructions.

Environmental autonomy The ability to remain free from environmental contingencies (i.e., to retain environmental autonomy) requires executive function. Impairment of this ability results in stimulus-bound (or utilization) behavior, whereby the patient responds automatically to the content or events in his surroundings. Observations for stimulus-bound responding are made throughout the clinical encounter, and may be apparent on some of the cognitive tests presented earlier in this chapter (e.g., stimulus-bound hand placement on clock drawing tests, echopraxic responding on tests of conflicting instructions and/or inhibitory control). The FAB [144] tests environmental autonomy with a test for prehension behavior. The examiner, seated in front of the patient, places the patient’s hands palms up on the patient’s knees. Without saying anything or looking at the patient, the examiner brings his or her hands close to the patient’s hands and places them in the palms of the patient’s hands to see if he or she will grab them spontaneously. If the patient grabs the examiner’s hands, the examiner will try again after saying to the patient: “Now, do not take my hands.” Importantly, this is not a test for the grasp reflex (or grasp response): the patient’s palms are not stroked and the response observed for is not finger–thumb flexion. This is a test in which the patient is presented with a relatively potent but entirely ambiguous social cue. When the examiner places his hands in the patient’s hands, most healthy patients are so uncertain of the socially appropriate response that they do not respond at all. Those who are modestly disinhibited respond with a question seeking guidance on the desired response. Those whose environmental autonomy is compromised respond to this ambiguous social cue by grabbing the examiner’s hands without hesitation and/or continuing to grab the examiner’s hands even when instructed not to do so.

Abstraction Abstraction is the ability to make complex associations from or among objects or concepts, to organize

observations and associations into themes and generalities, and then to interpret them beyond their apparent or literal meaning (as in double meaning, inference, sarcasm, and satire). The assessment of abstract (or, conversely, concrete) thinking occurs throughout the clinical encounter. Observations as simple as the way a patient responds to the examiner’s opening question may offer immediate clues as to a patient’s ability to think abstractly. For example, the ostensibly simple question “What brings you here today?” is semantically ambiguous. Providing an answer that describes the reason for the clinical encounter (e.g., “I’m having trouble with my memory”) requires the patient to infer the intended meaning of the examiner’s question intent – that is, to perform an abstraction. Patients with limited ability to perform abstractions respond concretely by describing the method of transportation used to reach the encounter’s location (e.g., “The bus”). Abstraction is assessed commonly using tests of similarities as well as interpretation of idioms and/or proverbs. Tests of similarities (conceptualization, categorization) assess the ability to identify the abstract concept or category to which two concretely dissimilar objects belong (Table 23.16). Interpretation of idioms assesses the patient’s ability to describe the meaning of common sayings such as “carrying a chip on one’s shoulder” (holding a grudge or grievance that readily provokes anger and/or argument) or being “hardheaded” (stubborn, willful) or having “all thumbs” (clumsy). A more challenging test of abstraction is proverb interpretation (Table 23.17). When testing abstraction using either idioms or proverbs, the examiner asks the patient to “Please describe what people mean when they say . . . ” Testing abstraction requires the examiner to consider the patient’s educational, sociocultural, and language background; idioms, similarities, and proverbs used to test abstraction in native English-speakers from the USA may not translate well or be understood similarly by persons from other cultures or among whom English is a second language. Additionally, tests of abstraction may elicit bizarre, paranoid, macabre, pessimistic, or hopeless responses from patients with psychotic and/or mood disorders [12]. When these confounds on test interpretation are not present, however, difficulty interpreting similarities, idioms, and/or proverbs is concerning for impaired executive function [12].

379


Table 23.16. Examples of item sets used to assess abstraction (categorization), as well as examples of concrete, semi-abstract, and abstract interpretations. The patient is asked “In what way are these things alike?” If a patient responds “They are not alike” or offers a dissimilarity, then encouragement to respond is offered. On the Frontal Assessment Battery, failure to produce an abstract response to the first test of similarity (banana and orange) prompts an attempt to help the patient generate one. The examiner says “Both a banana and an orange are . . . ” but no points are given for the interpretation offered in response to this cue. Additional tests of similarities are then performed; cueing is not provided regardless of the patient’s responses.

Test stimulus

Statement of dissimilarity

Concrete interpretation

Semi-abstract interpretation

Abstract interpretation (conceptualization)

Banana and orange

One is round, the other is long

They have peels

They both are edible

They are fruits

Table and chair

You sit in a chair and eat at a table

They are made of wood They have four legs

You find them in a kitchen

They are furniture

Tulip, rose, and daisy

They are different colors

They have petals

They are in the garden

They are flowers

Painting and poem

You look at a painting and listen to a poem

They are written on paper

They are enjoyable

They are works of art

Fly and tree

A fly has wings, a tree has leaves

One is small and one is big

You usually find them outside

They are living things

Table 23.17. Examples of proverbs used to assess abstraction, as well as examples of concrete, semi-abstract, and abstract interpretations. Unfamiliarity with the proverb does not preclude the patient interpreting it. If the patient responds to the request for interpretation with “I don’t know” or “I don’t understand it” then encouragement to attempt an interpretation is offered (i.e., “If you heard someone say this expression, what might he or she be trying to communicate?”).

Concrete interpretation

A stitch in time saves nine

One stitch is less than nine

It takes less time to sew one stitch than nine

Fixing a problem when it is small prevents it from become a larger and more difficult one to fix

Even monkeys fall from trees

Monkeys fall out of trees

Some trees are difficult to climb, even for monkeys

Even experts make mistakes

Don’t judge a book by its cover

Don’t judge the cover

There is more to the book than its cover

The value of something should not be determined by superficial observation

People who live in glass houses shouldn’t throw stones

Throwing stones will break the glass

Some things are very vulnerable to damage

Those vulnerable to criticism should not criticize others

Interpreting cognitive test results Potential confounds on cognitive test results Before interpreting cognitive examination findings, several potential confounds on cognitive test performance require consideration. Age, neurodevelopmental disabilities, learning disorders, education level, social, cultural, and language backgrounds, and thought process disturbances may affect performance on cognitive tests [162]. Where possible, using tests with demonstrated validity and reliability among subjects demographically similar to the patient being evaluated is encouraged. When such tests are not available,

380

Semi-abstract interpretation

Proverb

Abstract interpretation

remaining circumspect about the meaning of test performance problems and the certitude with which one declares a patient impaired is essential. Depression, anxiety, psychosis, sensory and motor impairments, medical disorders, medication intoxication, and substance misuse-related conditions, among many others, may impair cognition directly and/or limit a patient’s ability to engage effectively in cognitive testing [12]. In the latter circumstance, “failure” on cognitive tests may reflect problems with engagement in testing rather than frank cognitive impairment. A qualitative assessment of effort and engagement during testing should be performed during all mental status examinations.


When a lack of effort is suspected (or when the context of the evaluation requires the examiner to be concerned a priori about limited effort, dissimulation, or malingering), quantitative assessment of effort is appropriate as well [180–182].

Qualitative interpretation of cognitive test results Qualitative interpretation of cognitive testing identifies the domains, character, and overall patterns of cognitive ability and impairment. This interpretation requires a thorough understanding of the cognitive functions upon which item-level performance is predicated. The clinician also must interpret performance on test items in a manner that considers, but is not restricted by, the boundaries implied by the domain(s) of cognition with which such tests are usually associated. Since most bedside tests rely on multiple cognitive functions, it is the overall pattern of performance across the entire set of tests that illuminates areas of cognitive deficit and strength. For example, a patient may demonstrate impaired performance on the vTMT-Part B, backward digit span, a clock drawing test, and test for similarities. Rather than presuming that impairments on these tests indicate impaired attention, working memory, constructional ability/visuospatial function, and executive function, the clinician performing qualitative interpretation of these findings analyzes the nature of the performance problems on these tests. This analysis might reveal perseveration on the vTMT-Part B, transpositions (rather than omissions) on backward digit span, poor planning and organization of the clock drawing test, and concrete interpretation of similarities, which collectively suggest that performance problems across this set of tests are most parsimoniously explained by executive dysfunction alone. Qualitative interpretation therefore emphasizes identification of the cognitive domains in which problems occur and the overall pattern of cognitive strengths and deficits. Recognition of those patterns suggests the anatomy of illness, and contributes to the development and refinement of the differential diagnosis.

Quantitative interpretation of cognitive test results Qualitative interpretation is complemented usefully by quantitative interpretation of cognitive test results using normative data for each measure administered. This permits not only characterization of the severity

of cognitive impairments but also, and perhaps most importantly, comparison of the patient’s performance on the measures administered to that expected of a person with similar demographic characteristics (e.g., age, education, premorbid intellectual quotient, culture, language background). Quantitative interpretation begins by transforming raw scores on the measures administered into Z-scores. These scores are calculated by identifying the mean and standard deviation (SD) of the patient’s demographically matched cohort described in the normative data table for each measure [138, 162, 169, 183]; those values are entered into this formula: Z-score = ([subject score] – [cohort mean]) ÷ [cohort standard deviation]

The Z-score places an individual patient’s performance on a cognitive screening test in context of the distribution of scores on that measure in the population to which he is compared (Figure 23.9). By convention, impairment is defined by Z-score ≤−2.0 [176], which corresponds roughly to the 2nd percentile in a normal distribution. In some contexts (e.g., evaluation for mild cognitive impairment) a more liberal threshold of Z-score ≤−1.5 is used, which corresponds roughly to the 7th percentile (at the borderline of impairment) in a normal distribution. The interpretation of cognitive performance on screening tests is improved by comparison against normative data: the risks of identifying a cognitively normal patient as impaired (false positive) and identifying a cognitively impaired patient as normal (false negative) entailed by reliance on “cut-offs” based on raw scores are reduced [140, 176, 184, 185] and a better appreciation of the patient’s performance relative to others of his age and/or education is afforded. This point is demonstrated by a brief exercise using the normative data for the MMSE developed by Crum et al. (1993) [169]. Using the above formula, the normative data table for the MMSE (Figure 23.10), and a liberal definition of impairment (Z-score ≤−1.5), a 65-year-old woman with 12 years of education must score 25 or less on the MMSE before her Z-score falls into the impaired range. By contrast, the performance of a 65-year-old woman with 8 years of education only falls into the impaired range with MMSE scores less than 23. An MMSE score of 23 is within the range of normal performance for an 85-year-old with 8 years of education, however, for whom impairment on this

381


x

−1.98σ

Probability of cases in portions of the curve ≈ 0.0013 Standard deviations −4σ from the mean Cumulative % Z scores T scores

−4.0

−2.58σ

1.98σ

95% of values

99% of values ≈ 0.1359 ≈ 0.3413 ≈ 0.3413

≈ 0.0214

2.58σ ≈ 0.1359

≈ 0.0013

≈ 0.0214

−3σ

−2σ

−1σ

0

+1σ

+2σ

+3σ

0.1%

2.3%

15.9%

50%

84.1%

97.7%

99.9%

−3.0

−2.0

−1.0

0

+1.0

+2.0

+3.0

20

30

40

50

60

70

80

+4σ +4.0

Figure 23.9. Illustration of the normal distribution and the relationships between standard deviations, cumulative percentages, percentile equivalents, Z-scores, and T-scores.

Figure 23.10. Population-based norms for the Mini-Mental State Examination (MMSE) stratified by age and education. Data were derived from the Epidemiologic Catchment Area household surveys of 18,056 individuals in New Haven, Connecticut, Baltimore, Maryland, St. Louis, Missouri, Durham, North Carolina, and Los Angeles, California between 1980 and 1984. The data are weighted based on the 1980 US population census by age, sex, and race. Each row provides information on the sample size (n), mean MMSE score, and standard deviation (SD) around that mean. Table adapted from Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level. J Am Med Assoc 1993;269(18):2386–91, with permission of the American Medical Association.

382


measure is liberally defined by an MMSE score ≤ 18. Given the substantial effects of age and education on MMSE performance, interpretation of raw score (i.e., using of raw “cut-off” scores) is not a reliable approach to determining impairment. This practice risks false positive and false negative impairment determinations as well as the diagnostic and therapeutic misadventures that such errors entail. The problems associated with using raw scorebased cut-offs to define cognitive impairment are not limited to the MMSE, and are encountered with most of the cognitive screening instruments used in BN&NP. For example, many clinicians working in settings providing services to older adults have adopted the Montreal Cognitive Assessment (MoCA) [142] as a cognitive screening assessment [6, 186–190]. Normative data derived from a population-based sample of 2653 ethnically diverse subjects [191] demonstrate markedly lower performance on this measure among healthy adults than reported in the MoCA validation sample [142]: more than 60% of participants performed below the previously suggested cut-off score of 26 for impairment, and the mean performance of all subgroups in which culture and language might influence test performance were below that cut-off. Education also exerted a significant effect on test performance, and the previously recommended 1-point education correction did not adjust adequately for that effect. There was an interaction between age and education such that MoCA scores decreased less with age among subjects with more than 12 years of education than among less educated subjects. The authors of this study [191], consistent with the recommendations of the ANPA CoR [140] and the standard practice in neuropsychology [162] (see also Chapter 24), recommend using population-based age- and educationbased norms to interpret and define impaired performance on the MoCA. This practice is prudent to apply to the interpretation of performance on all cognitive measures, especially when there are normative data available to guide those interpretations.

Cognitive impairment and functional status One counterargument to norm-based interpretation of cognitive test results suggests that comparison of an individual patient’s cognitive performance to that of a demographically matched cohort risks normalizing functionally important age-related (or educationrelated) cognitive dysfunction. A possible approach by

which to minimize this risk is comparing the cognitive test performance among older adults to that of functionally capable younger persons, and establishing cut-off scores for normal performance based on the mean and SD of the younger cohort. The success of this approach rests on the presumption that functional status depends principally on cognition. Although cognition plays an important role in many daily activities, the proportion of variance in functional status accounted for by most cognitive tests is relatively modest [176]. It is for this reason that cognitive impairments are necessary but usually not sufficient for the diagnosis of many cognitive disorders, including the dementias; these diagnoses also require that the observed cognitive impairments produce, or contribute substantially to, limitations in personal, social, occupational, or other important areas of everyday function [14, 192]. Assessing functional status therefore is an important part of the evaluation performed by subspecialists in BN&NP, and it is an undertaking distinct from (albeit often informed by) cognitive examination. In many cases, careful history-taking often makes clear the relationship between cognitive impairments and functional status. When it does not, or when there are questions about everyday functional abilities, consultation with and/or evaluation by rehabilitation specialists with expertise in standardized evaluations of functional status (e.g., rehabilitation psychologist, occupational therapist) may be necessary. Similarly, cognitive impairments (especially in the mild to moderate range) do not necessarily indicate a lack of decisional capacity or de facto incompetence. As with functional status, the assessment of decisional capacity may be informed by cognitive examination but is neither limited to nor adequately accomplished by this examination alone. Specific assessment of decisional capacity for the type of decision-making about which there are questions (e.g., medical issues, financial management, disposition, research) is required [193]. Interpretation of cognitive examination findings therefore is limited to establishing the presence, severity, and overall pattern of cognitive abilities and impairments. These findings are interpreted with respect to brain–behavior relationships, which in turn are used to construct both an anatomy of illness and also a differential diagnosis. Contextualizing cognitive examination findings within a comprehensive assessment, including history, neurological examination,

383


relevant neurodiagnostic assessments, and functional evaluation, is necessary to move from interpretation of the cognitive examination to diagnostic formulation. When cognitive impairments are very severe, this movement may be straightforward and rapid. When cognitive impairments are mild, focal, or fluctuating, however, it is appropriate to remain circumspect about the implications of cognitive impairments on functional status and to undertake the additional assessments needed to clarify that relationship.

Documenting the cognitive examination The written record of the cognitive examination begins with a statement describing the rationale for performing cognitive testing (e.g., cognitive complaints by patient, concerns about cognition expressed by others, referred for evaluation of a suspected cognitive disorder). The patient’s engagement in the cognitive examination, the quality of his effort during testing (e.g., excellent, fair, poor), and the examiner’s opinion on the validity of the test results are stated. When testing results are considered valid for interpretation, then the scope of the assessment (i.e., comprehensive, limited, domain-specific) and type of assessment (i.e., qualitative, quantitative, both) are characterized. When a qualitative assessment of cognition is performed, a concise narrative describing the domains of cognition assessed, the methods and/or bedside tests administered, and the patient’s performance on those tests should be provided. In general, the narrative description of the examination is organized most usefully by cognitive domain. When standardized cognitive tests are used, raw and Z-scores (for measures with reliable normative data) are recorded. These scores are supplemented by a description of itemlevel impairments on these tests (i.e., “named only one object, unable to name parts of objects,” “unable to repeat an agrammatical statement,” “did not perform correctly two steps in a three-step task”); areas in which normal performance is observed also should be identified.

Coding the cognitive examination as a neurobehavioral status examination Comprehensive and detailed domain-specific assessments performed and documented in this manner fulfill the requirements of the American Medical Association’s Current Procedural Terminology (CPT)

384

manual [4] for coding as a Neurobehavioral Status Exam (CPT 96116). Given the time and effort this procedure can entail, the availability of a billing code provides a mechanism by which to support performing it as a part of the everyday practice of BN&NP. The American Academy of Neurology provides advice on the performance and documentation of this procedure (http://www.aan.com/go/practice/coding/faqs#11). The Neurobehavioral Status Exam also requires that the clinician (physician or psychologist) spend no less than 31 minutes providing this service, which is coded as a “per hour” procedure. The time spent performing this procedure includes face-to-face administration of cognitive tests, scoring and interpreting test results, and preparing a report describing those results. The Neurobehavioral Status Exam may include, but cannot be limited to, the MMSE; other cognitive tests also must be performed and documented. This requirement is consistent with the position of the ANPA CoR [140], who recommend that clinicians using the MMSE supplement it with specific measures of spatial functions, delayed memory, and executive abilities. For example, combining the MMSE or MoCA with the FAB and/or a clock drawing test meets the content requirements for coding these procedures as a Neurobehavioral Status Examination. Critical to garnering support for this procedure in clinical practice is its documentation. The American Academy of Neurology recommends that documentation of the Neurobehavioral Status Examination be entered as a stand-alone document in the medical record. Alternatively, this documentation may be included as a section of the record for the clinical encounter during which it was performed provided that the report describing it is separately identifiable as such. The total time spent providing this service also must be documented clearly in report of the Neurobehavioral Status Examination.

Insight Insight, or self-awareness, refers to the capacity for understanding one’s own mental processes, problems, and circumstances, as well as the ability to understand the mental processes of others and the significance of events or actions. These are related but distinct capacities [194, 195], supporting the thesis that insight is not a unitary construct [196]. There also are substantial inter-individual differences in these capacities, even among healthy individuals [194].


Anosognosia, or unawareness of deficit, is a prototypic impairment of insight. It is associated historically with left hemiparesis and/or left hemi-neglect resulting from right hemisphere (especially parietal) injury. This association has been reconsidered in recent years, and studies of the neuroanatomy of self-awareness deficits across multiple syndromes suggest a broader network involving at least frontal and parietal areas [196, 197] as well as the networks involved in spatial attention [174]. Impaired insight relates more closely to executive dysfunction than to global cognitive impairment [198–203]. The assessment of insight during the interview and examination focuses on determining the extent to which a patient understands his own mental state, is able to identify relevant symptoms and signs as products of brain dysfunction, understands the effect of such problems on functional status and other people, and recognizes a need for treatment. The patient’s ability to formulate realistic hypotheses about the intentions and actions of others also merits assessment. Although psychological denial is sometimes observed in persons with neuropsychiatric conditions, this interpretation of self-awareness deficits is dubious among persons with marked cognitive impairments. It also is often countertherapeutic when made a focus of treatment. Educating family members, caregivers, and others about insight deficits associated with neuropsychiatric disorders may permit a constructive reframing that allows them to engage with the patient in a manner that facilitates adaptive function and avoids unproductive, albeit well-intentioned, attempts to help the patient recognize, accept, and “come to terms with” his condition. Structured interviews using measures designed specifically for these purposes, including the Awareness Questionnaire [86], Self-Awareness of Deficits Interview [204], or the Scale to Assess Unawareness of Mental Disorders [205], may facilitate the evaluation of insight. Information derived from their administration may inform not only on the patient’s insight but also approaches to the education and support of family, caregivers, and other clinicians. The information obtained from these scales also may contribute usefully to the development of interventions targeting treatment adherence problems, to the data entered into civil commitment or criminal proceedings, and to clinical decisions about the need for guardianship or proxy decision-making.

Judgment Judgment is the process of using reason to draw conclusions about an issue or situation and, in many instances, to make decisions or take actions based on those conclusions [2]. Making judgments requires motivation and insight sufficient to make an issue or situation personally meaningful, or at least personally relevant and important enough to prompt consideration. A relevant and accessible fund of knowledge as well as cognitive abilities (especially executive function) sufficient to process information about that issue or situation are needed to reason about the issue. Executive function is required to consider the range of outcomes likely to follow from decisions made or actions taken on the basis of one’s judgments. Social cognition is required to contextualize the matters and outcomes considered, their effects on others, and to guide considerations of what others might (or might not) consider sound reasoning and rational judgments. Some clinicians assess judgment by asking patients to describe their likely responses in hypothetical situations. For example, “If you were in a crowded movie theater and noticed a fire, what would you do?” or “If you found a stamped, addressed envelope on the ground, what would you do with it?” (NB: the “good judgment” answers to these questions are “Calmly tell the ushers so they can get people out of the theater safely.” and “Put it in a mailbox.”, respectively) However, this approach to assessing judgment is very simplistic, unlikely to be personally relevant to the patient, and usually uninformative. Exceptions to this general rule are patients offering bizarre or dangerous responses to these questions, but these are relatively uncommon. It is more informative to assess the patient’s ability to make judgments about matters that are personally relevant. These include proposed medical treatments, social and financial matters, advanced directives and the assignment of proxy medical decision-makers, and other personally important decisions. The ability to reason soundly and draw conclusions is the foundation of decisional capacity, the assessment of which is informed by, but distinct from, the mental status examination (see Chapter 25).

Conclusion The mental status examination is a systematic evaluation of a broad range of operations supporting mentation. The overall pattern of cognitive, emotional,

385


and behavioral function revealed by this examination provides information about brain function and dysfunction critical to evaluation and management in BN&NP. Information derived from this examination is integrated into a comprehensive assessment, inclusive of clinical history, general physical and neurological examinations, and relevant neurodiagnostic assessments. In conjunction with information obtained by all these means, the mental status examination helps clarify the anatomy of illness, permits construction of the differential diagnosis, directs additional examinations, investigations, and consultations, and establishes a baseline against which the course of illness and the effects of treatment are compared. Performing a complete mental status examination can be a daunting and time-consuming task, especially for clinicians relatively early in their training. However, experience fosters the ability to rapidly and efficiently survey each aspect of mental functioning and to focus detailed assessments on areas needed to reach an accurate diagnosis [1]. Whereas time constraints in medical practice often preclude the highly detailed assessment described in this chapter, the mental status examination is a foundation of BN&NP, and its expert application in selected settings is indispensible. Gaining experience with a wide range of mental status examination methods, including structured assessments of cognition, emotion, and behavior across a broad range of clinical populations, therefore is an important goal for those seeking to practice as subspecialists in BN&NP [11]. It is hoped that the information provided in this chapter will be of use to all those interested in achieving this goal or otherwise improving their mental status examination knowledge and skills.

References 1. Strub RL, Black FW. The Mental Status Examination in Neurology. 2nd edition. Philadelphia, PA: F.A. Davis; 1985. 2. Trzepacz PT, Baker RW. The Psychiatric Mental Status Examination. New York, NY: Oxford University Press; 1993. 3. Yudofsky SC, Kim HF. Neuropsychiatric Assessment. 1st edition. Washington, DC: American Psychiatric Publishers; 2004. 4. Abraham M, Ahlman JT, Boudreau A et al. CPT 2011: Current Procedural Terminology, Standard Edition. Fourth Revised Edition. Chicago, IL: American Medical Association Press; 2011.

386

5. Arciniegas DB, Beresford TP. Neuropsychiatry: An Introductory Approach. Cambridge: Cambridge University Press; 2001. 6. Faber RA. The neuropsychiatric mental status examination. Semin Neurol. 2009;29(3): 185–93. 7. Centers for Medicare & Medicaid Services, Department of Health and Human Services. Evaluation and Management Services Guide. Washington, DC: American Medical Association; 2010. 8. Strub RL, Black FW. The Mental Status Examination in Neurology. Philadelphia, PA: F. A. Davis Co.; 1977. 9. Schachter SC, Devinsky O. Behavioral Neurology and the Legacy of Norman Geschwind. Philadelphia, PA: Lippincott-Raven; 1997. 10. Hofmann WW. The mental status examination: an archaic instrument. Pract Neurol. 2008;7(12):26–8. 11. Arciniegas DB, Kaufer DI, Joint Advisory Committee on subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13. 12. Cummings JL, Mega MS. Neuropsychiatry and Behavioral Neuroscience. Oxford: Oxford University Press; 2003. 13. Stedman TL. Stedman’s Medical Dictionary. 28th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. 14. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision: DSM–IV–TR. 4th edition. Washington, DC: American Psychiatric Association; 2000. 15. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: DSM–IV. Washington, DC: American Psychiatric Association; 2000. 16. American Psychiatric Association. Work Group to Revise DSM–III. Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised: DSM–III–R. Washington, DC: American Psychiatric Association; 1987. 17. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–76. 18. Kay SR, Opler LA, Fiszbein A. Genetics of schizophrenia and the positive-negative dimension. Am J Psychiatry 1985;142(8):994–6. 19. Jardri R, Pouchet A, Pins D, Thomas P. Cortical activations during auditory verbal hallucinations in


schizophrenia: a coordinate-based meta-analysis. Am J Psychiatry 2011;168(1):73–81.

disorder. J Neuropsychiatry Clin Neurosci. 2008;20(4): 390–408.

20. Jones SR. Do we need multiple models of auditory verbal hallucinations? Examining the phenomenological fit of cognitive and neurological models. Schizophr Bull. 2010;36(3):566–75.

33. Sharp DJ, Bonnelle V, De Boissezon X et al. Distinct frontal systems for response inhibition, attentional capture, and error processing. Proc Natl Acad Sci USA 2010;107(13):6106–11.

21. van der Gaag M. A neuropsychiatric model of biological and psychological processes in the remission of delusions and auditory hallucinations. Schizophr Bull. 2006;32(Suppl. 1):S113–22.

34. Groman SM, James AS, Jentsch JD. Poor response inhibition: at the nexus between substance abuse and attention deficit/hyperactivity disorder. Neurosci Biobehav Rev. 2009;33(5):690–8.

22. Ismail Z, Nguyen MQ, Fischer CE et al. Neurobiology of delusions in Alzheimer’s disease. Curr Psychiatry Rep. 2011;13(3):211–18.

35. Soyka M. Neurobiology of aggression and violence in schizophrenia. Schizophr Bull. 2011;37(5): 913–20.

23. Krishnan RR, Kraus MS, Keefe RS. Comprehensive model of how reality distortion and symptoms occur in schizophrenia: could impairment in learning-dependent predictive perception account for the manifestations of schizophrenia? Psychiatry Clin Neurosci. 2011;65(4):305–17.

36. Heinz AJ, Beck A, Meyer-Lindenberg A, Sterzer P, Heinz A. Cognitive and neurobiological mechanisms of alcohol-related aggression. Nat Rev Neurosci. 2011;12(7):400–13.

24. Voss M, Moore J, Hauser M et al. Altered awareness of action in schizophrenia: a specific deficit in predicting action consequences. Brain 2010;133(10):3104–12. 25. Synofzik M, Thier P, Leube DT, Schlotterbeck P, Lindner A. Misattributions of agency in schizophrenia are based on imprecise predictions about the sensory consequences of one’s actions. Brain 2010;133(Pt 1): 262–71. 26. Assaf M, Rivkin PR, Kuzu CH et al. Abnormal object recall and anterior cingulate overactivation correlate with formal thought disorder in schizophrenia. Biol Psychiatry 2006;59(5):452–9. 27. Kircher T, Liddle P, Brammer M, Murray R, McGuire P. Neural correlates of “negative” formal thought disorder. Nervenarzt 2003;74(9):748–54. 28. Shenton ME, Kikinis R, Jolesz FA et al. Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. N Engl J Med. 1992;327(9):604–12.

37. Diaz JL. The psychobiology of aggression and violence: bioethical implications. Int Soc Sci J. 2010; 61(200–201):233–45. 38. Seo D, Patrick CJ, Kennealy PJ. Role of serotonin and dopamine system interactions in the neurobiology of impulsive aggression and its comorbidity with other clinical disorders. Aggress Violent Behav. 2008;13(5): 383–95. 39. Parvizi J, Anderson SW, Martin CO, Damasio H, Damasio AR. Pathological laughter and crying: a link to the cerebellum. Brain 2001;124(Pt 9):1708–19. 40. Wilson SA. Some problems in neurology. II. Pathological laughing and crying. J Neurol Psychopathol. 1924;4(16):299–333. 41. Wortzel HS, Oster TJ, Anderson CA, Arciniegas DB. Pathological laughing and crying: epidemiology, pathophysiology and treatment. CNS Drugs 2008;22(7):531–45. 42. Vuilleumier P. Hysterical conversion and brain function. Prog Brain Res. 2005;150:309–29. 43. Fundukian LJ, Gale Group. The Gale Encyclopedia of Medicine. 4th edition. Detroit, MI: Gale; 2011.

29. Seese RR, O’Neill J, Hudkins M et al. Proton magnetic resonance spectroscopy and thought disorder in childhood schizophrenia. Schizophr Res. 2011; 133(1–3):82–90.

44. Mosby Inc. Mosby’s Medical Dictionary. 8th edition. St. Louis, MO: Mosby; 2009.

30. Insel TR. Toward a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiatry 1992;49(9):739–44.

45. Miller BF. Encyclopedia & Dictionary of Medicine, Nursing, and Allied Health. 7th edition. Philadelphia, PA: Saunders; 2003.

31. Modell JG, Mountz JM, Curtis GC, Greden JF. Neurophysiologic dysfunction in basal ganglia/limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 1989;1(1):27–36.

46. Stevenson A. Oxford Dictionary of English. 3rd edition. Oxford: Oxford University Press; 2010.

32. Huey ED, Zahn R, Krueger F et al. A psychological and neuroanatomical model of obsessive-compulsive

47. Lee S, Tsang A, Mak A et al. Concordance between telephone survey classification and face-to-face interview diagnosis of one-year major depressive episode in Hong Kong. J Affect Disord. 2010;126(1–2): 155–60.

387


48. Hajebi A, Motevalian A, Amin-Esmaeili M et al. Telephone versus face-to-face administration of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for diagnosis of psychotic disorders. Compr Psychiatry 2012;53(5):579–83. 49. Crippa JA, de Lima Osorio F, Del-Ben CM et al. Comparability between telephone and face-to-face structured clinical interview for DSM-IV in assessing social anxiety disorder. Perspect Psychiatr Care 2008;44(4):241–7. 50. Hallerod SL, Larson T, Stahlberg O et al. The Autism–Tics, AD/HD and other Comorbidities (A-TAC) telephone interview: convergence with the Child Behavior Checklist (CBCL). Nord J Psychiatry 2010;64(3):218–24. 51. Steffens DC, Maytan M, Helms MJ, Plassman BL. Prevalence and clinical correlates of neuropsychiatric symptoms in dementia. Am J Alzheimers Dis Other Demen. 2005;20(6):367–73. 52. Cook SE, Marsiske M, McCoy KJ. The use of the Modified Telephone Interview for Cognitive Status (TICS-M) in the detection of amnestic mild cognitive impairment. J Geriatr Psychiatry Neurol. 2009;22(2): 103–9.

62. Derogatis LR. SCL-90-R: Administration, Score, and Procedures Manual. 3rd edition. Minneapolis, MN: National Computer Systems, Inc.; 1994. 63. Butcher JN, Dahlstrom WG, Graham JR, Tellegen A, Kaemmer B. Minnesota Multiphasic Personality Inventory-2 (MMPI-2): Manual for Administration and Scoring. Minneapolis, MN: University of Minnesota Press; 1989. 64. First MB. Structured Clinical Interview for DSM Disorders (SCID). New York, NY: Biometrics Research Department, Columbia University at NYSPI; 2011. 65. Sheehan DV, Lecrubier Y, Sheehan KH et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59 (Suppl. 20):22–33;quiz 4–57. 66. Millon T. Millon Clinical Multiaxial Inventory-III (MCMI-III) Manual. 3rd edition. Minneapolis, MN: Pearson Assessments; 2006.

53. Brandt J, Spencer M, Folstein M. The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol. 1988;1(2):111–17.

67. McCauley SR, Levin HS, Vanier M et al. The neurobehavioural rating scale-revised: sensitivity and validity in closed head injury assessment. J Neurol Neurosurg Psychiatry 2001;71(5):643–51.

54. Crooks VC, Petitti DB, Robins SB, Buckwalter JG. Cognitive domains associated with performance on the telephone interview for cognitive status–modified. Am J Alzheimers Dis Other Demen. 2006;21(1):45–53.

68. Roth RM, Isquith PK, Gioia GA. Behavioral Rating Inventory of Executive Function–Adult Version. Lutz, FL: Psychological Assessment Resources; 2005.

55. Ray R, Perkins E, Meijer B. The evolution of practice changes in the use of special observations. Arch Psychiatr Nurs. 2011;25(2):90–100. 56. Novaco RW, Taylor JL. Assessment of anger and aggression in male offenders with developmental disabilities. Psychol Assess. 2004;16(1):42–50. 57. Sclafani MJ, Humphrey FJ, 2nd, Repko S et al. Reducing patient restraints: a pilot approach using clinical case review. Perspect Psychiatr Care. 2008; 44(1):32–9. 58. Hsee CK, Hatfield E, Chemtob C. Assessments of the emotional states of others – conscious judgments versus emotional contagion. J Soc Clin Psychol. 1992;11(2):119–28. ¨ un TB. Diagnosis and 59. Wing JK, Sartorius N, Ust¨ Clinical Measurement in Psychiatry: A Reference Manual for SCAN. Cambridge: Cambridge University Press; 1998. 60. Overall JE, Gorham DR. The brief psychiatric rating scale. Psych Rep. 1962;10:799–812.

388

61. Kreutzer JS, Marwitz JH, Seel R, Serio CD. Validation of a neurobehavioral functioning inventory for adults with traumatic brain injury. Arch Phys Med Rehabil. 1996;77(2):116–24.

69. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14(6):540–5. 70. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213. 71. Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101(4):323–9. 72. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. 73. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory–II. San Antonio, TX: Psychological Corporation; 1996. 74. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978;133:429–35.


75. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–5. 76. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56(6):893–7. 77. Spielberger CD, Gorsuch RL, Lushene R. Test Manual for the State–Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press; 1970. 78. Blanchard EB, Jones-Alexander J, Buckley TC, Forneris CA. Psychometric properties of the PTSD Checklist (PCL). Behav Res Ther. 1996;34(8):669–73. 79. Goodman WK, Price LH, Rasmussen SA et al. The Yale–Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989;46(11):1006–11. 80. Goodman WK, Price LH, Rasmussen SA et al. The Yale–Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry 1989;46(11):1012–16. 81. Moore SR, Gresham LS, Bromberg MB, Kasarkis EJ, Smith RA. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63(1):89–93. 82. Corrigan JD. Development of a scale for assessment of agitation following traumatic brain injury. J Clin Exp Neuropsychol. 1989;11(2):261–77. 83. Corrigan JD, Bogner JA. Factor structure of the Agitated Behavior Scale. J Clin Exp Neuropsychol. 1994;16(3):386–92. 84. Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D. The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986;143(1):35–9. 85. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 1991;38(2):143–62. 86. Sherer M, Bergloff P, Boake C, High W, Jr., Levin E. The Awareness Questionnaire: factor structure and internal consistency. Brain Inj. 1998;12(1):63–8. 87. Grisso T, Appelbaum PS. MacArthur Competence Assessment Tool for Treatment (MacCAT-T). Sarasota, FL: Professional Resource Press; 1998. 88. Cummings JL, Mega M, Gray K et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44(12):2308–14. 89. Rohrer JD, Warren JD. Phenomenology and anatomy of abnormal behaviours in primary progressive aphasia. J Neurol Sci. 2010;293(1–2):35–8. 90. Angelelli P, Paolucci S, Bivona U et al. Development of neuropsychiatric symptoms in poststroke patients: a cross-sectional study. Acta Psychiatr Scand. 2004; 110(1):55–63.

91. Kulisevsky J, Pagonabarraga J, Pascual-Sedano B, Garcia-Sanchez C, Gironell A. Prevalence and correlates of neuropsychiatric symptoms in Parkinson’s disease without dementia. Mov Disord. 2008;23(13):1889–96. 92. Krishnamoorthy ES, Trimble MR. Prevalence, patterns, service needs, and assessment of neuropsychiatric disorders among people with epilepsy in residential care: validation of the Neuropsychiatric Inventory as a caregiver-rated measure of neuropsychiatric functioning in epilepsy. Epilepsy Behav. 2008;13(1):223–8. 93. Figved N, Klevan G, Myhr KM et al. Neuropsychiatric symptoms in patients with multiple sclerosis. Acta Psychiatr Scand. 2005;112(6):463–8. 94. Aarsland D, Bronnick K, Alves G et al. The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease. J Neurol Neurosurg Psychiatry 2009;80(8):928–30. 95. Masanic CA, Bayley MT, VanReekum R, Simard M. Open-label study of donepezil in traumatic brain injury. Arch Phys Med Rehabil. 2001;82(7): 896–901. 96. Ciurli P, Formisano R, Bivona U, Cantagallo A, Angelelli P. Neuropsychiatric disorders in persons with severe traumatic brain injury: prevalence, phenomenology, and relationship with demographic clinical and functional features. J Head Trauma Rehabil. 2011;26(2):116–26. 97. Cummings JL, McRae T, Zhang R. Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders. Am J Geriatr Psychiatry 2006;14(7):605–12. 98. Wood S, Cummings JL, Hsu MA et al. The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 2000;8(1):75–83. 99. de Medeiros K, Robert P, Gauthier S et al. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. Int Psychogeriatr. 2010;22(6):984–94. 100. Kaufer DI, Cummings JL, Ketchel P et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci. 2000;12(2):233–9. 101. Burns A, Lawlor B, Craig S. Assessment Scales in Old Age Psychiatry. London: Martin Dunitz; 1999. 102. Tate RL. A Compendium of Tests, Scales, and Questionnaires: The Practitioner’s Guide to Measuring Outcomes after Acquired Brain Impairment. Hove: Psychology Press; 2010.

389


103. Damasio AR. Descartes’ Error: Emotion, Reason, and the Human Brain. New York, NY: Putnam; 1994. 104. Hinson JM, Jameson TL, Whitney P. Somatic markers, working memory, and decision making. Cogn Affect Behav Neurosci. 2002;2(4):341–53. 105. Fulcher E. Cognitive Psychology. Exeter: Crucial; 2003. 106. LeDoux JE. The Emotional Brain: The Mysterious Underpinnings of Emotional Life. New York, NY: Simon & Schuster; 1996. 107. Sagala J, Gilmour L. Thesaurus: A Dictionary of Synonyms. New edition. New York, NY: HarperResource; 2002. 108. Kleinke CL. Gaze and eye contact: a research review. Psychol Bull. 1986;100(1):78–100. 109. MacDonald K. Patient–clinician eye contact: social neuroscience and art of clinical engagement. Postgrad Med. 2009;121(4):136–44. 110. Senju A, Johnson MH. The eye contact effect: mechanisms and development. Trends Cogn Sci. 2009;13(3):127–34. 111. Davidhizar R. Interpersonal communication: a review of eye contact. Infect Control Hosp Epidemiol. 1992;13(4):222–5.

121. Haviland MG, Warren WL, Riggs ML. An observer scale to measure alexithymia. Psychosomatics 2000; 41(5):385–92. 122. Mehrabian A. Silent Messages: Implicit Communication of Emotions and Attitudes. 2nd edition. Belmont, CA: Wadsworth Publishing Co.; 1981. 123. Argyle M, Salter V, Nicholson H, Williams M, Burgess P. Communication of inferior and superior attitudes by verbal and non-verbal signals. Br J Soc Clin Psych. 1970;9:221–31. 124. Titze IR. The human instrument. Sci Am. 2008;298(1): 94–101. 125. Liotti M, Ramig LO, Vogel D et al. Hypophonia in Parkinson’s disease: neural correlates of voice treatment revealed by PET. Neurology 2003;60(3): 432–40. 126. Basso A, Cattaneo S, Girelli L et al. Treatment efficacy of language and calculation disorders and speech apraxia: a review of the literature. Eur J Phys Rehabil Med. 2011;47(1):101–21. 127. Parry WD. Stuttering and the valsalva mechanism – a hypothesis in need of investigation. J Fluency Disord. 1985;10(4):317–24.

112. Damasio AR. Looking for Spinoza: Joy, Sorrow, and the Feeling Brain. 1st edition. Orlando, FL: Harcourt; 2003.

128. Nisbett RE, Peng K, Choi I, Norenzayan A. Culture and systems of thought: holistic versus analytic cognition. Psychol Rev. 2001;108(2):291–310.

113. Cornelius RR. The Science of Emotion: Research and Tradition in the Psychology of Emotions. Upper Saddle River, NJ: Prentice Hall; 1996.

129. Nisbett RE, Miyamoto Y. The influence of culture: holistic versus analytic perception. Trends Cogn Sci. 2005;9(10):467–73.

114. Jackson M. Emotion and Psyche. Ropley, UK: John Hunt Publishing; 2010.

130. Goh JO, Park DC. Culture sculpts the perceptual brain. Prog Brain Res. 2009;178:95–111.

115. Gregory RL. The Oxford Companion to the Mind. 2nd edition. Oxford: Oxford University Press; 2004.

131. Dyche L, Swiderski D. The effect of physician solicitation approaches on ability to identify patient concerns. J Gen Intern Med. 2005;20(3): 267–70.

116. Arciniegas DB, Topkoff J, Silver JM. Neuropsychiatric aspects of traumatic brain injury. Curr Treat Options Neurol. 2000;2(2):169–86. 117. Gallo JJ, Rabins PV, Lyketsos CG, Tien AY, Anthony JC. Depression without sadness: functional outcomes of nondysphoric depression in later life. J Am Geriatr Soc. 1997;45(5):570–8. 118. Gallo JJ, Anthony JC, Muthen BO. Age differences in the symptoms of depression: a latent trait analysis. J Gerontol. 1994;49(6):P251–64. 119. Taylor GJ, Bagby RM, Parker JDA. Disorders of Affect Regulation: Alexithymia in Medical and Psychiatric Illness. Cambridge: Cambridge University Press; 1997. 120. Luminet O, Bagby RM, Wagner H, Taylor GJ, Parker JD. Relation between alexithymia and the five-factor model of personality: a facet-level analysis. J Pers Assess. 1999;73(3):345–58.

390

132. Li HZ, Krysko M, Desroches NG, Deagle G. Reconceptualizing interruptions in physician-patient interviews: cooperative and intrusive. Commun Med. 2004;1(2):145–57. 133. Rhoades DR, McFarland KF, Finch WH, Johnson AO. Speaking and interruptions during primary care office visits. Fam Med. 2001;33(7):528–32. 134. Vanier M, Mazaux JM, Lambert J, Dassa C, Levin HS. Assessment of neuropsychologic impairments after head injury: interrater reliability and factorial and criterion validity of the Neurobehavioral Rating Scale-Revised. Arch Phys Med Rehabil. 2000;81(6): 796–806. 135. Shulman KI. Clock-drawing: is it the ideal cognitive screening test? Int J Geriatr Psychiatry 2000;15(6): 548–61.


136. Royall DR, Cordes JA, Polk M. CLOX: an executive clock drawing task. J Neurol Neurosurg Psychiatry 1998;64(5):588–94. 137. Mendez MF, Ala T, Underwood KL. Development of scoring criteria for the clock drawing task in Alzheimer’s disease. J Am Geriatr Soc. 1992;40(11): 1095–9. 138. Freedman M. Clock Drawing: A Neuropsychological Analysis. New York, NY: Oxford University Press; 1994. 139. Borson S, Scanlan J, Brush M, Vitaliano P, Dokmak A. The mini-cog: a cognitive ‘vital signs’ measure for dementia screening in multi-lingual elderly. Int J Geriatr Psychiatry 2000;15(11):1021–7. 140. Malloy PF, Cummings JL, Coffey CE et al. Cognitive screening instruments in neuropsychiatry: a report of the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 1997;9(2):189–97. 141. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98. 142. Nasreddine ZS, Phillips NA, Bedirian V et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9. 143. Kaplan E. The process approach to neuropsychological assessment of psychiatric patients. J Neuropsychiatry Clin Neurosci. 1990;2(1):72–87. 144. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment Battery at bedside. Neurology 2000;55(11):1621–6. 145. Teng EL, Chui HC. The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987;48(8): 314–18. 146. Tariq SH, Tumosa N, Chibnall JT, Perry MH, 3rd, Morley JE. Comparison of the Saint Louis University mental status examination and the mini-mental state examination for detecting dementia and mild neurocognitive disorder – a pilot study. Am J Geriatr Psychiatry 2006;14(11):900–10.

and diagnostic utility. Arch Phys Med Rehabil. 2004;85(12):2020–9. 150. Trzepacz PT, Mittal D, Torres R et al. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci. 2001;13(2):229–42. 151. Levin HS, O’Donnell VM, Grossman RG. The Galveston Orientation and Amnesia Test. A practical scale to assess cognition after head injury. J Nerv Ment Dis. 1979;167(11):675–84. 152. Jackson WT, Novack TA, Dowler RN. Effective serial measurement of cognitive orientation in rehabilitation: the Orientation Log. Arch Phys Med Rehabil. 1998;79(6):718–20. 153. Power E, Code C, Croot K, Sheard C, Gonzalez Rothi LJ. Florida Apraxia Battery-Extended and Revised Sydney (FABERS): design, description, and a healthy control sample. J Clin Exp Neuropsychol. 2010;32(1):1–18. 154. Weintraub S, Peavy GM, O’Connor M et al. Three words three shapes: a clinical test of memory. J Clin Exp Neuropsychol. 2000;22(2):267–78. 155. Mesulam MM. Principles of Behavioral Neurology. Philadelphia, PA: F.A. Davis; 1985. 156. Lowery N, Ragland JD, Gur RC, Gur RE, Moberg PJ. Normative data for the symbol cancellation test in young healthy adults. Appl Neuropsychol. 2004;11(4):218–21. 157. Kiernan RJ, Mueller J, Langston JW, Van Dyke C. The Neurobehavioral Cognitive Status Examination: a brief but quantitative approach to cognitive assessment. Ann Intern Med. 1987;107(4):481–5. 158. Schwamm LH, Van Dyke C, Kiernan RJ, Merrin EL, Mueller J. The Neurobehavioral Cognitive Status Examination: comparison with the Cognitive Capacity Screening Examination and the Mini-Mental State Examination in a neurosurgical population. Ann Intern Med. 1987;107(4):486–91. 159. Grigsby J, Kaye K, Robbins LJ. Reliabilities, norms and factor structure of the Behavioral Dyscontrol Scale. Percept Mot Skills 1992;74(3 Pt 1):883–92.

147. Nakase-Thompson R, Manning E, Sherer M et al. Brief assessment of severe language impairments: initial validation of the Mississippi aphasia screening test. Brain Inj. 2005;19(9):685–91.

160. Kaye K, Grigsby J, Robbins LJ, Korzun B. Prediction of independent functioning and behavior problems in geriatric patients. J Am Geriatr Soc. 1990;38(12): 1304–10.

148. Seel RT, Sherer M, Whyte J et al. Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil. 2010;91(12):1795–813.

161. Bernstein IH, Lacritz L, Barlow CE, Weiner MF, DeFina LF. Psychometric evaluation of the Montreal Cognitive Assessment (MoCA) in three diverse samples. Clin Neuropsychol. 2011;25(1):119–26.

149. Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics

162. Strauss E, Sherman EMS, Spreen O. A Compendium of Neuropsychological Tests: Administration, Norms, and

391


Commentary. 3rd edition. Oxford: Oxford University Press; 2006. 163. Plum F, Posner JB. The Diagnosis of Stupor and Coma. Philadelphia, PA: F. A. Davis Co.; 1966. 164. Ricker JH, Axelrod BN. Analysis of an oral paradigm for the Trail Making Test. Assessment 1994;1(1): 47–52. 165. Ruchinskas RA. Limitations of the Oral Trail Making Test in a mixed sample of older individuals. Clin Neuropsychol. 2003;17(2):137–42. 166. Bischoff B, Romstock J, Fahlbusch R, Buchfelder M, Strauss C. Intraoperative brainstem auditory evoked potential pattern and perioperative vasoactive treatment for hearing preservation in vestibular schwannoma surgery. J Neurol Neurosurg Psychiatry 2008;79(2):170–5. 167. Weintraub S. Neuropsychological assessment of mental state. In Mesulam M-M, editor. Principles of Behavioral and Cognitive Neurology. Oxford: Oxford University Press; 2000, pp. 121–73. 168. Lehto JH. Are executive function tests dependent on working memory capacity? Q J Exp Psychol–A. 1996;49(1):29–50. 169. Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level. J Am Med Assoc 1993;269(18):2386–91. 170. .Karrasch M, Myllyniemi A, Latvasalo L et al. The diagnostic accuracy of an incidental memory modification of the Boston Naming Test (memo-BNT) in differentiating between normal aging and mild Alzheimer’s disease. Clin Neuropsychol. 2010;24(8):1355–64. 171. Kusev P, Ayton P, van Schaik P et al. Judgments relative to patterns: how temporal sequence patterns affect judgments and memory. J Exp Psychol Hum Percept Perform. 2011;37(6):1874–86. 172. Fuhrman RW, Wyer RS, Jr. Event memory: temporal-order judgments of personal life experiences. J Pers Soc Psychol. 1988;54(3):365–84. 173. Didic M, Barbeau EJ, Felician O et al. Which memory system is impaired first in Alzheimer’s Disease? J Alzheimers Dis. 2011;27(1):11–22. 174. Mesulam M-M. Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system, and hemispheric specializations. In Mesulam MM, editor. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 1–120. 175. Royall DR, Lauterbach EC, Cummings JL et al. Executive control function: a review of its promise and challenges for clinical research. A report from the

392

Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2002;14(4):377–405. 176. Royall DR, Lauterbach EC, Kaufer D et al. The cognitive correlates of functional status: a review from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2007;19(3):249–65. 177. Royall DR, Mahurin RK, Gray KF. Bedside assessment of executive cognitive impairment: the executive interview. J Am Geriatr Soc. 1992;40(12):1221–6. 178. Luria AR. Higher Cortical Functions in Man. 2nd edition. New York, NY: Basic Books; 1980. 179. Gurevich M, Ozeretskii N. Psychomotor Functions. Moscow: Medgiz; 1930. 180. Reznek L. The Rey 15-item memory test for malingering: a meta-analysis. Brain Inj. 2005;19(7): 539–43. 181. Tan JE, Slick DJ, Strauss E, Hultsch DF. How’d they do it? Malingering strategies on symptom validity tests. Clin Neuropsychol. 2002;16(4):495–505. 182. Rohling ML, Demakis GJ. Bowden, Shores, & Mathias (2006): failure to replicate or just failure to notice. Does effort still account for more variance in neuropsychological test scores than TBI severity? Clin Neuropsychol. 2010;24(1):119–36. 183. Appollonio I, Leone M, Isella V et al. The Frontal Assessment Battery (FAB): normative values in an Italian population sample. Neurol Sci. 2005;26(2): 108–16. 184. Arciniegas DB, Kellermeyer GF, Bonifer NM, Anderson-Salvi KM, Anderson CA. Screening for cognitive decline following single known stroke using the Mini-Mental State Examination. Neuropsychiatr Dis Treat. 2011;7:189–96. 185. Oskarsson B, Quan D, Rollins YD et al. Using the Frontal Assessment Battery to identify executive function impairments in amyotrophic lateral sclerosis: a preliminary experience. Amyotroph Lateral Scler. 2010;11(1–2):244–7. 186. Chou KL, Amick MM, Brandt J et al. A recommended scale for cognitive screening in clinical trials of Parkinson’s disease. Mov Disord. 2010;25(15): 2501–7. 187. Cumming TB, Bernhardt J, Linden T. The Montreal cognitive assessment: short cognitive evaluation in a large stroke trial. Stroke 2011;42(9):2642–4. 188. Harkness K, Demers C, Heckman GA, McKelvie RS. Screening for cognitive deficits using the Montreal cognitive assessment tool in outpatients ⬎/=65 years of age with heart failure. Am J Cardiol. 2011;107(8): 1203–7.


189. Olson RA, Chhanabhai T, McKenzie M. Feasibility study of the Montreal Cognitive Assessment (MoCA) in patients with brain metastases. Support Care Cancer 2008;16(11):1273–8. 190. Damian AM, Jacobson SA, Hentz JG et al. The Montreal Cognitive Assessment and the mini-mental state examination as screening instruments for cognitive impairment: item analyses and threshold scores. Dement Geriatr Cogn Disord. 2011;31(2): 126–31. 191. Rossetti HC, Lacritz LH, Cullum CM, Weiner MF. Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology 2011;77(13):1272–5. 192. Petersen RC, Stevens JC, Ganguli M et al. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56(9): 1133–42. 193. Etchells E, Sharpe G, Elliott C, Singer PA. Bioethics for clinicians: 3. Capacity. Can Med Assoc J 1996;155(6): 657–61.

197. Sherer M, Hart T, Whyte J, Nick TG, Yablon SA. Neuroanatomic basis of impaired self-awareness after traumatic brain injury: findings from early computed tomography. J Head Trauma Rehabil. 2005;20(4): 287–300. 198. Young DA, Davila R, Scher H. Unawareness of illness and neuropsychological performance in chronic schizophrenia. Schizophr Res. 1993;10(2):117–24. 199. Mohamed S, Fleming S, Penn DL, Spaulding W. Insight in schizophrenia: its relationship to measures of executive functions. J Nerv Ment Dis. 1999;187(9): 525–31. 200. McEvoy JP, Apperson LJ, Appelbaum PS et al. Insight in schizophrenia. Its relationship to acute psychopathology. J Nerv Ment Dis. 1989;177(1):43–7. 201. Lysaker P, Bell M. Insight and cognitive impairment in schizophrenia. Performance on repeated administrations of the Wisconsin Card Sorting Test. J Nerv Ment Dis. 1994;182(11):656–60. 202. David A, van Os J, Jones P et al. Insight and psychotic illness. Cross-sectional and longitudinal associations. Br J Psychiatry 1995;167(5):621–8.

194. Gardner H. Frames of Mind: The Theory of Multiple Intelligences. New York, NY: Basic Books; 1983.

203. Cuesta MJ, Peralta V, Caro F, de Leon J. Is poor insight in psychotic disorders associated with poor performance on the Wisconsin Card Sorting Test? Am J Psychiatry 1995;152(9):1380–2.

195. Bach LJ, David AS. Self-awareness after acquired and traumatic brain injury. Neuropsychol Rehabil. 2006;16(4):397–414.

204. Fleming JM, Strong J, Ashton R. Self-awareness of deficits in adults with traumatic brain injury: how best to measure? Brain Inj. 1996;10(1):1–15.

196. Flashman LA. Disorders of awareness in neuropsychiatric syndromes: an update. Curr Psychiatry Rep. 2002;4(5):346–53.

205. Amador XF, Strauss DH, Yale SA et al. Assessment of insight in psychosis. Am J Psychiatry 1993;150(6): 873–9.

393

Section II


Chapter

Neuropsychological assessment

24

C. Munro Cullum

Neuropsychological, or neurocognitive, assessment is an important component of the comprehensive neurodiagnostic evaluation of many patients with suspected or known brain dysfunction. The neurocognitive tests that comprise these evaluations reflect an extension and refinement of the Behavioral Neurology & Neuropsychiatry (BN&NP) examination through the use of highly standardized tests that assess various aspects of cognition and behavior. These tests sample cognitive output of the brain in a standard, objective fashion that forms the basis of the neuropsychological evaluation and allows for a quantified assessment of the neurocognitive effects of various neuromedical conditions. As such, they provide an indirect measure of brain function and represent the most sensitive means we have of assessing human cognitive/brain function. A cornerstone of neuropsychological assessment is the use of norm-referenced data that allow for an individual’s performance on a particular test or group of tests to be compared with general or specific population-based results. This allows for a statistical comparison of test performance characteristics, which help determine level of functioning in multiple cognitive domains. Individual neurocognitive strengths and weaknesses can be determined based upon careful analysis of qualitative as well as quantitative test performance features. Analysis of performance patterns within and across neurocognitive measures can yield important information regarding levels of functional ability and disability that have implications for differential diagnosis as well as carrying out everyday activities. From the results of these tests, recommendations can be derived to help patients with cognitive impairments maximize their cognitive functioning. There are many neurocognitive tests available for use in neuropsychological evaluation, although some

are much more widely used than others in clinical and research settings. These techniques represent accepted medical diagnostic procedures. The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology regarded neuropsychological assessment as an accepted procedure that is useful in a variety of suspected or known neurologic diseases [1]. Furthermore, the Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association and the Society for Behavioral and Cognitive Neurology include neuropsychological assessment as one of the key areas in which advanced knowledge is recommended for fellowship training in BN&NP [2]. Thus, subspecialists in BN&NP need to be aware of the various tools available, as well as the applications, strengths, and limitations of neuropsychological assessment techniques. It is the purpose of this chapter to provide an overview of these issues.

Brief background By way of history, the field of neuropsychology derived its emphasis on the measurement of brain–behavior relationships from its parent disciplines of psychology and neurology. Early on, it was observed that specific mental or cognitive abilities were affected by damage to particular regions of the brain, and many different ability tests were developed in an attempt to depict and characterize changes in cognitive functioning as a result of focal brain lesions and disorders. Much of the focus of early work in this burgeoning field was on the detection of “organicity” and the localization of central nervous system (CNS) damage, particularly as World War I veterans returned with a variety of brain injuries. Many test instruments were developed in experimental and clinical laboratories in the USA


394

Chapter 24: Neuropsychological assessment

Box 24.1. Common applications of neuropsychological assessment to the practice of Behavioral Neurology & Neuropsychiatry. Detection and documentation of cognitive dysfunction Quantification and characterization of cognitive strengths and weaknesses Assistance with differential diagnosis Detection of subtle cognitive deficits Pre–post assessment following neurosurgical intervention Assessment of medication side effects on cognition Return to work or school evaluations Return to play following sports-related concussion Education of patients and families Assisting treatment teams dealing with cognitively impaired patients Cognitive rehabilitation determination Determination of need for special services (e.g., special education) Disability and competency evaluations Forensic evaluations

and Europe that proved successful in demonstrating sensitivity to the presence and general location of brain dysfunction, and in many settings, neuropsychological procedures eventually became “front-line” measures for the detection and localization of brain damage. With the advent of modern neuroimaging tools such as computed axial tomography in the 1970s and magnetic resonance imaging in the 1980s, the role of neuropsychology began to shift away from the detection and localization of focal brain lesions to more of a focus on the characterization of cognitive and behavioral changes and deficits that accompany disorders of the brain. While neuropsychology is used in different ways across settings (Box 24.1), a primary purpose is often to document the presence, extent, and nature of cognitive dysfunction. Neuropsychological evaluations are covered by most major insurance carriers using the American Medical Association’s Current Procedural Terminology (CPT) codes for the procedures, although coverage varies by carrier and region. There also exist limitations on the allowable disorders for which neuropsychological testing is considered medically necessary. It should be noted that the neuropsychology CPT codes (96118–96120) fall under medical procedures; unlike other psychological testing and

Box 24.2. Disorders which, when suspected clinically, suggest that referral for neuropsychological evaluation is an appropriate element of a comprehensive clinical evaluation in Behavioral Neurology & Neuropsychiatry. Alzheimer’s disease Frontotemporal lobar degeneration Parkinson’s disease Huntington’s disease Lewy body disease Mild cognitive impairment (to clarify type and differential diagnosis) Traumatic brain injury Epilepsy (including pre- and post-surgical treatment) Brain tumor Multiple sclerosis Cerebral aneurysm Stroke and vascular disorders Normal pressure hydrocephalus Cerebral anoxia Central nervous system infections Toxic exposures Psychiatric conditions (e.g., schizophrenia, major depressive disorder)

intervention techniques, neuropsychological testing is not intended to be considered part of a patient’s “mental health” benefits. Some of the more common neurologic conditions for which neuropsychological evaluation is sought are presented in Box 24.2.

Qualifications to practice neuropsychology Because the unique knowledge and set of skills required for the practice of neuropsychology (e.g., additional knowledge of neuroanatomy, neurologic disorders, and brain–behavior relationships) are beyond the scope of most traditionally trained clinical psychologists, postdoctoral specialization in clinical neuropsychology grew rapidly beginning in the early to mid 1980s. Specialty training guidelines in clinical neuropsychology were outlined in the Proceedings of the Houston Conference on Specialty Education and Training in Clinical Neuropsychology [3], which include recommended didactic and training experiences at the doctoral, internship, and postdoctoral levels. Much of this training occurs at the postdoctoral level, and typically entails a 2-year postdoctoral residency with neuropsychology mentors and didactics

395


in a medical school or teaching hospital setting. Extensive applied experience working with neurologic and neuropsychiatric populations is central to the training goals of most residency programs in neuropsychology, in addition to experience working with neurologists, psychiatrists, neurosurgeons, and multidisciplinary teams. Didactics and hands-on experiences in neuropsychological techniques for neurology and neuropsychiatry residents and fellows can be arranged through many neuropsychology laboratories in medical settings. The American Board of Professional Psychology (ABPP) established board certification in neuropsychology (patterned after medical board specialty examination procedures) in 1981. Clinical Neuropsychology (CN) became a recognized specialty in the field of psychology by the American Psychological Association in 1996. Whereas board certification in neurology and psychiatry is the norm in the medical field, it should be noted that not all practicing neuropsychologists are board-certified, although ABPP certification in Clinical Neuropsychology (ABPP/CN) represents the most widely recognized credential in the field that helps to promote and ensure competence in this specialty area. Board-eligibility can also be a useful criterion in selecting a neuropsychologist, in addition to information based upon local/national reputation.

Neuropsychological evaluation procedures Record review The neuropsychological evaluation typically begins with a review of the referral question and available medical records. In addition to providing background information on the patient and the type(s) of neuropsychological problems that might be expected, it helps the neuropsychologist begin to develop ideas about the specific neuropsychological measures that he or she may wish to utilize in the examination. Thought should be given to the wording of the referral question, i.e., what does the referring physician most want to glean from the neuropsychological evaluation? If the reason for referral and specific questions of interest are not made clear, then the information provided at the end of the evaluation may not match with what was desired. As noted, this helps guide hypotheses about what the neuropsychologist may expect, what tests to consider, and how extensive an examination may be

396

indicated. For example, requests to “document level of impairment” or “aid in determining need for nursing home placement” call for different assessments than requests to “evaluate for mild cognitive impairment versus depression,” or “assist with the diagnosis of Alzheimer’s disease.”

Clinical interview The next step is a clinical interview with the patient, focusing upon the presenting complaint(s) and history of potential CNS risk factors (e.g., neurologic and neuropsychiatric disorders, substance abuse, etc.) or other demographic and background characteristics that might contribute to symptoms or impact current test performance (e.g., history of developmental problems, special education, learning disability, first language other than English, level and quality of education, etc.). Collateral information from a family member or other person who knows the patient well is also useful when attempting to evaluate current neuropsychological complaints. Obtaining information on the nature, onset, and changes in presenting symptoms is critical. For example, in evaluating a patient who reports problems with directions, it is essential to try and ascertain whether the problems are new, longstanding, or an exacerbation of longstanding difficulties. Additional material that should be collected in the initial interview includes information regarding major medical illnesses, surgeries, current medications, problems with pain, psychological symptoms (e.g., depression), and family history of neurologic/neuropsychiatric disorders, as such information may assist with test interpretation as well as diagnostic formulation.

Mental status examination As part of the clinical interview, a neurocognitive mental status examination, whether qualitative or supplemented by the use of specific cognitive screening tools (e.g., Mini-Mental State Examination [4], Montreal Cognitive Assessment [5], Mini-Cog [6]), is often conducted. In addition to information obtained during the interview and review of records and referral question, mental status testing can help with initial hypotheses about the nature of the presenting symptoms as well as assist with the selection of tests and procedures for the neuropsychological evaluation. As with other neuropsychological tests, performance on brief cognitive screening tasks and measures


are susceptible to the influence of demographic factors such as age, education, and ethnicity. As such, appropriate norms for screening tests must be utilized; the normative data available to guide interpretation of the Mini-Mental State Examination derive from the Epidemiologic Catchment Area study [7], and include more than 18,000 adult subjects stratified by 5-year age and 4-year education ranges. The normative data for most of the other bedside screening tests are considerably more limited. Even more limited are norms for individual mental status screening items, wherein variations in instructions, administration procedures, and/or scoring may significantly affect results. As one example, three-word recall tasks often vary in terms of the words used, although factors such as word frequency, concreteness, length, associability, and specific recall instructions may influence delayed recall performance [8, 9]. Brief cognitive screening tools are notorious for being insensitive to subtle cognitive impairment, particularly since so much scoring weight is given in some cases to only a few items, and performance errors can occur for a variety of reasons other than brain dysfunction. The use of a quantifiable mental status examination nevertheless enhances communication among professionals, may help guide the selection of neuropsychological tests (e.g., depending upon level of overall impairment or specific areas of suggested deficiency), and may provide the basis for brief serial assessments that may be indicated.

Neuropsychological test selection There is an enormous array of neuropsychological tests available, and test selection is highly dependent upon the neuropsychologist’s background as well as the presenting complaint, with attention paid to test characteristics and utility for the case in question. Some hallmark features of those tests in common clinical use are that they are well-standardized, have known psychometric properties (i.e., validity, reliability), have well-established and representative norms, and have demonstrated sensitivity to various neurologic disorders. Table 24.1 lists some commonly used neuropsychological measures; for descriptions of these tests and their administration, scoring, and interpretation, see [10–13]. As indicated above, the comprehensive neuropsychological evaluation should assess a variety of cognitive domains. Sometimes referring physicians ask why so many tests are needed to evaluate their patient, but

the complexity of the brain and its myriad of functions and interconnected abilities must be kept in mind when we attempt to even begin to assess its capabilities. The length and depth of any particular set of neuropsychological tests depend to a great extent upon the referral question, known or suspected diagnosis, and level of functioning of the patient. For example, a thorough evaluation of the cognitive abilities of an 80-year-old retired individual with dementia may require less than an hour of testing in order to document their level of impairment and characterize their cognitive strengths and weaknesses, whereas examination of a 50-year-old attorney following rupture of an anterior communicating artery aneurysm may require 4–6 hours of testing, particularly when return to work is an issue. Another example is the evaluation of a patient with a memory complaint: because there are various types of memory (e.g., declarative, semantic, working), and because memory can fail for a variety of reasons and at different stages (i.e., attention, encoding, consolidation, retrieval), it would not be appropriate to administer a single memory test in isolation without considering the other cognitive abilities that might be affected (e.g., attention, language, executive function, visuospatial skills) and thereby lead to poor performance on a particular test. Measures are selected for the purpose of increasing the likelihood of detecting impairment when it is present (sensitivity) and ascribing it correctly to the most likely etiology (specificity). For example, some tests include unique qualitative performance features that may help with diagnosis (e.g., the various scores from the California Verbal Learning Test-II (CVLT-II) that depict many aspects of learning and memory that are unavailable in some other verbal learning tests). Other factors to be considered in the test selection process include time and expense of various measures in relation to the referral question and case at hand.

Fixed versus flexible test batteries The best-known omnibus neuropsychological test battery (or group of tests) is the Halstead–Reitan Battery, developed by Halstead and modified by Reitan [14]. Whereas it is still used in its entirety by some practitioners in certain settings, most neuropsychologists have moved away from the use of large, rigid, fixed batteries such as this (i.e., wherein all tests are routinely administered to all patients). It

397


Table 24.1. Neurocognitive domains and commonly used neuropsychological measures for the evaluation of adults. Additional information describing these measures can be found in [10–12]. This is a selective list of commonly used tests, and some tests listed under certain domains would not be administered together due to their overlap in functional skills assessed. These tests were designed for use with adults; neuropsychological measures for children can be found listed in [10–12] as well as in [13].

Neuropsychological domain

Assessment measures

Intellectual ability

Wechsler Adult Intelligence Scale–III or IV (WAIS–III/IV)

Premorbid intellectual function

Wechsler Test of Adult Reading (WTAR) or Test of Premorbid Function (TOPF) Wide Range Achievement Test–4 (WRAT–4), Reading Subtest National Adult Reading Test–Revised (NART–R) North American Adult Reading Test (NAART)

Academic achievement

Wide Range Achievement Test–4 (WRAT–4) Wechsler Individual Achievement Test (WIAT)

Attention/concentration

Digit Span (WAIS–III/IV) Spatial Span (WAIS–III/IV) Trail Making Test, Part A Digit Vigilance Test

Language

Letter and Category Fluency Boston Naming Test Vocabulary subtest (WAIS–III/IV) Boston Diagnostic Aphasia Exam

Learning and memory Verbal

398

California Verbal Learning Test–II (CVLT–II) Rey Auditory Verbal Learning Test Hopkins Verbal Learning Test–Revised Wechsler Memory Scale III/IV (Logical Memory, Paired Associate Learning subtests, Auditory Memory Index)

Non-verbal

Rey–Osterrieth Complex Figure Wechsler Memory Scale III/IV (Visual Reproduction subtest, Visual Memory Index) Benton Visual Retention Test Brief Visuospatial Memory Test–Revised

Visuospatial skills

Clock drawing tests Block Design subtest (WAIS–III/IV) Rey–Osterrieth Complex Figure (Copy Subtest)

Executive function

Wisconsin Card Sorting Test Delis–Kaplan Executive Function Scale (DKEFS) Trail Making Test, Part B Letter Fluency (e.g., Controlled Oral Word Association) Category Fluency Test (e.g., animal naming) Stroop Color–Word

Psychomotor skills

Finger Tapping Test Grooved Pegboard Hand Dynomometer

Emotion and Personality

Minnesota Multiphasic Personality Inventory–2 Personality Assessment Inventory Beck Depression Inventory–2 Quick Inventory for Depressive Symptoms (QIDS) Beck Anxiety Inventory

Effort Assessment

Test of Memory Malingering (TOMM) Rey 15 Item Test Dot Counting Test Portland Digit Recognition Test Reliable Digit Span Computerized Assessment of Response Bias (CARB)


Box 24.3. An example of a core neuropsychological battery for use in the evaluation of adults with suspected or definite cognitive impairment. Additional information describing these measures can be found in [10–12]. Vocabulary (WAIS–III/IV) Digit Span (WAIS–III/IV) Block Design (WAIS–III/IV) Coding/Digit Symbol (WAIS–III/IV) Clock Drawing Wisconsin Card Sorting Test Trail Making Test Letter and Category Fluency Boston Naming Test California Verbal Learning Test Rey–Osterrieth Complex Figure Quick Inventory for Depressive Symptoms (QIDS)

is common practice to adopt a more flexible approach to assessment that focuses on targeted evaluations directed to specific referral questions, presenting complaints, known or suspected disorder, and individual patient characteristics. Many neuropsychologists use a core set of tests that are administered to most patients or those within certain diagnostic categories (e.g., dementia), and they may have different core batteries for different patient populations. These core assessments often include portions of the Wechsler Adult Intelligence Scale–III/IV (WAIS–III/IV), along with preferred measures of memory and other cognitive abilities. Box 24.3 offers an example of a core neuropsychological test battery for adults. Brief or “intermediate” assessment batteries have also been developed which sample a variety of cognitive domains and may suffice as a neuropsychological examination in some situations (e.g., to document impairment, screen for specific deficits that might be followed up with more detailed testing, or provide a quick overview of cognitive functioning). The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [15, 16] is one such instrument that has shown good clinical utility and offers the advantage of having an equivalent alternate form that can be used in test–retest situations.

Specialty test batteries A variety of test batteries or groups of tests have been developed or assembled with an emphasis on a specific evaluation goal or diagnostic group in mind. Some of

Table 24.2. Examples of specialty test batteries and their applications. Abbreviations: CERAD – Consortium to Establish a Registry for Alzheimer’s Disease; MATRICS – Measurement and Treatment Research to Improve Cognition in Schizophrenia; BACS – Brief Assessment of Cognition in Schizophrenia; MACFIMS – Minimal Assessment of Cognitive Function in Multiple Sclerosis; NIMH HIV – National Institute of Mental Health Human Immunodeficiency Virus; NFL – National Football League.

Specialty test battery

Target population

CERAD Neuropsychological Battery

Dementia

MATRICS Consensus Battery

Schizophrenia

MACFIMS

Multiple sclerosis

NIMH HIV Consensus Battery

HIV infection

NHL/NFL Battery

Sports concussion

the representative specialty batteries are presented in Table 24.2. Whereas some computer-administered tasks have existed for many years (e.g., continuous performance tests to assess sustained concentration), a number of computerized test batteries have been developed in the past decade, and this continues to be an area of interest and growth. Most computerized neuropsychological testing batteries are designed for use in specific contexts and/or clinical populations, although some are more generic and have been used in a variety of settings such as clinical trials. Such measures are generally considered specialty tests, and are usually included within a larger traditional group of measures for the purposes of general neuropsychological assessment. In some situations, they are used as screening tools such that additional neuropsychological evaluation will be pursued if screening results suggest abnormality. Some of the more common computerized test batteries are listed in Box 24.4. Computer-administered tests have some advantages such as the ability to precisely measure reaction times and quickly score and print test results, and some require much less examiner time or can even be administered to groups of individuals. Some of the disadvantages include less examiner interaction (which can lead to less well-controlled test conditions), computer or technical problems that interfere with administration or scoring, the lack of truly equivalent alternate forms and limited test norms in some cases, and the inherent limitations of the computer environment in terms of the types of tasks that can be administered.

399


Box 24.4. Examples of computerized neuropsychological test batteries. Additional information regarding these tests may be found at the websites of their publishers. Automated Neuropsychological Assessment Metrics (ANAM) Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) MicroCog: Assessment of Cognitive Functioning HeadMinder CogState ClinicalTrials Cambridge Neuropsychological Test Automated Battery (CANTAB) CNS Vital Signs Concussion Vital Signs Mindstreams

Test administration As noted, a plethora of measures of neuropsychological functioning are available from test publishers and from the clinical and experimental literature. Most tests are of the paper–pencil, stimulus–response, question–answer variety that require face-to-face interaction between patient and examiner, and some are computer-administered. Standard administration procedures are included in test manuals and must be followed to ensure uniformity of administration and applicability of test norms. Even variations in instructions to simple mental status test items (e.g., three-word recall, as noted earlier) can affect results; for example, whether credit is given if a patient misses the date by a single day or cannot produce the precise name of the hospital, and so forth. Thus, both standard administration of test items and standard scoring of test protocols are imperative. Deviations from standard protocols should be duly noted in behavioral observations. As part of the testing endeavor, it is essential that a patient’s cooperation be enlisted during testing in order to ensure validity of test results. Specific measures of effort or malingering have been developed (see Table 24.1). The utility of some of these measures relies upon easy tasks being presented as “difficult” whereas others employ statistical principles to detect performance that falls below chance level and hence indicate that the patient was trying to do poorly. Such tasks are particularly important in forensic evaluations wherein secondary gain issues may be paramount. Many neuropsychologists utilize psychometrists or neuropsychological technicians to administer

400

the selected tests to patients. Psychometrists are bachelors or masters degree level professionals who are trained and supervised by the neuropsychologist. As the tests have highly standardized instructions and administration rules, they lend themselves to administration by well-trained psychometrists. In some settings, the neuropsychologist will conduct some of the tests (often for screening or specialized assessment purposes) and delegate others to the psychometrists, while some neuropsychologists prefer to conduct all of their own testing. Any of these approaches are considered appropriate in the clinical setting [17].

Scoring and interpretation of neuropsychological tests Valid interpretation of test results depends first upon the use of standardized administration and scoring procedures to obtain the samples of behavior that are the cornerstone of neuropsychological assessment. Once tests are scored according to published guidelines (and ideally, double-checked), the uncorrected (raw) test scores for most measures in common clinical use must be reviewed, and adjusted or standard scores obtained through the use of normative references for the tests utilized. Neuropsychological tests vary in terms of their available normative comparison groups, although some represent large databases comprised of representative samples of the general population. For example, the Wechsler scales (currently in the fourth edition of the popular intelligence and memory scales) are excellent examples of state-of-the art normative reference databases and robust psychometric properties. A limitation of many experimental tests is the lack of norm-referenced scores, which makes interpretation and comparison with the general population difficult. The larger and more representative the sample, the better the accuracy of score estimations and inferences about neuropsychological functioning. Furthermore, test interpretation may require use of normative samples appropriate to the patient examined: comparability of standard scores across tests is related to the extent the normative groups used to derive those scores are similar to each other. That is, not all groups used to create normative databases are comparable with each other, they may or may not be representative of the general population, and they may not include adequate numbers of individuals similar to a particular patient


Table 24.3. Conversion table for percentiles and standard scores for the Weschler Adult Intelligence Scale.

Wechsler Percentile Z-score T-score scaled score IQ score 99.9

3.00

80

19

145

99.6

2.67

77

18

140

99

2.33

73

17

135

98

2.00

70

16

130

95

1.67

67

15

125

91

1.33

63

14

120

84

1.00

60

13

115

75

0.67

57

12

110

63

0.33

53

11

105

0

50

50

10

100

37

−0.33

47

9

95

25

−0.67

43

8

90

16

−1.00

40

7

85

9

−1.33

37

6

80

5

−1.67

33

5

75

2

−2.00

30

4

70

1

−2.33

27

3

65

0.4

−2.67

23

2

60

0.1

−3.00

20

1

55

in question. As such, test users must be familiar with the psychometric properties of tests as well as the normative reference samples with which individual comparisons are made. Many cognitive abilities have bell-shaped distributions in the normal population, and the more tests that fall below the expected level the greater the likelihood of impairment in an area. Norm-referenced test scores therefore are typically reported in standard scores or percentiles in relation to average or normal functioning (or combinations thereof). Standard scores may be reported differently (e.g., Z-scores, T-scores, scaled scores), but since they all are based upon a Gaussian or normal distribution, they can be converted into the same metric (Table 24.3). Interpretation, however, depends upon the characteristics of the normative reference group, such that scores may not be completely interchangeable across metrics derived from different samples. Additional comments are warranted on the use and interpretation of normative/standard scores needed before considering other issues related to neuropsychological test scoring interpretation.

First, some test scores of normal or cognitively intact people will fall in the impaired or lower-thanexpected range; this is particularly true if a large number of tests are administered. Everyone has relative cognitive strengths and weaknesses; at any given intellectual level, it is not uncommon for a few test performances to be below expectations. For example, from an expanded Halstead–Reitan Battery that includes multiple tests and individual test scores, the modal number of scores falling in the impaired range (i.e., more than one standard deviation below the mean) in a large normative sample was four [18]. Isolated impaired scores therefore must be considered carefully, as they may not be meaningful indicators of brain function. Second, the terms “impaired” and “deficit” are relative, and it is important to interpret individual test scores not only with respect to normative data, but also in relation to the patient’s individual situation. Interpretation of neuropsychological tests often uses, as a reference point, an estimate of overall cognitive functioning or general intelligence (“g”), followed by an examination of which other cognitive abilities fall at, above, or below this general level, considering the patient’s background (e.g., education, occupation, ethnicity, etc.). Estimates of premorbid cognitive functioning are also important, and these can be based upon patient demographics, patterns of certain current test scores (e.g., vocabulary or general fund of knowledge), and through the use of sight–word reading tests (e.g., WTAR, WRAT-Reading, NART-R, TOPF). The latter correlate with premorbid intellectual functioning (except at the highest and lowest IQ ranges) and tend to be relatively resistant to change despite acquired cerebral dysfunction. Based on such scores, comparison of specific abilities with global cognitive level can be made, and changes can be inferred in particular cognitive domains. The newest versions of the WAIS–IV and Wechsler Memory Scale (WMS–IV) include standardized contrast scores which allow for a ready comparison of verbal and non-verbal memory with overall intellectual level, in addition to other areas such as working memory, processing speed, verbal comprehension, and perceptual organization. Importantly, the new contrast scores for the WAIS–IV and WMS–IV were derived from the same large normative dataset, thereby enhancing the comparability and clinical utility of these contrast scores. Third, the concept of impairment is relative, as it is not an all-or-none phenomenon. There are levels

401


Table 24.4. Representative continuum of levels of functioning. These are general guidelines presented as an example of descriptive labels corresponding to T-score ranges. Such labels should not be rigidly employed and may vary depending upon a variety of factors, including the normative reference sample used, patient background, and situational factors.

T-score range

Level of function

⬎70

Very superior

60–69

Superior

55–59

High average

45–54

Average

40–44

Low average

35–39

Mild

30–34

Mild to moderate

25–29

Moderate

20–24

Moderate to severe

⬍20

Severe

of impairment with various associated terms, and while terminology may differ, the concept of a continuum of functioning based upon quantitative samples of cognition is central to most neuropsychologists (Table 24.4). Finally, comparison of the individual test findings and overall neuropsychological profile with groups of individuals with known disorders will inform on the nature of any observed deficits. The extent to which an individual profile departs from normal (i.e., expected) levels of function and fits with common neuropsychological patterns in various disorders will help determine the likelihood of a particular disorder [19–21]. When the neuropsychological pattern of scores fits with known underlying neuroanatomical involvement and/or specific disorders, diagnostic confidence is enhanced. Of course, other potential nonneurologic causes of abnormal scores on tests and/or functional disability in everyday life must be carefully considered first (e.g., effort, medication effects, fatigue, psychological factors, pain, etc.); in fact, parsimony in test interpretation within the context of a patient’s life context is the rule.

Effects of serial administration In terms of assessing for neurocognitive changes over time, consideration must be given during test selection to the clinical question at hand as well as the time frame for likely follow-up examination. Additional issues include the availability of alternate test forms

402

and known susceptibility of tests to the effects of serial administration, also referred to as “practice effects” – that is, the tendency of test scores of an individual to improve simply as a result of prior exposure to the test. Some measures are highly sensitive to repeated administrations (e.g., WCST), while others show little practice effect (e.g., WAIS–III/IV Coding). Tests must be chosen and interpreted carefully with such factors in mind, and patients should routinely be asked if they have taken similar tests in the past. In general, practice effects can be minimized with a longer duration between test administrations. In many settings, a test–retest interval of no less than 9– 12 months is used to follow either recovery or disease progression (when repeat testing is performed at all). Situations in which shorter test–retest intervals are used include those surrounding neurosurgical procedures (e.g., pre- and post-surgical assessments for epilepsy surgery or deep brain stimulation), assessment of neurostimulation effects (e.g., electroconvulsive therapy, magnetic seizure therapy), or response to lumbar drainage treatment of normal pressure hydrocephalus. Depending upon the test–retest interval and the purpose of the examination, some tests may be re-administered at follow-up, while others may call for an alternate form (when available) to be used (although alternate forms do not necessarily yield equivalent results). Drug studies or other intervention protocols that call for frequent, serial examinations also require careful planning. Some protocols use more detailed neurocognitive evaluations at set intervals wherein other key clinical information is collected, sometimes interspersed with briefer assessments to track cognitive changes more globally in the interim. Many drug study and serial testing protocols would benefit from the inclusion of a control group tested at the same intervals, as most existing test norms are based upon a one-time administration. In order to demonstrate that changes in test scores are not simply a matter of practice effect, statistical approaches to address this issue have been used, including the Reliable Change Index (RCI) and other methods that adjust for expected test– retest improvement resulting from serial administration [22]. Regardless of the method used for assessing improvement or decline, clinical as well as statistical significance should be kept in mind, as well as information from other sources regarding patients’ functional capabilities and behaviors.


Effects of emotion and personality on neuropsychological performance In addition to evaluating specific cognitive domains, as noted earlier, a common component of the comprehensive neuropsychological evaluation is some assessment of a patient’s emotional status and/or personality. In addition to information obtained through clinical interview (keeping in mind that most licensed neuropsychologists are also trained in clinical psychology), additional quantitative (usually self-report) measures of mood and/or personality are administered. This information is used to evaluate potential psychological factors that may be reflective of change or influencing neurocognitive functioning, as well as to detect comorbid existing psychological problems that may contribute to or cloud neurodiagnosis, affect treatment compliance, or otherwise compromise functioning. When summarizing neuropsychological test data, conclusions should be based upon factors such as: validity of test results (including patient effort); comparison of test results with appropriate norms; analysis of the consistency of the neurocognitive profile (e.g., what to make of an isolated abnormal result); qualitative as well as quantitative performance features (e.g., examination of error types and strategies used to approach tasks); exclusion of other causes of poor test scores (e.g., low education, limited language skills or other cross-cultural factors, medication effects, current emotional and physical state of the patient); knowledge of potential diagnoses and conditions and how neuropsychological results correspond to these; and integration of all available information to provide the best possible assessment and information for feedback to referral sources as well as patients and their families.

The neuropsychological report Neuropsychological reports vary widely depending upon the practitioner, his or her background and current setting, the nature and extent of the evaluation, and the referral base of the neuropsychologist’s practice. Many reports, whether they use individual headings or not, contain a reason for referral, background history, behavioral observations, list of tests administered, results, summary, and recommendations. Such information is essential for billing purposes as well.

In general, many referring physicians will go directly to the summary section for the neuropsychologist’s conclusions, although those with a background in BN&NP may take more of an interest in some of the individual test results. It therefore is helpful to include the neuropsychological test scores (or at least standard scores or percentiles) in addition to a narrative describing a patient’s performance on a particular test or domain area; since interpretations of scores can vary between neuropsychologists, it may be informative for the reader to have more of the data available so as to gain insight into the reasoning behind the interpretations and conclusions offered in a neuropsychological report. Accordingly, some neuropsychological reports include a summary sheet that lists all test scores. There is debate about how much detailed information should be included, as some test scores can reflect sensitive data (e.g., IQ scores) that could potentially be misinterpreted by patients or those without training or expertise in the interpretation of neuropsychological tests. As noted earlier, standard scores developed on different normative populations may also affect interpretation of results; non-experts in this area may not be aware of this issue and thus may under- or over-interpret test scores accordingly. Many factors therefore must be considered and great care must be taken in the interpretation and reporting of any test scores, and neuropsychologists are well advised to caution readers of their reports against over-reliance upon test scores without considering qualitative performance features that depict the process of an individual’s thinking. In terms of the final neuropsychological report that summarizes the findings and renders interpretations, many different formats are used. Some tend to be rather lengthy (e.g., as often seen in forensic evaluations when an extensive record review is conducted), and in some cases, report length can be excessive and filled with jargon. Nevertheless, neuropsychologists should strive to make their reports as user-friendly as possible for their referral sources.

Conclusion Neuropsychological assessment may contribute usefully to the evaluation of persons by BN&NP subspecialists. The use of norm-referenced data gathered with standardized neuropsychological instruments allows for the evaluation of individual neurocognitive

403


Box 24.5. Future directions in neuropsychological assessment. Improved normative data for commonly used neuropsychological tests Development of more and improved cross-cultural tests and normative data Integration with neuroimaging techniques Translational research and test development Ecological validity – more emphasis on implications for everyday functioning Streamlined assessments with robust psychometric properties Computer-based testing with enhanced user interfaces

6. Borson S, Scanlan J, Brush M, Vitaliano P, Dokmak A. The mini-cog: a cognitive ‘vital signs’ measure for dementia screening in multi-lingual elderly. Int J Geriatr Psychiatry 2000;15(11): 1021–7. 7. Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level. J Am Med Assoc 1993;269(18):2386–91. 8. Cullum CM, Thompson LL, Smernoff EN. Three-word recall as a measure of memory. J Clin Exp Neuropsychol. 1993;15(2):321–9. 9. Chandler MJ, Lacritz LH, Cicerello AR et al. Three-word recall in normal aging. J Clin Exp Neuropsychol. 2004;26(8):1128–33. 10. Lezak MD, Howieson D, Bigler ED, Tranel D. Neuropsychological Assessment. 5th edition. Oxford: Oxford University Press; 2012.

strengths and weaknesses, changes in cognitive function over time, and a better understanding of the implications of these impairments in the context of brain–behavior relationships. As neuropsychology continues to mature as an academic discipline, its utility in both clinical and research settings will undoubtedly expand (Box 24.5).

12. Mitrushina MN. Handbook of Normative Data for Neuropsychological Assessment. 2nd edition. New York, NY: Oxford University Press; 2005.

References

13. Baron IS. Neuropsychological Evaluation of the Child. Oxford: Oxford University Press; 2004.

1. American Academy of Neurology. Assessment: neuropsychological testing of adults. Considerations for neurologists. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1996; 47(2):592–9. 2. Arciniegas DB, Kaufer DI, Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1): 6–13. 3. Hannay HJ, Bieliauskas LA, Crosson BA et al., editors. Proceedings of the Houston Conference on Specialty Education and Training in Clinical Neuropsychology. Arch Clin Neuropsychol. 1998;13:160–6.

404

11. Strauss E, Sherman EMS, Spreen O. A Compendium Of Neuropsychological Tests: Administration, Norms, and Commentary. 3rd edition. Oxford: Oxford University Press; 2006.

14. Reitan RM, Wolfson D. The Halstead–Reitan Neuropsychological Test Battery for Adults: theoretical, methodological, and validational bases. In Goldstein G, Beers SR, Hersen M, editors. Comprehensive Handbook of Psychological Assessment. Volume 1. Intellectual and Neuropsychological Assessment. Hoboken, NJ: John Wiley and Sons; 2004. 15. Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20(3): 310–19. 16. Randolph C. Repeatable Battery for the Neuropsychological Status (RBANS). San Antonio, TX: The Psychological Corporation; 1998.

4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98.

17. Axelrod B, Heilbronner R, Barth J et al. The use of neuropsychology test technicians in clinical practice: official statement of the National Academy of Neuropsychology. Arch Clin Neuropsychol. 2000;15(5): 381–2.

5. Nasreddine ZS, Phillips NA, Bedirian V et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9.

18. Heaton R, Grant C, Matthews C. Comprehensive Norms for an Expanded Halstead–Reitan Battery. Odessa, FL: Psychological Assessment Resources; 1991.


19. Grant I, Adams KM. Neuropsychological Assessment of Neuropsychiatric and Neuromedical Disorders. 3rd edition. Oxford: Oxford University Press; 2009. 20. Naugle RI, Cullum CM, Bigler ED. Introduction to Clinical Neuropsychology: A Casebook. Austin, TX: PRO-ED, Inc.; 1998.

21. Morgan JE, Ricker JH. Textbook of Clinical Neuropsychology. New York, NY: Taylor & Francis; 2007. 22. Maassen GH, Bossema E, Brand N. Reliable change and practice effects: outcomes of various indices compared. J Clin Exp Neuropsychol. 2009;31(3): 339–52.

405

Section II


Chapter

Forensic assessment

25

Hal S. Wortzel and Robert L. Trestman

The rapid rate of development in the neurosciences has broad implications, not only for medicine and patients, but also for society and humanity at large. Many believe that as the secrets underlying brain function are gradually unraveled, the ability to comprehend, anticipate, and ultimately alter human behaviors will be realized. Such notions have profound implications, particularly when basic assumptions about human thought and behavior, like free will and responsibility, are challenged. Unfortunately, the excitement surrounding these scientific developments, and their potential seductive power, has resulted in many instances of premature and questionable applications of neuroscience to the law. The medical expert in behavior, cognition, and emotion can, in our litigious society, expect to be consulted in efforts to link an individual’s behaviors and choices to neuropsychiatric conditions. The challenges surrounding the integration of neuroscience and the law are well articulated by The Law and Neuroscience Project [1]. The project, funded with a $10 million MacArthur grant, seeks to bridge the fields of neuroscience and law, tackling difficult questions such as how new brain-imaging techniques should be handled by courts. The Project’s website (www.lawandneuroscienceproject.org) reminds readers that while these difficult questions are garnering more attention than ever before, the issues have existed for decades, touching upon many cases of historical prominence. Many will recall hearing about the assassination of John F. Kennedy, and the subsequent shooting of Lee Harvey Oswald. But few are aware of the neuropsychiatric defense advanced by Jack Ruby, claiming that he shot Oswald during a seizure, and was thus unable to appreciate the nature and wrongfulness of his actions. The battle of experts that ensued surrounded different interpretations of

a rhythmic temporal theta burst electroencephalographic abnormality [2]. In a similar clash of experts, the significance of John Hinckley Jr.’s widened sulci on computed axial tomography (CAT) was hotly contested, with defense experts arguing the pattern was evidence for a proper diagnosis of schizophrenia [3]. Many were outraged by the not-guilty-by-reasonof-insanity verdict in the Hinckley case, and it is often cited as a powerful impetus to major reforms, at the national level, surrounding the insanity defense [4]. The use of neuroscientific evidence is not exclusive to the past, or to cases surrounding major historic events. To the contrary, it appears to be growing in both frequency of appearance and scope of purpose. In the 1998 case of Rhilinger v. Jancics [5], cerebral singlephoton emission computed tomography (SPECT) results were allowed as evidence to establish injuries consistent with toxic encephalopathy, and in the 2002 case of In re: Air Crash at Little Rock Arkansas [6], the court opined that SPECT evidence might have been useful had it been entered as evidence to establish the requisite physical injury from post-traumatic stress disorder. In the 2003 case of Harrington v. Iowa [7], the electrophysiologic technique of “brain fingerprinting” was admitted as evidence in an effort to overturn a murder conviction despite lack of independent review of the technique, and published data based upon only a handful of individuals [8]. The courthouse doors are open, and neuroscientific evidence will continue to make appearances. The responsibility to ensure that such evidence is used in a scientifically valid and ethical fashion must ultimately fall to the medical expert offering such testimony. It is therefore incumbent upon the would-be neuropsychiatric expert to develop not only the medical knowledge and skill commensurate with that status,


406

Chapter 25: Forensic assessment

but familiarity with ethical and legal issues specific to this role. Both the fields of Behavioral Neurology & Neuropsychiatry (BN&NP) and forensic psychiatry are extraordinarily broad in scope, and they converge at all points at which human behavior, cognition, or emotion might become legally relevant. The nature and scope of the present chapter precludes an exhaustive review. Instead, objectives include an introduction to the basic tenets of forensic practice and provision of a foundation for select legal areas likely to be encountered by the neuropsychiatric expert.

General forensic practice considerations At the outset, it is vital to note that the law varies between jurisdictions, and what may be legally valid in one area may prove to be false in neighboring ones. There is no substitute for familiarity with the precise legal terms and definitions, whether established by case law or legislation, for the applicable jurisdiction. The medical expert, when serving in new legal territories, must research the applicable legal criteria, and ought to not shy away from seeking assistance in this regard from consulting counsel; that being said, there remain many broadly applicable concepts that may serve the medical expert well.

Conceptual framework Forensic practice is, in several ways, a peculiar niche of medicine, often requiring a different approach and thought process than that routinely utilized in clinical practice. Rosner [9] offers a very useful conceptual framework for approaching matters within the medicolegal arena. He endorses a four-step thought process progressing through the issue, the legal criteria, the relevant data, and the reasoning process. The issue involves defining precisely the specific neuropsychiatric question at hand. Legal criteria represent the legally defined terms applicable to the appropriate jurisdiction. Relevant data include all the information pertinent to and useful in resolving the precise medicolegal issue. Finally, the reasoning process is the manner in which relevant data are synthesized with the legal criteria to arrive at a compelling medicolegal opinion. This process is greatly facilitated by defining, with the consulting attorney, the precise medicolegal issue at hand, and by avoiding general psychiatric

or neurological forensic evaluations [9]. Absent a specific medicolegal inquiry, the clinical data offered by the medical expert lose context, precluding the synthesis of law and medicine vital to worthwhile expert opinions.

Ethical considerations In clinics and on wards, a physician’s objectives include maintaining the health and alleviating the suffering of patients. While serving in this capacity, the typical medical ethical hierarchy of autonomy, beneficence, non-malfeasance, and justice is both appropriate and commonly accepted. However, when the clinician leaves the hospital and enters forensic arenas, new objectives and responsibilities surface, necessitating reconsideration of this ethical framework. Clearly, if objectivity is to be possible, and expert opinions are to have any meaning, then the forensic neuropsychiatrist must be able to provide testimony that is potentially disadvantageous to the evaluee, and with possibly harmful consequences such as incarceration or loss of compensation. The medical expert’s responsibilities to the retaining attorney, the court, and to society frequently trump duties owed to the individual under examination, and mandate striving towards objectivity while maintaining professionalism (with truth-telling and respect for persons). For these reasons, alternate ethical hierarchies have been offered for the forensic practitioner, ones placing paramount emphasis on justice [10, 11]. A detailed exploration of the ethical issues surrounding forensic practice is offered by Candilis and colleagues [12]. Given the need to restructure the ethical hierarchy for forensic work, and the potential for justice to come into direct conflict with autonomy, beneficence, and non-malfeasance, specific consideration and actions are warranted on the part of the forensic neuropsychiatric expert. The most vital of these are outlined by the American Academy of Psychiatry and the Law (AAPL) in their ethics guidelines [13]. Informed consent continues to play an important role in forensic practice. The forensic evaluator must inform the subject under examination of the exact nature and purpose of the evaluation, and make clear that a typical doctor–patient relationship is not being established. The forensic neuropsychiatrist should not perform forensic evaluations for the prosecution or the government before the defendant has had the opportunity to consult with legal counsel. However,

407


examinations for the purpose of rendering medical care or treatment are permissible under such circumstances. Confidentiality is often limited in forensic evaluations, and such limitations should be clearly articulated [13]. In abiding by the principle of strict honesty and striving towards objectivity, several guidelines are worthy of close adherence. To the greatest extent possible, expert opinions should always incorporate a personal examination. When circumstances preclude direct examination by the expert offering the opinion, this must be explicitly stated, and the limitations inherent in such an opinion acknowledged. Contingency fees “undermine honesty and efforts to attain objectivity” and should never be accepted [13]. A final point meriting brief mention surrounds the potential hazards of dual agency. Mixing a clinical role with a forensic role may have detrimental effects on both. Testimony offered may undermine a viable treatment relationship, and the drive to advocate for a patient might interfere with striving towards objectivity. Therefore, clinicians may serve appropriately as fact witnesses regarding their care of their patients, but they ought to avoid serving as expert witnesses for patients under their care [13]. When engaged to offer an opinion in a legal proceeding, it therefore is important for the subspecialist in BN&NP to clarify whether he or she is being asked to opine as a fact or as an expert witness.

Legal areas of particular importance in Behavioral Neurology & Neuropsychiatry Medical decision-making Consent to medical treatment or medical research is a vital component of ethical clinical and scientific practice. The question of whether or not a patient possesses the capacity to consent to or refuse treatment frequently arises on psychiatric consultation-liaison services. Unlike most matters of competency, which are generally resolved in courts of law, medical decision-making capacity often arises in emergency situations, necessitating prompt competency opinions from consulting physicians. Absent an emergency portending potentially serious health consequences, the most prudent course of action is obtaining a legal determination of incompetency prior to proceeding

408

with medical interventions. However, when emergencies preclude awaiting a legal judgment, medical providers may arrive at a clinical determination of incompetency to make medical decisions and proceed with vital care. Careful documentation of the medical situation (including risks and benefits with and without treatment) and the competency assessment is of paramount importance. Given the potential for emergency situations calling for important competency determinations absent legal guidance, neuropsychiatric consultants should be familiar with pertinent law in their jurisdiction of practice. The role of the patient, though not clearly legally defined, certainly involves the capacity to make medical decisions. This functional ability can be broken down into four components: (1) the ability to comprehend information pertinent to the medical situation, such as diagnosis, proposed treatments, and associated risks and benefits; (2) being able to appreciate this information on a personal level, meaning that the patient can apply the relevant knowledge to his or her specific situation; (3) the ability to apply a rational thought process to all this information (for instance, is not making erroneous choices based upon delusional beliefs); and (4) being able to articulate a consistent choice [14, 15]. All four elements are important, and failures at any of these levels may result in decisional incompetency. In real-life situations, the risk associated with a given treatment option will vary enormously, thereby justifying the use of a sliding-scale threshold for incompetency. Multiple structured assessments of decisional capacity exist and are available to the clinician. However, as indicated in a review of instruments by Dunn and colleagues [14], all such assessments have limitations, and many lack supporting psychometric data or fail to generalize across the spectrum of clinical contexts. Of the tools presently available, the MacArthur Competence Assessment Tool for Clinical Research [16] enjoys the most empirical support [14].

Competency Competency is a broad area of forensic practice, with important applications to routine clinical medicine as well as criminal and civil law. Whether choosing among medical treatment options, criminal defense strategies, or potential heirs for a will, the individual must possess specific abilities and knowledge in order


to validly participate in the decision-making process. While this theme of competency is broadly applicable in medical practice and the law, it is vital to recognize that competency is very context-specific, and that any judgment of competency must be rooted to the precise situation at hand. This necessitates evaluating the individual’s functional abilities, including the knowledge, comprehension, and reasoning process crucial to the specific context. The neuropsychiatrist’s ability to assess cognition, emotion, and behavior, and to relate these domains to functional ability, will make opinions on competency an area of forensic practice especially applicable to the neuropsychiatric skill set. Given the limited scope of this chapter, competency assessment and the principles that follow may serve as a model broadly applicable to forensic practice in general. As noted above, competency is context-specific. An individual may be incompetent for one legal role, while capable in many others. Competency evaluations should identify and focus upon the specific role in question. There are however, cases in which the individual’s functional deficits broadly impact multiple social and legal roles. In such cases, findings of global or general incompetency may be the appropriate forensic opinion and legal remedy. Maximal deference to the individual’s right to autonomy should always persist, allowing for personal choice whenever a reasonable ability to decide for oneself exists. In most jurisdictions, the globally incompetent individual will be assigned a guardian with substitute decision-making authority. The law establishes specific criteria applicable to a given domain of competency. Although the neuropsychiatric expert must know and apply these criteria in formulating an opinion, the ultimate determination of competency is a legal one, rendered by the court. While these criteria vary considerably, it is important to recognize that any given neuropsychiatric diagnosis does not equate with incompetency. Medical diagnoses are pertinent to the assessment of competency only if they interfere with the precise abilities specified by law. It is not enough to offer a diagnosis and an opinion of incompetency; the effective expert will articulate exactly how the medical diagnosis offered impairs functioning, and how this relates to the established legal standards. The World Health Organization’s International Classification of Impairments, Disabilities, and Handicaps (ICIDH) [17] offers a useful construct in approaching competency and linking a given

neuropsychiatric condition to a specific domain of competency. The ICIDH denotes three levels of deficits. Impairments involve the malfunction of a body part or domain (e.g., dementia represents impairment in brain function). Disability involves deficits in the performance of age-appropriate activities (the demented patient may be unable to shop for herself). Handicap involves failures in the performance of social roles (the demented patient may be unable to function effectively as an employee or parent). This construct may be usefully applied in linking clinical findings to forensic opinions. The demented patient should not be found incompetent simply because he or she is demented, or performs poorly on a specific clinical scale. Rather, the impairments uncovered in the clinical evaluation should be linked to a disability that creates a handicap for the specific social or legal role to be played by the individual. For example, the demented patient’s memory impairment precludes the ability to remember and discuss legal options, interfering with his or her performance in the legally defined role of a defendant. Thus, incompetency entails impairments that result in functional handicaps as regards a legally defined role. Merely demonstrating impairment is inadequate for such a finding, and the neuropsychiatric expert must be aware of the limitations and challenges that surround transcribing clinical impairments into functional capacities. This is particularly true in the realm of cognition, which, on most psychometric batteries, accounts for only a modest degree of the variance in functional status [18]. Ultimately, it is the combination of cognitive, emotional, and behavioral skills and deficits that must be synthesized within the relevant legal role. Three roles commonly encountered in the realm of competency assessment are that of patient, criminal defendant, and testator.

Competency to stand trial The 1960 Supreme Court decision in Dusky v. United States [19] firmly established the competency requirements surrounding a criminal defendant’s ability to participate and cooperate in his or her own defense. The Dusky court states, “the test must be whether he [the defendant] has sufficient present ability to consult with his lawyer with a reasonable degree of rational understanding and whether he has a rational as well as factual understanding of the proceeding against him” [19]. The court’s language may be understood to

409


denote two aspects of competency, cognitive and volitional. The cognitive aspect requires that the defendant possess the ability to understand relevant legal concepts and rules. The volitional aspect involves the ability to apply the cognitive information in a reasonably appropriate fashion in service of one’s own defense. The 1993 Supreme Court case of Godinez v. Moran [20] is noteworthy in that it extends these competency criteria to essentially all aspects of the criminal trial. For instance, the choice to plead guilty or to waive the right to counsel entails no higher standard of competency. Competency to proceed to trial is a major source of forensic psychiatric evaluations, so major in fact that crises involving considerable backlogs of patients have ensued in several states. Often, the defendant awaiting a competency examination languishes in jail, receiving little to no treatment. Such situations have resulted in tragic medical outcomes as well as heated legal battles [21]. Mossman [22] reported recent estimates suggesting that currently 50,000–60,000 defendants are evaluated for competency to stand trial each year, and that nearly 20% of these defendants are found to be incompetent by courts. At any given time, defendants hospitalized for restoration to competency occupy nearly 4,000 psychiatric hospital beds in the USA, or over 10% of the nation’s state psychiatric hospital beds. The need for skilled evaluators in the area of competency to proceed is apparent. The AAPL recently published practice guidelines for the forensic psychiatric evaluation of competence to stand trial; the expert embarking on such examinations should be familiar with this document [23].

Testamentary capacity Gutheil [24] concisely articulates the major issues and common pitfalls surrounding testamentary capacity. Competency to author a will, or testamentary capacity, is based upon legal criteria that, despite some variation in language, are fairly straightforward. The legal criteria tend to erect a relatively low threshold for competency, likely reflecting societal interests in maintaining property via appropriate inheritance. The testator, at the time of executing, must know the nature and extent of his or her estate and property, know his or her natural heirs, realize the significance of a will as it pertains to the allocation of property following death, and (in some instances) have a rational plan for distributing the property after death.

410

Despite these seemingly simple criteria, the evaluation of testamentary capacity frequently becomes complicated by surrounding circumstances and nuances particular to this sort of forensic work. For instance, because these evaluations frequently arrive only after a will has been contested, often, after the testator has passed on, post-mortem evaluation becomes necessary, obviously precluding direct examination of functional abilities. Additionally, the simple legal criteria do not mitigate family dynamics that often erupt in the wake of a death. Gutheil [24] identifies several problems that may compromise the expert opinion on testamentary capacity: (1) failure to presume competence; (2) failure to allow for unusual bequests; (3) failure to accurately determine assets; (4) over-reliance on a diagnosis, structural change of the brain, or standardized test performance; and (5) misapplication of delusions. For the subspecialist in BN&NP, the potential pitfall of pinning a forensic opinion to a diagnosis or particular clinical finding, absent a clear relationship to the specified legal criteria, is worthy of particular caution. Individuals with neuropsychiatric disorders frequently suffer impairments (in cognition, emotion, and behavior) related to a multitude of clinical conditions, many of which increase in frequency late in life; these impairments may complicate drafting of a will. The essential point is that no diagnosis (even dementia) or examination finding (such as a Mini-Mental State Examination [25] score) directly speaks to the legal criteria, and the specified functional abilities require direct assessment. As we move on from competency assessment to other areas of forensic practice, this common theme that permeates forensic neuropsychiatry bears repeating: opinions of incompetency, like all forensic opinions, must comport with the precise legal criteria. Determinations of incompetency should result only from the functional inability to perform the legally specified tasks or duties. Diagnoses and clinical finding may heighten our suspicion for or explain the underlying cause of incompetency, but the two do not directly equate.

Criminal responsibility Criminal responsibility is an area of tremendous importance to forensic practice. In any given case, the potential consequences related to expert opinions are enormous, for both the individual under evaluation (typically the defendant) and for society. The serious


implications of opinions on criminal responsibility merit some reflection prior to embarking on such endeavors. The manner in which individual jurisdictions approach criminal responsibility, including the legal language used and the options available to criminal defendants, varies considerably from state to state. There is no substitute for knowing the precise legal definitions applicable to any given case. That being said, matters of criminal responsibility may be broadly conceived of as falling into three main categories: insanity, diminished capacity, and mitigating circumstances.

Not guilty by reason of insanity Insanity generally refers to the “not guilty by reason of insanity” (NGRI) defense. A verdict of NGRI essentially eliminates all criminal responsibility for the alleged crime, although the defendant will often be committed to a state psychiatric facility. However, the 1992 Supreme Court case of Foucha v. Louisiana [26] established that the NGRI defendant may only be committed to a psychiatric facility so long as he or she is both mentally ill and dangerous. The criteria for NGRI are legally defined, and the vast majority of clinical determinations of mental illness (or neuropsychiatric impairment) do not equate to legal standards for insanity. In most US jurisdictions, despite variation in the language used, the applicable NGRI standard derives from the 1843 English case of M’Naghten [27]. The standard is a cognitive one, based upon the defendant’s ability to appreciate the nature, quality, and wrongfulness of his or her actions at the time of the alleged criminal behaviors. While not applicable in most jurisdictions, there are other criteria for legal insanity in use, some of which involve volitional components or product tests. The American Law Institute offered a volitional component wherein the inability “to conform his conduct to the requirements of law” [28] equates with insanity. As mentioned earlier, the Hinckley verdict prompted considerable reformation of NGRI statutes, and most jurisdictions have since eliminated volitional clauses. This largely reflects the reality that distinguishing between the irresistible impulse and the impulsenot-resisted is not medically possible at present. The product test, embodied by the 1954 case of Durham v. United States, and the resulting Durham Rule, is simply, “an accused is not criminally responsible if his unlawful act was the product of mental disease or defect” [29]. Much like the volitional prong, this more expansive test of insanity has rather indistinct

boundaries relative to cognitive tests, and is presently applicable in very few jurisdictions. As with incompetency, a viable opinion on insanity necessitates linking mental illness and the related symptoms to the functional inabilities specified by law. This endeavor is frequently more complicated in NGRI evaluations given the need to retrospectively ascertain the defendant’s state of mind and functional capacities at the time of the alleged criminal act. Forensic practice is not routine clinical practice, and the defendant’s selfreports, while always worthy of consideration, need to be balanced with collateral data from witnesses, police reports, and details of the specific crime.

Diminished capacity and mitigating circumstances Various neuropsychiatric conditions will contribute to legitimate claims of diminished capacity and mitigating circumstance with much greater frequency than with claims of NGRI. Diminished capacity, unlike a finding of NGRI, does not completely obviate criminal responsibility, but may reduce the charge, or severity of the crime, for which the defendant is convicted. Consider, for example, a defendant who acted in the midst of mania and intoxication facing charges of first-degree murder. This is a charge usually requiring premeditation. While the defendant’s mental state may have been consistent with a knowing and willful killing, the impairments might have precluded premeditation, arguing for an impulsively violent murder, equivalent to a lower charge (e.g., second-degree murder or manslaughter). Mitigating circumstances typically will not impact on conviction (i.e., guilty or not guilty). Rather, mitigating circumstances may support reduced culpability and therefore warrant lighter sentencing. For instance, the defendant convicted of firstdegree murder and potentially facing execution might advance evidence of mental illness and a personal history of abuse in hopes of receiving lesser punishment. The rules surrounding these forms of evidence vary considerably from state to state.

Free will and criminal responsibility “Free will is regarded by some as the most and by others as the least relevant concept for criminal responsibility” [30]. Felthous, in the preceding quote, refers to an evolving debate surrounding the implications of recent neuroscientific developments for free will. Arguments against the existence of free will often cite the works of Libet [31, 32] and evidence suggesting that our brains are active and determine movement

411


several hundred milliseconds prior to any conscious awareness of the choice to move. The argument essentially goes that if brains are automatic, and choice is merely an illusion created after the fact, then free will cannot exist, nor can responsibility. Gazzaniga and Steven, in thoughtfully synthesizing the neuroscientific, legal, and ethical aspects of the debate, conclude, “brains are automatic but people are free” [33]. As these authors point out, responsibility is a human construct, defined by society and the people who comprise it, and not by neuroscience. This being the case, “no pixel on a brain scan will ever be able to show culpability or nonculpability” [33]. Morse [34], in an equally compelling essay, arrives at similar conclusions. He points out the analytic error in the frequent belief that causation is an excusing condition, and argues that “deciding who is blameworthy and deserves to be punished is a moral and ultimately political question about which mental health science must fall silent” [34].

Torts Tort law covers an expansive range of legal issues, only some of which are likely to involve the use of neuropsychiatric experts. In brief, tort law serves to settle disputes over blame for harms that have occurred, emphasizing restitution and deterrence. The party suffering harm is compensated while the responsible individual is punished (usually financially). For the forensic neuropsychiatrist, torts involving medical malpractice and personal injury hold particular relevance. Again, as in other areas of law, the rules applicable to torts will vary from state to state, and adhering to precise definitions for the relevant jurisdiction will be essential in shaping solid medicolegal opinions. Communication with the consulting attorney to determine the proposed legal strategy and applicable statutory and case law is essential. In general, a successful tort will establish negligence on the part of the defendant, based upon the existence of a duty, breach of that duty, harm that resulted, and a direct causal relationship between the harm suffered and the breach of duty. In medical malpractice cases, these are often referred to as the “four Ds:” duty, dereliction (of duty), damages, and direct causation. Unlike criminal law, where intent and mental state feature prominently, negligence in tort law does not require intent [35]. For the neuropsychiatric expert, tort law may present some extraordinary challenges. Many

412

neuropsychiatric conditions, even in routine clinical practice, are difficult to diagnose, and perhaps even more difficult to explain in terms of etiology. Consider, for example, the complicated and diverse presentations that might surround potential traumatic brain injuries (TBI) and toxic encephalopathies. Add to these challenging clinical presentations the inherent confounds in an adversarial process involving considerable financial incentives for patients and families, and sorting through such syndromes and etiologies becomes a tricky endeavor. This should not necessarily discourage participation in such torts, but should motivate the would-be expert to engage such cases in a very thorough and precise manner. Up-to-date knowledge of the relevant neuropsychiatric condition must be wed to relevant legal concepts. The status of the brain going into an injury, as well as the environment in which it arrives following injury, should be part of the etiologic formulation for any given presentation. Gathering collateral data and information illustrating the evaluee’s premorbid level of functioning is vital to a thorough evaluation. Given the stakes frequently involved in torts, it is not surprising that objective evidence proving or disproving an injury and etiology is highly soughtafter. Litigation surrounding mild TBI is an excellent example, with the often vague clinical complaints that follow such injuries as well as the difficulties entailed by needing to sort out contributions from TBI, pre-existing conditions, and post-injury circumstances yielding an atmosphere of adversaries hungry for objective proof. Numerous technologies have been advanced in efforts to satisfy this desire, most notably quantitative electroencephalography (qEEG), SPECT, and diffusion tensor imaging (DTI). The neuropsychiatric expert must be aware however that rules surrounding the admission of scientific evidence do exist, as do the ethical requirements previously discussed. Presently, the rules surrounding the admission of expert testimony stem from the 1993 Supreme Court case of Daubert v. Merrell Dow [36]. In this case, the court determined that testimony must be relevant, reliable, and derived by the scientific method. To assist the trial judge in this determination, four questions (commonly referred to now as the Daubert criteria) are proposed for reflection: (1) can the theory behind the evidence be tested?; (2) has that theory been subjected to peer review and publication?; (3) is there a known rate of error and established standards surrounding the technique/practice?;


and (4) has the theory, technique, and/or practice been generally accepted within the pertinent scientific community? No single factor is required to pass the test, and no factor is necessarily sufficient. Rather, these inquiries are to be flexibly applied on a case-by-case basis to assist in the gate-keeping process and determination of admissibility. In neuropsychiatric forensic practice, such determinations can be enormously complicated, necessitating evaluation of both the literature surrounding the proposed technique and literature detailing its application to a particular condition. For examples of these considerations, see the discussion of mild TBI and qEEG offered by Nuwer and colleagues [37] as well as the challenges described by Wortzel and colleagues surrounding the application of Daubert to the technology of SPECT [38] and DTI [39] to mild TBI-related litigation.

Conclusion The interface between the law and the neurosciences is huge and growing. The neuropsychiatrist who accepts a forensic role also assumes tremendous responsibilities involving up-to-date medical knowledge, familiarity with pertinent law, and ethical duties particular to the medical expert role. When taken lightly, these responsibilities frequently go unfulfilled, potentially yielding unjust outcomes and ethical violations. But, when embraced with enthusiasm for both medicine and the law, the role and responsibilities of the forensic neuropsychiatrist open up new and exciting avenues for specialized knowledge realizing societal benefits. The intellectual challenges and opportunities to contribute to a rapidly growing field encompassing medicine, law, and ethics entail ample rewards.

References 1. The Law & Neuroscience Project. Nashville, TN: Vanderbilt University Law School; [accessed March 27, 2008]; available from: http://www. lawandneuroscienceproject.org/. 2. Gutmann L. Jack Ruby. Neurology 2007;68(9):707–8. 3. Linder D. The trial of John W. Hinckley, Jr. [accessed March 25, 2008]; available from: http://www.law. umkc.edu/faculty/projects/ftrials/hinckley/ hinckleyaccount.html. 4. Cirincione C, Jacobs C. Identifying insanity acquittals: is it any easier? Law Hum Behav. 1999;23(4):487–97. 5. Rhilinger v. Jancics et al.: Mass. Super.; 1998.

6.

In re: Air Crash at Little Rock Arkansas on June 1, 1999 v. American Airlines, Inc.: U.S. Court of Appeals, Eighth Circuit; 2002.

7. Harrington v. Iowa (State of). Iowa Supreme Court; 2003. 8. Appelbaum PS. Law & psychiatry: The new lie detectors: neuroscience, deception, and the courts. Psychiatr Serv. 2007;58(4):460–2. 9. Rosner R, editor. A conceptual framework for forensic psychiatry. In Principles and Practice of Forensic Psychiatry. 2nd edition. New York, NY: Hodder Arnold; 2003, pp. 3–6. 10. Appelbaum PS. A theory of ethics for forensic psychiatry. J Am Acad Psychiatry Law 1997;25(3): 233–47. 11. Sen P, Gordon H, Adshead G, Irons A. Ethical dilemmas in forensic psychiatry: two illustrative cases. J Med Ethics 2007;33(6):337–41. 12. Candilis PJ, Weinstock, R., Martinez, R. Forensic Ethics and the Expert Witness. New York, NY: Springer; 2007. 13. American Academy of Psychiatry and the Law. Ethics Guidelines for the Practice of Forensic Psychiatry. Bloomfield, CT 2005. Adopted May 1987; Revised October 1989, 1991, 1995, and 2005. 14. Dunn LB, Nowrangi MA, Palmer BW, Jeste DV, Saks ER. Assessing decisional capacity for clinical research or treatment: a review of instruments. Am J Psychiatry 2006;163(8):1323–34. 15. Grisso T, Appelbaum PS. Assessing Competence to Consent to Treatment: a Guide for Physicians and other Health Professionals. New York, NY: Oxford University Press; 1998. 16. Appelbaum PS, Grisso T. MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). Sarasota, FL: Professional Resource Press; 2001. 17. World Health Organization. International Classification of Impairments, Disabilities and Handicaps. Geneva: WHO; 1993. 18. Royall DR, Lauterbach EC, Kaufer D et al. The cognitive correlates of functional status: a review from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2007;19(3):249–65. 19. Dusky v. United States; 1960. 20. Godinez v. Moran. Supreme Court; 1993. 21. Wortzel H, Binswanger IA, Martinez R, Filley CM, Anderson CA. Crisis in the treatment of incompetence to proceed to trial: harbinger of a systemic illness. J Am Acad Psychiatry Law 2007;35(3):357–63. 22. Mossman D. Predicting restorability of incompetent criminal defendants. J Am Acad Psychiatry Law 2007;35(1):34–43.

413


23. Mossman D, Noffsinger SG, Ash P et al. AAPL practice guideline: forensic psychiatric evaluation of competence to stand trial. J Am Acad Psychiatry Law 2007;34(4):S3–S72.

32. Libet B. Conscious vs neural time. Nature 1991;352(6330):27–8.

24. Gutheil TG. Common pitfalls in the evaluation of testamentary capacity. J Am Acad Psychiatry Law 2007;35(4):514–17.

33. Gazzaniga MS, Steven MS. Free will in the twenty-first century: a discussion of neuroscience and the law. In Garland B, editor. Neuroscience and the Law: Brain, Mind, and the Scales of Justice. Washington, DC: Dana Press; AAAS; 2004.

25. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3):189–98.

34. Morse SJ. New neuroscience, old problems. In Garland B, editor. Neuroscience and the Law: Brain, Mind, and the Scales of Justice. Washington, DC: Dana Press; AAAS; 2004.

26. Foucha v. Louisiana. Supreme Court; 1992.

35. Shuman DW, Heinlen M. An introduction to tort law. In Rosner R, editor. Principles and Practice of Forensic Psychiatry. 2nd edition. New York, NY: Hodder Arnold; 2003, pp. 3–6.

27. M’Naghten’s Case. House of Lords; 1843. 28. Model penal code, Tentative Draft No. 4: Code Provisions and Their Present Status; Preliminary; General Principles of Liability; Responsibility; Authorized Disposition of Offenders; Authority of Court in Sentencing; Offenses Against Property; Sexual Offenses; Suspension of Sentence; Probation Sect. 401.1 (1) (1955).

36. Daubert v. Merrell Dow Pharmaceuticals, Inc. U.S. Court of Appeals for the Ninth Circuit 1993. 37. Nuwer MR, Hovda DA, Schrader LM, Vespa PM. Routine and quantitative EEG in mild traumatic brain injury. Clin Neurophysiol. 2005;116(9):2001–25.

30. Felthous AR. The will: from metaphysical freedom to normative functionalism. J Am Acad Psychiatry Law 2008;36(1):16–24.

38. Wortzel HS, Filley CM, Anderson CA, Oster T, Arciniegas DB. Forensic applications of cerebral single photon emission computed tomography in mild traumatic brain injury. J Am Acad Psychiatry Law 2008;36(3):310–22.

31. Libet B. The timing of mental events: Libet’s experimental findings and their implications. Conscious Cogn. 2002;11(2):291–9; discussion 304–33.

39. Wortzel H, Kraus MF, Filley CM, Anderson CA, Arciniegas D. Diffusion tensor imaging in mild traumatic brain injury litigation. J Am Academy Psychiatry Law 2011;39(4):511–23.

29. Durham v. United States. United States Court of Appeals District of Columbia Circuit; 1954.

414

Section II


Chapter

Structural neuroimaging

26

Robin A. Hurley, Deborah M. Lucas, and Katherine H. Taber

The twentieth and twenty-first centuries brought many advances in technology to medicine, from which the practice of Behavioral Neurology & Neuropsychiatry (BN&NP) benefited greatly. Not only are structural disorders of the brain becoming better understood, but also the biological underpinnings of many traditional mental illnesses are now being described in terms of their anatomy and physiology. Many evaluative modalities, particularly neuroimaging (both structural and functional), are vitally important to broadening and deepening anatomical understanding of behavioral, cognitive, and emotional disorders. Imaging applications can include not only diagnostic assistance, but also estimations of the course of the illness and treatment response. Computed tomography (CT) and magnetic resonance imaging (MRI) are the techniques used for imaging brain structure. These widely used modalities provide information about the physical state of the brain, including structural integrity, and are not affected by the patient’s mood or emotional state. As the cost of medical care continues to rise, it is essential that the subspecialists in BN&NP both understand and are able to explain why these diagnostic techniques are necessary in the evaluation of their patients. This chapter will focus on the basic principles of CT and MRI, as they apply to the patients evaluated in this area of medicine. Illustrative examples of classic disorders are provided because an in-depth discussion of these diseases and conditions is beyond the scope of this chapter.

Clinical indications for brain imaging Historically, brain-imaging studies were performed to “rule-in” or document structural brain lesions after findings were elicited on neurological examination.

Imaging in psychiatric patients, however, was less useful: research studies of the classic conditions of schizophrenia, major depression, and bipolar disorder produced conflicting and at times disappointing results – typically no more specific than ventricular atrophy or general cortical atrophy. As BN&NP evolved and understanding of the advantages and disadvantages of imaging techniques expanded, so did insights attained from structural imaging. Wide dissemination of knowledge of the circuitry associated with emotion, behavior, and memory led to a more detailed examination of patients with small cortical and subcortical lesions [1]. Researchers then appreciated symptom presentation in the context of localized lesions, particularly psychiatric presentations after traumatic brain injury (TBI), multiple sclerosis (MS), ruptured aneurysms, and stroke. For the astute clinician, this knowledge often yields prognostic information that informs on patient assessments and treatment planning [2–5]. For example, a study of psychiatric patients without dementia found that treatment was changed in 15% of patients after imaging exams were performed [2]. Indications for brain imaging in BN&NP patients include: poison or toxin exposures (including significant alcohol abuse and workplace contact with toxic substances), dementia or cognitive decline of unknown etiology, delirium, brain injuries of any type (i.e., TBI or hypoxic-ischemic) with ongoing symptoms, new-onset psychiatric symptoms after age 50, abnormal neurological findings suggesting brain pathology, and new-onset atypical psychosis. In addition, any patient with symptoms that do not match with the “clinical norm” for the history merits neuroimaging (Table 26.1). With the increase in spatial resolution (1 mm) and sensitivity


415


Table 26.1. Clinical indications for structural neuroimaging in Behavioral Neurology & Neuropsychiatry. Clinical factors

Medical conditions

Psychiatric symptoms outside “clinical norms” New-onset mental illness after age 50 years Atypical age onset for the working diagnosis Initial psychotic break with atypical findings Focal neurological signs Catatonia Dementia or cognitive decline Sudden personality changes Traumatic and other acquired brain injuries Alcohol abuse with neuropsychiatric symptoms or subtle neurological signs Seizure disorders Movement disorders Autoimmune disorders Eating disorders Poison or toxic exposure Delirium

to new aspects of tissue offered by new imaging techniques, once undetectable lesions can now be identified. The BN&NP literature consistently documents case reports and case series of patients with positive imaging studies whose clinical symptoms were unexpected given the available history. Identification of a brain lesion can significantly alter treatment in many ways, ranging from medication or surgical options to

the institution of a cognitive rehabilitation program. To illustrate, mild cognitive impairment supported by structural imaging may be treated with acetylcholinesterase inhibitors [6], and periventricular white matter abnormalities may, in patients with hypertension, indicate the need for more aggressive control of blood pressure [7].

Pre-imaging considerations It is the responsibility of the ordering clinician to assure that the neuroradiologist is provided a clear and informative history on the imaging request. General phrases such as “rule out pathology” or “new-onset mental status changes” are not sufficient and limit the ability of the neuroradiologist to provide the ordering clinician with clinically useful information. Instead, all relevant information is needed, including any history of trauma, poison or toxin exposure, specific symptoms, suspected diagnoses, and so forth. If the ordering clinician suspects a lesion in a particular circuit or area, mentioning that suspicion to the neuroradiologist is helpful. It is also critical that any conditions that might impact the imaging process (e.g., delirium, agitation, paranoia, or anxiety) be noted so the staff are properly prepared. A successful imaging exam also requires that the patient be fully prepared. The ordering clinician should explain the procedure to the patient and always include a description of the loud noises and tightly Figure 26.1. Pictures of typical magnetic resonance imaging (MRI) hardware. The standard MRI scanner is presented in image (A), and the patient is introduced into the scanner in the bore indicated by the arrows. The receiving coils used in MRI fit closely to the head (B, C).

416

Chapter 26: Structural neuroimaging

enclosed space of an MRI scanner (Figure 26.1). The patient will also need to be reminded of the need to be immobile during the exam. Sedation is always an option if the clinician feels that the patient cannot complete the exam without undue distress. The regimen chosen should be one with which the clinician is familiar and comfortable. A sedating antipsychotic and/or a benzodiazepine can be suggested for physically healthy patients with no contraindications to these agents. In addition, an MRI screening questionnaire must be completed before the exam to assure that there are no contraindications to the procedure itself (these will be discussed below). Contrast agents are used to identify lesions that are of the same signal intensity as the surrounding brain tissue. In most cases, the neuroradiologist will review the imaging request and make the decision on the use of these agents. However, the clinician may suggest this type of imaging if a disorder is suspected where contrast-enhancement would provide further information. Such conditions include autoimmune or inflammatory conditions (e.g., multiple sclerosis or lupus), infectious diseases, tumors, suspected aneurysms, or other vascular processes (e.g., temporal arteritis, or arteriovenous malformations). Under normal conditions, contrast agents do not penetrate an intact blood–brain barrier. If this barrier is leaking, the contrast agent can move into tissue in the areas of abnormality [3–5, 8].

Post-imaging considerations When possible, the behavioral neurologist or neuropsychiatrist should review the images and the report with the neuroradiologist. This is not always possible in a busy clinical practice, and if so, keeping abreast of the latest imaging technologies with the help of review articles and the like will assist the clinician in incorporating imaging appropriately into clinical practice. Key points for clinicians to remember include: (1) All images are in the radiologic view: the radiologic view places images of the patient’s left on the reader’s right and the patient’s right on the reader’s left. (2) Observe patient demographics and scan data: although there is less potential for patient and film misidentification with digital imaging and computerized medical records, it is still important to assure that the reader is looking at the correct patient’s imaging (using name, age, identification

number, etc.), and that the scan date is as expected in patients with multiple examinations. Attention should be paid to whether contrast has been administered, and which MRI pulse sequences were used (pulse sequences will be explained below). (3) Look for normal anatomical markers: the images are first reviewed for normal anatomical markers. These include but are not limited to structures in the frontal and temporal lobes (including the hippocampus and amygdala), anterior cingulate, corpus callosum, mammillary bodies, basal ganglia, thalamus, and cerebellum. After review of the normal anatomy, the reader should then proceed to a review of any pathology. It is imperative that if the clinician has any questions about pathology or normal anatomy, the neuroradiologist should be consulted to discuss the case.

Computed tomography Computed tomography is similar to conventional radiography in that it uses an X-ray tube as a source of photons. With CT, the photons are collected by detectors rather than exposing film. What is measured is tissue density. Air is black (least dense) and bone is white (most dense). Tissues of intermediate density are shades of gray (Table 26.2 and Figure 26.2). Multiple rings of detectors allow simultaneous acquisition of several slices. The computer generates a twodimensional image from the detector data that is either displayed on a computer monitor or printed onto X-ray film. A standard head CT exposes the patient to radiation; while CT is often helpful and even lifesaving, the clinician should be aware that long-term effects of brain irradiation from CT have not been well studied. A more detailed discussion of radiation exposure can be found in [9]. The eyes are not traditionally scanned, as one precaution, and a lead apron can be worn by the patient if a head CT scan must be performed during pregnancy. In conventional CT, the table is advanced and the detectors are reset between acquisitions. A faster technique called helical (spiral) CT has been developed in which the detectors continuously rotate around the patient. Scanners with multiple arrays of detectors are now in use, allowing simultaneous acquisition of up to 64 slices. Imaging is sufficiently rapid that it can be combined with administration of a contrast agent

417


Table 26.2. Tissue appearance on computed tomography and magnetic resonance imaging. Abbreviations: FLAIR = fluid attenuated inversion recovery.

Magnetic resonance imaging Tissue type

Computed tomography

T1-weighted

T2-weighted

FLAIR

Bone

White

Black

Black

Black

Calcified tissue

White

Variable, usually gray



Gray matter

Light gray

Medium gray

Medium gray

Medium gray

White matter

Medium gray

Light gray

Dark gray

Dark gray

Cerebrospinal fluid

Nearly black

Black

White

Black

Water

Nearly black

Black

White

Black

Air

Black

Black

Black

Black

Blood – acute

White

Dark gray

Black

Black

Blood – subacute

Variable, usually gray (becomes isointense to brain after ∼1–2 weeks)

White

White

White

Other pathology

Gray

Gray

White

White Figure 26.2. Normal images of the brain acquired using computed tomography (CT; far left image) or magnetic resonance imaging (MRI; three images to the right) FLAIR MRI is fluid attenuated inversion recovery MRI.

to perform non-invasive diagnostic angiography [10]. Spiral CT has the added advantages of reducing scan times and radiation exposure and providing threedimensional imaging. Slice thickness can vary from 0.5–10 mm, with most scans using 3–5 mm. There are advantages and disadvantages to thinner sections. The thinner slices have less contrast (difference between white and gray matter) and mandate longer examinations, but provide identification of smaller areas of abnormality. Thicker slices may have more volume averaging (creating greater artifact), obscure the brainstem or mesial temporal structures, and miss very small lesions, but they have much better gray–white discrimination.

Contrast agents Lesions that are not clearly visible on a non-contrast head CT scan can be made more visible if there is any disruption in the blood–brain barrier. Once the blood–brain barrier has been breached, the contrast

418

agent collects in the lesional area of the brain parenchyma. This phenomenon creates an increased density, making the area appear white on the scan. Contrast agents are administered intravenously, are iodinated, and can be given in “double-dose” to improve identification of lesions with very small breaks in the blood–brain barrier. A fast bolus can be given to calculate mean blood transit time, cerebral blood flow (CBF), or cerebral blood volume [11]. Comparison of contrast and non-contrast scans will also avoid misidentification of calcifications as areas of pathology. Iodinated contrast agents are available in two types: non-ionic and ionic. There are contraindications as well as allergic reactions with both. These reactions can occur immediately (within one hour) or be delayed (within seven days) in onset and present as classic anaphylaxis or chemotoxic reaction including nausea/vomiting, hypotension, warmth at injection site, and arrhythmias [12–18]. Recent studies indicate varying rates of reaction. One study noted an overall


low mortality rate at 1/100,000; ionic reactions at 4– 12% and non-ionic at 1–3% [19, 20]. Another study noted mild ionic dye allergic reactions to be as low as 2.2% and 0.59% for non-ionic [21]. Most institutions use non-ionic agents, although they are more expensive. For those patients with previous allergic reactions to shellfish or contrast media, asthma, diabetes, renal insufficiency (creatinine ≥1.5 mg/dL), or other chronic health problems, the American College of Radiology recommends the use of non-ionic dyes [13, 22, 23]. Metformin (an antihyperglycemic agent) must be held for 24 hours before administration of iodinated CT contrast. It can be restarted after 48 hours with normal renal function [13]. For a more in-depth discussion of allergic reactions from CT contrast, see [9].

Magnetic resonance imaging Soft tissue is largely comprised of water molecules and hydrogen is a major component of water. Imaging of the brain with MRI depends on the polar characteristics of the water molecule and its unique behavior within a strong magnetic field. MRI technology is based on inducing temporary alternations of the small magnetic field that surrounds the nucleus of the hydrogen atom (proton). To attain the scan, the patient must be placed inside a large magnet that is tightly enclosing and loud when in operation (Figure 26.1). The strength of the magnets used for MRI is measured in tesla (T), and as the decades of MRI technology have passed, the strength of clinical magnets has increased. Most clinical magnets now have field strengths between 1.5–3 T, while some academic centers are using 4 T magnets for basic and clinical research. The stronger the magnet, the higher the resolution of the images; however, higher field-strength magnets are more costly. Open-design magnets are becoming more widely available to accommodate patients with larger girth and for those with severe anxiety in tightly enclosed spaces. Magnetic resonance images are created by exposing a patient’s hydrogen atoms to radiofrequency (RF) pulses while the patient is in the scanner’s magnetic field. The RF pulses change the magnetization of the hydrogen atoms. This change is registered by a receiver (imaging coil) located very close to the body area being scanned. These coils (Figure 26.1) can prove quite problematic for certain BN&NP patients, particularly those with anxiety, dementia, or psychosis. Huge coils

of wire are embedded in the magnet to create magnetic field gradients. They are driven by large current audio amplifiers and create very loud noises during the scan that can also distress patients. Unlike CT, which is sensitive only to tissue density, the many MRI techniques that have been developed are sensitive to different aspects of tissue. The magnetic resonance pulse sequence is the combination of the magnetic field and RF pulses that are used by the computer to transform energy signals into an image. This pulse sequence determines what information is available on the image. Most clinical MRI facilities use either a spin echo (SE) or a fast spin echo (FSE) sequence. Normal anatomy is best visualized on a T1-weighted image (Table 26.2 and Figure 26.2). Pathology, on the other hand, is best viewed on a T2-weighted or fluid attenuated inversion recovery (FLAIR) sequence. Cerebrospinal fluid (CSF) poses a problem as it is very light on a traditional T2-weighted image, and visualization of pathology near the ventricles is often challenging. The FLAIR image is also T2weighted, but the CSF appears as dark, allowing easier identification of pathology near CSF-filled spaces. Several other types of MRI are useful in detecting specific types of pathology. Gradient echo imaging (also called susceptibility weighted imaging) allows visualization of quite small areas of hemorrhage or calcium, as it is sensitive to the magnetic field inhomogeneity caused by their presence in tissue. However, artifacts can be severe with gradient echo imaging – especially near bone and brain interfaces – as these tissues have very different magnetic susceptibilities. Diffusion weighted imaging (DWI) is used to visualize areas of ischemic stroke – especially in the first few hours after onset. This sequence also is being explored for other conditions such as the neurodegenerative diseases. In short, DWI allows evaluation of the movement of water molecules within cells and across membranes. Water molecules are always in motion and the rate of diffusion across a permeable membrane is related to kinetic energy, temperature, and concentration differences of solutes across the membrane. In living tissue, cell membranes can be nonpermeable or selectively permeable, altering the direction of movement and diffusion of water molecules. Due to the complex effects of other interactions with water molecules in brain tissue, water movement is referred to as apparent diffusion. Diffusion weighted imaging uses the addition of strong gradient pulses to the imaging sequences to

419


de-phase and re-phase the water molecule spins. If the water molecules do not move between the first and second gradient pulse, there is loss of signal. This phenomenon is displayed qualitatively as a DWI. The loss of signal can also be quantified (measured), allowing calculation of an apparent diffusion coefficient (ADC) map. Areas of restricted diffusion will have high signal on DWI and low signal on the ADC map. Conversely, areas that have unrestricted diffusion will show low signal on DWI and high signal on the ADC map. In acute stroke, the cell membranes lose the ability to pump sodium out of the cell. As excess sodium accumulates within the cell, water also diffuses into the cell, producing cytotoxic edema. Water is thus restricted from leaving the cell via the cell membrane. On imaging, this process produces bright signal on DWI and low signal on the ADC map, signifying an acute ischemic event. These changes are demonstrable within minutes to hours of the onset of an acute stroke. As such lesions mature into subacute and chronic infarcts, the cell membranes change and diffusion is no longer restricted, and thus the lesions will no longer be bright on the DWI sequences. Other causes of restricted diffusion include bacterial abscess, epidermoid tumors, acute demyelination, and malignant tumors with central necrosis.

Contrast agents Contrast agents for MRI are formed by combining paramagnetic metal ions (e.g., gadolinium) with a ligand that binds them tightly, assuring that the complex will be excreted intact by the kidneys [24–28]. Like CT contrast agents, MRI contrast agents are administered intravenously and do not pass an intact blood–brain barrier. Thus, as with CT contrast agents, they can be used to improve visualization of pathologies that disrupt the blood–brain barrier, and to image CBF (e.g., first-pass or bolus perfusion MRI) [29, 30]. However, these agents are quite different from CT contrast agents in that they are not imaged directly. MR contrast agents change the relaxation properties of water in nearby tissues, seen on a T1-weighted image as a bright or white area (i.e., increased signal) [31, 32]. The incidence of adverse side effects with MRI contrast agents appears to be less than 3–5%, with any single type of side effect occurring in less than 1% of patients [24–26, 32]. Immediate reactions at the injection site include warmth or a burning sensation, pain, and local edema. Delayed reactions (including

420

erythema, swelling, and pain) appear 1–4 days after the injection. Immediate systemic reactions include nausea (sometimes vomiting) and headache. Anaphylactoid reactions have been reported, particularly in patients with a history of allergic respiratory disease. The incidence of these reactions appears to be somewhere between one and five in 500,000. Patients with severe renal insufficiency who receive gadolinium-based contrast agents are at risk for developing a debilitating and potentially fatal disease called nephrogenic systemic fibrosis (NSF) [33, 34]. In addition, patients with chronic liver disorders, and patients just before and just after liver transplantation, are at risk, especially if there is associated renal insufficiency of any severity. Nephrogenic systemic fibrosis is a diseases process that causes marked thickening and fibrosis in the skin and connective tissues, including tissues around major organs. No known effective treatment is available at this time. The exact cause of NSF is not known, but it seems to be related to single and multiple administrations of gadolinium-based contrast agents, especially in patients with limited renal function. Current recommendations are to screen patients for kidney problems prior to contrast administration. Patients with glomerular filtration rates (GFR) values ⬎ 60 are felt to be safe to scan with contrast. Patients with GFR values below 30 are at very high risk, and should not be scanned with contrast unless no other diagnostic procedure is available, and the study is extremely necessary for medical care. Patients must give consent and accept the risks associated with contrast use if they are to receive it. The presence of some of these contrast agents (OmniScan, OptiMark) has been reported to interfere with colorimetric assays for serum calcium, resulting in an incorrect diagnosis of hypocalcemia in 15% of patients in one recent study [26]; for a more extensive review of the biosafety aspects of MRI contrast agents, see [24]. Many new MRI contrast agents are under development [35]. As new contrast agents become available for MRI of the brain, the range of applications in BN&NP may well expand [36].

Safety and contraindications The brief exposure to high magnetic field and RF pulses required for clinical MRI do not pose any known clinical risks [37–39]. The much higher magnetic field and RF exposure associated with research MRI systems (≥4 T), however, can have certain


Table 26.3. Considerations in the selection of structural imaging method. Abbreviations: CT – computed tomography, MRI – magnetic resonance imaging, mm – millimeter.

Contrast between tissues

Resolution (mm)

Sectional planes

CT

Good

1.0

MRI

Excellent

1.0

Advantages

Disadvantages

Contraindications

Axial

Short-duration scan time Widely available Lower cost Sensitive to calcified lesions, skull fracture, and other bony lesions

Radiation exposure Limited resolution Poor visualization of posterior fossa (cerebellum and brainstem) Single imaging plane

Contrast-related: history of anaphylaxis or severe allergic reaction, renal insufficiency, and/or metformin administration on day of scan

All

Multi-axial imaging Excellent resolution and anatomical detail, especially temporal lobe, posterior fossa (cerebellum and brainstem), and white matter

Longer duration scan time Less available Higher cost Patient characteristics: claustrophobia, morbid obesity

Irremovable MRI-incompatible metals in body MRI-incompatible implanted devices Contrast-related: renal insufficiency

bioeffects (e.g., nausea, headaches, dizziness, peripheral nerve stimulation) [38–42]. Contraindications to MRI scanning come from the interaction between the required high magnetic field and RF pulses and certain metallic objects patients may carry with them. These can be magnetic, electrical, or mechanical devices attached to or implanted within the body. Examples include foreign objects such as metal shavings in the eyes from welding, bullets or shrapnel, and implanted medical devices such as dental or cochlear implants, stoma plugs, stimulators, and infusion pumps. Pacemakers are particularly problematic, and problems can include induced arrhythmias, fibrillation, and movement or burns along the wires. Metal also causes local distortion in the images and reduces diagnostic utility [37, 38, 40, 43]. Consideration of risks and benefits should be undertaken and documented before performing MRI on a pregnant woman, especially during the first trimester. To date, there is no evidence of fetal harm from MRI [44, 45]. Certainly for conditions such as suspected subarachnoid hemorrhage, ruptured aneurysm, or stroke, imaging can be life-saving and should be undertaken. Chronic disease states may afford delays until the post-partum period for imaging [38, 40, 44–46]. Metallic objects are very dangerous when taken into the vicinity of a magnet. They can be pulled towards the magnet at very high speed and cause death or severe injury to anyone in their path.

Another issue arises when contemplating neuroimaging of very ill hospitalized patients. Patients requiring physiologic monitoring or transportation to the scanner via stretcher or wheelchair can in fact be scanned. The process requires use of MRI-compatible respirators, blood pressure and heart rate monitors, and MRI-compatible stretches or wheelchairs. When the compatible equipment is not available, then all standard non-compatible medical equipment must be located a minimum of eight feet from the magnet. This line is indicated on the floor of most scanner rooms.

Use of CT versus MRI Factors important to consider when choosing an imaging modality include type of suspected pathology, acuity of the illness, and desired planes of section (Table 26.3). Magnetic resonance imaging is generally more expensive than CT, but offers higher resolution, multiple planes of sections, and visualization of a wider range of pathologies and anatomic locations. Computed tomography is considerably faster and better for acute hemorrhage, bone fractures, and calcifications.

Advanced imaging techniques Magnetic resonance imaging techniques sensitive to other aspects of tissue state have been developed, but are more challenging to apply to clinical practice [5, 47]. Magnetization transfer (MT) imaging approaches (based on interactions between free water and water bound to macromolecules) are sensitive

421


to microstructural changes, particularly within white matter. Thus, MT imaging may provide a basis for better assessment of pathological processes affecting white matter [47–49]. This approach also shows potential for high resolution imaging of deep gray matter structures [50, 51]. Diffusion tensor imaging (DTI) is a more complex version of DWI in which gradient pulses in six or more directions are used and vectors of water movement can thus be calculated. If there is restriction to movement in certain directions and not in others, the pathways of preferred diffusion can be mapped. If a tissue is homogeneous, the movement of water molecules and diffusion is equal in all directions, or isotropic. Gray matter areas of brain are usually isotropic. In contrast, diffusion in white matter tends to occur faster along the direction of the fibers, and is restricted in other directions due to cell membranes and axon walls. The preferential movement of water molecules in a specific direction within a voxel of tissue is known as anisotropic diffusion [52–58]. Many pathological processes that alter diffusion can be identified with DTI. These include ischemia, gliosis, demyelination, or disruption of fiber tracts associated with TBI. Although DTI remains a research technique to date, it has great potential for the study of altered brain connectivity in many BN&NP conditions, including a host of white matter disorders not well identified by the above techniques. Diffusion tensor imaging has also been applied to determine the location of white matter fiber tracts and the connections they make within the brain, a process known as tractography (Figure 26.3) [57, 58]. Current drawbacks of the DTI technique include limited spatial resolution, in that fiber bundles less than 2.5 mm cannot be imaged or evaluated. In addition, there is no directional information, so there is no way to differentiate afferent or efferent neuronal pathways within the fiber tracts. Analyzing the data continues to require prior knowledge of white matter anatomy. Diffusion tensor imaging has been used in evaluation of BN&NP disorders for many years [58], but much of this work is still investigational [59]. As with other investigative techniques, there is much overlap between normal and disease patterns, which limits the specificity of DTI. However, the combination of techniques such as DTI tractography and MR spectroscopy (MRS, see discussion below) may provide improved specificity, and increase the understanding of many underlying pathologic processes.

422

Figure 26.3. An example of diffusion tensor imaging (DTI) as applied to the study of traumatic brain injury (TBI) (axial T1-weighted image with DTI overlaid). White matter tractography using TBI is used here to visualize the anterior forceps of the corpus callosum in a male who experienced multiple concussions due to blast forces. This case is provided courtesy and with the permission of Dr. Rajendra Morey, Duke University and Mid-Atlantic Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 6, Durham, North Carolina. This figure is presented in color in the color plate section.

There are two major approaches to MRI-based perfusion (CBF) studies [60]. The first involves intravenous injection of contrast material (e.g., first-pass or bolus perfusion MRI) [29, 30]. As the MRI contrast agent enters the microvasculature, it causes a loss of signal in the surrounding tissue. The loss of signal is proportional to the concentration of contrast agent in the blood. A concentration time curve can be constructed, and, from that curve, a calculation of CBF can be generated. Flowing blood itself can be used as a contrast agent for MRI. This second technique is called arterial spin labeling (ASL). Water molecules within the carotid arteries are “tagged” with RF pulses, thus changing the signal intensity of the blood flowing up into the brain [12, 60]. Magnetic resonance imaging of perfusion has been utilized vigorously in both research and clinical settings to evaluate microvascular and circulatory changes within the brain related to ischemia, atherosclerotic vascular occlusive disease, vasospasm, and vascular malformations. It is primarily still a research tool in BN&NP, but there is great potential for the evaluation of subtle brain perfusion changes that can occur in many conditions [60]. Perfusion analysis with MRI is comparable to nuclear


medicine perfusion studies. The key concept is that an abnormality in blood flow alters delivery of nutritional support and oxygen to the neurons, adversely affecting neuronal firing and function. Nuclear magnetic resonance (NMR) or magnetic resonance spectroscopy (MRS) has long been used to investigate chemical make-up and alterations in tissue samples in vitro. In parallel with the development of MRI, which uses the characteristics of the hydrogen molecules in water to create images of living tissue, the application of MRS to evaluate chemical composition and characteristics of metabolic processes in vivo has also progressed [61]. Magnetic resonance spectroscopy can be used to localize malignant cells within a volume of tissue, or it can be targeted to identify specific molecules related to drug distribution within tissue. This investigational technique is currently being studied to better understand chemical alterations and regional brain involvement in various psychiatric diseases such as autism, schizophrenia, major depression, bipolar disorder, and panic disorder. Magnetic resonance spectroscopy takes advantage of unique energy spectra produced by certain atoms when they are subjected to a RF pulse while in a strong magnetic field. The spectral peaks produced can be used to identify chemical alterations in tissue. Certain atoms can assume magnetic properties when placed into a magnetic field due to their unpaired atomic particles (nucleons, protons, or neutrons). These atoms include hydrogen (1-H), phosphorus (31-P), lithium (7-Li), fluorine (19-F), and carbon (13-C). These atoms already exist in tissue and, with the help of a strong enough magnetic field and appropriate receptor settings, the presence of these atoms can be detected and measured. These atoms can also be incorporated into manufactured products or pharmaceuticals and then selectively studied in patients with specific disorders. Current limitations for this investigative technique include the need for high-field magnets to improve signal-to-noise ratios. Some sites are using 9.4 T magnets which are not currently approved by the FDA [62]. The characteristics of 19-fluorine (19-F; fluorine’s stable isotope) make it favorable for in vivo MRS [63]. Fluorine is present in many medicinal and non-medicinal compounds. Currently, investigational studies are testing methods of targeting the 19-F molecule that will allow it to be used as a tag to identify how certain drugs and psychoactive agents are absorbed, distributed, metabolized, and excreted.

Figure 26.4. Acute subdural hygroma. Axial computed tomography (CT) of acute subdural hygroma in a young male following severe trauma. Acute hemorrhage most commonly appears hyperintense on CT due to the high density of aggregated red blood cells (RBCs), whereas acute subdural hygroma (consisting mostly of cerebrospinal fluid) appears hyperdense.

Many agents accumulate slowly in the brain, and reach high enough levels in brain tissue to be detected with 19-F MRS [63]. Concentrations can be calculated by comparing signal from tissue to a reference phantom containing a known concentration of the drug. This technique can detect micromolar quantities (in the range of therapeutic concentrations), and has a spatial resolution of several centimeters. The benefits of an in vivo technique include documentation that the drug under investigation has reached the target tissue and is in a bio-available form. This technique may help determine how a drug is metabolized, and whether there are inactive or competitive metabolites, and it might eliminate the need for actual tissue collection to determine distribution of a drug. Plasma levels of a drug cannot necessarily predict concentration of a drug within the target tissue. Preliminary studies have been useful in demonstrating that certain antidepressants accumulate more slowly in brain tissue than plasma, and clear more quickly from the circulation than from the brain once therapy has been discontinued. Since therapeutic response and withdrawal symptoms correlate with brain levels, not plasma levels, a method of actually monitoring the brain levels could be helpful in medication management [63]. Functional MRI (fMRI) utilizes blood oxygen level-dependent (BOLD) sequences. These indirectly

423


measure increases in glucose and oxygen used by brain cells. The BOLD signal is based on changes in the deoxyhemoglobin level of blood [64]. These changes are proportional to local neural activity, and can be used to study areas of brain activity during periods of brain stimulation such as asking subjects to do simple calculations or solve puzzles [65]. fMRI is used extensively in BN&NP research. Particular areas of interest include post-traumatic stress disorder, depression, and a wide range of cognitive impairments [66, 67]. Whereas it is both exciting and promising, this technique is complex, expensive, and often difficult to interpret [68]. Functional imaging is taken up in greater detail in the next chapter. Morphometric analysis of differences in brain tissue volume between normal subjects and patients with BN&NP disorders has been investigated, with the aim of seeking specific patterns of abnormality

Figure 26.5. Subarachnoid hemorrhage. Computed tomography (CT) is the preferred imaging modality for visualization of acute hemorrhage. Acute hemorrhage is bright on CT. This figure presents an axial CT without contrast in a 46-year-old male with severe headache. Images demonstrate a focal area of increased attenuation at the left anterior Circle of Willis due to an aneurism (arrowheads). Blood is seen in the subarachnoid spaces and cisterns (arrows).

Figure 26.6. Remote traumatic brain injury (TBI). T1-weighted (axial), T2-weighted (axial), and fluid attenuated inversion recovery (FLAIR, axial and sagittal) magnetic resonance imaging (MRI) of a middle-aged man with a history of assault to the head with a blunt object approximately 10 years prior to this neuroimaging exam. Three years prior to exam the patient experienced multiple combat-related exposures to explosions. Note the severe bilateral encephalomalacia and gliosis in the parasagittal frontal cortex.

Figure 26.7. Parasagittal meningioma. Axial images from a middle-aged female with anterior fossa meningioma. Note the improved visualization on computed tomography (CT) with and without contrast enhancement (center and left images, respectively). This finding is revealed in greater detail on magnetic resonance imaging (MRI, right image). Meningiomas are commonly very slow growing and do not elicit formation of vasogenic edema in spite of size. This meningioma appears to originate from the falx cerebri and is growing symmetrically in the longitudinal fissure between the cerebral hemispheres.

424


Figure 26.8. Astrocytoma. Axial magnetic resonance imaging (MRI) of the brain without and with contrast in a female child. Note the prominent slightly lobulated heterogeneously enhancing mass arising from the right thalamus, with mass effect and midline shift.

Figure 26.9. Metastatic melanoma. Axial magnetic resonance imaging (MRI) of the brain of a middle-aged female with removal (from back) several years prior to this exam of melanoma. T1-weighted, T2-weighted, and fluid attenuated inversion recovery (FLAIR) images demonstrate a large oval mass within the brain surrounded by vasogenic edema in the white matter.

Figure 26.10. Central nervous system lymphoma. Axial T1-weighted gadolinium-enhanced magnetic resonance imaging (MRI) of primary cerebral lymphoma in the right medial temporal lobe (arrows). Note the bright appearance of the contrast-enhanced lesions.

that may help differentiate disease processes [69]. The simplest approach to evaluation of brain volume is to manually draw regions of interest (ROI) around the specific tissue to be studied. However, this procedure is time-consuming, and there is variability between individuals implementing this approach. A more automated approach is to compare signal differences between voxels on an MRI image. This technique is called voxel-based morphometry (VBM). By comparing inherent differences in signal between various

Figure 26.11. Toluene abuse. Axial T2-weighted magnetic resonance imaging (MRI) of a woman in her mid-20s who regularly inhaled toluene over a 10-year period. Note the global decrease in myelin (demyelination) as indicated by increased signal intensity of the white matter. The normal image is included in this figure in order to facilitate identification of the abnormal white matter signal in the patient’s image.

tissue types, images can be segmented into separate components, such as gray matter, white matter, CSF spaces, etc. The technique allows for faster throughput of patients and for faster extraction of data from a larger number of subjects. There are some limitations, as brains vary in shape, and there is also a wide range of normal variation in derived values. However, useful data have been obtained using this method [69].

425


Figure 26.12. Cyanide poisoning. Serial axial computed tomography (CT) images of a teenage male following ingestion of cyanide illustrate the progression of diffuse edema (indicated by loss of cortical sulci due to compression) and loss of the normal density difference between gray matter and white matter by day seven (arrows). The acute pathology resolved by approximately 6 months post-ingestion.

technique to be useful in certain diagnostic realms as well as in predicting outcomes and likelihood of response to therapy.

Transcranial Doppler ultrasound analysis

Figure 26.13. Frontal lobotomy. Axial computed tomography images of elderly male with bilateral severe encephalomalacia subsequent to a frontal lobotomy that was performed approximately 30 years prior to this neuroimaging examination. Note the significant loss of white matter bilaterally.

Data from morphometric studies have documented reproducible abnormalities in certain disease classes [69]. For example, enlarged lateral ventricles as well as medial temporal lobe and neocortical temporal lobe volume loss are noted in schizophrenia. Abnormalities tend to involve the gray matter more than the white matter. These specific abnormalities are not seen in patients with affective psychosis or bipolar disorder with psychotic features, lending credence to the use of this technique for diagnosing and differentiating illness. In patients with attention-deficit hyperactivity disorder, data have shown asymmetry in brain pathways along the right cingulate cortex, which is smaller in non-treated patients than in post-treatment and control group patients. These findings suggest that morphometric techniques may be useful for monitoring therapy. Currently there is much overlap between normal controls and patients, and sensitivity and specificity are low, but potential exists for this

426

Doppler ultrasound (US) evaluation has been used successfully in clinical neurology as a screening tool to evaluate internal carotid artery (ICA) disease. The use of a similar technique has been investigated as a means of evaluating the middle cerebral artery (MCA) in patients who have already had a stroke or transient ischemic attack (TIA). Identification of an MCA stenosis ≥50% increases the risk for subsequent ischemic events or TIAs. However, there is currently no consensus on a reliable velocity threshold for diagnosis of MCA stenosis. Velocities are measured at the point of maximal arterial narrowing. Based on review of the current literature, a peak systolic velocity of 80 cm/s had a sensitivity of 92%, specificity of 92%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 98% for identifying a stenosis ≥50% [70]. Peak systolic velocities of greater than 140 cm/s are strongly predictive of recurrent ischemic events. An important limitation of transcranial Doppler US is that there is currently no method to correct for velocity alterations due to hemodynamic factors. In the neck, the ICA velocity is divided by the common carotid artery velocity to “normalize” the value at the ICA for any secondary process that may elevate overall velocities such as high output anemia. Further investigation is needed to determine optimal velocity end-points for prediction of recurrent ischemic events when utilizing transcranial Doppler US for evaluation of MCA stenoses.


Illustrative case examples The past two decades, in particular, have brought many new advances in imaging to the field of BN&NP. This chapter has provided an overview of the current state of structural imaging as it applies to clinical practice in this field. Techniques presently valuable for research and with potential for future clinical application have also been introduced. Figures 26.4– 26.13 present selected images from patients with selected neuropsychiatric conditions. This collection is not all-inclusive, but serves to introduce the use of imaging in BN&NP and to familiarize the reader with the appearances of various pathologies on CT and/or MRI.

References 1. Mega MS, Cummings JL. Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci. 1994;6(4):358–70. 2. Erhart SM, Young AS, Marder SR, Mintz J. Clinical utility of magnetic resonance imaging radiographs for suspected organic syndromes in adult psychiatry. J Clin Psychiatry 2005;66(8):968–73. 3. Diwadkar VA, Keshavan MS. Newer techniques in magnetic resonance imaging and their potential for neuropsychiatric research. J Psychosom Res. 2002; 53(2):677–85. 4. Gupta A, Elheis M, Pansari K. Imaging in psychiatric illnesses. Int J Clin Pract. 2004;58(9):850–8. 5. Symms M, Jager HR, Schmierer K, Yousry TA. A review of structural magnetic resonance neuroimaging. J Neurol Neurosurg Psychiatry 2004; 75(9):1235–44. 6. Diniz BS, Pinto JA, Jr, Gonzaga ML et al. To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci. 2009;259(4):248–56.

Publishing Textbook of Neuropsychiatry and Clinical Neurosciences. 5th edition. Washington, DC: American Psychiatric Publishing; 2008, pp. 245–300. 10. Willmann JK, Wildermuth S. Multidetector-row CT angiography of upper- and lower-extremity peripheral arteries. Eur Radiol. 2005;15(Suppl. 4): D3–9. 11. Halpin SF. Brain imaging using multislice CT: a personal perspective. Br J Radiol. 2004;77(Spec No 1): S20–6. 12. Detre JA, Alsop DC. Arterial spin labeled perfusion magnetic resonance imaging. In Latchaw RE, Kucharczyk J, Moseley ME, editors. Imaging of the Nervous System: Diagnostic and Therapeutic Applications. Philadelphia, PA: Elsevier-Mosby; 2005, pp. 323–31. 13. Cohan RH, Matsumoto JS, Quaglianao PV. ACR Manual on Contrast Media. Reston, VA: American College of Radiology; 1998. 14. Federle MP, Willis LL, Swanson DP. Ionic versus nonionic contrast media: a prospective study of the effect of rapid bolus injection on nausea and anaphylactoid reactions. J Comput Assist Tomogr. 1998;22(3):341–5. 15. Mortele KJ, Oliva MR, Ondategui S, Ros PR, Silverman SG. Universal use of nonionic iodinated contrast medium for CT: evaluation of safety in a large urban teaching hospital. AJR Am J Roentgenol. 2005; 184(1):31–4. 16. Jacobs JE, Birnbaum BA, Langlotz CP. Contrast media reactions and extravasation: relationship to intravenous injection rates. Radiology 1998;209(2): 411–16. 17. Oi H, Yamazaki H, Matsushita M. Delayed vs. immediate adverse reactions to ionic and non-ionic low-osmolality contrast media. Radiat Med. 1997; 15(1):23–7. 18. Yasuda R, Munechika H. Delayed adverse reactions to nonionic monomeric contrast-enhanced media. Invest Radiol. 1998;33(1):1–5.

7. Hurley RA, Tomimoto H, Akiguchi I, Fisher RE, Taber KH. Binswanger’s disease: an ongoing controversy. J Neuropsychiatry Clin Neurosci. 2000;12(3):301–4.

19. Cochran ST, Bomyea K, Sayre JW. Trends in adverse events after IV administration of contrast media. AJR Am J Roentgenol. 2001;176(6):1385–8.

8. Hurley RA, Hayman LA, Taber KH. Clinical imaging in neuropsychiatry. In Yudofsky SC, Hales RE, editors. The American Psychiatric Publishing Textbook of Neuropsychiatry and Clinical Neurosciences. 4th edition. Washington, DC: American Psychiatric Publishing; 2002, pp. 245–83.

20. Cochran ST. Anaphylactoid reactions to radiocontrast media. Curr Allergy Asthma Rep. 2005;5(1):28–31.

9. Hurley RA, Fisher RE, Taber KH. Clinical and functional imaging in neuropsychiatry. In Yudofsky SC, Hales RE, editors. The American Psychiatric

21. Valls C, Andia E, Sanchez A, Moreno V. Selective use of low-osmolality contrast media in computed tomography. Eur Radiol. 2003;13(8):2000–5. 22. Konen E, Konen O, Katz M et al. Are referring clinicians aware of patients at risk from intravenous injection of iodinated contrast media? Clin Radiol. 2002;57(2):132–5.

427


23. Halpern JD, Hopper KD, Arredondo MG, Trautlein JJ. Patient allergies: role in selective use of nonionic contrast material. Radiology 1996;199(2):359–62. 24. Shellock FG, Kanal E. Safety of magnetic resonance imaging contrast agents. J Magn Reson Imaging 1999; 10(3):477–84. 25. Runge VM. Safety of magnetic resonance contrast media. Top Magn Reson Imaging 2001;12(4):309–14. 26. Kirchin MA, Runge VM. Contrast agents for magnetic resonance imaging: safety update. Top Magn Reson Imaging 2003;14(5):426–35. 27. Baker JF, Kratz LC, Stevens GR, Wible JH, Jr. Pharmacokinetics and safety of the MRI contrast agent gadoversetamide injection (OptiMARK) in healthy pediatric subjects. Invest Radiol. 2004;39(6):334–9. 28. van der Molen AJ, Bellin MF. Extracellular gadolinium-based contrast media: differences in diagnostic efficacy. Eur J Radiol. 2008;66(2):168–74. 29. Latchaw RE. Cerebral perfusion imaging in acute stroke. J Vasc Interv Radiol. 2004;15(1 Pt 2):S29–46. 30. Sunshine JL. CT, MR imaging, and MR angiography in the evaluation of patients with acute stroke. J Vasc Interv Radiol. 2004;15(1 Pt 2):S47–55. 31. Mitchell DG. MR imaging contrast agents – what’s in a name? J Magn Reson Imaging 1997;7(1):1–4. 32. Runge VM, Muroff LR, Wells JW. Principles of contrast enhancement in the evaluation of brain diseases: an overview. J Magn Reson Imaging 1997;7(1):5–13. 33. Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology 2007; 242(3):647–9.

review. Int J Environ Res Public Health 2009;6(6): 1778–98. 40. Shellock FG. Bioeffects and safety considerations. In Atlas SW editor. Magnetic Resonance Imaging of the Brain and Spine. New York, NY: Raven Press; 1991, pp. 87–107. 41. Bourland JD, Nyenhuis JA, Schaefer DJ. Physiologic effects of intense MR imaging gradient fields. Neuroimaging Clin N Am. 1999;9(2):363–77. 42. Hoffmann A, Faber SC, Werhahn KJ, Jager L, Reiser M. Electromyography in MRI – first recordings of peripheral nerve activation caused by fast magnetic field gradients. Magn Reson Med. 2000;43(4):534–9. 43. Shellock FG. Magnetic resonance safety update 2002: implants and devices. J Magn Reson Imaging 2002; 16(5):485–96. 44. De Wilde JP, Rivers AW, Price DL. A review of the current use of magnetic resonance imaging in pregnancy and safety implications for the fetus. Prog Biophys Mol Biol. 2005;87(2–3):335–53. 45. Thompson SK, Goldman SM, Shah KB et al. Acute non-traumatic maternal illnesses in pregnancy: imaging approaches. Emerg Radiol. 2005;11(4): 199–212. 46. Shellock FG, Kanal E. Policies, guidelines, and recommendations for MR imaging safety and patient management. SMRI Safety Committee. J Magn Reson Imaging 1991;1(1):97–101. 47. Pagani E, Bizzi A, Di Salle F, De Stefano N, Filippi M. Basic concepts of advanced MRI techniques. Neurol Sci. 2008;29(Suppl. 3):290–5.

34. Kanal E, Broome DR, Martin DR, Thomsen HS. Response to the FDA’s May 23, 2007, nephrogenic systemic fibrosis update. Radiology 2008;246(1):11–14.

48. Hurley RA, Ernst T, Khalili K et al. Identification of HIV-associated progressive multifocal leukoencephalopathy: magnetic resonance imaging and spectroscopy. J Neuropsychiatry Clin Neurosci. 2003;15(1):1–6.

35. Bulte JW, Kraitchman DL. Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed. 2004;17(7):484–99.

49. Filippi M, Rocca MA. Magnetization transfer magnetic resonance imaging in the assessment of neurological diseases. J Neuroimaging 2004;14(4):303–13.

36. Hoehn M, Himmelreich U, Kruttwig K, Wiedermann D. Molecular and cellular MR imaging: potentials and challenges for neurological applications. J Magn Reson Imaging 2008;27(5):941–54.

50. Helms G, Draganski B, Frackowiak R, Ashburner J, Weiskopf N. Improved segmentation of deep brain grey matter structures using magnetization transfer (MT) parameter maps. Neuroimage 2009;47(1):194–8.

37. Price RR. The AAPM/RSNA physics tutorial for residents. MR imaging safety considerations. Radiological Society of North America. Radiographics 1999;19(6):1641–51.

51. Gringel T, Schulz-Schaeffer W, Elolf E et al. Optimized high-resolution mapping of magnetization transfer (MT) at 3 Tesla for direct visualization of substructures of the human thalamus in clinically feasible measurement time. J Magn Reson Imaging 2009;29(6): 1285–92.

38. Shellock FG, Crues JV. MR procedures: biologic effects, safety, and patient care. Radiology 2004;232(3):635–52. 39. Hartwig V, Giovannetti G, Vanello N et al. Biological effects and safety in magnetic resonance imaging: a

428

52. Taber KH, Pierpaoli C, Rose SE et al. The future for diffusion tensor imaging in neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2002;14(1):1–5.


53. Kubicki M, Westin CF, Maier SE et al. Uncinate fasciculus findings in schizophrenia: a magnetic resonance diffusion tensor imaging study. Am J Psychiatry 2002;159(5):813–20. 54. Taylor WD, Hsu E, Krishnan KR, MacFall JR. Diffusion tensor imaging: background, potential, and utility in psychiatric research. Biol Psychiatry 2004; 55(3):201–7. 55. Sundgren PC, Dong Q, Gomez-Hassan D et al. Diffusion tensor imaging of the brain: review of clinical applications. Neuroradiology 2004;46(5): 339–50. 56. Dong Q, Welsh RC, Chenevert TL et al. Clinical applications of diffusion tensor imaging. J Magn Reson Imaging 2004;19(1):6–18. 57. Catani M. Diffusion tensor magnetic resonance imaging tractography in cognitive disorders. Curr Opin Neurol. 2006;19(6):599–606. 58. White T, Nelson M, Lim KO. Diffusion tensor imaging in psychiatric disorders. Top Magn Reson Imaging 2008;19(2):97–109. 59. Kyriakopoulos M, Frangou S. Recent diffusion tensor imaging findings in early stages of schizophrenia. Curr Opin Psychiatry 2009;22(2):168–76. 60. Theberge J. Perfusion magnetic resonance imaging in psychiatry. Top Magn Reson Imaging 2008;19(2): 111–30. 61. Dager SR, Corrigan NM, Richards TL, Posse S. Research applications of magnetic resonance spectroscopy to investigate psychiatric disorders. Top Magn Reson Imaging 2008;19(2): 81–96. 62. Schneider F, Backes V, Mathiak K. Brain imaging: on the way toward a therapeutic discipline. Eur Arch

Psychiatry Clin Neurosci. 2009;259(Suppl. 2): S143–7. 63. Reid DG, Murphy PS. Fluorine magnetic resonance in vivo: a powerful tool in the study of drug distribution and metabolism. Drug Discov Today 2008;13(11–12): 473–80. 64. Sava S, Yurgelun-Todd DA. Functional magnetic resonance in psychiatry. Top Magn Reson Imaging 2008;19(2):71–9. 65. Paloyelis Y, Mehta MA, Kuntsi J, Asherson P. Functional MRI in ADHD: a systematic literature review. Expert Rev Neurother. 2007;7(10):1337–56. 66. Morey RA, Petty CM, Cooper DA, Labar KS, McCarthy G. Neural systems for executive and emotional processing are modulated by symptoms of posttraumatic stress disorder in Iraq War veterans. Psychiatry Res. 2008;162(1):59–72. 67. Moores KA, Clark CR, McFarlane AC et al. Abnormal recruitment of working memory updating networks during maintenance of trauma-neutral information in post-traumatic stress disorder. Psychiatry Res. 2008; 163(2):156–70. 68. Taber KH, Rauch SL, Lanius RA, Hurley RA. Functional magnetic resonance imaging: application to posttraumatic stress disorder. J Neuropsychiatry Clin Neurosci. 2003;15(2):125–9. 69. Fleck DE, Nandagopal J, Cerullo MA et al. Morphometric magnetic resonance imaging in psychiatry. Top Magn Reson Imaging 2008;19(2): 131–42. 70. Navarro JC, Lao AY, Sharma VK, Tsivgoulis G, Alexandrov AV. The accuracy of transcranial Doppler in the diagnosis of middle cerebral artery stenosis. Cerebrovasc Dis. 2007;23(5–6):325–30.

429

Section II


Chapter

Advanced neuroimaging

27

Deborah M. Little, David B. Arciniegas, and John Hart, Jr.

Advances in neuroimaging are improving our understanding of, and diagnostic approach to, many neurologic and neuropsychiatric conditions by identifying disturbances in brain structure and/or function that underlie neurobehavioral disturbances. In addition to detailed structural information, some types of advanced neuroimaging also provide non-invasive assessments of the metabolic and biochemical characteristics of brain tissue. Although some of these techniques are primarily used for research purposes, advanced neuroimaging methods are increasingly being applied to the evaluation and management of persons with neuropsychiatric disorders. As discussed in Chapter 26, conventional neuroimaging is used routinely in the practice of Behavioral Neurology & Neuropsychiatry (BN&NP) and its application in clinical contexts is a core clinical competency in this field [1]. There is increasing interest in the application of more recently developed magnetic resonance imaging (MRI) techniques such as diffusion tensor imaging (DTI), diffusion spectrum imaging (DSI), magnetic resonance spectroscopy (MRS), arterial spin labeling (ASL), functional MRI (fMRI), and functional connectivity MRI (fcMRI) to clinical practice. At the present time, however, the use of these techniques in clinical medicine is neither widespread nor generally accepted. Nuclear medicine technologies, including single-photon emission computed tomography (SPECT) and positron emission tomography (PET), are applied in select circumstances to the practice of BN&NP and they remain commonly employed research techniques. Although advanced neuroimaging techniques may not be used commonly by many BN&NP subspecialists, a basic understanding of these techniques is essential [1] for practitioners in this field.

This chapter therefore focuses on the principles of advanced neuroimaging, their current clinical applications and limitations, and also their emerging indications. It will be emphasized that, unlike standard structural MRI, advanced neuroimaging is most useful as a guide to understanding relationships between behavior, cerebral function, and the interaction of disease with normal structure and function. Beyond their value for moving the field forward through clinical research, these applications may also be important at the individual case level. In order to frame the potential applications of advanced neuroimaging to clinical BN&NP, two illustrative cases are presented here. Following their presentation, an overview of common types of advanced neuroimaging technologies and techniques, including xenon enhanced computed tomography (Xe-CT) imaging, advanced MRI techniques, PET, and SPECT, is provided.

Case 1 A 32-year-old woman was referred for neurosurgical evaluation for deep brain stimulation (DBS) to manage debilitating chronic pain resulting from a motor vehicle accident. This referral followed multiple unsuccessful attempts to control her pain by other methods by specialists in anesthesiology, psychiatry, neurology, and orthopedic surgery. As part of the neurosurgical evaluation, both structural MRI and fMRI were obtained. Because of the pain, the patient required general anesthesia for the MRI. An fMRI paradigm involving light pain stimulation was used and alternated with rest. As shown in Figure 27.1, the patient exhibited significant thalamic activation during pain, even while under general anesthesia. Given the


430

Chapter 27: Advanced neuroimaging

revealed a small lesion in the posterior aspect of the splenium of the corpus callosum that branched into the forceps major (see Figure 27.2A). On DTI, the effects of this lesion on fiber tract integrity were evident on the color-coded fractional anisotropy (FA) map (Figure 27.2B). Fiber tracking was undertaken by placement of a small region of interest (ROI) in the corpus callosum; this approach showed a lack of connectivity between the posterior radiation of the splenium of the corpus callosum and the ipsilateral parietal lobules. More directed neuro-ophthalmologic testing revealed a deficit in the visual field consistent with this lesion location. In this case, the use of DTI provided diagnostic information and directed additional rehabilitation interventions. Figure 27.1. Functional magnetic resonance imaging (fMRI) using a light pain stimulation paradigm, which produced bilateral thalamic activation. This figure is presented in color in the color plate section.

extensive literature implicating the thalamus in the gating of pain, these data provided additional information to the neurosurgeon planning her DBS procedure.

Case 2 A 41-year-old man was struck by a car while riding his bicycle. He experienced event-related alteration of consciousness, and was evaluated in the emergency department of a nearby hospital. Computed tomography (CT) imaging of the head performed in the emergency room was unremarkable, and he was discharged home. Over the following 2 years, he experienced cognitive and behavioral symptoms, eventually prompting consultation with a subspecialist in BN&NP. High-resolution T2-weighted imaging

Xenon enhanced computed tomography imaging Xenon enhanced CT imaging (Xe-CT) is a widely used and highly available imaging technique for the quantification of cerebral blood flow (CBF). Stable xenon gas – which is radiodense, lipid soluble, and diffuses easily across the blood–brain barrier – is used as the contrast agent. Following the collection of a baseline head CT scan, this method of imaging requires the patient to inhale a mixture of xenon gas (26–33%) and oxygen, after which additional scanning either during inhalation, after inhalation, or both is performed. Xenon gas alters the signal characteristics of the tissues into which it diffuses, thereby providing an indirect measure of cerebral blood flow. Because it is particularly useful for the study of CBF, Xe-CT is often used in the acute setting to rule out an ischemic event. Identifying areas of decreased CBF, indicating ischemic tissue, allows the opportunity Figure 27.2. Magnetic resonance imaging (MRI) of a man with remote traumatic brain injury (TBI). High-resolution T2-weighted imaging (A), diffusion tensor imaging (DTI) with color-coded fractional anisotropy (FA) mapping (B), and fiber tracking (C) based on the identification of the region of interest (boxed area in A). This figure is presented in color in the color plate section.

431


for early intervention to reduce the neurological burden. This imaging method also is practical as an evaluation of carotid artery stenosis as well as ongoing assessment for cerebral vasospasm (especially following subarachnoid hemorrhage). Although the clinical utility of Xe-CT for traumatic brain injury (TBI) has not been established, research suggests that it may help predict outcome by assessing ischemic tissue and changes in metabolism. By assessing global CBF, Xe-CT may also allow determination of the optimal CO2 level to control intracranial pressure after TBI. Xe-CT adds only five minutes of scanning time to a routine head CT acquisition. Because xenon is rapidly metabolized following inhalation, a Xe-CT scan can be performed as often as every 15 minutes, if needed. This method of imaging is non-invasive, accurate, and capable of providing high-resolution quantification of CBF. In addition, stable xenon is not radioactive. The most common side effect of inhaling a xenon mixture is sleepiness, which is usually transient; some patients have reported nausea and transient dysphoria. Like most neuroimaging techniques, Xe-CT can be compromised by artifact from patient movement and adjacent bone.

Advanced magnetic resonance imaging techniques Detailed information on basic MRI is presented in Chapter 26; accordingly, we offer here only a brief review of the general principles of MRI for the purpose of framing our consideration of advanced MRI techniques and applications. Magnetic resonance imaging measures the responses of magnetically active protons in water molecules within brain tissue. When these protons are placed in a sufficiently strong magnetic field, they become aligned along the lines of the direction of the magnetic field. When a high radiofrequency (RF) pulse is then sent through the field, the protons align briefly in the direction of the pulse (i.e., away from the direction of the standing magnetic field). After the pulse is discontinued, the protons will “relax” back to their resting state, thereby realigning themselves in the standing magnetic field. As they relax, they emit the energy absorbed from the RF pulse. Because tissues of different compositions vary in the amount of protons they contain, and in the interaction of their nuclei with other macromolecules, the protons do not relax back to the plane of the magnetic field at uniform

432

rates. These differences in the proton relaxation times confer different magnetic “signatures” (also known as relaxation times) to different brain tissues. These relaxation responses can be recorded, and are used to reconstruct an image based on the differences among the magnetic signatures of different brain tissues. The magnetic signatures are typically recorded at two time intervals, designated T1 and T2. The T1 (longitudinal or spin-lattice) relaxation time is the time at which atomic nuclei have lost 63% of the energy produced following their exposure to an RF pulse, and are reorienting to the plane of the magnetic field. The T2 (transverse or spin-spin) relaxation time is the time following application of an RF pulse when the atomic nuclei retain 63% of their excitation energy (or, when they have returned to 37% of their resting energy state). Accordingly, T1 times are longer than T2 times. Images may also be created based on measurement of the density of protons in tissues (called proton density weighted images), enhanced by variations in the pulse sequences applied, and enhanced by use of suppression techniques to reduce signals from other tissue components such as lipids. Each type of brain tissue has characteristic T1 and T2 values, which reflect the response of the protons in the magnetic environment of each tissue. These tissue-specific T1 and T2 characteristics allow for the construction of images that differentiate between gross tissue types – gray matter, white matter, and cerebrospinal fluid (CSF). Many neuropathophysiologic processes (e.g., demyelination, edema, hemorrhage) alter the T1 and T2 values of the tissue in which such processes occur; alterations of these values permits identification of abnormal signal characteristics associated with neurological injury and/or disease. Advanced MRI techniques build upon these basic principles to enhance the evaluation of brain structure and/or function.

Magnetic resonance angiography Magnetic resonance angiography (MRA) is commonly used for assessment of the integrity of arteries and veins in the human body. The level of anatomic detail provided by MRA is related both to signal quality and also the field strength of the MRI system used. When compared with CT angiography, MRA provides better spatial resolution and anatomic detail, particularly in smaller vessels (Figure 27.3). In BN&NP, standard clinical MRA is primarily used for assessment of


Figure 27.3. Magnetic resonance angiography (MRA) at the level of the great vessels of the neck.

vascular occlusion, aneurysm, and arteriovenous malformations. A recent MRA-related advance is the development of phase-contrast angiography (PCA). Coupled with MRA, PCA characterizes the diameter of and flow velocity within large- and medium-sized vessels, and thereby affords a measure of CBF (estimated as the sum of total flow in the three main cerebral arteries). This innovation transitions MRA from a purely diagnostic assessment tool to one that may provide a method of estimating risk for cerebrovascular disease. Phase-contrast angiography is sensitive to the effects of age and cerebrovascular disease on CBF [2,3]. It also may permit dynamic cerebrovascular risk assessment in relation to the presence and treatment of stroke risk factors like hypertension and diabetes mellitus as well as atypical antipsychotics or other treatments that affect the cerebrovascular system.

Functional (echoplanar) magnetic resonance imaging Functional MRI (fMRI) allows for the visualization of task-related brain activation [4] based on the link between neural activity and the hemodynamic response to it. During an fMRI study, a series of images (or volumes) is acquired as a participant performs a given task. When an area of the brain is activated by the demand to perform a task, the local neurons purportedly begin to fire and increase local metabolic activity (i.e., increased utilization of oxygen and glucose). This

Figure 27.4. Functional magnetic resonance imaging (fMRI) of a visual task. In this example, a 40-year-old subject was asked to fixate on a small fixation cross while concentric circles expanded from this central point at a rate of 8 Hz for 20 seconds. This 20-second period was followed by a rest condition when the subject was presented the same stimulus with eyes closed. This cycle was repeated three times. This figure is presented in color in the color plate section.

increase in local metabolic activity leads to an increase in CBF to the activated area [5], referred to as the hemodynamic response. The increase in CBF exceeds the demands of the activated neurons, resulting in an increase in the concentration of local oxyhemoglobin and a relative decrease in deoxyhemoglobin. As a result of the differences between the paramagnetic properties of oxyhemoglobin and deoxyhemoglobin, this concentration change can be visualized as a transient blood oxygenation level-dependent (BOLD) increase in local signal in the capillary bed of activated neurons. Figure 27.4 demonstrates the fluctuation of the MRI signal as it correlates with functional changes in the area of the brain associated with task performance and rest. For the purposes of visual presentation of fMRI data, the relatively limited spatial resolution of fMRI is addressed by mapping fMRI results onto conventionally acquired (and, therefore, higher resolution) two- or three-dimensional anatomic magnetic resonance images. One of the major advantages of fMRI is that it is a non-invasive method of assessing brain function that requires neither intravenous contrast nor exposure to ionizing radiation. As a result, it is possible to obtain many scans and/or to prolong the in-scanner

433


time experienced by a patient without sacrificing his or her health or safety and without concern for time-dependent changes in contrast concentrations. Additionally, analyses of activation correlations between areas of brain interest – an analytic technique referred to as fcMRI, or resting-state fMRI – permits identification of not only areas of task-related brain activation but also the functional relationships between activated areas [6,7]. Adaptation of fMRI to this purpose extends importantly the potential research and clinical relevance of this neuroimaging technique. Although the spatial resolution of fMRI is lower than that of structural MRI, the dense vasculature of cortical tissue still allows for relatively high spatial resolution: ∼1–3 mm3 [8]. Some fMRI paradigms (such as the one illustrated in Figure 27.4) are able to detect activation changes at the individual level; however, most studies of cognitive tasks cannot be statistically resolved at a single subject level. Additional fMRI techniques that measure neuronal activity directly and that achieve better temporal resolution than BOLD fMRI are under development. These techniques presently do not afford spatial resolution comparable with that of BOLD fMRI, which itself is substantially less than that of structural MRI sequences. As these advances in fMRI imaging proceed, the applications of fMRI to the evaluation of individual patients or research subjects will expand and the information they yield will inform more fully and usefully on neurobehavioral health and disease. There are limitations of fMRI about which clinicians should be aware. In a healthy adult, the time to peak hemodynamic response following initiation of cognitive or motor activity is approximately 4–7 seconds. As such, the temporal resolution of fMRI is necessarily quite limited [5]. Stressors including claustrophobia may transiently elevate blood pressure and increase CBF, thereby introducing a non-neural confound on the generation and interpretation of BOLD signals [9]. Conditions that result in uncoupling of the hemodynamic response (e.g., acute TBI) [10] also may produce artifactual or uninterpretable data. Additionally, acquiring fMRI, even with passive activation paradigms, is time consuming and easily interfered with by movement, including respiratory effort. Obtaining usable data necessitates the cooperation, and often the active engagement, of the individual being imaged; patients who are agitated, confused, or otherwise unable to adhere to in-scanner

434

instructions therefore are not good candidates for fMRI assessments. Finally, optimizing scanner parameters and the imaging environment requires excellent technical support, and post-acquisition data processing is time-, labor-, technical expertise-, and cost-intensive. The technical and fiscal requirements of fMRI are not easily accommodated by many community healthcare environments, and thereby tend to limit the clinical and research use of fMRI to tertiary clinical and academic healthcare settings.

Magnetic resonance spectroscopy Using the principles of nuclear MRS developed for use in the basic sciences, clinical MRS measures the quantities of various cerebral metabolites in brain tissue. Magnetic resonance spectroscopy data may be used to evaluate the composition and metabolic activity of the brain. The ability of MRS to quantify metabolites in brain tissue derives from the fact that each chemical compound has a distinct magnetic resonance signature. In the presence of a magnetic field of sufficient intensity, homogeneity, and stability, the different chemical signatures of the chemical constituents of brain tissue can be detected. Based on the assumption that the strength of the magnetic resonance signature at a specific frequency is proportional to the amount of the substance that resonates at that frequency, the amount of a given chemical in the brain can be quantified. The main types of MRS are proton (1H), phosphorus-31 (31P), carbon-13 (13C), or fluorine-19 (19F). Proton (1H) MRS is the most commonly used form of MRS, and can measure the quantities (i.e., the spectral peaks) of several major metabolic components, including N-acetyl aspartate (NAA), choline, inositol, lactate, and creatine. NAA is relatively restricted to neuronal cells in the brain (i.e., not found in glial cells), and the amount of NAA is thought to reflect the number of viable neurons (Figure 27.5). When neuronal damage or loss occurs, as from stroke or TBI, decreases in NAA can be detected spectroscopically [11]. Choline is an important constituent of membrane synthesis and breakdown; its spectroscopic peak is increased when membrane integrity is compromised. Inositol is likewise involved in membrane metabolism, and increases in its spectroscopic peak occur when there is a breach in membrane integrity. Lactate is a product


and TBI. Magnetic resonance spectroscopy may be used to neurochemically characterize neurological and neuropsychiatric disorders in a manner that is relatively cost effective and more convenient than either PET or SPECT scanning. Additionally, MRS may become useful for assessing both the distribution and metabolic effects of pharmacologic agents.

Diffusion tensor imaging

Figure 27.5. Proton magnetic resonance spectroscopy (MRS). The chemical spectrum (peaks expressed in parts per million) acquired from a voxel encompassing the hippocampus (illustrated by the box overlaid on the coronal brain slice on the right side of the figure) is presented. Peaks associated with several major metabolic components are labeled: N-acetyl aspartate (NAA), choline (Cho), lactate (Lac), and creatine/creatine phosphate (Cr).

of anaerobic metabolism; its concentration in the brain increases under conditions of oxidative stress. Creatine and creatine phosphate are relatively stable, and the peak representing these compounds is often used to establish a reference signal against which to measure other spectroscopic readings. Most other spectroscopic peaks, therefore, are reported as ratios to the creatine/creatine phosphate peak. Proton MRS can also be used to assess other compounds such as glutamate, aspartate, and gamma-amino butyric acid (GABA) concentrations. Phosphorus-31 (31P) MRS may be used to obtain information about membrane phospholipids and stability, and is particularly useful for assessing highenergy phosphate metabolism involving adenosine triphosphate (ATP). Carbon-13 (13C) and fluorine-19 (19F) may be used to radiolabel pharmacologic agents; 13C and 19F MRS is therefore capable of assessing the distribution of pharmacologic agents in the brain, and, in principle, could be used to identify neurotransmitter systems or other substances (e.g., beta-amyloid, myelin basic protein) that bind those agents in a manner analogous to PET or SPECT imaging. Although most often used for research, MRS has emerging diagnostic and therapeutic clinical applications in neurodegenerative diseases, tumors, strokes,

Diffusion tensor imaging (DTI) is a special form of diffusion-weighted MRI that allows the assessment and visualization of white matter and its constituents on a millimeter-level scale [12]. This permits visualization of the orientation and connectivity of the white matter fiber tracts based on their principal diffusion directions [13–15], and provides a means of correlating functional activation maps of the cerebral cortex with structural changes in associated fiber tracts, such as thickening, thinning, and sprouting of white matter in states of either neurological health or disease (Figure 27.6). Diffusion tensor imaging takes advantage of the diffusivity of water and the extent to which white matter fiber tracts restrict diffusion of water – i.e., the extent to which that diffusion is isotropic or anisotropic. The concepts of isotropic and anisotropic diffusion are understood most easily by considering the diffusion of an ink drop in water. If a drop of ink is introduced into a large body of water, the ink diffuses equally in all directions – i.e., the direction of diffusion is ‘iso-’ (equal) ‘tropic’ (turn, way, or manner). In contrast, when an ink drop is placed in a narrow tube, the diffusion of that ink drop is constrained by the shape of the tube, and does not proceed equally in all directions – i.e., its diffusion is ‘an-’ (without) ‘iso-’ (equal) ‘tropic’ (turn, way, or manner). The shape, or anisotropy, of diffusion is assessed with DTI: when fiber tracts are dense and well organized (i.e., healthy), diffusion is directionally dependent or relatively anisotropic. Where the white matter tracts are less dense or disorganized (i.e., within gray matter or CSF, or within white matter damaged by demyelination or axonal loss), the shape of water diffusion is less anisotropic (i.e., relatively isotropic). The degree of signal attenuation related to the diffusion gradient within an MRI voxel can be converted into a measure of apparent diffusion, the apparent diffusion coefficient (ADC). Estimates of the axial diffusivity (AD) and radial diffusivity (RD)

435


Figure 27.6. Examples of various diffusion tensor images generated using data acquired from a 30-year-old healthy adult. This figure is presented in color in the color plate section.

also may be calculated [16–20], with AD reflecting diffusivity parallel to axonal fibers and RD reflecting diffusivity perpendicular to axonal fibers. Increases in AD are thought to reflect pathology of the axon itself, whereas RD appears to be more strongly correlated with myelin abnormalities (e.g., demyelination or dysmyelination). Detailed analyses of AD and RD also provide potential measures of the mechanisms that underlie changes in white matter [17,21]. Based on the shape of diffusion (eigenvalues) and the primary direction of diffusion (eigenvectors), the degree of alignment and anisotropy is calculated as the fractional anisotropy (FA). Fractional anisotropy values range from zero to one, where zero represents isotropic diffusion and one represents anisotropic diffusion. These values therefore may be used as a measure of myelination and axonal density, with higher FA values generally reflecting healthier white matter. Diffusion tensor imaging shares many of the advantages and disadvantages of standard MRI discussed above. Its principal advantage is in vivo assessment of white matter, including myelin and axonal, integrity. Diffusion tensor imaging is relatively fast at higher field strengths (requiring about 5 minutes) and does not require the same degree of patient compliance as fMRI. There are multiple applications for postprocessing, and most major MRI manufacturers provide on-scanner packages to quickly produce these images. Unfortunately, there remain many uncertainties about the interpretation of DTI data, including the manner in which edema affect local signal, and how white matter lesions affect local DTI signal

436

measurements. Perhaps most important for clinical practice is the absence of reference large-scale normative databases for ADC, AD, RD, and FA values, and a well-developed literature describing the differential diagnoses for abnormal ADC, AD, RD, and FA values, both at the group and the single-patient levels. When these issues are addressed, DTI may become an important neuroimaging tool in clinical BN&NP.

Arterial spin labeling Arterial spin labeling (ASL), an alternative to the BOLD method of neuroimaging, combines the ability of MRI to measure CBF without the use of exogenous contrast agents and thus remaining a non-invasive technique. Arterial spin labeling allows for the characterization and direct visualization of blood flow within brain tissue (as contrasted with the indirect measure provided by the BOLD method). Perfusion is quantified by measuring the magnetic state of inflowing blood in relation to the magnetic state of static tissue. Arterial spin labeling allows for rapid quantitative measurements of perfusion in the brain [22]. Arterial blood water is magnetized, or labeled, immediately below the region of interest (ROI) via a 180-degree RF inversion pulse. The application of this pulse to the region below the slice of interest results in inversion of the net magnetization of the blood water; that is, the water molecules in the blood are now magnetically labeled and can be detected with MRI. After a period of transit time, the magnetically labeled (i.e., paramagnetic) blood water travels to the ROI and exchanges with the un-magnetized water present in


the tissue altering total tissue magnetization. During this inflow of the inverted spin water molecules, total tissue magnetization is reduced, thereby reducing the magnetic resonance signal and image intensity. At this point, an image (known as the tag image) is taken. The procedure is then repeated without labeling the arterial blood to create another image (known as the control image). To produce an image showing blood perfusion, the tag image is subtracted from the control image. The resulting image reflects the total amount of arterial blood delivered to each voxel in the ROI within the transit time [23]. Several methods of ASL perfusion imaging exist. In continuous ASL (CASL), a continuous RF pulse is applied to the targeted region below the slice of interest, resulting in continuous inversion of the magnetization of arterial blood water. Because of this continuous inversion, a steady state develops in which regional magnetization in the brain is directly related to CBF [24]. In pulsed ASL (PASL), a short (approximately 10 milliseconds) RF pulse is used to label blood water spins over a very specific area [23], which allows for minimization of the distance between the labeling region and the imaging slice [24]. A principal advantage of the ASL technique over other contrast-based imaging is that the contrast agent used is water and does not expose the patient to ionizing radiation. The contrast provided by the inverted magnetization of arterial blood water allows for effective characterization of perfusion difference when a specific brain region is activated. Unlike the BOLD technique, in which signal drift results in decreased ability to detect slow variations in neural activity, ASL allows for the characterization of slow variations because drift effects are minimized in the successive paired subtraction of images acquired with and without labeling [25]. Changes in ASL signal as a result of regional brain activation are better defined than those changes observed via the BOLD technique; this advantage allows for more concrete definition of regions of activation and characterization of CBF.

Positron emission tomography Positron emission tomography (PET) scanning is currently the most technologically sophisticated and expensive functional brain imaging technique available. Positron emission tomography images are created by mathematical reconstruction based on the distribution of gamma (photon) emissions produced during

the collision of a local electron with a positron emitted from an injected radionuclide [26]. The images produced are of very high spatial resolution, limited only by the distance the positron must travel from the point of emission to collision with an electron in its local environment. Radiolabeled tracers are available for use in PET to assess regional glucose or dopamine metabolism, CBF, protein synthesis, monoamine oxidase activity, and neurotransmitter receptor distribution, including benzodiazepine, serotonin, dopamine, muscarinic, and opioid radioligands, among others. However, the availability of PET is limited by its relatively high cost as well as the need for a geographically co-located cyclotron (which is necessary to generate the short half-lived radionuclide tracers used in PET imaging). Although PET scanning is used clinically in cardiology and in neuro-oncology [27], the only consistently accepted indications for its use in BN&NP are as an aid to distinguishing between Alzheimer’s disease and frontotemporal dementia [28] and, potentially, as an aid to the in vivo identification of Alzheimer’s disease pathology among individuals with or at risk for this condition (Figure 27.7) [29]. Outside these contexts, there are multiple barriers to other clinical uses of PET. These include difficulties in matching imaging physiology data obtained in an individual patient with the values determined for groups of subjects (i.e., lack of clear reference ranges for data generated by cerebral PET) and managing within-individual variability of the PET data (i.e., test–retest reliability issues at the single-subject or patient level). Nonetheless, some centers do use PET to provide adjunctive information about brain function in neurodegenerative diseases, TBI, obsessive-compulsive disorder, and some other neuropsychiatric conditions. Information derived from PET data may prove useful in correlating functional and structural abnormalities, identifying pathophysiological disturbances despite apparently normal brain structure, or refining the differential diagnosis based on patterns of conditionspecific metabolic disturbances (Figure 27.8) [30]. Additionally, the development of pathophysiologyspecific radioligands may increase the relevance of PET scanning in the routine clinical practice of BN&NP – for example, PET imaging using the amyloid-binding Pittsburgh compound B (11C-PIB) [31–33] as an element of the evaluation of persons with or at risk for Alzheimer’s disease. However, the cost, logistical difficulties, and uncertain interpretation

437


Figure 27.7. Typical patterns of cerebral metabolism as imaged using fluorodeoxyglucose positron emission tomography (FDG-PET) among persons with mild, moderate, and severe Alzheimer’s disease (AD). FDG-PET scans are displayed as three-dimensional stereotactic surface projection (SSP) maps normalized to pons generated with the software program Neurostat. Maps are shown with relative cerebral metabolism or statistical significance increasing on the color scale from the lowest values shown in blue to the highest values in red and white. For orientation, a reference brain is shown in row A with regions of interest in dementia evaluations in color; orange areas usually hypometabolic in AD, blue and purple areas typically hypometabolic in frontotemporal dementia. Row B shows the pattern of metabolism in 27 normal elderly subjects. This is used for statistical comparisons with metabolism in individual patients (rows D, F, and H). There are increasing severity and extent of cerebral glucose hypometabolism as AD progresses from mild (rows C and D) and moderate (rows E and F) to severe (rows G and H). Reproduced from Foster NL, Wang AY, Tasdizen T et al. Realizing the potential of positron emission tomography with 18F-fluorodeoxyglucose to improve the treatment of Alzheimer’s disease. Alzheimers Dement. 2008;4(1 Suppl. 1):S29–36, with permission from Elsevier. This figure is presented in color in the color plate section.

of PET imaging are likely to continue limiting its widespread use in clinical BN&NP practice.

Single-photon emission computed tomography Single-photon emission computed tomography (SPECT) images are obtained by mathematical reconstruction based on the pattern of distribution of direct gamma emissions produced by singlephoton emitting radionuclide tracers. Unlike PET, the

438

gamma emissions in SPECT come from the injected radionuclide itself, not from the energy released by the emitted particle’s collision with electrons in the local brain environment. Radionuclide tracers are available for use in SPECT to assess CBF [34], amino acid concentration (such as alpha-methyltyrosine), and receptor distribution and activity (including acetylcholine, benzodiazepine, serotonin, dopamine, and norepinephrine receptors). The spatial resolution of SPECT is good but relatively inferior to that of PET [35]. The potential


Figure 27.8. Statistical parametric mapping of metabolic activity using fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with relatively common neurodegenerative disorders. Statistical parametric mapping of regions of decreased metabolic activity (relative to the global mean, thresholded at p ⬍ 0.001 with cluster cut-off of 20 voxels) are overlaid onto a single subject T1 magnetic resonance image. Abbreviations: PD – Parkinson’s disease; MSA – multisystem atrophy; PSP – progressive supranuclear palsy; CBD – corticobasal degeneration; DLB – dementia with Lewy bodies; AD – Alzheimer’s disease; FTD – frontotemporal dementia. Reproduced from Teune LK, Bartels AL, de Jong BM et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord. 2010;25(14):2395–404, with permission from John Wiley and Sons. This figure is presented in color in the color plate section.

advantages of SPECT over PET include its lower cost and the ability to use radionuclides with relatively long half-lives (which permit imaging at facilities relatively more distant from their place at which the radionuclides are produced). A potential disadvantage is that many of the SPECT nuclides, such as iodine123, may interfere with the chemical activity of the molecule to which they are tagged. This can result in imaging method-related misrepresentation of the metabolic activity with which these molecules are involved. Like PET, SPECT presently has no generally accepted clinical application in BN&NP. Nonetheless, it is used in some centers to evaluate conditions including the neurodegenerative dementias, stroke, and TBI. Because SPECT may provide evidence of decreased metabolic activity, it may be a useful adjunct to structural neuroimaging studies in cases in which structural-functional neuroimaging correlations

might be useful clinically. For example, clinicians commonly observe focal or diffuse cerebral atrophy in dementia cases without knowing whether this finding is meaningful with respect to brain function. Decreased function on SPECT associated with structural neuroimaging findings could potentially enhance interpretation of the conventional neuroimaging; an example might be temporoparietal hypoperfusion in Alzheimer’s disease. Similarly, many patients with mild TBI report cognitive impairments in the absence of structural neuroimaging abnormalities, and SPECT might provide useful information about brain function despite grossly normal brain structure. However, SPECT is not a stand-alone test for any neuropsychiatric disorder, and, if it is obtained, interpretation should be carefully integrated with all clinical and neuroimaging data and subjected to a review of the differential diagnosis in every case in which it is acquired.

439


Conclusion All of the neuroimaging techniques described in this chapter are used extensively in neuropsychiatric research. Clinical application of these advanced techniques is typically constrained by factors including limited availability and high costs, labor-intensive processing requirements, and uncertainty regarding the meaning and clinical implications of abnormal findings. However, some functional neuroimaging and most structural neuroimaging studies do have a role in clinical BN&NP and advanced neuroimaging is likely to become an increasingly important element of practice in this field. For the present, however, clinical use of functional neuroimaging methods is probably best reserved for centers with expertise derived from extensive research experience and with sufficiently large databases to permit interpretation of individual findings in the context of a reference range for that technique. Additionally, given the lack of normative data for fMRI, PET, and SPECT, interpretation of the data derived from these studies should be undertaken with caution regardless of the experience of the center in which it is performed. As a general guideline (and as suggested in Chapter 26), structural neuroimaging studies should be performed at least once in all patients with potential brain disease, including patients whose psychiatric presentations are atypical in any manner. Additionally, patients with chronic and progressive neurological or neuropsychiatric disorders as well as those that fail to respond to standard therapies merit structural neuroimaging, and may reveal neurologic or medical conditions that masquerade as primary mental illness. Additionally, acute alterations in mental status (i.e., delirium, acute confusional states) merit neuroimaging. The evaluation of patients with many other disorders, ranging from TBI to multiple sclerosis to new-onset psychosis, also may be aided with cerebral neuroimaging (usually MRI). With the possible exception of differentiating Alzheimer’s disease from frontotemporal dementia, however, nuclear imaging technologies (i.e., PET or SPECT) are not generally accepted elements of clinical evaluation. Similarly, Xe-CT, fMRI, and other advanced neuroimaging techniques remain research tools whose clinical promise may be realized in the coming decades.

440

References 1. Arciniegas DB, Kaufer DI, Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13. 2. Amin-Hanjani S, Du X, Zhao M et al. Use of quantitative magnetic resonance angiography to stratify stroke risk in symptomatic vertebrobasilar disease. Stroke 2005;36(6):1140–5. 3. Buijs PC, Krabbe-Hartkamp MJ, Bakker CJ et al. Effect of age on cerebral blood flow: measurement with ungated two-dimensional phase-contrast MR angiography in 250 adults. Radiology 1998;209(3): 667–74. 4. Dickerson BC. Advances in functional magnetic resonance imaging: technology and clinical applications. Neurotherapeutics 2007;4(3):360–70. 5. Delaney JS, Lacroix VJ, Leclerc S, Johnston KM. Concussions among university football and soccer players. Clin J Sport Med. 2002;12(6):331–8. 6. Cohen AL, Fair DA, Dosenbach NU et al. Defining functional areas in individual human brains using resting functional connectivity MRI. Neuroimage 2008;41(1):45–57. 7. Zhang D, Snyder AZ, Fox MD et al. Intrinsic functional relations between human cerebral cortex and thalamus. J Neurophysiol. 2008;100(4): 1740–8. 8. Atkinson RC, Lindzey G, Thompson RF. Imaging the brain’s activity. In Kolb B, Whishaw IQ, editors. Fundamentals of Human Neuropsychology. 5th edition. New York, NY: Worth Publishers; 2003, pp. 168–9. 9. Wang R, Foniok T, Wamsteeker JI et al. Transient blood pressure changes affect the functional magnetic resonance imaging detection of cerebral activation. Neuroimage 2006;31(1):1–11. 10. Kelly DF, Martin NA, Kordestani R et al. Cerebral blood flow as a predictor of outcome following traumatic brain injury. J Neurosurg. 1997;86(4): 633–41. 11. Holshouser BA, Tong KA, Ashwal S et al. Prospective longitudinal proton magnetic resonance spectroscopic imaging in adult traumatic brain injury. J Magn Reson Imaging 2006;24(1):33–40. 12. Le Bihan D, Mangin JF, Poupon C et al. Diffusion tensor imaging: concepts and applications. J Magn Reson Imaging 2001;13(4):534–46. 13. Basser PJ, Mattiello J, LeBihan D. MR diffusion tensor spectroscopy and imaging. Biophys J. 1994;66(1): 259–67.


14. Basser PJ, Pierpaoli C. Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B. 1996;111(3):209–19. 15. Basser PJ, Pajevic S, Pierpaoli C, Duda J, Aldroubi A. In vivo fiber tractography using DT-MRI data. Magn Reson Med. 2000;44(4):625–32. 16. Kraus MF, Susmaras T, Caughlin BP et al. White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study. Brain 2007;130(Pt 10):2508–19. 17. Song SK, Sun SW, Ramsbottom MJ et al. Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 2002;17(3):1429–36. 18. Harsan LA, Poulet P, Guignard B et al. Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging. J Neurosci Res. 2006;83(3): 392–402.

25. Wang J, Aguirre GK, Kimberg DY et al. Arterial spin labeling perfusion fMRI with very low task frequency. Magn Reson Med. 2003;49(5):796–802. 26. Derdeyn CP. Positron emission tomography imaging of cerebral ischemia. PET Clinics 2007;2(1):35–44. 27. Miletich RS. Positron emission tomography for neurologists. Neurol Clin. 2009;27(1):61–88, viii. 28. Foster NL, Wang AY, Tasdizen T et al. Realizing the potential of positron emission tomography with 18F-fluorodeoxyglucose to improve the treatment of Alzheimer’s disease. Alzheimers Dement. 2008; 4(1 Suppl. 1):S29–36. 29. Weiner MW, Aisen PS, Jack CR, Jr. et al. The Alzheimer’s disease neuroimaging initiative: progress report and future plans. Alzheimers Dement. 2010;6(3): 202–11 e7. 30. Teune LK, Bartels AL, de Jong BM et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord. 2010;25(14): 2395–404.

19. Arfanakis K, Haughton VM, Carew JD et al. Diffusion tensor MR imaging in diffuse axonal injury. AJNR Am J Neuroradiol. 2002;23(5):794–802.

31. Klunk WE, Engler H, Nordberg A et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–19.

20. Song SK, Sun SW, Ju WK et al. Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 2003;20(3):1714–22.

32. Jack CR, Jr., Wiste HJ, Vemuri P et al. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain 2010;133(11):3336–48.

21. Pierpaoli C, Barnett A, Pajevic S et al. Water diffusion changes in Wallerian degeneration and their dependence on white matter architecture. Neuroimage 2001;13(6 Pt 1):1174–85. 22. van Laar PJ, van der Graaf Y, Mali WP, van der Grond J, Hendrikse J. Effect of cerebrovascular risk factors on regional cerebral blood flow. Radiology 2008;246(1): 198–204. 23. University of Michigan. Arterial Spin Labeling. 2007; available from: http://www.umich.edu/∼fmri/asl.html. 24. Calamante F, Thomas DL, Pell GS, Wiersma J, Turner R. Measuring cerebral blood flow using magnetic resonance imaging techniques. J Cereb Blood Flow Metab. 1999;19(7):701–35.

33. Meyer PT, Hellwig S, Amtage F et al. Dual-biomarker imaging of regional cerebral amyloid load and neuronal activity in dementia with PET and 11C-labeled Pittsburgh compound B. J Nucl Med. 2011;52(3):393–400. 34. Jennings JR, Muldoon MF, Price J, Christie IC, Meltzer CC. Cerebrovascular support for cognitive processing in hypertensive patients is altered by blood pressure treatment. Hypertension 2008;52(1): 65–71. 35. Ficzere A, Csiba L. Comparison of different methods evaluating the functional and structural abnormalities in hypertension. Eur Neurol. 2002;48(2):71–9.

441

Section II


Chapter

Electroencephalography

28

Lauren C. Frey and Mark C. Spitz

Electroencephalography (EEG) is a graphic representation of electrical activity produced by the brain over time, and more specifically the difference in voltage between electrodes at two locations on the head [1]. Electroencephalography is among the oldest and most commonly used neurodiagnostic techniques in Behavioral Neurology & Neuropsychiatry (BN&NP). Although EEG is most often applied to the evaluation of persons with suspected seizure disorders or encephalopathies, digital recording methods and advanced software analyses broaden the potential applications of this and related electrophysiologic assessment techniques to the evaluation and study of a broad range of neurological and/or psychiatric conditions [2–4]. Conventional clinical EEG, quantitative EEG (qEEG), evoked potentials, event-related potential, and magnetoencephalography (MEG) may be used to assess cerebral electrophysiologic activity (see Chapter 29). With relatively few exceptions [5, 6], however, advanced electrophysiologic and MEG techniques are regarded as tools for use in neuropsychiatric research rather than the practice of BN&NP. Accordingly, this chapter focuses on the principles of conventional EEG recording and interpretation and the typical applications of EEG to the assessment of persons with neurological and psychiatric conditions [7]. Application of this information to clinical practice requires substantial training and experience, and a brief review of this subject will not obviate this requirement. It will serve as a foundation upon which subspecialists in BN&NP may build their understanding of clinical electrophysiology and develop the expertise and skills needed to use the potentially valuable information yielded by clinical EEG to the care of their patients.

Physiologic basis of electrophysiologic activity The electrical activity measured at the scalp with EEG is generated by cerebral cortical neurons underlying the scalp where the recording electrodes are placed. The electrical activity generated by a single neuron, even if it is near the surface, is much too small to be recorded. Instead, the scalp-recorded EEG reflects synchronous electrical activity of groups of neurons that are oriented in parallel to one another and radially with respect to the scalp surface. The majority of EEG activity is generated by groups of pyramidal neurons. Neurons in the cortex are oriented such that current flows up and down the six cortical layers, whether that cortex is on a gyral or a sulcal surface. The bodies of these cells are located primarily in cortical layers three and five and have multiple dendritic extensions in the cerebral cortex. Concurrent activation of these groups of neurons creates relatively large electrical phenomena. As a result of their cortical organization, the orientation of neurons on gyral surfaces produces radial currents, while those on sulcal surfaces produce tangentially oriented currents; radially oriented currents are those most amenable to recording at the scalp using EEG. Groups of pyramidal cells located near each other are similar to one another with respect to their afferent and efferent connections, and therefore tend to activate as a group (though not necessarily in exact synchrony). Each electrode collects, at a minimum, the relatively synchronous activity generated by approximately 6 cm2 of cortex. The type of neuronal activity generating the scalprecorded electrical signals is not action potentials, the duration of which are too short to be recorded by


442

Chapter 28: Electroencephalography

Table 28.1. Major electroencephalography (EEG) frequency bands and their characteristic location in conventional EEG recordings.

Band

Frequency

Characteristic location in scalp recordings

␤ (beta)

13 to 30 Hz

Frontal (in awake records of adults)

␣ (alpha)

8–13 Hz

Posterior (with eyes closed)

␪ (theta)

4 to ⬍ 8 Hz

Central

␦ (delta)

⬍4 Hz

Frontal/central (most prominent during deep sleep)

conventional EEG. Instead, the summated inhibitory or excitatory post-synaptic potentials (IPSPs, and EPSPs, respectively) occurring within large groups of pyramidal cells underlying scalp electrodes create the electrical signal recorded at scalp electrodes. An exception to this general rule are interictal spikes, which historically are thought to reflect massive depolarizations of cell somata (paroxysmal depolarization shifts); however, recent investigations into the neurophysiologic bases of interictal spikes suggest that these EEGrecorded events may reflect a more complex interplay between multiple distinct neuronal types within the neuronal networks generating these signals [8]. There are systematic interconnections between cortical neurons, as well as cortical to subcortical connections to structures such as the thalamus that have well-developed feedback linkages. This allows for the classical rhythmic activity observed on an EEG. For example, sleep spindles, as well as generalized spike and wave activity, have been shown to be created by interconnections between deep thalamic neurons and cerebral cortical neurons. Although the brain produces activity at a wide range of frequencies (hertz [Hz] = cycles/second), clinical electroencephalographers typically divide these frequencies into four major bands (from higher to lower frequency): beta, alpha, theta, and delta (Table 28.1). The pattern of firing of cortical neurons is influenced by relatively distant structures controlling arousal and sleep, including the reticular formation and the thalamus. During wakefulness, the reticular formation produces widespread cortical activation, which is reflected by asynchronous cortical electrical activity on EEG; in other words, neurons are not firing together, and instead are firing relatively independently and at relatively high frequencies. Accordingly, waking EEG is characterized by fast (usually high alpha and/or beta) activity.

At sleep onset, ascending reticular activation decreases and, consequently, so does the frequency of cortical neuronal activity. This produces slower rhythms such as theta and delta activity on EEG. When the ascending drive to higher and relatively asynchronous activity is reduced, the activity of groups of neurons in the cortex becomes relatively more synchronized. It has been suggested that there are brain “pacemakers” that determine the frequency of these slower and more synchronous rhythms, and that the thalamus may be one such pacemaker [1]. Without ascending drive from the reticular formation, the intrinsic firing rate of the thalamus dominates the frequency of activity in the widespread thalamocortical circuits of both cerebral hemispheres. Consequently, sleep onset permits these thalamocortical rhythms to become unmasked, cortical activity to become relatively more synchronous, and EEG to show slower and higher-amplitude waveforms.

EEG signal recording and processing Signal recording The standardized system for electrode placement on the scalp is called the international 10–20 system and provides for uniform coverage of the entire scalp (Figure 28.1). The 10–20 system uses the distances between bony landmarks on the head to create a system of lines. Recording electrodes are then placed at intervals of 10 or 20% of their total length. The standard set of electrodes for adults consists of 21 recording electrodes plus one ground electrode. In addition, electrodes to record the electrocardiogram and eye movements are usually added. The 10–20 system is flexible, and additional scalp electrodes may be placed to more accurately define an abnormality. For example, the best localization to detect an anterior temporal spike in a patient is often not ideally covered by the 10–20 system arrangement, and special anterior temporal electrodes (T1 and T2) can be added.

Amplification and filtering Sweat, scalp, muscle and connective tissue, skull, dura, and cerebrospinal fluid attenuate and diffuse cortical electrical activity before it reaches the scalp. As a result, amplification of EEG signals recorded at the

443


Nasion 10% Fp1

Fp2

20% F7

F3

Fz

F4

F8

20%

20%

20%

20%

20%

10%

Cz

C3

T3

10%

T4

C4

A2

A1

20% P3

Pz

P4

T5

T6

20% 01

02

10% Inion Figure 28.1. The 10–20 International System of Electrode Placement. On the left, the head is labeled with a circumferential line running through the nasion and inion, another running over the top of the head in the sagittal midline from the nasion to inion, and a third running over the top of the head (coronal midline) from one pre-auricular point to the other. Sagittal midline electrodes are placed above the circumferential line by a distance equal to 10% of the length of the sagittal midline, and spaced apart by 20% of the length of the sagittal midline as they converge up to the central point. Coronal midline electrodes are placed in similar fashion. Circumferential electrodes are spaced apart by 10% of the distance of the circumferential line created by the most frontal (Fp1 and Fp2), most occipital (O1 and O2), and lateral temporal (T3 and T4) electrodes. The rest of the electrodes are placed in lines running sagittally and coronally as defined by these placements. On the right is the 10–20 system with labeled electrodes, including the A1 and A2 reference electrodes. Reprinted from Arciniegas DB, Beresford TP, Neuropsychiatry: An Introductory Approach, Cambridge University Press; 2001, with permission from Cambridge University Press.

scalp is necessary. For this purpose, EEG activity is recorded using differential amplifiers. These devices measure the electrical activity at one electrode relative to another to eliminate artifact, both biologic and ambient. If one were to record from a scalp electrode relative to a true ground the brain activity would be lost to artifact. Fortunately, the brain-ground artifact is relatively similar around the entire head, allowing differential amplifiers to filter much of it out of the recorded signal and reveal electrical activity of the brain. These amplifiers also increase between-electrode voltage differences in a manner that allows them to be graphically represented and easily visualized. This process is described as EEG sensitivity, which is the ratio of the input voltage to EEG-displayed signal deflection, and is measured in microvolts per millimeter. The most commonly used default EEG

444

sensitivity is seven microvolts per millimeter, but this sensitivity is easily increased or decreased to optimize the waveforms displayed (whether on paper or a video monitor). Even with the use of differential amplifiers, scalprecorded clinical EEG is generally limited to detection of electrical activity generated relatively close to the recording electrodes, i.e., at the gyral cortical surfaces. Although software analyses of digitally acquired EEG may permit mathematically derived inferences about electrical activity in deeper areas of the brain, the use of such analytic methods is generally restricted to specific clinical situations. When deeper sources are of clinical interest, special electrode placement techniques are possible, including use of sphenoidal or nasopharyngeal electrodes, intracranial depth electrodes, or intracranial electrode grid placement. Locating electrodes near cortical areas of


Figure 28.2. Illustration of three common EEG montages, including referential (A), parasagittal bipolar (B; “double-banana”), and transverse bipolar (C). Reprinted from Arciniegas DB, Anderson CA, Rojas DC. Electrophysiological techniques. In Silver JM, McAllister TW, Yudofsky SC, editors. Textbook of Traumatic Brain Injury. Washington, DC: American Psychiatric Publishing Inc.; 2004, pp. 135–57, with permission from American Psychiatric Publishing Inc.

interest permits the use of conventional recording equipment and signal enhancement techniques (discussed below) to address the clinical questions to which they are most relevant. Filters are used to minimize activity of relatively high or low frequency so that the waveforms in the most important range (1–30 Hz) can be recorded clearly and with minimal distortion. Most EEG machines offer three types of filters: low frequency filters, which remove low frequency activity (i.e., slow waves); high frequency filters, which remove high frequency activity (i.e., fast waves); and notch filters, which selectively reduce frequencies related to electrical line interference. In North America, the notch filter is set at 60 Hz. Analog filters do not cleanly remove or preserve all frequencies above or below their specific settings, and instead provide a continuum of gradual filtering. Consequently, recordings of good technical quality involve not only effective application of filters but also efforts to eliminate primary sources of artifact and signal distortion. For example, the adverse effects of muscle artifact on EEG outputs may be improved by applying a robust high frequency filter. However, filters of this type not only blunt muscle artifact but also distort pathologic spikes and sharp waves. This distortion may be severe enough that pathological waveforms are no longer recognizable as such. It therefore is best to intervene first at the level of the patient, rather than at the recording equipment, by coaching him or her to relax the jaw and facial musculature in order to reduce the amount of muscle artifact introduced into the recorded signals.

EEG signal displays The electrical activity recorded during EEG by pairs of electrodes (channels) is displayed by arranging those channels into specific sets (montages) (Figure 28.2). As a general rule, modern montages allow for easy visualization of comparable scalp areas so they may be assessed for symmetry.

Bipolar montage The bipolar parasagittal (longitudinal) pattern is commonly referred to as the “double banana” montage, and is among the most commonly used EEG montages (Figure 28.2B). In this montage, channels are created by connecting adjacent electrodes in two lines (anterior to posterior), essentially covering the parasagittal and temporal areas bilaterally. Additionally, the midline electrodes also are linked to each other (anterior to posterior). The bipolar transverse montage links adjacent electrodes in a chain going from left to right (Figure 28.2C). Localization of abnormalities in a bipolar recording system involves identifying the head region with the phase reversal (i.e., a point at which the electrical activity in two adjacent channels is of opposite polarity). A major disadvantage of bipolar signal collection is in-phase cancellation of biologic activity: when biologic waveforms at two locations of comparison are relatively synchronous with respect to both timing and amplitude, differential amplification “cancels” such signals, and may lead to false localization of low amplitude phenomena. It therefore is important to employ multiple montages when interpreting EEG

445


data in order to determine: (a) whether abnormalities identified on one montage are corroborated by abnormalities on others; and (b) that signal abnormalities are pathological and not simply reflections of coincidental in-phase synchronization.

Referential montage Referential montages compare activity at scalp electrodes to another at a location that represents (in theory) an electrical “zero” (or reference point) (Figure 28.2A). An electrode placed on or near the ear is used commonly as a reference in such montages. Unfortunately, there is no perfect reference point for such montages, and reference electrodes placed on or near the ear are susceptible to muscle artifact (often from masseter muscle activity) as well as sensitive to mid-temporal cerebral activity. A commonly used reference is the “average reference.” This montage represents the average signal created by summing at least ten scalp electrodes. It is presumed that these electrodes are detecting unrelated (i.e., relative random) electrical activity that, when summated, cancels out and generates a theoretical “zero” electrical state. Localization of abnormalities in a referential system involves identifying the head region with the highest amplitude abnormalities and assuming that the abnormal signal was generated within this head region. When compared with bipolar montages, a strength of referential montages is the much limited risk of inphase cancellation and related problems they pose for EEG interpretation. A problem with these montages is that normal biological brain activity is sometimes both widespread and relatively synchronous, thereby risking its cancellation (and misinterpretation) in these montages.

Types of EEG recordings In contrast to functional neuroimaging, EEG provides a real-time assessment of normal and abnormal brain function. Most EEG is now collected and processed as a digital signal. The primary advantage of digital collection over paper collection is that filters, montages, etc., can be changed to suit the reviewer, markedly improving the flexibility of the data display and facilitating data interpretation. The primary modes of EEG collection are described below, along with how the information available from each method might be used clinically.

446

Conventional EEG The conventional, or routine, EEG is a 20–30 minute recording of ongoing cerebral electrical activity. Routine EEGs can offer useful diagnostic information about epilepsy type, evaluate patients with delirium or dementia, and determine if seizure activity may be causing a patient’s altered mentation. Each conventional EEG consists of essentially three standardized conditions: relaxed wakefulness with eyes closed, a series of provocation maneuvers, and a quiet period for sleep. During the relaxed wakefulness with eyes closed condition, patients are asked to open and then reclose their eyes several times; so doing facilitates distinguishing the posterior dominant rhythm from other background activity that is present during wakefulness (see below). Patients also are asked general knowledge questions to assess the effect of mental activation on EEG background activity. Patients unable to engage in such exchanges (e.g., comatose or severely encephalopathic patients) undergo other forms of sensory stimulation, including verbal and tactile, in order to evaluate the effect of so doing on EEG activity (i.e., reactivity to stimuli). Provocative maneuvers are included in the EEG assessment of some patients, and include activities such as hyperventilation and exposure to repetitive flashes of light (photic stimulation). The purpose of these maneuvers is to provoke the appearance of EEG abnormalities through induction of mild hypocarbia (hyperventilation) and by stimulus-related neuronal activity (photic stimulation) that otherwise would not be apparent in the waking EEG record. It also is customary to provide a period of quiet during recording in which patients are encouraged to sleep. This process facilitates assessment of the brain’s ability to generate sleep rhythms. It also increases the likelihood of capturing sleep–wake transition-related and sleep-facilitated phenomena, including epileptiform discharges, in the EEG record.

Continuous EEG The advent of digital collection of EEG records markedly expanded the capacity for EEG collection. Continuous EEG refers to the collection of ongoing cerebral electrical activity on a long-term, continuous basis, ranging from hours up to days or weeks at a time. Although this is usually an inpatient procedure, portable recordings can be done on outpatients for up


to 24 hours at a time (so-called “ambulatory EEG”). Inpatient continuous EEG also may include concurrent video recordings of patients’ behaviors. The primary advantage of continuous EEG recordings (as opposed to routine recordings) is that the continuous EEG offers a much longer sampling of ongoing activity. Since many EEG phenomena, such as interictal epileptiform discharges or seizures, are transient, increasing sampling time will statistically increase diagnostic yield. Additionally, the concurrent recording of video with EEG data allows for comparison of EEG activity with behavior, and may facilitate distinguishing between behaviors reflective of seizure activity and those that are attributable to other causes.

Epilepsy monitoring unit Epilepsy monitoring units (EMUs) are specialized centers for continuous EEG and video recordings. In these centers, patients are behaviorally monitored by trained personnel; this allows for interaction between monitoring personnel and patients during clinical events and improves their characterization (and, therefore, diagnosis). This type of EEG study is regarded as the definitive study when attempting to distinguish between epileptic (i.e., being driven by abnormal electrical activity in the brain) and non-epileptic events.

Quantitative EEG Quantitative EEG (qEEG) is an umbrella term for various methods of secondary mathematical processing of EEG signals (see Chapter 29). Examples of qEEG techniques include spectral analysis, coherence analysis, topographic EEG displays (“EEG brain maps”) and diagnostic discriminant analysis. qEEG techniques have been increasingly used in neuropsychiatry as a way to attempt to find potentially important diagnostic information contained in brain wave recordings. These techniques have been employed to categorize patient illness or to predict treatment response, but these uses are not supported by a strong body of clinical evidence. A complete review of all qEEG techniques and their potential uses is beyond the scope of this chapter; interested readers are directed to the Committee on Research of the American Neuropsychiatric Association [2] report on qEEG for a comprehensive review of this subject.

EEG interpretation Once recorded, the EEG should be visually inspected. The morphology of abnormal rhythms and the clinical significance of these findings are historically established, and visual inspection by an experienced electroencephalographer should be performed on every recorded study, even those undergoing additional quantitative analysis such as qEEG. Visual inspection of an EEG recording includes the following steps, each of which is discussed in the paragraphs below: (1) determination of the age and state of alertness of the patient; (2) assessment of the posterior dominant rhythm; (3) assessment of EEG activity in other head regions; (4) determination of presence/absence of abnormal EEG findings; (5) assessment of EEG reactivity to stimulation and/or provocative maneuvers; (6) assessment of recorded sleep architecture, if any is present.

Determination of the patient’s age and state of alertness The interpretation of EEG waveforms is age- and statedependent. The norms for EEG activity vary with both the age (pre-term, infant, child, adolescent, or adult) and the state of the patient (awake, drowsy, or asleep). For example, the diffuse “slowing” seen in a child or in the drowsy patient could be misinterpreted as indicative of encephalopathy if the patient is mistakenly assumed to be adult and fully awake and alert. The EEG technologist should comment on the patient’s state at the beginning of the record as well as at multiple time points during the recording. Additional findings in the EEG data also may indicate the patient’s state of alertness, including: (1) movement artifact, scalp/facial muscle artifact, and eye blink artifact in the awake state; (2) diminished movement, muscle and eye blink artifact, and the appearance of roving eye movements (Figure 28.3) in drowsiness; and (3) the appearance of sleep architecture during sleep (Figure 28.4).

Assessment of the posterior dominant rhythm The posterior dominant rhythm (PDR) is the most consistent rhythm present in the posterior head regions (Figure 28.5). The PDR is best seen in the occipital head regions, but can be seen rarely in more

447


Figure 28.3. Roving eye movements presented in a bipolar montage. The arrow indicates slow shifting potentials in the frontal electrodes bilaterally that are caused by the conjugate, horizontal, back and forth movements of the eyes during drowsiness. During these movements, the negatively charged retinal nerve layer changes position and, therefore, changes the absolute negativity sensed by the frontal recording electrodes.

anterior head regions in younger patients. The PDR is best seen in a relaxed patient with eyes closed, and it will attenuate with eye opening or mental concentration. In an adult, the normal frequency for the PDR ranges between 8.5 and 13 Hz, but can decrease by 1 Hz or more in the drowsy state. Rarely, a slower, variant PDR can be present (“slow alpha variant”). A slow alpha variant is 3.5 to 6.5 Hz rhythmic activity seen in the posterior head regions that mixes with the normal PDR (may be as subtle as notching of the waveforms) and reacts like the PDR to maneuvers such as eye opening and mental concentration (Figure 28.6). The PDR is abnormal if: (a) the frequency is less than 8.5 Hz in an awake adult and is not a slow alpha variant; (b) there is a difference in frequency ⬎1 Hz between the two hemispheres; (c) there is a greater than 50% difference in amplitude between the two hemispheres; and/or (d) the PDR only attenuates on one side with activating stimuli (Bancaud’s phenomenon) [4].

448

Assessment of EEG activity in other head regions After complete assessment of the frequency, amplitude, and reactivity of the PDR, the rhythms of the other head regions should be assessed to ensure that they are normal as well. Specific other rhythms that can be seen in a normal adult study include beta range activity, mu rhythms, and lambda waves. Beta range activity consists of rhythms with frequencies greater than 13 Hz. While their existence is highly dependent on normal cortical function, their absence is not necessarily indicative of disease. Three types of normal beta range activity are seen: (1) frontal beta, which typically appears symmetric over the frontal head regions; (2) widespread beta, which may be symmetric over both hemispheres (Figure 28.7); and (3) posterior beta, also known as a fast alpha variant. This rhythm, like the slow alpha variant, will mix with or replace the PDR and will react like the PDR.


Figure 28.4. Sleep architecture presented in a bipolar montage. The stages of sleep are identified by their typical EEG findings and cycle throughout the night among lighter (Stages 1 and 2) and deeper (Stages 3, 4, and REM) stages of sleep. Stage 1 sleep (top left) is characterized by loss of the posterior dominant rhythm, further diminishment of movement and muscle artifact and increasing diffuse slowing of background activity. Stage 2 sleep (top right) is characterized by the appearance of sleep spindles and K-complexes. Stages 3 and 4 sleep (bottom left) are characterized by various percentages of higher amplitude delta range activity. REM sleep (bottom right) is characterized by a low-voltage, irregular background with multiple rapid eye movements. Muscle artifact is virtually absent during normal REM sleep. This figure is presented in color in the color plate section.

Beta rhythms are abnormal if they are asymmetric, either in location or amplitude, or if the beta is subjectively excessive. Mu rhythms are 7–11 Hz rhythms seen in the central or central-parietal head regions (Figure 28.8). They are more common in younger adults and may be asymmetric. Mu rhythms will attenuate with movement or tactile stimulation of the patient’s contralateral arm. Lambda waves are sharp transients with positive polarity that occur in the occipital head regions when patients look at images with visual detail (Figure 28.9). They are best seen in children and will disappear with eye closure or with shifting gaze to a blank piece of paper. Despite their sharp appearance, they are not considered to be epileptiform.

Identification of abnormal EEG findings The two main categories of EEG abnormalities are: (1) slowing, or the presence of slower frequency waveforms than what should be present, and (2) epileptiform discharges, or specific EEG waveforms that signify cortical hyper-irritability and an increased risk for clinical seizures. There are two main varieties of EEG slowing: (1) irregular, or polymorphic, and (2) rhythmic. For polymorphic (or irregular) slowing, the location and persistence of the slow waveforms has clinical significance. Focal polymorphic slowing suggests a structural or functional disruption of supratentorial white matter underlying the cortical region recorded at the scalp electrodes (Figure 28.10). Superimposed

449


Figure 28.5. Normal posterior dominant rhythm with attenuation upon eye opening (black arrow) and reappearance with eye closure (purple arrow). This figure is presented in color in the color plate section.

Figure 28.6. Slow variant of posterior dominant rhythm.

attenuation, or loss of faster frequency activity, suggests additional gray matter dysfunction in the same cortical area. Focal polymorphic slowing that is continuous, or present throughout the record, is highly suggestive of a structural lesion in the area in question, while intermittent slowing can indicate either a structural lesion or a more non-specific alteration in cerebral function, such as that which occurs post-ictally or during some migrainous phenomena. Diffuse polymorphic slowing (whether continuous or intermittent) is a non-specific finding indicative of diffuse or multifocal bi-hemispheric dysfunction, such as

450

that seen in dementia or metabolic encephalopathies (Figure 28.11). Rhythmic slowing is often non-specific in etiology and can be caused by both infra- and supratentorial (often midline) structural lesions as well as encephalopathy from a variety of causes. Intermittent rhythmic delta activity (IRDA) is the most common type of rhythmic slowing seen outside of ictal discharges. The IRDAs are characterized by “saw-tooth” shaped waveforms, with an abrupt rising phase followed by a longer descending phase. Frontal intermittent rhythmic delta activity (FIRDA) is usually seen


Figure 28.7. Widespread, or diffuse, beta activity. This figure is presented in color in the color plate section.

Figure 28.8. Mu rhythm, indicated by black arrows.

in adolescents and adults (Figure 28.12), while occipital intermittent rhythmic delta activity (OIRDA) is primarily seen in children. Most IRDA is symmetric. Asymmetric IRDA indicates a supratentorial lesion ipsilateral to higher amplitude slowing. Epileptiform discharges (EDs) are sharply contoured waveforms that have been specifically associated with seizures or epilepsy. Sharp transients are sharply contoured waveforms not considered to be epileptiform. In a person with known epilepsy, one routine EEG will identify EDs in 50%, three will identify EDs in 84% and four will identify EDs in up to 92% [9]. Spikes are sharply contoured epileptiform waveforms with a duration of 20–70 ms. Sharp

waves are sharply contoured epileptiform waveforms with a duration of 70–200 ms. Classifying a specific EEG waveform as epileptiform is largely subjective, although, historically, electroencephalographers have attempted to develop descriptive criteria. Figure 28.13 presents two segments of EEG recordings containing sharp transient EEG waveforms and applies five commonly used criteria for “epileptiformicity” used to differentiate between epileptiform discharges and small sharp spikes (a common, benign type of sharp EEG transient) [4]. The fourth of these criteria, “epileptiform discharges are often, but not invariably, seen in the setting of focal slowing” is controversial; very frequent epileptiform discharges can, of themselves,

451


Figure 28.9. Lambda waves.

Figure 28.10. Focal polymorphic slowing, indicated by black arrow.

create focal slowing in the head regions where they occur.

Assessment of EEG reactivity to stimulation and/or provocative maneuvers The most commonly used provocative maneuvers used for the EEG outpatient are hyperventilation and photic stimulation. Provocative maneuvers are not always done in inpatient studies as the photic

452

equipment can be unwieldy to deploy in many clinical settings and tends not to travel well (especially as regards to durability). Additionally, encephalopathic patients often cannot follow the commands necessary for adequate hyperventilation. For these patients, stimulating maneuvers such as talking to the patient, clapping loudly, or introducing more noxious stimulation (e.g., pain) are used to assess for EEG reactivity and ensure that at least a portion of the EEG is recorded in the most wakeful state the patient


Figure 28.11. Diffuse polymorphic slowing.

Figure 28.12. Frontal intermittent rhythmic delta activity (FIRDA).

is capable of achieving. The presence of cortical reactivity, or “the capacity for making transitions between slower, synchronous rhythms and faster, asynchronous rhythms in response to stimulation,” suggests that the reticular activating system, thalamus,

and connected cortical structures are still functional in an otherwise encephalopathic patient [10]. The normal response to hyperventilation is the appearance of generalized slow waves that end within one minute of stopping hyperventilation. The response

453


Figure 28.13. Evaluation of transient EEG waveforms for epileptiformicity. Panels A (left) and B (right) feature sharp transient EEG waveforms; an electroencephalographer determines whether these are epileptiform using the following criteria: 1. Asymmetric contour – fast upstroke, slower downstroke (A – yes, B – no); 2. Complex, stereotyped morphology (A – yes, B – no); 3. After-going slow wave (A – yes, B – no); 4. In the setting of focal slowing (A – no, B –no). 5. Disrupts ongoing background activity (A – yes, B – no). Based on these criteria, the sharp transient EEG waveforms in panel A, but not panel B, are epileptiform.

to hyperventilation is abnormal if: (1) the slowing persists beyond one minute post-hyperventilation, (2) slowing reappears after stopping hyperventilation, (3) the slowing is asymmetric, or (4) epileptiform discharges appear (3 Hz generalized spike-and-wave complexes are particularly sensitive to hyperventilation) [4]. Photic stimulation consists of exposing the patient to lights flashing at a standardized series of repetitive flash frequencies (i.e., 1 Hz, 3 Hz, 5 Hz, etc.). A normal response to photic stimulation is photic driving, or the appearance of a rhythm with the same frequency as the flash frequency in the posterior head regions. Photic driving may mix with or replace the PDR, but should only be present during the actual period of flashing. Abnormal responses to photic stimulation include: (1) photomyogenic response, or brief muscle contractions in susceptible individuals triggered by flashes, and (2) a photoparoxysmal response, which refers to spikes or other epileptiform activity (usually generalized) that appear without clear relationship to ongoing flash frequency (Figure 28.14). Photoparoxysmal responses seen over the frontal or central head

454

regions and those that outlast the flash period are most commonly associated with higher risk of epilepsy [4].

Assessment of recorded sleep architecture Outside of the formal sleep lab, the assessment of EEG sleep activity is usually restricted to characterization of sleep stages and an assessment of symmetry. Poorly developed sleep architecture over a hemisphere is suggestive of a focal structural or functional lesion within that hemisphere.

EEG in Behavioral Neurology & Neuropsychiatry The EEG is commonly used in clinical assessment of BN&NP patients. Much of the literature on EEG in these patients is devoted to documentation and confirmation of the EEG findings that are commonly seen in various disease states. More recently, however, investigators and clinicians have used EEG and various forms of secondary signal processing (see Chapter 29) as prospective diagnostic tools. Table 28.2 [2, 11–15]


Figure 28.14. Photoparoxysmal response. This figure is presented in color in the color plate section.

summarizes both the common EEG findings in a number of disease entities seen in neuropsychiatric practice as well as more recent evidence for the diagnostic power of EEG in these diseases.

Impact of medications on EEG appearance In general, the severity of electrographic changes related to a single medication is dependent on: (1) the quantity of the specific medication in the brain (dependent on drug dose, volume of distribution, and rate of clearance); (2) the presence and quantity of any active metabolites; and (3) the duration of drug exposure. As a general rule, acute administration of a new drug is more likely to produce electrographic changes than is chronic exposure to that agent. Electrographic effects will also vary considerably from one patient to another. Total drug load, or number of medications, may also impact EEG appearance. The final EEG pattern observed is a result of a combination of these factors as well as the secondary systemic effects of medications.

As a general rule, EEG changes produced by medications are expected to be present over both hemispheres and relatively symmetric. Exceptions to this rule arise when there is an underlying cerebral or extra-cerebral pathology (e.g., skull defect, subdural hematoma), in which cases the effects of medications on EEG may appear relatively asymmetric [16, 17].

Specific medication effects Slowing of the posterior dominant rhythm Any medicine that can cause encephalopathy has the potential to slow the PDR. This effect is more likely at higher doses of such medications, and is frequently reported in association with older anticonvulsants, such as phenytoin. The effects of newer anti-epileptic drugs and psychiatric medications on EEG require further investigation.

Excessive intermixed theta or delta during wakefulness or drowsiness Medications commonly associated with slowing on EEG include clozapine, tricyclic antidepressants, and

455

Table 28.2. Electroencephalographic (EEG) findings associated with common conditions evaluated by subspecialists in Behavioral Neurology & Neuropsychiatry. Abbreviation: qEEG – quantitative electroencephalography.

Condition

Common EEG findings

Comments

Epilepsy

Focal or generalized spikes, sharp waves, and spike-and-wave complexes

Infantile spasms: hypsarrhythmia – nearly continuous high-voltage multifocal spikes or sharp waves and arrhythmic slow waves Absence: Generalized, bilaterally synchronous 3 Hz spike-and-waves (ictal) Primary generalized: Generalized, bilaterally synchronous spike-and-slow waves (ictal), or typical spike-and-wave discharges (2–5 Hz) Complex partial: focal spike or sharp-wave discharges

Delirium

Diffuse slowing with irregular high-voltage delta activity

Acute agitated delirium: low-voltage fast activity Uremic, hepatic, or anoxic encephalopathy: diffuse slowing and intermittent triphasic waves; also observed in other metabolic encephalopathies

Alzheimer’s disease (AD)

Generalized increase in theta, then delta, slowing Slowing of the PDR (especially later stages) Reduced or absent beta range activity Sleep may be disorganized Epileptiform discharges are rare May see posterior-dominant triphasic waves late Severity of EEG abnormalities correlates well with degree of dementia

A normal EEG in a demented individual suggests that the diagnosis is unlikely to be AD A moderately to severely abnormal EEG in the first 4 years of illness is highly suggestive of an AD diagnosis EEG and some qEEG techniques may be useful in discriminating between specific dementing illnesses, such as AD, and disorders such as depression, alcoholism, and delirium

Frontotemporal dementias

EEG abnormalities, if present, are mild May see slowing in anterior quadrants bilaterally PDR often well-preserved


Often very low voltage background, especially late (less than 10 microvolts) In one study, all patients had abnormal sleep patterns

Vascular dementia

May see focal slowing

Tumor or stroke

Focal slowing at the borders of the tumor or infarction and absence of activity overlying necrotic tissue

Herpes simplex encephalitis

Periodic lateralized epileptiform discharges (PLEDS)

PLEDS are also observed in association with other viral encephalidities

Anterior brainstem/ diencephalic injury

Frontal intermittent rhythmic delta activity (FIRDA), bilateral, reactive to stimuli, and not apparent during sleep

Bifrontal theta may be seen with slow-growing deep midline tumors

Severe white matter pathology

Continuous unreactive polymorphic delta activity

Entails a very broad differential diagnosis

Schizophrenia

May see relatively low mean PDR frequency May see left hemisphere slowing, especially temporally May see abnormal sleep structure

EEG may have some utility in discriminating between schizophrenic and depressed patients

Mood disorders

May see right hemisphere abnormalities, including less variation in alpha bursts and increased frontal activation with stimulation in depression May see abnormal sleep structure

Some qEEG techniques have been shown to differentiate between: (1) depressed and healthy individuals; (2) depressed and demented, schizophrenic or alcoholic individuals; and (3) unipolar and bipolar patients

Learning and attentional disorders of childhood

About one-half of autistic children show abnormalities and epileptiform activity is not uncommon Mild non-specific abnormalities are seen in about 40% of dyslexics

qEEG may be a useful adjunct to behavioral testing and clinical evaluation in the diagnosis of children suffering from learning or attentional problems

Focal slowing more common in patients with vascular dementia, compared with patients with dementias of other etiologies


lithium [18, 19], but nearly any psychiatric or antiepileptic drug may produce such slowing. Mild theta during wakefulness is a common observation in patients taking therapeutic doses of anti-epileptic drugs or psychiatric medications. At higher doses excessive theta or delta range activity may develop. In either circumstance, slow activity is expected to be diffuse. The exception is clozapine, which may cause frontal slowing more specifically. Additionally, the degree of EEG changes produced by clozapine and/or lithium is not infrequently out of proportion to the clinical effects of these agents (i.e., the EEG appears worse than does the patient).

Although triphasic waves are traditionally associated with uremic, hepatic, and anoxic encephalopathies, they are not specific to these conditions. There is no specific aspect of triphasic waves that distinguishes between the metabolic or toxic encephalopathies, or clarifies the differential diagnosis of encephalopathy. Additionally, medications such as valproate, lithium, and serotonergic agents [20–22] may produce triphasic waves, and drugs producing secondary metabolic encephalopathies (i.e., medication-induced renal or hepatic dysfunction) also may produce this EEG finding.

Excessive beta activity

Coma patterns

As discussed earlier in this chapter, beta frequencies are normal EEG findings. However, barbiturates and benzodiazepines may produce increases in amplitude and frequency of this otherwise normal frequency [18, 19]. Other agents which cause increased beta to a lesser degree include amphetamines, methylphenidate, and tricyclic antidepressants. Augmentation of beta as a medication effect appears to be more prominent in children as opposed to adults.

There are a number of coma patterns that have been associated with drug intoxication. These include spindle coma, alpha/beta coma, burst suppression, and electro-cerebral inactivity. These patterns may be due entirely to the pharmacologic effects of the drug. If that is the case, then the electrographic and clinical compromise may be completely reversible. However, when drug overdose is complicated by other factors such as hypotension and hypoxia, the clinical and EEG effects may not be reversible.

Epileptiform activity High doses of several types of medications may be associated with bisynchronous symmetric spikes or poly-spikes. These include clonazepam, lithium, phenothiazines, selective serotonin reuptake inhibitors, and tricyclic antidepressants. In addition, withdrawal of alcohol or barbiturates may bring on generalized epileptiform activity. Patients with a genetic disposition to have generalized spike-and-wave activity at baseline can have this pattern reduced by certain anti-epileptic medications such as valproic acid or ethosuximide. However, antiepileptic drugs do not influence localized epileptiform activity. Therefore the initiation of an anti-epileptic drug therapeutically does not as a general rule interfere with the likelihood of observing specific epileptiform activity on an interictal EEG performed as part of the evaluation for epilepsy.

Triphasic waves Triphasic waves usually arise from a diffusely abnormally slow background, and are a classic EEG abnormality associated with metabolic encephalopathy.

Conclusion This chapter reviewed the principles of conventional EEG recording and interpretation, and their common use in the practice of BN&NP. The neurophysiologic basis of scalp-recorded EEG was discussed, as were the methods of EEG recording and interpretation. The most common clinical applications were considered, including characterization of rhythms common in wakefulness and sleep as well as findings associated with seizure disorders and encephalopathies. The principles of electrophysiologic assessment presented in this chapter are complemented in Chapter 29 of this volume. Together, these chapters serve as a foundation upon which subspecialists in BN&NP may build their understanding of clinical electrophysiology, and develop the expertise and skills needed to apply the potentially valuable information yielded by clinical EEG to the care of their patients.

References 1. Olejniczak P. Neurophysiologic basis of EEG. J Clin Neurophysiol. 2006;23(3):186–9.

457


2. Coburn KL, Lauterbach EC, Boutros NN et al. The value of quantitative electroencephalography in clinical psychiatry: a report by the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2006; 18(4):460–500. 3. Evans JR, Abarbanel A. Introduction to Quantitative EEG and Neurofeedback. San Diego, CA: Academic Press; 1999. 4. Fisch BJ, Spehlmann R. Fisch and Spehlmann’s EEG Primer: Basic Principles of Digital and Analog EEG. 3rd revision and enlarged edition. Amsterdam: Elsevier; 1999. 5. Nuwer MR. Assessing digital and quantitative EEG in clinical settings. J Clin Neurophysiol. 1998;15(6): 458–63. 6. Nuwer M. Assessment of digital EEG, quantitative EEG, and EEG brain mapping: report of the American Academy of Neurology and the American Clinical Neurophysiology Society. Neurology 1997;49(1): 277–92. 7. Arciniegas DB, Kaufer DI, Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13.

12. Robinson DJ, Merskey H, Blume WT et al. Electroencephalography as an aid in the exclusion of Alzheimer’s disease. Arch Neurol. 1994;51(3):280–4. 13. Scott DF, Heathfield KW, Toone B, Margerison JH. The EEG in Huntington’s chorea: a clinical and neuropathological study. J Neurol Neurosurg Psychiatry 1972;35(1):97–102. 14. Sishta SK, Troupe A, Marszalek KS, Kremer LM. Huntington’s chorea: an electroencephalographic and psychometric study. Electroencephalogr Clin Neurophysiol. 1974;36(4):387–93. 15. Hughes JR. A review of the usefulness of the standard EEG in psychiatry. Clin Electroencephalogr. 1996;27(1):35–9. 16. Blume WT. Drug effects on EEG. J Clin Neurophysiol. 2006;23(4):306–11. 17. Blume WT, Kaibara M, Young GB, editors. Atlas of Adult Electroencephalography. 2nd edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. 18. Bauer G, Bauer R. EEG drug effects and central nervous system poisoning. In Niedermeyer E, Lopes da Silva FH, editors. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 5th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2005, pp. 701–24.

8. Keller CJ, Truccolo W, Gale JT et al. Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex. Brain 2010;133(Pt 6): 1668–81.

19. Van Cott A, Brenner RP. Drug effects and toxic encephalopathies. In Ebersole JS, Pedley TA, editors. Current Practice of Clinical Electroencephalography. 3rd edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2003, pp. 463–83.

9. Salinsky M, Kanter R, Dasheiff RM. Effectiveness of multiple EEGs in supporting the diagnosis of epilepsy: an operational curve. Epilepsia 1987;28(4): 331–4.

20. Kifune A, Kubota F, Shibata N, Akata T, Kikuchi S. Valproic acid-induced hyperammonemic encephalopathy with triphasic waves. Epilepsia 2000; 41(7):909–12.

10. Arciniegas DB, Anderson CA, Rojas DC. Electrophysiological techniques. In Silver JM, McAllister TW, Yudofsky SC, editors. Textbook of Traumatic Brain Injury. 1st edition. Washington, DC: American Psychiatric Publishing; 2005, pp. 1–26.

21. Chatrian G-E, Turella G. Electrophysiological evaluation of coma and other states of diminished responsiveness. In Ebersole JS, Pedley TA, editors. Current Practice of Clinical Electroencephalography. 3rd edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.

11. Ebersole JS, Pedley TA, eds. Current Practice of Clinical Electroencephalography. 3rd edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.

458

22. Dike GL. Triphasic waves in serotonin syndrome. J Neurol Neurosurg Psychiatry 1997;62(2):200.

Section II


Chapter

Advanced electrophysiology

29

Donald C. Rojas

Over the past decade, there has been a profound change in the analytic techniques typically applied to electrophysiologic data derived from electroencephalography (EEG) and magnetoencephalography (MEG) recordings. Although there is still much research done completely within either the time or frequency domain, new and exciting techniques for integrating time and frequency space have developed. Time–frequency analyses are now routine in research electrophysiology and have substantially improved our knowledge of traditional time domain analyses such as evoked potentials. Traditional analyses of the EEG at the electrodes (signal space) are also giving way to source analytic techniques that allow investigators to view accurate models of the current distributions within the brain. While these developments have become relatively standard practice in the hands of research scientists, clinicians are not yet widely familiar with the new tools and terminologies. The purpose of this chapter is to introduce some of the key concepts that will be changing clinical EEG and MEG in the next decade. While applications to clinical or research problems will not be reviewed, the purpose of the chapter is to give the reader an appreciation for a number of available techniques, including when it might be appropriate to consider the application of the technique to a particular problem.

Magnetoencephalography Magnetoencephalography systems (see Figure 29.1) use superconducting electronics and magnetic shielding to detect the magnetic fields generated by synaptic neuronal activity. In the sense that both EEG and MEG record complementary aspects of the same

Figure 29.1. Magnetoencephalography (MEG) system. A 248-channel, whole head system is shown inside a magnetically shielded room enclosure (door is open for picture, but closed for recordings).

electrophysiological events within the brain, they are related technologies. Magnetoencephalography systems are quite a bit more expensive, however. A modern system would require approximately US $2 million to purchase and several hundred thousand dollars per year to operate, in contrast to the relatively cheaper EEG systems. The main difference in cost is due to the superconductivity requirement – for sensitivity to small magnetic fields generated by the brain, liquid helium is used to keep the detection electronics cooled to below 4.2 K – about −452 ◦ F. Conceptually, MEG is quite simple. All electrical currents, in the brain and outside the brain, generate a proportional magnetic field that can be described by the right hand rule of magnetism (sticking the right hand out like a hitchhiker, point the thumb in the direction of current flow – the other four fingers illustrate the direction of magnetic field surrounding the current). As this magnetic field emerges (at the speed


459


Figure 29.2. Electroencephalography (EEG) and magnetoencephalography (MEG) tracings. Top: Four seconds of EEG record (O2 referenced to Cz) with prominent alpha (8–12 Hz) rhythm. Bottom: Same four seconds from same subject, but simultaneously recorded MEG signal from posterior channel.

of light) from the current source, it can exit and reenter the head as it encircles the current, where it can be detected by superconducting electronics coupled with sensors. Because of the orthogonality between the magnetic and electric field directions, their topography across an array of sensors will be rotated at 90 degrees to each other for any discrete current distribution in the brain. The sensors are often simply coils of wire and when magnetic fields change within the coil loops, current is induced in the loops and measured in the system hardware and software. A variety of MEG detection coils are available, each differing in their signal sensitivity and capacity for noise reduction. Modern MEG systems may have as many as 300 or more individual magnetic detectors (analogous to EEG electrodes). The high cost of MEG compared with EEG comes with some benefits. It is much easier to record very high numbers of MEG sensors in a dense array than using EEG because MEG does not require skin contact and conductivity. Unlike EEG, MEG sensors do not need to be paired for differential recording, so that MEG measurements are free of the EEG reference electrode problem. The varying tissues between the brain

460

and the sensors do not disrupt or distort the transmission of magnetic fields in the same manner as is commonly seen in EEG (e.g., changes in conductivity between cortex and skull act as a spatial low-pass filter in EEG, reducing the resolution [1]). These advantages make it somewhat easier to infer underlying current distributions from the observed activity at the sensor, a technique generally known as source analysis and discussed later in this chapter. Although many subtle details differ between EEG and MEG, they can be considered in general to reflect aspects of the same underlying signal from the brain. Most of the processing that applies to EEG (see Chapter 28) likewise applies to MEG and all of the techniques pertinent to EEG also apply to MEG data. In fact, without reference to the scale of measurement, it would be nearly impossible to distinguish MEG from EEG time series (see Figure 29.2).

Domains of electrophysiological analysis Clinical review of spontaneous EEG and MEG data is beyond the scope of this chapter and can easily be found elsewhere (e.g., [2, 3]). Here, the focus will be

Chapter 29: Advanced electrophysiology

Figure 29.3. Time versus frequency domain. Top: Three seconds of EEG recorded from T3 (referenced to Cz) illustrating mixed low-frequency content. Bottom: FFT of same time period shows multiple peaks in theta along with smaller beta contribution.

on two types of quantitative analyses of human electrophysiological data: (1) spectral analysis methods and (2) evoked potentials. In the not too distant past, inked pens wrote out EEG data on paper pulled under the pens at various speeds. Although this procedure might still be routine in a minority of clinical and/or research EEG laboratories today, most have long since transitioned into the digital age. In that bygone EEG era, EEG signals were naturally observed and interpreted in the time domain – that is, a signal representing the amplitude of a waveform varying over time (see Figure 29.2). Although time domain analyses and interpretations remain the focus of both research and clinical practice in the digital age, computers allow easy transformation between the time domain and the frequency domain.

Spectral techniques and quantitative EEG Frequency domain, or spectral analyses, of the EEG and MEG are motivated by the well-known frequency bands, alpha (8–12 Hz), beta (13–30 Hz), theta (5– 7 Hz) and delta (⬍5 Hz), which under certain states

can become predominant in the EEG (e.g., awake but eyes-closed, posterior dominant alpha rhythm). These can often appear very sinusoidal in the time domain. Although one can, and often does without computer assistance, simply count the cycles in the EEG (trying to ignore the “noise” from other frequency components of the EEG) per unit time of EEG, it is often much easier to find peaks in the EEG spectrum from transformation to a frequency representation. The reason why this approach is often easier is that the frequency content of the EEG is not always readily apparent in the time domain because it is a mix of the various bands, making it difficult to determine by eye how to count the relevant cycles. Transformation into the frequency domain is usually accomplished using some variant of the Fourier transform, usually the fast Fourier transform (FFT). Figure 29.3 illustrates a 3-second EEG tracing from electrode T3 (reference to Cz in the 10–20 International Electrode System) that contains a mixture of high amplitude slow activity and low amplitude fast activity. It can be seen from the FFT of the signal that the frequency content is a mixture of the various EEG bands, with prominent delta and theta peaks and less prominent alpha and beta contributions.

461


Table 29.1. Some common measures and terms in electroencephalography (EEG) and magnetoencephalography (MEG).

Measure

Brief definition

Typical scale or range, or comments

Amplitude

Magnitude of activity

uV (EEG), fT (MEG)

Absolute power

Squared amplitude, usually in a given frequency band

uV2 (EEG), fT2 (MEG)

Relative power

Power in a frequency band, divided by the total power across frequency bands

Because it is a ratio, it is a unit-less measure

Cordance

Measure that integrates absolute and relative power for a given electrode, using information from its nearest neighboring electrodes

Unit-less

Coherence

Frequency-specific cross-spectra (i.e., cross correlation) between two signals, usually originating from two separate EEG channels

Usually normalized so that measure ranges from 0 (zero coherence) to 1 (perfect coherence)

Phase

A circular measure of angle based on an arbitrary reference point set at 0.

0–360◦ , or in units of radians (0–2␲)

Phase-consistency

Measure of trial by trial consistency of phase – a metric of latency jitter around an event

Various normalized measures exist – most common is inter-trial coherence (ITC) or phase-locking factor (PLF), which has range from 0 (no consistency, or maximal jitter) to 1 (perfect consistency, or no jitter)

Evoked potential (EP) (Event-related potential; ERP)

Time-domain average of multiple trials of EEG response to stimulus or response. Relatively high degree of phase-consistency between trials

See Amplitude, above; abbreviated EP or ERP

Evoked field (EF) (Event-related field; ERF)

Same as EP, except for MEG

See Amplitude, above; abbreviated EF or ERF

Induced response

For EEG or MEG, a time-locked, but not phase-locked, response to an event, captured by averaging in the frequency domain

Usually expressed in spectral terms (e.g., induced power), but can also be expressed in time-domain in units of amplitude

Event-related de-synchronization (ERD)

Time-frequency measure of decrease in spectral power to stimulus or response

Expressed in dB or % decrease from a baseline interval of EEG or MEG

Event-related synchronization (ERS)

Time-frequency measure of increase in spectral power to stimulus or response

Expressed in dB or % increase from a baseline interval of EEG or MEG

Event-related spectral perturbance (ERSP)

Time-frequency term that encompasses both ERD and ERS

Same as for ERD and ERS

Current dipole

A physical model representing a current source and sink in the brain. Current dipoles form the basis of all EEG and MEG source modeling techniques

nA-m, a measure of current strength over the distance between the current source and sink (also called a dipole moment)

Using digital EEG and computerized algorithms, consideration of the EEG signal in terms of its spectral composition is often called quantitative EEG or qEEG (less commonly encountered is qMEG). There are many metrics for quantification of spectral data found in the qEEG literature (see Table 29.1 for some common terms and their definitions). Spectral analysis of EEG and MEG signals across multiple sensor locations often reveals clear spatial patterns, either associated with specific frequencies, mental states, or both. The most widely appreciated of these spatial patterns is that of the posterior alpha band, seen quite prominently over parietal and

462

occipital electrodes in the EEG (see Figure 29.4). This particular type of alpha, accentuated during periods of eyes-closed wakefulness and attenuated upon opening the eyes, has been known since the advent of EEG [4]. This type of spectral mapping across EEG channels is sometimes called brain electrical activity mapping (BEAM) [5], although this term is less frequently employed in the past decade than in the 1980s and early 1990s. The more commonly employed, but broader term, encompassing both methods of analysis and display of data, is qEEG [6]. While EEG alpha has classically been interpreted as a sign of idling visual cortex [7], more recent evidence based on modern


the next decade as methodological standards and database developments become available.

Evoked and induced responses

Figure 29.4. Scalp topography of posterior-dominant alpha. A flat projection of the top of the head is shown and the circles indicate approximate electrode locations (nose is up in figure). The power distribution across electrodes exhibits a typical posterior dominance for alpha, mapped at 10 Hz. This figure is presented in color in the color plate section.

EEG and MEG analyses such as those described in this chapter suggests that alpha, which is generated in multiple cortical regions, not simply the visual cortex, may reflect active, top-down inhibition of cortical processing [8]. Analyses of spectral domain signals in the EEG and MEG have been of significant interest in clinical neuroscience for many years. Deviations from normally expected frequency expression or from expected spatial patterns or expressed EEG features are observed in numerous, if not all, disorders studied using qEEG and/or qMEG. Prominent examples include, but are not limited to, Alzheimer’s disease [9], traumatic brain injury [10] and attention-deficit disorder [11]. Although these types of data are very exciting, and may one day lead to EEG- and MEG-based diagnosis, treatment selection, treatment evaluation or other clinically relevant use, physicians should be extremely wary of claims made by commercial vendors concerning the applicability of these data to clinical practice. Much of the qEEG literature suffers from a lack of comprehensive normative data, stratified appropriately by age, gender, and education [12, 13]. In general, diagnostic comparisons have been limited to relatively unchallenging endeavors such as the separation of any particular clinical diagnosis from a sample of healthy comparisons, although more useful comparisons between mild cognitive impairment and probable Alzheimer’s disease have been published [9]. In the near future, qEEG will probably remain a supplement to traditional clinical EEG interpretation, although this seems very likely to change rapidly in

EEG and MEG activity can be subdivided into three major subdivisions: (1) spontaneous activity, unrelated to any external or internal events, (2) evoked responses, and (3) induced responses. The latter two types of activity are generated in response to stimuli or other discrete events. The meaning of spontaneous activity (also called background activity) is relatively straightforward compared with the other two types, which will be the focus in this section of the chapter. Evoked responses (in EEG these are called evoked potentials or EPs, and in MEG evoked fields or EFs) are time domain averages across multiple trials of a repeating stimulus or response (i.e., the mean is taken across trials at each time point, or sample). The usual procedure involves presenting a stimulus multiple times in discrete trials to a subject. Assuming that an EEG response is clearly time-locked (or, more precisely, phase-locked – more on this below) to that stimulus on each trial (i.e., it occurs at the same latency after the stimulus on every trial), then the average, or EP, will exhibit that response while any processes randomly distributed with respect to the stimulus will tend to average to zero if enough trials are averaged. Examples of processes that are presumably randomly distributed include environmental noise and ongoing EEG unrelated to the stimulus processing. Figure 29.5 illustrates the effect of averaging multiple trials of a motor EF (response-locked, rather than stimulus-locked). In the past decade, a much greater appreciation for the information in the EEG and MEG data that might be lost to averaging has accumulated. Motivated in part by time-frequency analyses (covered below) and by the development of metrics to assess the underlying assumption of time/phase-locking of the response to a stimulus, researchers have uncovered (or recovered) a substantial amount of genuine electrophysiological signal that had been routinely discarded by time-locked averaging methods. The concepts and terminology that will be introduced in this discussion require a basic understanding of phase (also called phase-angle) as it is used in MEG and EEG signal processing. Phase is a circular measure of the angle between a point on an EEG or MEG signal and an arbitrary reference point, often the onset of a stimulus. Figure 29.6 illustrates

463


Figure 29.5. Effect of averaging across varying numbers of trials on evoked response. An MEG motor evoked field (MEF) to finger flexions is illustrated from a single channel of data. From the top panel to the bottom panel, the number of trials in the average is increased from 1 to 80. Note the relative preservation of amplitude of the MEF components and the substantial decrease in noise when more trials are added to the average. See the text for a more nuanced discussion of noise and evoked responses.

Figure 29.6. The effect of phase-locking on time-domain averages. In the left and right panels, nine single trials of a simulated electroencephalography (EEG) evoked potential (EP) to an arbitrary stimulus are illustrated (time zero is stimulus onset). For trials on the left, although the amplitude of the individual trials at each time point varies between trials, the phase of the EEG response is identical (you can use the solid vertical line at time 0.4 s and the corresponding EEG peak as an aid). For trials on the right, however, although the frequency of the EEG response remains unchanged (8 Hz), there is jitter between trials in the phase of the EEG signal. The bottom row illustrates the effect of averaging on these trials. Note that for the non-phase-locked average, there is little to no EP visible, while a strong EP is seen in the phase-locked average.

464


Figure 29.7. Averaging in the frequency domain. The top and middle panels illustrate the effect of first converting single trials to the frequency domain, then averaging by frequency bin. The data for the single trials (not illustrated) are the same as in Figure 29.6. The resulting frequency domain average for the non-phase-locked, or induced response (middle panel), is identical to that for the phase-locked, or evoked response (top panel). Compare this with the resulting averages in the time domain in Figure 29.6. The bottom panel illustrates the inverse of the FFT of the induced response – just as time domain signals can be converted to frequency representations, so can the operation be reversed to recover the time signature.

conceptually what is assumed by the process of signal averaging, illustrating one case where the signal of interest shows high phase-locking, or phaseconsistency, between trials. It is this case that is often referred to in the sense of time-locking when discussing EPs. The other case illustrated, however, demonstrates the effect of averaging on a loosely time-locked, but non-phase-locked EEG signal. Timedomain averaged EPs are therefore considered to be a case of inter-trial activity that is highly phase-locked with respect to the stimulus or response. Activity that is not phase-locked to the averaging event (stimulus or response) is called an induced response, assuming that there is some degree of temporal consistency in the response. Producing measurable averaged induced responses requires averaging in a different manner than for EPs. While EPs are averaged in the time domain (i.e., time point by time point), induced responses are averaged in the frequency domain. To do so, the original signal is converted to a frequency representation, trial by trial (e.g., using an FFT), and then averaged by frequency across trials. The phase of the EEG response in this case is irrelevant to the averaged result (Figure 29.7).

It is important to note that induced EEG and MEG activity account for a very high portion of stimulusrelated changes in most experimental paradigms and are mostly discarded from consideration in classical EP studies [14]. This is very unfortunate, because modern views of event-related EEG and MEG activity suggest that evoked and induced responses are not fundamentally different in their physiology or generation [15]. Methods that capture both types of activity have become much more popular in the past 10 years, particularly with the emphasis on time-frequency domain analytical techniques.

Time–frequency transformations The difficulties with pure time-domain or frequencydomain representations are easy to imagine. For the time-domain, it can be challenging to discern peak frequencies when there is a mixture of several dominant frequency bands in the record. With a pure frequency-domain representation, however, one loses the change in frequency content and amplitude over time that is characteristic of EEG and MEG signals (Figure 29.8 illustrates both problems with a known

465


Figure 29.8. Time, frequency, and time–frequency representations. The signal in the left column is a mixture of two pure tones (20 and 80 Hz). The signal in the right column is the same complex tone as the left, but amplitude modulated at 5 Hz. Top panels: Time domain; Middle panels: Frequency domain (FFT); Bottom panels: Time–frequency domain (Short-Time Fourier Transform). The reds in the color scale indicate greater spectral power. Note that for the stationary signal on the left, a simple frequency representation (middle panel) conveys as much information as the time–frequency representation (bottom). For the non-stationary signal on the right, however, the amplitude modulation effect is lost in the FFT (middle panel), but captured effectively in the time–frequency representation (bottom panel). This figure is presented in color in the color plate section.

signal). For such signals, called non-stationary, it is therefore desirable to have a middle-ground representation, one that captures both the frequency content of the signal and the change in that content over time. This is accomplished using time–frequency transformations. Figure 29.8, bottom row, illustrates how multiple frequencies and time-varying amplitudes can be observed using a time-frequency transformation. Various methods exist for this type of transformation, including those based on a time-windowed FFT (e.g., short-time Fourier transform), wavelet transformations (e.g., Morlet), pseudo-Wigner distribution, and complex demodulation, among many others. The advantages and disadvantages of these methods are beyond the scope of this chapter, but as one may not know both the time and the frequency with precision at any given moment, the methods differ in terms of trade-offs in time and frequency resolution (see Figure 29.9) as well as computational efficiency. Electroencephalographic and MEG methods based on time–frequency transformation are usually concerned with capturing changes in the brain’s oscillatory phenomena (i.e., alpha, beta, gamma, etc.) produced by stimuli, mental events, or responses. Table 29.1 lists some common terminology associated with such methods. An example of event-related de-synchronization (ERD) and event-related synchronization (ERS) in response to a simple index finger flexion is illustrated in Figure 29.10. The advantages

466

of visualizing a time–frequency transformation can easily be discerned by comparing the averaged evoked field to the ERD/ERS plot, the latter of which clearly illustrates a pre-movement beta ERD and post-movement beta rebound (ERS). Together, ERD and ERS techniques fall under the general term event-related spectral perturbation (ERSP). Time–frequency methods have also been employed with great success to examine the relative amount of spectral change associated with greater or lesser degrees of phase-locking (evoked versus induced EEG). Figure 29.11 illustrates this with the data from the cued motor experiment also shown in Figure 29.10. In Figure 29.10, what is illustrated in the ERS/ERD plot is total spectral power change relative to a baseline period from −3 to −2 seconds before movement onset. In Figure 29.11, the activity is further subdivided into evoked and induced spectral power change along with a measure of phase-locking (phase-locking factor, also known as inter-trial coherence). Here one can discern that the prominent beta ERD/ERS seen in Figure 29.11 is not highly phaselocked and does not appear in the evoked power plot or phase-locking measure. However, it can be easily seen in the induced response, indicating that most of the spectral activity associated with finger flexion is induced rather than evoked. The low-frequency motor evoked field, however, is strongly phase-locked and observed prominently in the evoked power and


Figure 29.9. Examples of time– frequency transformations. Top panel: Original signal in the time domain. The signal is linearly decreasing in frequency across time (i.e., it is a chirp signal). Middle panel: Short-time Fourier Transform of chirp. Bottom panel: Pseudo-Wigner Distribution of chirp. Note the increased frequency resolution of the Pseudo-Wigner Distribution. Reds in the color scale indicate greater spectral power. This figure is presented in color in the color plate section.

phase-locking plots. This component is the only portion that would be observable in the time-domain averaged EP (see Figure 29.10, top panel). A final comment about time–frequency techniques is that they have ignited interest in a phenomenon called phase-resetting, in which the ongoing oscillatory activity’s phase is affected by incoming stimuli. Phase-resetting can, without causing any increase or decrease in spectral power (ERD/ERS), cause an EP to occur in the time-averaged response [16, 17]. That is because if the phases of the ongoing activity are random prior to stimulus onset, and the stimulus causes a systematic shift, or reset, of the oscillatory phase poststimulus, then the post-stimulus waveform phases will be non-random while the pre-stimulus phases are random. As long as the frequency or amplitude of oscillation does not change, then an EP will emerge from the time-domain averaging. An EP can occur even if the amplitude of the oscillation decreases post-stimulus relative to the baseline.

Source analysis Source analysis is a general term for the construction of models of EEG or MEG data in the brain, or source space rather than in sensor space. Although source analysis methods have existed for many years for both technologies, source analysis developed more quickly as a standard approach in MEG for various reasons, including early integration of physics expertise in the field, ease of recording large numbers of channels without scalp contact, greater computational simplicity, and less spatial distortion in MEG due to the effects of varying conducting layers between sources and sensors. First, because valid source models require adequate spatial sampling (i.e., the spacing between channels, or channel density) of the measured sensor topography, many channels spaced closely together are typically required. As more EEG researchers have become interested in and familiar with source analysis techniques, however, solutions to various difficulties in source reconstruction have emerged. In particular, it is

467


Figure 29.10. Magnetic response to visually cued index finger flexions. Top panel: Averaged evoked field (EF) (101 trials) from a single channel over the right hemisphere. Time zero indicates movement onset. The evoked responses seen in the immediate post-movement period are known as motor evoked fields (MEF, or MEP for EEG recordings) and reflect the somatosensory feedback from motor cortex and from the peripheral sensation of movement. Bottom panel: Wavelet-based time-frequency transformation of same trials in same channel used to create averaged EF (color scale: blues indicate event-related de-synchronization (ERD) and reds indicate event-related synchronization (ERS)). Note the prominent beta-band changes in the panel, including ERD in the pre- and peri-movement period and then ERS following the ERD. The power increase from the evoked response in the top panel is evident immediately following movement onset at the lower frequencies (⬍10 Hz). The ERD/ERS in the beta-band is difficult to visualize in the averaged evoked response, although a small change in amplitude may be discerned. This figure is presented in color in the color plate section.

Figure 29.11. Subdividing the spectral response into evoked and induced components. The data illustrated in Figure 29.10 are shown here, focusing more clearly on the relevant time and frequency windows. Top panel: evoked power, relative to pre-movement baseline period (−3 to −2 s); Middle panel: relative induced power; Bottom panel: phase-locking factor. Color scales: reds indicates greater power (top two panels) or phase-locking (bottom panel) – blues indicate lower power or phase-locking. This figure is presented in color in the color plate section.

468


now much easier to model individual differences in the conducting layers using anatomical data from magnetic resonance imaging (MRI) and automated, computerized methods for extracting the brain, skull, and scalp boundaries [18]. The mathematical and physical foundation of source analytic techniques traces to James Clerk Maxwell’s four equations relating electric and magnetic fields to current sources. These equations form the basis of what is called the forward solution in EEG and MEG (i.e., solving from a known source configuration in the brain to the spatial distribution in the sensor array). It is solving the so-called inverse solution – a known spatial distribution in the sensors but unknown source configuration – that is challenging. In theory, an infinite number of current distributions can be shown to lead to the same scalp distribution, which is why the inverse problem is considered ill-posed. It is, of course, possible to overcome this seemingly hopeless problem by introducing constraints on the solution space through the use of mathematical, anatomical, and functional restrictions. Through these restrictions, very reasonable electromagnetic source solutions can be obtained. Although there are far too many different approaches to source analysis to discuss in this chapter, techniques may be subdivided generally into discrete versus distributed models. In a discrete source model, one or more equivalent current dipoles (ECD: see Current dipole, Table 29.1) are solved to represent the sensor topography, either independently time-point by time-point (moving dipole model) or over a period of time (spatiotemporal dipole model). The word equivalent in ECD refers to the fact that the underlying distribution is probably a larger, less discrete patch or volume of activity being abstractly represented by a single source with a higher dipole moment, or magnitude. In contrast, distributed source modeling techniques allow for many smaller dipoles, usually regularly spaced in a volume or surface model of the brain, to represent the activity of the brain in a somewhat more intuitive manner. Figure 29.12 illustrates a source analysis derived from a combined MEG and EEG dataset of the visual evoked response at 100 ms, termed P100 in the EEG literature (or M100 for MEG). Although distributed models have some advantages, such as the freedom from specifying dipole locations a priori, they also have disadvantages, such as their tendency to represent inherently discrete sources as smoother, or more

Figure 29.12. Distributed source analysis of the visual evoked magnetic field and electric potential at 100 ms (M/P100) produced by averaging EEG and MEG data to repeated presentations of a central visual fixation crosshair. A cortically constrained minimum norm solution was used for source reconstruction in this case. This figure is presented in color in the color plate section.

distributed, than they really are in the brain. Nonetheless, source analysis has become relatively commonplace in modern EEG and MEG data processing for research studies. In clinical practice, MEG centers use source analysis to aid presurgical evaluations of epilepsy cases by localization of spikes and eloquent cortex [19].

Independent components analysis Researchers have long known that EEG and MEG, whether spontaneous or evoked, have an underlying component structure that is not always readily apparent to the naked eye. In this chapter, two forms of component structure have already been discussed – the averaged EP/EF (e.g., the P300) and spectral components (e.g., the posterior dominant alpha rhythm). Usually, these components are identified subjectively after time- or spectral-domain averaging or timefrequency analysis. In other words, the clinician or researcher, having some familiarity with the expected form of the data, defines time and/or frequency windows within which to define peaks and troughs of interest. There are, however, objective and automated methods for extracting the underlying component structure of electrophysiological data. One such increasingly popular approach is called independent components analysis (ICA).

469


Figure 29.13. Independent component analysis example. The top three time-series (A-C) are sine waves of different frequencies. The middle six panels (I–VI) are different linear mixtures of those three signals: (I) A+C, (II) A+B+C, (III) .5∗ A+2∗ B, (IV) A-.5∗ B, (V) A-B+2∗ C, (VI) C-B. The bottom three time-series are the first three ICA components derived using the FastICA algorithm [33]. Note that the frequencies are perfectly reconstructed, although the phase is reversed in components one and three from the original. Only three components are returned out of a maximum of six because there were only three original components among the six mixtures.

Independent components analysis is a very powerful method for extracting the underlying component structure of electrophysiological data into statistically independent signals. Statistical independence is a weaker constraint than orthogonality, which constrains the older principle components analysis (PCA) technique. Brain signals from different regions and/or frequencies are often correlated and cannot be extracted using the PCA technique, which has a long history in EEG and MEG analysis. Independent components analysis has shown advantages in that it can return linearly mixed components that exhibit phasereversals in their topography and that can be resolved using single dipole source analysis. Figure 29.13 illustrates the technique used to un-mix three sine wave signals from their appearance in six different mixtures. Figure 29.14 illustrates the use of ICA in extracting signals of interest and artifacts in a real MEG dataset from a patient with temporal lobe epilepsy. Independent components analysis has become very widely employed for not only the extraction of signals

470

of interest, but in artifact removal from EEG and MEG datasets. Since the signals and noise (i.e., artifacts) are linearly mixed, ICA can un-mix them – then one simply remixes all of the extracted components minus the artifactual ones. In this manner, for example, trials containing large eye-movements in EEG EP experiments can be retained, rather than rejected, from the time-domain averaged EP [20, 21]. Another exciting application of ICA is in the analysis of single-trials, since with properly extracted components that are separated from noise, there is little need for signal averaging [22, 23].

Connectivity A valid measure of connectivity between regions of the brain engaged in the same cognitive process or behavior is among the most highly prized uses of EEG and MEG data. Although the brain is currently conceived as a highly interconnected series of networks, it has been technically difficult to develop measures


Figure 29.14. Independent component analysis of a 248-channel MEG dataset from a child with medial temporal lobe epilepsy. The first 20 (of 248) ICA components are illustrated (top: waveforms; bottom: topography). Component 14 shows a spike at approximately 232 seconds from the initiation of recording. The spike shows a dipole-like phase-reversal over the left temporal cortex in the topography. Follow-on source analysis revealed a hippocampal origin. Also of interest are component 16, which reflects eyeblinks, and component 19, a magnetocardiographic artifact (note the broad phase-reversal over the left and right sensors reflecting a very distant source). A significant amount of slowing in the MEG record (mixed delta/theta) is also seen in the first 10 components. Color scale: reds are positive and blues negative component values. This figure is presented in color in the color plate section.

that tap into the coordinated activity of networks over long distances. Short-range connectivity (less than a centimeter or two) is already reflected to some extent in such EEG measures as amplitude and power, because the non-invasive measurement using sensors with finite sensitivity and density requires the summation of large numbers of temporally coordinated, or synchronous, neurons. Long-range connectivity, for example between occipital and frontal regions

of the brain, cannot be as easily measured in terms of summated activity at single sensors. Information from multiple sensors or sources must be integrated somehow for such analyses. Traditional EEG long-range connectivity analysis is accomplished via calculation of coherence between pairs of EEG channels (or coils, for MEG). Coherence is essentially a cross-correlation type of measure between the spectra of two channels

471


(see Table 29.1). Coherence taken this way is problematic for two reasons: (1) it is well known that volume conduction from a single brain source can induce coherence between even widely spaced electrodes in EEG [1] and (2) traditional coherence estimates reflect both the correlation between amplitudes of the two sensors as well as the correlation between their phases. This last point holds true for MEG calculations as well, which are not influenced by volume conduction. It is the phase relationship between two sensors (i.e., coupled oscillations) that is most reflective of joint processing. For this reason, more modern analyses compute the cross-coherence of phase between sensors [24], typically derived from time-frequency analytic methods, although such phase-only coherence measures do not resolve the problems of EEG volume conduction and field spread in MEG. Volume conduction artificially inflates all coherence estimates at even moderately large inter-electrode distances (e.g., ∼10 cm). To reduce this effect, spatial filtering of the sensor data to increase the spatial resolution is recommended using techniques such as the surface Laplacian (also known as current source density), which requires a higher density of sensors (⬎ 64) than traditional clinical EEG typically employs [25]. Another approach is to conduct coherence analysis within source-, rather than sensor-space which also necessitates a higher initial spatial sampling than is acquired with typical clinical EEG montages [26]. Ultimately, measures of correlation, coherence, and phase-synchrony between EEG channels, independent components, and/or sources can only tell us the strength of an interaction, presumably between two or more regions in a network. Such metrics do not provide us with any information about the direction of information flow (i.e., correlation does not equal causation). Statistical measures that attempt to address this causality issue have been developed and are increasingly applied to EEG and MEG data. Two very popular methods for doing this type of analysis are Granger causality [27] and Dynamic Causal Modeling (DCM) [28]. Granger causality is reasonably simple to understand in the following manner: if event X causes event Y, then (a) it precedes Y and (b) past instances of X and Y predict the presence of Y better than past instances of Y alone. X and Y could be signals in two different sensors or from two or more sources. Several EEG and MEG papers have now included Granger causality in their analytic approach [29, 30]. DCM differs from Granger causality in at least

472

one important way – in DCM one must specify an explicit model of how the observed data in the EEG or MEG were caused [31]. DCM is a popular approach in analyzing causal models in functional magnetic resonance imaging studies and has been recently extended to evoked responses derived from MEG and EEG [32].

Conclusion More information is available in the EEG or MEG signal than is typically considered in routine clinical practice. These rich, additional data are currently not yet ready for clinical practice and are restricted to research purposes, although spectral analyses, qEEG/qMEG and source analyses are making significant inroads into advanced interpretation of electrophysiological data from patients with epilepsy, dementia, and other conditions. The next decade of EEG/MEG clinical practice will see the incorporation of more sophisticated techniques into the clinical armamentarium, allowing a more nuanced and accurate interpretation of the brain in health and disease.

Acknowledgments Funding for this effort was provided by US Public Health Service grant 1-R01-MH81920 (Rojas). The author thanks Mr. Dan Collins for his assistance with data collection and analysis related to this manuscript.

References 1. Nunez PL, Srinivasan R. Electric Fields of the Brain: The Neurophysics of EEG. 2nd edition. Oxford: Oxford University Press; 2006. 2. Tatum WO, Husain A, Benbadis S, Kaplan P. Handbook of EEG Interpretation. 1st edition. New York, NY: Demos Medical Publishing; 2007. 3. Papanicolaou AC. Clinical Magnetoencephalography and Magnetic Source Imaging. Cambridge: Cambridge University Press; 2009. ¨ 4. Berger H. Uber das Elektroenkephalogramm des Menschen. Arch Psychiatrie Nervenkrankh. 1929;87: 527–70. 5. Duffy FH. Brain electrical activity mapping (BEAM): computerized access to complex brain function. Int J Neurosci. 1981;13(1):55–65. 6. Thakor NV, Tong S. Advances in quantitative electroencephalogram analysis methods. Annu Rev Biomed Eng. 2004;6:453–95.


7. Pfurtscheller G, Stancak A, Jr., Neuper C. Event-related synchronization (ERS) in the alpha band – an electrophysiological correlate of cortical idling: a review. Int J Psychophysiol. 1996;24(1–2):39–46. 8. Klimesch W, Sauseng P, Hanslmayr S. EEG alpha oscillations: the inhibition-timing hypothesis. Brain Res Rev. 2007;53(1):63–88. 9. Jelic V, Kowalski J. Evidence-based evaluation of diagnostic accuracy of resting EEG in dementia and mild cognitive impairment. Clin EEG Neurosci. 2009; 40(2):129–42. 10. Nuwer MR, Hovda DA, Schrader LM, Vespa PM. Routine and quantitative EEG in mild traumatic brain injury. Clin Neurophysiol. 2005;116(9):2001–25. 11. Snyder SM, Hall JR. A meta-analysis of quantitative EEG power associated with attention-deficit hyperactivity disorder. J Clin Neurophysiol. 2006;23(5): 440–55. 12. Nuwer M. Assessment of digital EEG, quantitative EEG, and EEG brain mapping: report of the American Academy of Neurology and the American Clinical Neurophysiology Society. Neurology 1997;49(1): 277–92. 13. Coburn KL, Lauterbach EC, Boutros NN et al. The value of quantitative electroencephalography in clinical psychiatry: a report by the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2006; 18(4):460–500. 14. Makeig S, Debener S, Onton J, Delorme A. Mining event-related brain dynamics. Trends Cogn Sci. 2004; 8(5):204–10. 15. David O, Kilner JM, Friston KJ. Mechanisms of evoked and induced responses in MEG/EEG. Neuroimage 2006;31(4):1580–91. 16. Sauseng P, Klimesch W, Gruber WR et al. Are event-related potential components generated by phase resetting of brain oscillations? A critical discussion. Neuroscience 2007;146(4): 1435–44. 17. Barry RJ. Evoked activity and EEG phase resetting in the genesis of auditory Go/NoGo ERPs. Biol Psychol. 2009;80(3):292–9. 18. Grech R, Cassar T, Muscat J et al. Review on solving the inverse problem in EEG source analysis. J Neuroeng Rehabil. 2008;5:25. 19. Lopes Silva F. What is magnetoencephalography and why it is relevant to neurosurgery? In Pickard J, Akalan N, Rocco C et al., editors. Advances and Technical Standards in Neurosurgery. Vienna: Springer; 2005, pp. 51–67.

20. Li R, Principe JC. Blinking artifact removal in cognitive EEG data using ICA. Conf Proc IEEE Eng Med Biol Soc. 2006;1:5273–6. 21. Dammers J, Schiek M, Boers F et al. Integration of amplitude and phase statistics for complete artifact removal in independent components of neuromagnetic recordings. IEEE Trans Biomed Eng. 2008;55(10):2353–62. 22. Lee PL, Wu YT, Chen LF et al. ICA-based spatiotemporal approach for single-trial analysis of postmovement MEG beta synchronization. Neuroimage 2003;20(4):2010–30. 23. Iyer D, Zouridakis G. Single-trial analysis of the auditory N100 improves separation of normal and schizophrenia subjects. Conf Proc IEEE Eng Med Biol Soc. 2008;2008:3840–3. 24. Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods. 2004;134(1):9–21. 25. Srinivasan R, Nunez PL, Tucker DM, Silberstein RB, Cadusch PJ. Spatial sampling and filtering of EEG with spline laplacians to estimate cortical potentials. Brain Topogr. 1996;8(4):355–66. 26. Hoechstetter K, Bornfleth H, Weckesser D et al. BESA source coherence: a new method to study cortical oscillatory coupling. Brain Topogr. 2004;16(4):233–8. 27. Granger CWJ. Investigating causal relations by econometric models and cross-spectral methods. Econometrica 1969;37(3):424–38. 28. Friston KJ, Harrison L, Penny W. Dynamic causal modelling. Neuroimage 2003;19(4):1273–302. 29. Zhang Y, Chen Y, Bressler SL, Ding M. Response preparation and inhibition: the role of the cortical sensorimotor beta rhythm. Neuroscience 2008;156(1):238–46. 30. Gow DW, Jr., Segawa JA, Ahlfors SP, Lin FH. Lexical influences on speech perception: a Granger causality analysis of MEG and EEG source estimates. Neuroimage 2008;43(3):614–23. 31. Friston K. Dynamic causal modeling and Granger causality. Comments on: The identification of interacting networks in the brain using fMRI: model selection, causality and deconvolution. Neuroimage 2011;58(2):303–5. 32. Kiebel SJ, Garrido MI, Moran R, Chen CC, Friston KJ. Dynamic causal modeling for EEG and MEG. Hum Brain Mapp. 2009;30(6):1866–76. 33. Hyvärinen A. Fast and robust fixed-point algorithms for independent component analysis. IEEE Trans Neural Netw. 1999;10(3):626–34.

473

Section II


Chapter

Neurotoxicology

30

Christopher M. Filley

The potential harm to the nervous system or other bodily structures from toxic substances is a common source of concern for patients and clinicians alike, and carries with it a variety of public policy implications. Individuals with obvious or putative toxic exposure often seek medical attention – and frequently legal recourse – for their ailments, while public anxiety about actual or potential exposure to toxic substances can reach epidemic proportions with far-reaching social and political ramifications. As recent world history documents, apprehension about the development of weapons with the potential to wreak havoc among millions because of toxic exposure has been proffered as a prime justification for a multiyear, multinational military conflict. The field of toxicology is vast and far from well understood, and encompasses the deleterious clinical impact of thousands of synthetic substances and natural products. As such, the issues arising from the practice of toxicology implicate not just the medical profession but also extend to epidemiology, industrial hygiene, regulatory agencies, economics, the legal profession, and the military. For subspecialists in Behavioral Neurology & Neuropsychiatry (BN&NP), the most relevant aspects of the field involve the assessment and care of individuals with complaints suggesting toxic nervous system injury, and this process, while often perplexing, offers many instructive insights into normal nervous system structure and function. The effects of toxic agents on the nervous system are particularly challenging because of the unique complexity of neural tissue. More than 450 substances have been identified as having the potential to produce toxic effects on the central (CNS) or peripheral nervous system (PNS), and even water may be neurotoxic if excessive ingestion leads to hyponatremia and seizures [1].

Despite the clear hazards associated with these toxins, much uncertainty persists in this field because many individuals present with symptoms suggesting neurotoxic exposure that cannot be clearly linked with any toxin. This chapter will introduce neurotoxicology, which includes an impressive range of toxins that target the nervous system. An overview of the discipline as a whole will serve to illustrate principles that apply to any neurotoxic disorder encountered in the practice of BN&NP, and, in particular, the field of neurobehavioral toxicology will be emphasized as the division of neurotoxicology concerned with the cognitive and emotional sequelae of toxic brain dysfunction.

Principles of neurotoxicology Neurotoxicology can be considered the science dealing with the adverse effects of naturally occurring or synthetic agents on the structure and function of the nervous system. A neurotoxin, therefore, is an agent of this type that exerts a detrimental structural or functional change in nervous tissue. A host of neural regions can be damaged by neurotoxins, but the most clinically relevant sites are the cerebral cortex, cerebral white matter, basal ganglia, cerebellum, cranial nerves, spinal cord, peripheral nerves, neuromuscular junction, and muscles. Table 30.1 gives prominent examples of agents that may harm each of these regions. The range of pathophysiological mechanisms is extremely broad [1], and one agent can damage many different regions; alcohol, for example, is familiar to clinicians as a neurotoxin with multiple CNS and PNS effects. The nervous system has unique features that render it vulnerable to toxic insults [1–4]. The exceptional complexity of the CNS and PNS implies that many


474

Chapter 30: Neurotoxicology

Table 30.1. Nervous system regions and examples of agents that are toxic to these regions.

Nervous system region

Regionally specific neurotoxins

Cerebral cortex

Lead Mercury Penicillin

Cerebral white matter

Toluene Radiation Methotrexate Carmustine

Basal ganglia

Chlorpromazine Haloperidol L-dopa Manganese

Cerebellum

Alcohol Phenytoin Mercury

Cranial nerves

Tobacco (CN I) Methanol (CN II) Trichloroethylene (CN V) Aminoglycoside antibiotics (CN VIII)

Spinal cord

Tetanospasmin ␤-oxalyl-L-␣,␤-diaminopropionic acid (Lathyrus sativus toxin) Heroin Nitrous oxide

Peripheral nerves

Vincristine Cisplatin Diphtheria toxin n-Hexane

Neuromuscular junction

Organophosphates Botulinum toxin Tick saliva

Muscles

Corticosteroids Simvastatin Clofibrate

sites of injury are possible, including neurons, glial cells, blood vessels, and muscles [1]. Neurons are at special risk because they are post-mitotic cells with high metabolic demand that can be injured by many potential mechanisms and which have limited restorative capacity. Moreover, neurons with long processes offer many target sites for neurotoxins, as damage can occur at the level of the cell body, dendrites, axon, myelin sheath, and terminal synapse [3]. Neurotoxins may interfere with nucleic acid and protein synthesis, mitochondrial metabolism, membrane stability, axonal transport, and neurotransmitter function [4]. Glial cells (astrocytes, oligodendrocytes, ependymal cells, and Schwann cells) can also be damaged by various toxins [4], and blood vessels are particularly

vulnerable to radiation injury [2]. While the blood– brain, blood–cerebrospinal fluid, and blood–nerve barriers may protect against the entry of chemical compounds that are hydrophilic or of large molecular weight, other agents such as lipophilic solvents and radiation can readily gain access, and there are areas of the CNS (e.g., the hypothalamus) and the PNS (e.g., motor and sensory nerve terminals) that are not protected by any barrier [3]. Neurotoxins may thus exert many adverse effects on the normal structure and function of the nervous system; this assault is nowhere more injurious than in the brain, where disruption of widespread distributed neural networks interferes with the intricate systems by which cognition, emotion, and behavior are organized. Other factors influence the effect of toxins on the nervous system. As the liver and kidneys are the main routes of toxin elimination, individuals with hepatic or renal impairment may experience proportionally greater neurotoxicity. Age is another important variable: the very young are vulnerable because neural tissue and its protecting barriers have not fully developed, and the very old because of age-related neuronal loss or dysfunction and diminished systemic clearance of neurotoxins [3]. Gender, on the other hand, appears to exert little effect on risk of neurotoxicity. Genetic factors play a role in some cases; individuals with hereditary neuropathy, for example, display enhanced vulnerability to agents capable of inducing peripheral neuropathy, and genetic polymorphisms may exert important effects on the hepatic biotransformation of potential neurotoxins [1]. In general, individuals with virtually any systemic illness are at higher risk because of both disease(s) and prescribed treatments that may markedly complicate the metabolic environment and potentiate neurotoxicity [5]. Neurotoxins may reach the nervous system by ingestion through the gastrointestinal tract, inhalation, transdermal absorption, intravenous administration, or via external radiation [6]. One of the cardinal features of neurotoxicology is a strong dose–response relationship, such that a given clinical neurotoxic profile occurs consistently in a pattern that is commensurate with the dose and duration of neurotoxin exposure [7]. In most cases, therefore, the clinical syndrome is closely related in time to the exposure, and symptoms appearing much later should raise clinical suspicion of alternative etiologies for patient complaints. A corollary of this principle is that the notion of “delayed” neurotoxicity – often invoked to explain

475


Box 30.1. Human neurotoxins: therapeutic agents.

Box 30.2. Human neurotoxins: drugs of abuse.

Barbiturates Benzodiazepines Other sedative-hypnotics Narcotics Neuroleptics Anticholinergic agents Antiepileptic drugs Antihypertensive agents Cardiac drugs H2 receptor antagonists Corticosteroids Non-steroidal anti-inflammatory drugs Antibiotics Antineoplastic drugs Immunosuppressive drugs Radiation

Ethanol Ethanol substitutes Methanol Ethylene glycol Isopropanol Cocaine Opiates Amphetamine Dextroamphetamine Methamphetamine Ephedrine Pseudoephedrine Phenylpropanolamine 3,4-methylenedioxymethamphetamine (“Ecstasy”) Lysergic acid diethylamide (LSD, or “Acid”) Psilocybin Mescaline

symptoms beginning far beyond the point of exposure – is typically on the order of days or weeks rather than years [7, 8]. Another key point is that idiosyncratic responses to neurotoxins are uncommon since most neurotoxins exert a direct pathogenetic effect on selected neural tissues and immunotoxic injury is rare [7]. Allergic reactions to neurotoxins are far less likely than dose-related effects on target regions, a phenomenon that explains why well-documented cases of idiosyncratic reactions to neurotoxins are unusual. The condition of “multiple chemical sensitivity” syndrome, for example, has not been established as a neurotoxic disorder despite much concern and publicity [7, 9].

Neurotoxins Given the large number of known and potential neurotoxins, a specific account of each is beyond the scope of this book. In this section, an overview of the major classes of neurotoxins will be provided, along with a consideration of selected agents that help illustrate common themes in neurotoxicology. More detail on the specific biological characteristics can be found in other sources [1, 2, 5, 6]. From a clinical perspective, three major categories of neurotoxic agents can be usefully considered: therapeutic agents (Box 30.1), drugs of abuse (Box 30.2), and environmental toxins (Table 30.2). The most common source of neurotoxicity in North America is in fact iatrogenic administration of medical therapy

476

Phencyclidine (PCP, “Angel Dust”) Marijuana Toluene Xylene Benzene Acetone Trichloroethane Trichloroethylene Carbon tetrachloride Methylene chloride Hydrogen sulfide Carbon disulfide N-hexane Methyl-n-butyl-ketone Gasoline Nitrous oxide Amyl nitrate Butyl nitrite Isobutyl nitrite

[1, 7, 8], and the agents in Box 30.1 are often culpable. Accidental and suicidal exposures to these agents are also regularly encountered. An impressive array of medications used in medical, neurologic, psychiatric, and surgical practice has the potential for neurotoxicity. Drugs can have diffuse effects on both the CNS and PNS, as with podophyllin [10], or confine their effects only to muscle, as is the case with statins [11]. Acute confusional state is the most common manifestation of medication-related neurotoxicity in hospital settings. Often in the setting of substance abuse, systemic infection with fever, or the post-operative period, the appearance of an acute confusional state plausibly related to the administration of drug therapy is a frequent occurrence in a general hospital and is commonplace in emergency rooms and outpatient clinics as well [2, 3]. While these observations are sobering, and serve to remind clinicians of the potential for adverse neurologic effects in many clinical settings, some perspective can be gained by recalling that patients treated with these medications are often very ill older patients with life-threatening diseases who may have multiple coexisting disorders, a long list of other prescribed medications, and impaired hepatic and renal metabolism. Thus, accurate diagnosis, selection of the minimal number and doses of medications,


Table 30.2. Human neurotoxins: environmental agents.

Class

Examples

Solvents

Toluene Benzene Xylene Styrene Trichloroethane Trichloroethylene Methylene chloride Hydrogen sulfide Carbon disulfide N-hexane Methyl-n-butyl-ketone Methanol

Gases

Carbon monoxide Carbon dioxide Nitric oxide Propylene gas

Heavy metals

Lead Arsenic Mercury Manganese Aluminum

Biological toxins

Tetanus toxin Botulinum toxin Diphtheria toxin Ergot alkaloids Mojave toxin (rattlesnake venom) Scorpion toxin Latrotoxin (black widow spider venom) ␤-oxalyl-L-␣,␤-diaminopropionic acid (Lathyrus sativus toxin) Amanita toxins Ciguatoxin Tetrodotoxin

Pesticides

Organophosphates (including triorthocresyl phosphate, sarin, soman, tabun, and VX gases) Carbamates

frequent monitoring, and close follow-up are essential to treat patients effectively while minimizing potential neurotoxicity. Clinical experience teaches that one of the most rewarding aspects of managing patients with complex, multisystem medical disorders is the recognition of medication toxicity and alleviation of symptoms by simple dose reduction or drug withdrawal. Drugs of abuse constitute another important source of neurotoxic syndromes [12]. The partial list of abused drugs shown in Box 30.2 testifies to the magnitude of the problem. The intended purpose of drug abuse is alteration of consciousness through a transient effect on the brain, but paradoxically, the result is often a toxic disorder of the brain or PNS that ranges from mild and reversible to devastating and

permanent. Encephalopathy is one of the most prominent syndromes associated with substance abuse, and may occur either acutely from the effects of intoxication or withdrawal, or chronically as a dementia syndrome that develops over time and with repeated abuse [6]. In addition, a host of other problems can be seen with drug abuse, including seizures, stroke, psychosis, movement disorders, cranial nerve involvement, cerebellar dysfunction, myelopathy, peripheral neuropathy, and myopathy. Drug abuse is an enormous and seemingly intractable societal problem, and an urgent need exists for better understanding of the neurotoxic effects of alcohol, cocaine, opiates, amphetamines including methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA, colloquially known as Ecstasy, XTC, or X), hallucinogens, phencyclidine, marijuana, and inhalants [12]. The effects of these drugs of abuse on the nervous system are not completely understood because abusers often take more than one drug simultaneously, legal issues complicate research on many drugs, and postmortem studies of the brain are relatively infrequent [12]. Alcohol abuse, however, can serve as a prototype for all these intoxications, as its many effects on the nervous system are reasonably well documented [12– 15] and have much in common with other drug abuse scenarios. Ethanol clearly produces an acute confusional state during the period of inebriation, and this syndrome may also develop during the withdrawal phase when a symptomatic seizure produces postictal confusion or delirium tremens appears after several days [12]. In the chronic phase of alcoholism, cerebellar ataxia and peripheral neuropathy are well recognized, and cognitive changes are also common [12–15]. One of the many unresolved controversies in neurotoxicology – one that illustrates the difficulty in conducting clinical research with these patients – is whether ethanol produces a direct toxic effect on the brain that leads to alcoholic dementia [12], or whether the cognitive disorder of alcoholics can be entirely attributed to the thiamine deficiency known to cause the Wernicke–Korsakoff syndrome [14, 15]. The problem is complicated by other brain insults to which alcoholics are susceptible, including traumatic brain injury, metabolic encephalopathy related to hepatic disease, and other substance abuse. Environmental agents can also prove toxic to the nervous system (Table 30.2). A wide spectrum of agents encountered in everyday life and used in

477


industry, agriculture, and warfare can be neurotoxic to the PNS, CNS, or both. Organic solvents are common in industry and the household, and some have clearly defined neurotoxicity, as in the case of n-hexane and methyl-n-butyl-ketone causing peripheral neuropathy [1]. Other solvents are capable of CNS damage, including toluene if the exposure is intense and prolonged, as in inhalant abusers [16, 17]. However, despite much alarm generated from Scandinavian studies purporting to show a “painters’ syndrome” related to occupational solvent exposure, no solid evidence exists for encephalopathy related to low-level exposure to solvents such as toluene, benzene, xylene, and mixed solvents [5, 9]. Carbon monoxide poisoning occurs accidentally or in the context of suicide attempt, and may produce a variety of syndromes, including acute encephalopathy, persistent dementia, or post-anoxic demyelination [2]. Heavy metal poisoning can be suspected in those at risk, such as workers in the chemical industry, and can be readily diagnosed with a clear acute exposure history; chronic exposure, however, presents more difficulty. Nearly all metals are neurotoxic, but the most commonly encountered in clinical settings are lead, arsenic, and mercury. Lead poisoning has attracted the most attention because of lasting public health considerations. Plumbism is rare in adults, in whom peripheral neuropathy is most likely [1], but in children, encephalopathy may develop and produce a host of cognitive and behavioral problems, or even a fatal outcome [2]. Economically disadvantaged children in older inner cities are most susceptible to lead encephalopathy because of exposure to leaded paint that still exists in millions of houses built in the twentieth century, and even very low levels of lead can be hazardous [18]. A number of biological neurotoxins also exist (Table 30.2); these toxins, which may be extremely potent, typically exert their primary effects on motor function by interfering with spinal cord or PNS function [2]. Pesticides (organophosphates, carbamates) are anticholinesterase agents widely used around the world for insect control, and organophosphate poisoning is a major health problem in developing countries [1]. The majority of cases of organophosphate poisoning result from suicide attempt, and most occur in the developing world where these compounds are widely used in public health programs to control vector-borne tropical infectious diseases [1]. Highly toxic organophosphates such as sarin,

478

soman, and tabun have been available as agents of chemical warfare (“nerve gas”) since the 1930s, and were employed by Iraq in its war with Iran in 1984 and by the Japanese religious cult Aum Shinrikio in 1994 [19]. The perceived threat of chemical warfare with these compounds was used to help justify the US invasion of Iraq in 2003 [20]. Organophosphate agents produce an acute, potentially life-threatening cholinergic crisis, and sometimes a delayed peripheral neuropathy 2–4 weeks after intoxication [20]. Long-term neurobehavioral effects as a result of organophosphate toxicity have been controversial, although hypoxic encephalopathy is recognized as a sequel of respiratory depression [1, 19].

Diagnosis The most important procedure for determining the presence of neurotoxic disease is the clinical history. More than any scan or test, a detailed, critically considered history of the possible exposure and the resultant clinical features is the sine qua non of the diagnostic process. The primary goal of the history is to establish whether or not clinical symptoms can plausibly be related to putative neurotoxin exposure. A guiding principle in this task is that most neurotoxins exhibit a convincing dose–response relationship, such that significant exposure to a given neurotoxin will lead to a consistent pattern of similar nervous system dysfunction or damage in most individuals [1]. Key elements of the history include the nature of the symptoms, documentation of the exposure and any quantitative data that may be available, the proximity of the exposure to neurotoxic clinical features, the response to toxin removal, the presence of coexisting medical, neurologic, or psychiatric disorders, the family history, and the occupational status of the patient. Intentional exposure for recreational purposes or as a suicide attempt must be kept in mind. Any previous clinical, laboratory, neuropsychological, or neuroimaging information is often helpful in conjunction with the history. This encounter is often highly time-consuming, colored as it may be by a plethora of vague and non-specific complaints (such as headache, fatigue, lassitude, malaise, dizziness, inattention, memory loss, dysphoria), and the common occurrence of multiple competing etiologies for symptoms such as unrelated illness, medication use, alcohol or other substance abuse, psychiatric disease, and litigation. A general familiarity with the clinical patterns


produced by neurotoxins helps the examiner determine whether or not the patient’s complaints signify a meaningful neurotoxic syndrome. The neurologic examination, including a detailed mental status examination in those who express cognitive or emotional complaints, is also crucial. The examination may disclose acute encephalopathy, dementia, psychiatric disease, cranial neuropathies, movement disorders, ataxia, spinal cord dysfunction, peripheral neuropathy, or muscle disease. Another important dictum is that neurotoxic disease is typically diffuse in its effects [1, 7]. Thus neurologic signs in affected patients are likely to be non-focal and symmetric, in a manner that mimics metabolic, degenerative, nutritional, and diffuse demyelinative diseases [1, 7]. Elicitation of focal neurologic signs should therefore raise the suspicion of other etiologies such as stroke or traumatic brain injury. The neurologic examination can often be usefully augmented by procedures such as neuropsychological testing, electroencephalography (EEG), nerve conduction studies and electromyography (NCS/EMG), blood, urine, and cerebrospinal fluid testing, and neuroimaging. Neuropsychological testing is a highly sensitive indicator of cognitive function that offers much information about the degree and pattern of impairment, if any, and the possible contribution of emotional and psychiatric factors [20]. Standard neuropsychological assessment has been widely employed for neurotoxicological evaluations, although computerized batteries have gained some popularity; the Cambridge Neuropsychological Test Automated Battery (CANTAB) [21], for example, has been given to experimental animals (monkeys) as well as human subjects to allow comparison of human cognitive dysfunction with animal models of neurotoxicity [22]. It is well to remember that, while neuropsychological assessment is indeed very sensitive, the testing is not particularly specific to the exact etiology, and interpretation of the findings in light of the complete clinical picture is critical. Electroencephalography is most useful for detecting slowing of the background activity, which suggests diffuse cerebral dysfunction from a host of etiologies; some patients will occasionally be found to have epileptiform activity, which implies a focal area of cortical injury but does not identify the cause. Nerve conduction and electromyography studies are reliable measures of peripheral nerve and muscle function, but again are not specific for a given toxic or other problem.

Laboratory testing, in general, is of more utility in the setting of acute intoxication than in the chronic phase of putative neurotoxicity. This dictum holds because laboratory tests can often detect the toxin while it is in the body, but not as well later on after much elimination has occurred. To illustrate how prompt testing can assist clinically, blood levels of anticonvulsant drugs, urinary screens for illicit substances, blood lead level, carboxyhemoglobin level for carbon monoxide poisoning, and red blood cell acetylcholinesterase inhibition for organophosphate poisoning can all be helpful for documenting acute intoxication. For those patients presenting beyond the point of intoxication, however, diagnosis can be challenging because laboratory tests do not exist for measuring the body burden of many neurotoxins, and because the patient is typically seen well beyond the point of exposure and the toxin has been eliminated from the body [7]. An exception to this rule is 24-hour urinary screening for lead, mercury, arsenic, and other heavy metals. Laboratory tests can also be helpful in cases where the discovery of an unrelated medical disorder (e.g., diabetes mellitus) may help explain some, or all, of the patient’s presenting complaints. Examination of the cerebrospinal fluid after lumbar puncture is rarely indicated in neurotoxicity evaluations unless the clinical presentation suggests the possibility of an unrelated process such as a nervous system infectious or inflammatory disease. Neuroimaging of the brain, both structural and functional, has had a dramatic impact on BN&NP for the past three decades, but its utility in the diagnosis of neurotoxic disorders must still be regarded as limited [23]. Structural neuroimaging began in the 1970s with computed tomography (CT), and whereas CT can disclose brain atrophy and many focal structural lesions, the depiction of brain neuroanatomy is not ideal. The more recent magnetic resonance imaging (MRI) has largely superseded CT as a structural neuroimaging technique because it is much more capable of delineating details of neuroanatomy and neuropathology. The cerebral white matter is especially well seen by MRI, and this advance has led to the recognition of a host of leukotoxic disorders that can readily be seen by routine MRI [24]. The depiction of toxic leukoencephalopathy by MRI is the notable exception to the rule that neuroimaging is not helpful in the diagnosis of brain neurotoxic disorders. Functional imaging techniques, including single-photon emission computed tomography (SPECT), positron emission

479


tomography (PET), and functional MRI (fMRI) have not yet been shown to have utility in ruling in or excluding a neurotoxic disorder of the brain [24].

Treatment The treatment of neurotoxic disorders revolves around prevention, removal of the toxin, specific treatment when available, and symptomatic therapy. Prevention of neurotoxic exposure is, of course, crucial when possible, but often the physician only sees the patient after the damage is done. In some cases, early detection of neurotoxicity can influence the clinical course, as in the alcoholic individual who can be advised of the first signs of alcoholic neuropathy and given the opportunity to become abstinent. Much of the area of prevention is more effectively pursued at the level of public health, in which social action can have widespread impact, e.g., the reduction of environmental pollutants such as organic lead in gasoline. Removal of the neurotoxin is a self-evident method of treatment. The most important intervention in neuroleptic malignant syndrome, for example, is prompt withdrawal of the offending neuroleptic drug(s). Such an intervention may be surprisingly difficult, however, in the common clinical setting where a medication is identified as culpable but where withdrawal may be difficult or even hazardous. For example, a chronically medically ill person may manifest clear signs of tardive dyskinesia from long-term neuroleptic use, but the risk of discontinuing the responsible medication is significant because of the potential for exacerbating possible life-threatening psychosis. Clinical judgment is often necessary to assist in such difficult dilemmas. Specific treatment can occasionally be offered, but in routine clinical practice few patients with neurotoxic disorders will prove to have the benefit of a specific antidote. Notable exceptions to this rule include atropine and 2-pralidoxime for the treatment of organophosphate poisoning, and antisera for snake, scorpion, and spider envenomation [1]. More relevant to BN&NP is the rare opportunity to administer dimercaprol and/or penicillamine for chelation after some cases of heavy metal poisoning [1]. Symptomatic therapy is an obvious and important course of action in patients with neurotoxic exposure. Such an approach may be straightforward if all that is needed is watchful waiting while a person regains normal coordination after cerebellar ataxia develops from a high phenytoin level, or complex, as

480

is the patient with delirium tremens who is critically ill and requires mechanical ventilation and vasopressor therapy. Thiamine administration is a routine procedure in those suspected of alcohol abuse to avoid the Wernicke–Korsakoff syndrome [12]. Clearly, all appropriate efforts to ensure as rapid and uncomplicated a recovery as possible are indicated in these cases.

Prognosis The prognosis of neurotoxic disease can be excellent if prompt attention is devoted to the recognition and treatment of the problem by elimination of the source or provision of specific antidotes or other therapy. In patients with lasting clinical dysfunction, the outcome is widely variable, depending on the degree and duration of exposure, age, coexistent neurologic, medical, and psychiatric conditions, and concurrent medications. A useful generalization is that neurotoxic syndromes typically improve following cessation of exposure to the culpable agent. Thus, acute neurotoxic illness evolves over days to weeks, and if symptoms worsen months or years later, another explanation should be sought. Recovery from neurologic intoxication may be prolonged, especially in older individuals with multiple other problems, but if gains are steadily apparent, the likelihood builds that neurotoxic disease has been sustained. Complete recovery is often observed, and implies that the intoxication was mild and brief enough that only transient biochemical and neurophysiological dysfunction occurred and no structural damage took place [1]. This is the case with many patients who have experienced acute confusional state, for example, seen in routine medical practice after excessive – or even appropriate – use of sedative-hypnotic drugs or other centrally active medications. More intense and prolonged exposure can produce more prominent symptoms and signs, and more protracted recovery, often prompting concern about another unrelated neurologic disorder. If the intoxication is sufficiently severe that it produces structural nervous system damage, recovery may be limited or absent, and permanent disability may result.

Neurobehavioral toxicology The most relevant area of neurotoxicology for BN&NP subspecialists is neurobehavioral toxicology. Patients often come to clinical attention after experiencing


known or suspected neurotoxic exposure and manifest a wide range of cognitive or emotional complaints. Whereas it is obvious in some cases what clinical events have transpired, as in a patient with dementia from documented carbon monoxide exposure, the situation is far less clear in a worker who claims to be cognitively impaired after an undocumented exposure to a mixture of solvents in the workplace. Thus, it is often the case that a link between the alleged toxic exposure and the presumed neurobehavioral sequelae cannot be easily established. Recent examples of this phenomenon include the painters’ syndrome (solvent encephalopathy), silicone breast implant neurotoxicity, and Gulf War illnesses [9, 25, 26], in which reconciling public concern with medical and scientific investigation often is challenging. Among individuals who clearly have experienced neurotoxic exposure causing neurobehavioral impairment, two familiar syndromes are generally accepted: acute encephalopathy and dementia. In general, acute encephalopathy is better understood than dementia because it is more common, readily recognizable, and more easily studied as a neurotoxic syndrome [1]. In keeping with the principle that neurotoxic syndromes are maximal at or near the time of intoxication, acute encephalopathy is characterized by a rapidly evolving syndrome that closely follows the exposure event. This syndrome produces the familiar acute confusional state, and most patients manifest a hypoaroused, lethargic presentation rather than an agitated delirium [27]. This acute encephalopathy is most often related to therapeutic drugs [27], and medications are the most common cause of delirium in hospitalized patients [28]. Dementia from neurotoxic exposure is less well documented, since there are many potential etiologies of dementia in addition to the exposure itself, and diagnosis often becomes challenging. For example, a patient with encephalopathy induced by carbon monoxide who makes no significant improvement may have superimposed Alzheimer’s disease (AD) as an alternative or additional explanation for dementia. However, dementia from neurotoxic exposure does occur, and as a general rule, it is more likely if the exposure is extended and prolonged, implying that structural damage supervenes when the exposure duration is sufficiently long [29]. The precise point at which prolonged exposure produces irreversible neuropathological changes is difficult to determine, and acute encephalopathy may blend into dementia

over a protracted period of neurotoxicity [1]. Toxic dementias, once established, typically manifest with features of fronto-subcortical dementia, including cognitive slowing, impaired sustained attention, and executive dysfunction, and some patients may also have extrapyramidal signs such as tremor, asterixis, and myoclonus [29]. Dementia may also appear even before permanent structural damage occurs, and drug-induced dementia is among the most common reversible dementias [27]. A particularly striking example of dementia from neurotoxins is the syndrome of toxic leukoencephalopathy (TL) [24]. Although the majority of neurotoxic disorders of the brain likely target the cortical and/or subcortical gray matter, both acutely [1] and in the chronic phase of dementia [29], an increasing number of white matter toxins have been identified in recent years. A wide variety of medications, cranial irradiation, drugs of abuse, and environmental agents display a predilection for the cerebral white matter, producing a spectrum of severity ranging from mild mental status alterations with subtle white matter changes to coma and death from severe white matter necrosis [24]. This leukotoxic insult is diffuse, symmetric, and highly imagible with MRI [24]. Cranial irradiation may produce notable TL, particularly as it is frequently combined with other leukotoxic drugs such as methotrexate and carmustine in the treatment of cancer [24], and toluene, when heavily abused for a period of years, is well known to produce a devastating dementia that is correlated with the degree of cerebral white matter pathology on MRI [17] and at autopsy [30, 31]. Toxic leukoencephalopathy exemplifies the principle that a dose–response relationship can be established in neurotoxicology that shows a consistent pattern of concurrent neurobehavioral impairment, white matter appearance on neuroimaging, and neuropathological abnormalities [17, 24, 30, 31]. While the neuropathological effects of toluene are clearly diffuse, reflecting widespread cerebral, cerebellar, and brainstem involvement, TL syndrome vividly demonstrates the impact of white matter tract damage in disrupting the distributed neural networks subserving higher brain function. One of the major challenges of clinical neurotoxicology is the confound of psychiatric disease. Whereas this dictum holds throughout all of medicine, neurobehavioral toxicology offers a particularly good example because many of the symptoms of intoxication – including fatigue, lassitude, inattention, poor

481


memory, depression, anxiety – are the same symptoms that can herald the onset of a host of psychiatric disorders. Moreover, a patient with documented neurotoxic exposure producing cognitive deficits is in no way protected from developing coincident psychiatric illness. Therefore the clinician must be especially diligent in identifying the complex interactions of psychiatric distress and measurable neurotoxic disease. Schaumburg and Albers [8] have introduced the concept of pseudoneurotoxic disease to describe the possible scenarios in an individual presenting with neurologic symptoms after exposure to a putative neurotoxin. In this formulation, four conditions may occur, only the first of which represents genuine neurotoxic disease; the other three possibilities are pseudoneurotoxic diseases: (1) the coincident occurrence of an unrelated, naturally occurring disorder of the nervous system, (2) the appearance of a psychogenic illness, or (3) the exacerbation of a preexisting neurologic or psychological disorder [8]. In Type 1 pseudoneurotoxicity, a disease such as multiple sclerosis or AD is misinterpreted as being related to a presumed neurotoxic exposure. In Type 2 pseudoneurotoxicity, a psychiatric disorder such as depression, anxiety, or somatoform disorder is precipitated by trivial exposure to a dangerous substance such as carbon monoxide, and the intoxication can be seen as causing the problem not because of injury to the nervous system but by emotional stress. In Type 3 pseudoneurotoxicity, a pre-existing disease is worsened by the exposure, as in a person with migraine who notes more severe headaches after brief exposure to lowlevel aerosolized hydrocarbon solvents in the workplace. Identification of each of these scenarios is crucial for accurate diagnosis, which then lends to the appropriate treatment of the patient as either having a neurotoxic syndrome or alternatively, some other neurologic or psychiatric illness [8]. The other psychiatric issue that often arises in neurobehavioral toxicology is malingering. Litigation revolving around claims of neurotoxic exposure is commonplace in our society, and there is no doubt that the intentional fabrication or exaggeration of symptoms may occur in cases where financial incentives are involved. Malingering is a difficult clinical problem, and can be suspected when a person seen in a medicolegal context has stress or disability that seems out of proportion to the objective findings of the case, a lack of cooperation with diagnostic and treatment plans, and the presence of antisocial personality [32]. While

482

it is likely that most patients with possible neurotoxicity who prove to have psychological dysfunction – especially those with pseudoneurotoxic disease Type 2 – are not malingerers [8], the prevalence of malingering is not trivial, with a reported rate of 20–40% in patients with financial incentive across a range of disorders including traumatic brain injury, chronic pain, and toxic exposure [33]. In a study of persons with cognitive complaints who claimed exposure to occupational and environmental substances and who had financial incentive, cognitive malingering was found in 40% [33]. The uncertainty inherent in establishing the presence of neurotoxic disease generally is particularly evident in the area of neurobehavioral toxicology, where symptoms can be vague and cause-and-effect relationships unconvincing, and the maintenance of a vigilant clinical attitude is critical for detecting the all too common cases of malingering.

Conclusion Neurotoxicology is an important and growing area of medicine with many implications for BN&NP subspecialists. A working knowledge of the myriad patterns by which toxins may injure the nervous system is crucial for patient care in general because neurotoxicity may involve structural or functional damage to structures ranging from the brain to the skeletal muscle. Most of the syndromes seen in routine practice will be related to licit or illicit drug use, areas familiar to physicians, but some neurointoxications involve unusual environmental or occupational exposures that may pose uncommon diagnostic and treatment challenges. Neurotoxic disorders are undoubtedly common, but pseudoneurotoxic conditions and malingering can also be seen. A careful history is the key to determining the plausibility of whether a neurotoxic exposure has occurred, and valuable information can also be obtained from neurologic examination, neuropsychological testing, EEG, NCS/EMG, laboratory testing, and neuroimaging. While many disabling neurotoxic syndromes involve elemental neurologic deficits, disorders disrupting higher brain function are increasingly encountered, and their complexities will implicate not only BN&NP but also society as a whole. For those intrigued by brain–behavior relationships, neurobehavioral toxicology has revealed new insights by disclosing previously unrecognized syndromes; TL, for example, has elucidated the effects of white


matter toxicity on the operations of distributed neural networks. For the public at large, concern about neurotoxicity is undeniable, and although often exaggerated, it is nonetheless fueled by a body of knowledge documenting neurotoxic disease from many agents. As the sequelae of neurotoxic exposure are better understood and new neurotoxins are identified with further observation and study, the relevance of this field will assuredly expand for physicians and society alike. Neurotoxic disorders, particularly those involving the brain, require a rigorous clinical approach, invoke a variety of public policy concerns, and can help illuminate the organization of cognition, emotion, and behavior.

14. Victor M, Adams RD, Collins GH. The Wernicke–Korsakoff Syndrome and Related Neurologic Disorders Due to Alcoholism and Malnutrition. 2nd edition. Philadelphia, PA: F.A. Davis Co.; 1989.

References

19. Newmark J. Nerve agents. Neurologist 2007;13(1): 20–32.

1. Spencer PS, Schaumburg HH, Ludolph AC. Experimental and Clinical Neurotoxicology. 2nd edition. New York, NY: Oxford University Press; 2000.

15. Victor M. Persistent altered mentation due to ethanol. Neurol Clin. 1993;11(3):639–61. 16. Hormes JT, Filley CM, Rosenberg NL. Neurologic sequelae of chronic solvent vapor abuse. Neurology 1986;36(5):698–702. 17. Filley CM, Heaton RK, Rosenberg NL. White matter dementia in chronic toluene abuse. Neurology 1990;40(3 Pt 1):532–4. 18. Lidsky TI, Schneider JS. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 2003;126(Pt 1):5–19.

20. Lezak MD. Neuropsychological Assessment. 4th edition. Oxford: Oxford University Press; 2004.

2. Ropper AH, Adams RD, Victor M, Brown RH. Adams and Victor’s Principles of Neurology. 8th edition. New York, NY: McGraw-Hill; 2005.

21. Robbins TW, James M, Owen AM et al. Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 1994;5(5): 266–81.

3. Harris JB, Blain PG. Neurotoxicology: what the neurologist needs to know. J Neurol Neurosurg Psychiatry 2004;75(Suppl. 3):iii29–34.

22. Fray PJ, Robbins TW. CANTAB battery: proposed utility in neurotoxicology. Neurotoxicol Teratol. 1996; 18(4):499–504.

4. Schaumburg HH, Spencer PS. Classification of neurotoxic responses based on vulnerability of cellular sites. Neurol Clin. 2000;18(3):517–24.

23. Frey KA. Neuroimaging in neurotoxicology. Neurol Clin. 2000;18(3):615–29.

5. Rosenberg NL. Occupational and Environmental Neurology. Boston, MA: Butterworth-Heinemann; 1995. 6. Sullivan JB, Krieger GR. Clinical Environmental Health and Toxic Exposures. 2nd edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2001. 7. Schaumburg HH, Spencer PS. Recognizing neurotoxic disease. Neurology 1987;37(2):276–8.

24. Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N Engl J Med. 2001;345(6): 425–32. 25. Research Advisory Committee on Gulf War Veterans’ Illnesses. Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations. Washington, DC: US Government Printing Office; 2008.

8. Schaumburg HH, Albers JW. Pseudoneurotoxic disease. Neurology 2005;65(1):22–6.

26. Blanchard MS, Eisen SA, Alpern R et al. Chronic multisymptom illness complex in Gulf War I veterans 10 years later. Am J Epidemiol. 2006;163(1):66–75.

9. Albers JW, Berent S. Controversies in neurotoxicology: current status. Neurol Clin. 2000;18(3):741–64.

27. Meador KJ. Cognitive side effects of medications. Neurol Clin. 1998;16(1):141–55.

10. Filley CM, Graff-Richard NR, Lacy JR, Heitner MA, Earnest MP. Neurologic manifestations of podophyllin toxicity. Neurology 1982;32(3):308–11. 11. Dalakas MC. Inflammatory and toxic myopathies. Curr Opin Neurol Neurosurg. 1992;5(5):645–54. 12. Brust JCM. Neurological Aspects of Substance Abuse. Boston, MA: Butterworth-Heinemann; 1993. 13. Brust JC. Acute neurologic complications of drug and alcohol abuse. Neurol Clin. 1998;16(2):503–19.

28. Chan D, Brennan NJ. Delirium: making the diagnosis, improving the prognosis. Geriatrics 1999;54(3):28–30. 29. Mendez MF, Cummings JL. Dementia: A Clinical Approach. 3rd edition. Philadelphia, PA: Butterworth-Heinemann; 2003. 30. Rosenberg NL, Kleinschmidt-DeMasters BK, Davis KA et al. Toluene abuse causes diffuse central nervous system white matter changes. Ann Neurol. 1988;23(6): 611–14.

483


31. Filley CM, Halliday W, Kleinschmidt-DeMasters BK. The effects of toluene on the central nervous system. J Neuropathol Exp Neurol. 2004;63(1):1–12. 32. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision: DSM–IV–TR.

484

Washington, DC: American Psychiatric Association; 2000. 33. Greve KW, Bianchini KJ, Black FW et al. The prevalence of cognitive malingering in persons reporting exposure to occupational and environmental substances. Neurotoxicology 2006;27(6):940–50.

Section II


Chapter

Neuropathological assessment

31

B. K. Kleinschmidt-DeMasters, Katherine L. Howard, Steven G. Ojemann, and Christopher M. Filley

Neuropathology is the division of pathology devoted to the study of diseases of the nervous system. In the brain, a host of diseases can produce pathology that can be acute or chronic, congenital or acquired, focal or diffuse, benign or malignant. In many cases, it is only through neuropathological examination that a complex case becomes understood, and neuropathology remains the gold standard for accurate diagnosis of structural brain disease. As in medicine and neurology generally, neuropathology fulfills three important roles in Behavioral Neurology & Neuropsychiatry (BN&NP). First, neuropathological examination can provide a definitive diagnosis by direct tissue examination either after brain biopsy or at autopsy. Second, neuropathology can provide the basis for direct correlation of the clinical presentation with the site and nature of the pathological lesion, thus advancing the understanding of brain–behavior relationships. Third, advancing the science upon which the diagnosis and treatment of persons with neurobehavioral disorders is predicated relies upon insights development through neuropathological study. Despite advances in clinical assessment and neuroimaging, neuropathological assessment remains the only definitive means by which to diagnose many of the conditions seen in BN&NP. In this chapter, a series of three cases is presented to illustrate the role of neuropathological assessment in BN&NP. We selected three cases in which white matter involvement of the cerebrum was noted in the context of prominent neurobehavioral dysfunction. All three were eventually diagnosed as hematopoietic tumors manifesting as white matter disease, and they demonstrate the value of neuropathological assessment in the

diagnosis of challenging clinical cases and in the study of brain–behavior relationships.

Clinical presentation of brain tumors Many neoplasms of the central nervous system (CNS) that involve the cerebral hemispheres present as discrete, well-demarcated masses. Metastatic tumors to the brain are the best example of this behavior, and typically show an almost pencil-line sharp distinction both grossly and microscopically between where the tumor cells are growing as a cohesive mass and the surrounding, reactive, uninvolved brain tissue. Some World Health Organization (WHO) grade I, primary brain tumors also show this feature of forming relatively discrete tumor masses, with a sharp cut-off between the tumor and the adjacent non-neoplastic brain. Examples of low-grade primary brain tumors with this type of characteristic growth pattern include pilocytic astrocytomas, gangliogliomas, and supratentorial ependymomas. But even primary glial tumors that manifest the ability to infiltrate the brain parenchyma as single cells and grow in less cohesive fashion, such as WHO grade II–IV diffuse astrocytomas and oligodendrogliomas, tend to involve relatively limited geographic regions of brain and are most often confined to one or two lobes of the cerebrum. As such, when any of these tumor types involve the cerebral hemispheres, patients with these neoplasms tend to present clinically with focal, or multifocal, discrete neurological signs and symptoms, and not with white matter dementia due to diffuse white matter brain damage. As such, most clinicians do not consider brain neoplasms high on their differential diagnostic


485


list when confronted by a patient with dementia, lethargy, and neuropsychiatric disturbances.

Gliomatosis cerebri as a prototypical neoplastic cause of white matter dementia An uncommon tumor type that is a well-recognized exception to this rule, and that can present with white matter dementia symptomatology, is gliomatosis cerebri (GC). Gliomatosis cerebri is defined in the recent 2007 revision of the WHO classification as a glial neoplastic process that involves at least three cerebral lobes, usually with bilateral involvement of the cerebral hemispheres and/or deep gray matter, and frequent extension to the brainstem, cerebellum, and even the spinal cord [1]. Gliomatosis cerebri is now recognized to be a variant of astrocytoma with a pattern of particularly extensive glioma infiltration [1]. This new definition reflects a change from the previous edition of the WHO classification system [2] in which GC was considered a neuroepithelial tumor of uncertain origin. Relatively few cases of GC have been reported in the literature, and, in the past, most examples were diagnosed post-mortem. Today, improved neuroimaging studies reveal that diffuse, bilateral, multi-lobe infiltration of brain by individual glioma tumor cells is not as rare as was previously appreciated. The cerebrum is the most common anatomic site involved in GC, and individual neoplastic cells have a predilection for diffuse permeation of the cerebral white matter, especially the centrum semiovale and corpus callosum. Although the neoplastic cells may also spread to cortical and subcortical gray matter, only 19% of cases show infiltration of the cerebral cortical gray matter, 43% of cases involve thalamus, 34% spread to basal ganglia, and 29% to cerebellum [1]. The centrum semiovale of the cerebral white matter is the most common site of involvement and more than three-quarters of cases are bilateral. Microscopic brain sections from a case of GC show elongated individual glial cells permeating the background neuropil, without forming a cohesive tumor cell mass. Little or no necrosis, microcyst formation, microvascular proliferation, calcification, or microglial clusters are present, accounting for the subtleness of pre-biopsy neuroimaging changes. Cells preferentially infiltrate the white matter as single cells

486

in a pattern parallel to myelinated fibers in the white matter, yielding the impression that they are aligned in linear fashion. Unlike most glial neoplasms that form a nidus of high-cell density tumor growth with destruction of underlying brain tissue, in GC the architecture of the brain remains largely intact. Myelin is mainly disrupted and axons are less injured, at least initially, accounting for this structural preservation when small numbers of tumor cells infiltrate any given area of the brain [3]. This relatively greater myelin loss correlates with magnetic resonance imaging (MRI) changes, especially on T2-weighted images, and occasionally can lead to neuroimaging consideration of demyelinating disorders such as multiple sclerosis or leukoencephalopathy until biopsy or autopsy proves the cytological atypia of the infiltrating tumor cells in GC. Clinical features can cause considerable diagnostic uncertainty for the clinician. Presentation with cognitive features often leads to a diagnosis of a neurodegenerative or psychiatric disorder until more focal findings (such as hemiparesis or seizures) manifest themselves in the patient. Artigas and colleagues [3] in their review of the literature on GC noted that the most common presenting features of GC were mental and behavioral changes (40%), as opposed to seizures (29%) or headache (29%). Mental and behavioral changes were also the most common persistent clinical features. While corticospinal tract deficits often are listed as the single most common clinical symptom of GC (58%), the neurobehavioral features, when considered collectively, are actually more common (dementia in 44%, lethargy and/or obtundation in 20%, and behavioral changes/psychosis in 19% of patients) [3]. Seizures [4] can also be seen, and we have recently emphasized the extent of neurobehavioral changes that can develop in these patients [5].

Hematopoietic tumors manifesting as white matter disease: entities underappreciated by clinicians Despite the infrequency of GC, most clinicians are at least aware of that entity. In contrast, an analogous, highly infiltrative variant of primary central nervous system lymphoma (PCNSL) is virtually unknown to most neurologists, neurosurgeons, neuropathologists, and neuropsychologists.

Chapter 31: Neuropathological assessment

Primary central nervous system lymphomas are defined as extranodal malignant lymphomas arising in the CNS in the absence of lymphoma outside the nervous system at the time of diagnosis [6]. Most are B-cell lymphomas that involve the supratentorial space (60%) where they usually present as large masses, with subependymal spread, or less commonly, meningeal disease. Even in the new 2007 WHO classification book, however, the diffusely infiltrative variant of PCNSL that spreads as individual cells throughout the cerebral white matter, without formation of a cohesive mass, remains unmentioned [6]. This variant has been dubbed “lymphomatosis cerebri” (LC), in recognition of its overlapping clinicopathological features with GC [7–11]. This chapter illustrates the features of a patient with a B-cell LC, as well as one with a similarly infiltrative lymphoma of brain, mycosis fungoides, a T-cell lymphoma of skin that can show late spread to CNS, occasionally diffusely infiltrating cerebral white matter. We also illustrate a third case of a hematopoietic tumor manifesting as white matter disease, intravascular (angiotropic) B-cell lymphoma of brain, with intralumenal plugs of lymphoma cells that lead to multifocal white matter infarctions and ischemic lesions. All three of the patients with these hematopoietic tumors manifested with clinical features suggestive of white matter dementia. The reader is provided with detailed clinical descriptions for the three patients with these three differing types of hematopoietic tumors manifesting as white matter disease.

Case 1: lymphomatosis cerebri This 58-year-old right-handed man presented with a 6week course of progressive confusion, emotional lability, lethargy, fatigue, diplopia, anorexia, nausea, and headache. He was admitted to a psychiatric facility because his mother had recently died and his symptoms suggested the possibility of depression. Past medical history was positive for hypertension, pulmonary sarcoidosis, and left leg injury with osteomyelitis and gait dysfunction. On examination, the patient was afebrile, but lethargic and inattentive. Nuchal rigidity was present. He was able to follow only one-step commands, and was confused by most questions. Cranial nerves were normal other than slight left lower facial weakness and spontaneous nystagmus. Motor exam was normal except for weakness in his left lower extremity from his prior injury. Gait was impaired

by left leg weakness and truncal ataxia. Reflexes were brisk in both upper and lower extremities but plantar responses were flexor. Routine laboratory tests for cognitive impairment were unremarkable. Brain MRI showed multifocal lesions, primarily in the white matter, some hemorrhagic and others enhancing; lesions were seen in the right lateral temporal lobe, left inferomedial frontal lobe, left parietal white matter, left frontal periventricular white matter, ventral left pons extending to the midbrain and thalamus, and left lateral brachium pontis. Lumbar puncture disclosed 9 white blood cells (WBCs; 67% lymphocytes), 2,210 red blood cells (RBCs), glucose 80 mg/dL, and protein 89 mg/dL. Angiography showed narrowing and irregular filling of multiple cerebral vessels, and the patient was diagnosed with CNS vasculitis. He was treated with steroids and cyclophosphamide. A right temporal lobe brain biopsy was performed 2 weeks after his presentation, but results were inconclusive. The initial response to treatment was positive, with improvement in alertness, cognition, and gait, and he was discharged to a rehabilitation hospital. Testing found severely impaired attention and information processing speed, and moderately impaired executive function. Memory was minimally affected. Spoken language was normal but he had deficits in reading and writing. There were mild visuospatial deficits and left hemineglect. Two months after the biopsy, he was observed to develop poor concentration, memory loss, increasing lethargy, poor balance, nausea, vomiting, and anorexia. On admission to the rehabilitation hospital, depression and suicidal ideation were noted. One week later he was not thought to be dangerous to himself, and he was discharged to home hospice. He died a week later, approximately 5 months after his presentation.

Pathological findings Most of the major abnormalities at autopsy were confined to the CNS, although, in conjunction with his reported history of sarcoidosis, granulomatous inflammation of mediastinal lymph nodes was found. No systemic lymphoma was identified. The gross brain showed no meningeal hemorrhage or opacification and the only abnormality recognizable from the surface of the cerebral hemispheres was the hemosiderin-stained site of the previous biopsy. Coronal sections showed no mass lesions or

487


Figure 31.1. Lymphomatosis cerebri. A: Coronal brain autopsy sections showed no mass lesions or hemorrhages, and no obvious abnormalities of the white matter except for very subtle discoloration best seen in the left inferior frontal gyrus (arrow). B: Whole mount sections stained with hematoxylin and eosin (H&E) (left) and CD45 for lymphocytes (right) showed that the densest lymphoma cell infiltrates were found in this same abnormal left inferior frontal gyrus, where they filled the subgyral white matter, with relative sparing of the overlying cortical gray matter. C: High-power photomicrograph of the white matter showing clusters of lymphoma cells that permeated, splayed, and disrupted the myelinated fibers, seen as elongate linear strands (Luxol fast blue-periodic acid Schiff (LFB-PAS)). D: High-power photomicrograph of the white matter from the same area as seen in Figure 31.1C, showing better preservation of axons. Anti-neurofilament immunostaining with light hematoxylin counterstain. This figure is presented in color in the color plate section.

hemorrhages, and no obvious abnormalities of the white matter except for very subtle discoloration best seen in the left inferior frontal gyrus (arrow, Figure 31.1A). Microscopic sections illustrated diffuse infiltration of the white matter of the brain by lymphoma cells, without formation of a cohesive or necrotic tumor mass. The densest lymphoma cell infiltrates were found in the abnormal left inferior frontal gyrus, where they filled the subgyral white matter, with relative sparing of the overlying cortical gray matter (Figure 31.1B, whole mount section stained with hematoxylin and eosin (H&E), (left) and CD45 for lymphocytes (right)). Within the white matter, clusters of lymphoma cells permeated, splayed, and disrupted the myelinated fibers; in Figure 31.1C, myelin is seen as elongated linear strands on Luxol fast blueperiodic acid Schiff (LFB-PAS), with better preservation of axons in the same section; in Figure 31.1D, axons are seen as linear strands on neurofilament immunostaining. Although the cerebral white matter was the most severely involved, less-dense lymphomatous infiltrates could be found in the cerebellar white matter (Figure 31.2A), where they again favored white matter over the cerebellar gray matter or molecular layer. Meningeal involvement was focally identified (arrow, Figure 31.2A). Subcortical gray matter was also

488

affected, and the gray matter of the pallidum, thalamus, and hypothalamus was severely over-run by lymphomatous infiltrates and more affected that cortical or cerebellar gray matter (Figures 31.1B, 31.2A). Again, however, even in the subcortical gray matter areas the preference of the cells for white matter over gray matter was obvious; Figure 31.2B demonstrates extensive white matter involvement with virtual stoppage cells at the boundary between the putamen and adjacent white matter (arrows). Nearly every tissue section sampled showed some involvement by the lymphoma cells, although the process was quite patchy in many areas, explaining the non-diagnostic biopsy pre-mortem. Some degree of perivascular accumulation of lymphoma cells was found (Figure 31.2C) but individual cell permeation by the cytologically malignant cells (arrows, Figure 31.2D) was more typical. Lymphoma cells were immunoreactive for CD20, a B-cell marker (Figure 32.2E), and only a few accompanying non-neoplastic T-cells were identified by CD3 (Figure 31.2F). In situ hybridization studies for Epstein Barr virus (EBV) were negative. White matter myelin was more disrupted than were the axons and CD68 immunostaining for macrophages showed a moderate influx of macrophages in response to the myelin damage. The diagnosis was lymphomatosis cerebri, B-cell type.


Figure 31.2. Lymphomatosis cerebri. A: Low-power photomicrograph illustrating that less-dense lymphomatous infiltrates could also be found in the cerebellar white matter (WM), where they again favored white matter over the cerebellar gray matter (GM) or molecular layer (ML). Meningeal involvement was focally identified (arrow). Hematoxylin and eosin (H&E) stain. B: Low power photomicrograph showing that in the subcortical gray matter areas the preference of the cells for white matter over gray matter still existed. Note extensive involvement of the white matter, with virtual stoppage cells where the gray matter of the putamen (P) meets the adjacent white matter (arrows); H&E stain used in this photomicrograph. C: High-power photomicrograph illustrates that while some degree of perivascular accumulation of lymphoma cells was found, individual cell permeation by the cytologically malignant cells (D: arrows) was more typical. E: Lymphoma cells were immunoreactive for CD20, a B-cell marker; CD20 immunostaining with light hematoxylin counterstain. F: Only a few accompanying non-neoplastic T-cells were identified; CD3 immunostaining with light hematoxylin counterstain. This figure is presented in color in the color plate section.

Lymphomatosis cerebri: literature review In 1999, Bakshi and colleagues [7] were the first to coin the term “lymphomatosis cerebri” (LC) for two cases they had examined of PCNSL that had spread within the brain, without formation of a cohesive tumor mass. In 2005, we added three additional cases to the literature [8], as well as a literature review. Most of the ten reported patients at the time of our paper [8], and published since then [9–11], have occurred in immunocompetent adults. Two patients with acquired immunodeficiency syndrome have been reported with PCNSLs presenting as “diffuse leukoencephalopathy” or “diffuse white matter signal abnormalities” and represent examples of LC, albeit not designated as such by the authors [12, 13]. Indeed, the varying terms used in the literature by different authors for the same disorder make it somewhat difficult to identify the exact number of cases in the literature [14–16]. Nevertheless, review of older literature series of PCNSLs in

immunocompetent patients suggests that the condition is uncommon, similar to GC [8]. Lymphomatosis cerebri may become more recognizable now that sensitive neuroimaging techniques for white matter disorders (T2-weighted and fluid attenuated inversion recovery (FLAIR) imaging) are available. Certainly, the striking neuroimaging findings in white matter seen by MRI today in cases of LC can also lead to more clinical confusion. Many patients with LC reported in the literature have borne pre-operative diagnoses of Binswanger’s disease, unknown leukoencephalopathy, viral infection [8], or autoimmune mediated encephalomyelitis [10] before the LC was documented by biopsy findings. Cerebrospinal fluid cytology is more often negative [10–12, 15, 16] than positive [8, 9]. Most cases of LC are in immunocompetent patients and EBV does not mediate the lymphoma. Thus, CSF polymerase chain

489


reaction (PCR) studies for EBV are also of little or no utility in making the diagnosis of LC. Indeed, CSF studies have occasionally added to the diagnostic confusion. A very recent report of a 77-year-old man with rapidly progressive dementia and positive 14–3-3 protein in CSF (a protein found in disorders where there is widespread destruction of neurons – or at least cerebral tissues – and not a specific test exclusively for prion disorders) led to a pre-biopsy presumptive diagnosis of Creutzfeldt–Jakob disease (CJD) [9]. Magnetic resonance imaging white matter abnormalities in the case, however, were not concordant with a diagnosis of CJD and eventually prompted biopsy that showed a T-cell example of LC [9]. Most examples of LC in the literature have been B-cell lymphomas, but this case, and another by Provinciali et al. [14] were T-cell LC. Lewerenz and colleagues [10] have recently suggested that the finding of hypermetabolism within the white matter in cases of LC on fluorodeoxy glucose position emission tomography (FDG-PET) may help distinguish the condition from Binswanger’s disease, which is typified by scattered regions of hypometabolism [10], but more cases will have to be studied to verify this observation. A recent report of LC diagnosed in an early phase and treated successfully with corticosteroids and whole brain radiation (36 Gy) suggests that making the diagnosis premortem has clinical utility [11].

Role of neuropathological assessment This case illustrates the usefulness of brain biopsy in the evaluation of select patients with neurobehavioral disturbances and identification of their potentially treatable or reversible causes. Despite exhaustive clinical and neuroimaging evaluation, biopsy (or autopsy) is almost always required for the diagnosis of LC and, unfortunately, no less-invasive procedures can be utilized. This is not to suggest that brain biopsy is a routine procedure in diagnostically challenging cases. Given the potential morbidity associated with this procedure, weighing the benefits of information it may provide against the risks of the procedure is essential. For example, in circumstances in which information provided by biopsy results is unlikely to alter treatment (e.g., probable CJD), the risks outweigh the benefits. In contrast, the case presented here illustrates an

490

occasion on which biopsy-derived diagnosis led to disease-specific treatment.

Case 2: mycosis fungoides This 62-year-old man was admitted to the hospital because of a 1-week history of confusion, somnolence, fever, and decreased hearing. Medical history included Parkinson’s disease and mycosis fungoides of the skin, both diagnosed at age 59. Parkinson’s disease was stable and being treated with carbidopa/levodopa, and the mycosis fungiodes had been treated with interferon and topical nitrogen mustard. The patient reported a 40-pound weight loss in the past 2–3 months. On examination, he was awake but lethargic, fully oriented, and appropriate. There was bilateral cogwheel rigidity but no tremor. He had reddish plaque-like discolorations on his face and multiple areas of reddened, exfoliative skin on both legs, with open sores and ulcers; there was also reddish discoloration in his feet, consistent with infection. Brain MRI showed no parenchymal lesions. Confusion and fever were initially ascribed to a skin infection complicating stage III mycosis fungoides. Topical nitrogen and interferon were discontinued and intravenous antibiotics were initiated. Mental status continued to deteriorate, with flat affect and marked psychomotor retardation. Audiology evaluation showed bilateral severe sensorineural hearing loss. Lumbar puncture disclosed a lymphocytic pleocytosis suggestive of high-grade lymphoma, with T-cell markers positive for CD-4 and CD8 and negative for CD-3. Protein was mildly elevated and glucose was normal, and tests for viral and other infections were negative. A clinical diagnosis of mycosis fungoides transformed into high-grade lymphoma with leptomeningeal involvement was given. Cytotoxic chemotherapy was begun with intrathecal methotrexate. Eosinophilia persisted throughout the hospital course and the patient continued to develop fevers as high as 101 ◦ F, with negative blood and urine cultures. Fever was eventually attributed to his neoplasm. All antibiotics were stopped when the family learned of the malignant pleocytosis, and care became supportive. His confusional state worsened, and his answers to questions produced a rambling, often inappropriate response. Brain MRI again revealed no acute parenchymal disease. The patient’s mental status deteriorated further, with onset of


Figure 31.3. Mycosis fungoides. A: Low-power photomicrograph of the skin from the lower extremities demonstrated increased numbers of lymphocytes within the upper dermis that were cytologically atypical, features diagnostic for mycosis fungoides. Hematoxylin and eosin (H&E) stain. B: At the same magnification and in the same region, the atypical lymphocytes are easily highlighted by their strongly positive reaction for CD8, an immunomarker for suppressor T-cells. Cases of mycosis fungoides with CD8+ predominance are far fewer than those with CD4+ strong staining. CD8 immunostaining with light hematoxylin counterstain. C: Same region of skin immunostained with CD4 shows that CD4-positive helper T-cells are far less frequent. CD4 immunostaining with light hematoxylin counterstain. D: Low power photomicrograph taken from the white matter of the cerebral hemispheres shows cytologically atypical lymphocytes that percolate through the white matter, yielding only subtle hypercellularity and only focal angiocentric arrangement (arrow). H&E stain. E: High-power magnification revealed the individual neoplastic T-cells of mycosis fungoides with classic “cerebriform,” folded and grooved nuclei (arrow). H&E stain. F: Immunohistochemical staining for CD8 highlighted these individual tumor cells far better in the white matter than did routine H&E staining. G: High-power photomicrograph of one of the mycosis fungoides cells in white matter immunostained for CD8. H: Leptomeningeal involvement could also be discerned in some areas. H&E stain. This figure is presented in color in the color plate section.

combativeness and then increasing lethargy. He developed staphylococcal bacteremia and died approximately 4 weeks after admission.

Pathological findings The skin from the lower extremities demonstrated atypical lymphocytes within the upper dermis, diagnostic for mycosis fungoides (Figure 31.3A). The atypical lymphocytes were strongly positive for CD8, an

immunomarker for suppressor T-cells (Figure 31.3B), with fewer CD4-positive, helper T-cells (Figure 31.3C). There was minimal staining for CD3 (a pan-T-cell marker), paralleling the pre-mortem flow cytometry results. Immunostaining highlighted the abnormal individual T-cells, which were otherwise admixed with neutrophils and eosinophils in the dermis. Grossly the brain was unremarkable on both surface and cross-section examination. Microscopically,

491


however, these same individual, cytologically atypical lymphocytes could be found in the meninges and especially in the cerebral white matter and corpus callosum. There was no formation of a cohesive mass and cells percolated through the white matter, yielding only subtle hypercellularity and only focal angiocentric arrangement (arrow, Figure 31.3D). High-power magnification revealed the individual neoplastic T-cells of mycosis fungoides with classic “cerebriform,” folded and grooved nuclei (arrow, Figure 31.3E). Immunohistochemical staining for CD8 highlighted these individual tumor cells far better in the white matter than routine H&E staining, both at low (Figure 31.3F) and high power (Figure 31.3G) magnification. Meningeal involvement could also be discerned in some areas (Figure 31.3H). Mycosis fungoides cells could be found as far distant as cerebellar white matter and brainstem. The diagnosis was mycosis fungoides with CNS involvement.

Mycosis fungoides involving the brain: literature review Mycosis fungoides is a T-cell lymphoma that originates in skin where it forms eczematous patches and progresses to formation of plaques and nodules. Extracutaneous dissemination occurs in 50–70% of cases and involves lymph nodes, lungs, spleen, liver, kidney, thyroid gland, pancreas, bone marrow, and heart, in decreasing order of frequency [17, 18]. Sézary syndrome denotes the leukemic phase of the disease. Central nervous system involvement is rare, being found in only one of 45 autopsied cases in one of the older, most-cited papers in the literature [18]. A series of nine cases of mycosis fungoides with CNS involvement has since been reported [19], but most remaining examples in the recent literature consist of individual case reports [20–27]. In the series of nine patients, altered mental status was the most frequent symptom referable to mycosis fungoides involvement of the CNS (8/9 patients), followed by cranial nerve deficits (4/9), gait disturbances (3/9), and leg weakness (1/9) [19]. Autopsies on six of these nine patients showed that the most frequent tissue pattern was meningeal and perivascular infiltration of the brain. Infiltration of cerebral parenchyma was identified in one of nine patients and of brainstem in another. Because of the meningeal involvement, CSF cytology was positive for lymphoma/Sézary cells in three of the five patients in whom CSF was analyzed [19], as it was in our case.

492

While other cases with positive CSF cytology [17, 24, 27] have been recorded, CSF cytology studies may also be negative [20, 21] and this does not exclude the diagnosis of mycosis fungoides involving the CNS.

Role of neuropathological assessment In this case, the principal contribution of neuropathological assessment to neurobehavioral evaluation is through autopsy, which confirmed the clinical diagnosis and justified the treatments undertaken. In cases like this one, neuropathological assessment serves several additional purposes. It affirms the diagnostic and therapeutic methods used in a challenging case, thereby providing an opportunity for clinicians to apply lessons learned in future similar circumstances. This information also informs discussion of diagnosis, treatment, and outcomes with the patient’s family and caregivers. When neuropathologic assessment derived from autopsy includes genetic information, this provides opportunities for discussion with the patient’s family of genetic risk (or lack thereof) and, when appropriate, referral for genetic counseling.

Case 3: intravascular lymphoma This 68-year-old man was well until one year before his demise when he developed bilateral lower extremity weakness and ataxia from a brainstem infarct. For the next 6 months he recovered well in his rehabilitation until he was noted to develop confusion, headache, incontinence, and increased lower extremity weakness. His medical history was notable for coronary artery disease and myocardial infarction. Ten months after the first stroke he was admitted for neurologic evaluation but quickly went into status epilepticus; he was treated with phenytoin and intubated. Seizure control was achieved and he was subsequently extubated; his medication was successfully changed to levetiracetam. However, his mental status thereafter was characterized by a persistent confusional state with inattention and prominent somnolence. Examination also demonstrated profound weakness in all limbs and areflexia. Routine laboratory studies were notable for an erythrocyte sedimentation rate of 101 mm/hr. CSF showed 14 WBCs (all lymphocytes), 12 RBCs, protein 79 mg/dL, and glucose 51 mg/dL; tests for viral and other infectious diseases were negative. Electroencephalography (EEG) was consistent with diffuse encephalopathy associated with sharp wave activity.


Figure 31.4. Intravascular lymphoma. A: Magnetic resonance imaging (MRI) performed soon after diagnosis reveals multiple bilateral areas of increased T2 signal in the cerebral white matter (illustrated) as well as in the pons and cerebellar hemispheres. B: Fluid-attenuated inversion recovery (FLAIR) imaging similarly demonstrates multiple foci with ill-defined borders scattered throughout the supratentorial region. The lesions principally occupy the white matter, but some cortical involvement is also present. Probable restrictive diffusion was noted, with definitive enhancement (not shown). C: T2-weighted MRI scan performed hours prior to demise shows even more extensive white matter lesions; these proved to be white matter infarctions devoid of intravascular tumor cells at the time of autopsy. D: FLAIR (pictured), diffusion, and post-contrast images prior to demise are similar in appearance to the MRI performed soon after diagnosis, despite the absence of tumor cells at autopsy. E and F: Coronal brain autopsy sections at the level of the mamillary bodies (E) and occipital horns (F) showed no mass lesions or hemorrhages, although obvious abnormalities of the white matter were seen bilaterally in the cerebral white matter as grayish areas of partial cavitation, indicative of multifocal white matter infarctions (arrows). This figure is presented in color in the color plate section.

Computed tomography of the brain revealed chronic small vessel white matter disease. Magnetic resonance imaging revealed multiple bilateral areas of increased T2 and FLAIR signal in the cerebral white matter, pons, and cerebellar hemispheres (Figure 31.4A, B). A work-up for rheumatologic disorders, including a four-vessel cerebral angiogram, was unrevealing. Differential diagnosis based on MRI included meningocerebritis, post-infectious encephalomyelitis, angiocentric lymphoma, and atypical vasculitis. Whereas

skin and sural nerve biopsies found no evidence of intravascular lymphoma, bone marrow biopsy was suspicious for B-cell lymphoma, although flow cytometry analysis was inconclusive. Repeat MRI revealed progression of the T2 and FLAIR white matter lesions (Figure 31.4C, D). The patient expressed suicidal ideation, and his depressive symptoms improved with sertraline. Brain biopsy confirmed a suspected diagnosis of intravascular B-cell lymphoma (Figure 31.5A–D).

493


Figure 31.5. Intravascular lymphoma. A: Low-power photomicrograph of the pre-mortem brain biopsy revealed that vessels of all sizes were packed with lymphoma cells; lymphoma was confined to the intralumenal space. Hematoxylin and eosin (H&E) stain. B: Medium-power photomicrograph shows that even individual small capillaries contained single lymphoma cells; no infarction of surrounding brain was found on the small biopsy sections (H&E stain). C: High-power photomicrograph illustrates the extreme cytological atypia of the individual lymphoma cells within blood vessels (H&E stain). D: These cells, including those in capillaries, were highlighted by their strong immunoreactivity for CD20 (CD20 immunostaining for B-cell lymphocytes, with light hematoxylin counterstain). E: Whole-mount section of the cerebral white matter discloses the discrete white matter areas of pallor and infarction (H&E stain). F: Whole-mount section of the lower spinal cord revealed multifocal areas of infarction, correlating with the patient’s lower extremity weakness noted in life (luxol fast blue-periodic acid Schiff stain for myelin). G: On lower power microscopic sections, infarcted white matter lesions could be recognized by their vacuolization, partial cavitation, and pallor (upper left in photograph; H&E stain). H: On high-power magnification, nearby blood vessels (seen at low power in block G) contained no residual intralumenal lymphoma cells after the patient’s chemotherapy treatment. Only reactive, perivascular non-neoplastic lymphocytes remained at autopsy near the infarcts. This figure is presented in color in the color plate section.

Chemotherapy was initiated, and some clinical response was observed, but his mental status waxed and waned because of intermittent acute confusional states. The hospital course was complicated by respiratory failure from repeated aspiration pneumonia. Slowing of the EEG became more pronounced over the hospital course. Pseudomonas aeruginosa bacteremia developed, and mental status steadily declined

494

to obtundation, stupor, and coma. The patient died of respiratory failure 9 weeks after admission to the hospital.

Pathological findings The pre-mortem brain biopsy was targeted to include samples of dura, leptomeninges, and cortical gray


and white matter; abnormalities were best seen in the latter. Vessels of all sizes, including capillaries, were packed with lymphoma cells (Figure 31.5A–C), but lymphoma was not identified within parenchyma or leptomeninges. No infarction of surrounding brain was found on the small biopsy sections. Individual lymphoma cells within blood vessels were strongly immunoreactive for CD20 (Figure 31.5D) and negative for EBV. The diagnosis was intravascular (angiotropic) high-grade, B-cell lymphoma. At autopsy, most of the major abnormalities were confined to the CNS; no systemic lymphoma was identified. Severe pulmonary congestion was the proximate cause of death. The gross brain showed no meningeal hemorrhage or opacification and coronal sections showed no mass lesions, although obvious abnormalities of the white matter were seen bilaterally in the cerebral hemispheres as grayish areas of partial cavitation, indicative of multifocal white matter infarctions (Figure 31.5E, F). Microscopic sections revealed that the pre-mortem chemotherapy had abrogated any intravascular lymphoma cells; only discrete cerebral white matter (Figure 31.5E) and lower spinal cord infarctions (Figure 31.5F) (correlating with the patient’s lower extremity weakness) could be discerned. Infarcted white matter lesions were vacuolated and partially cavitated (Figure 31.5G) and nearby blood vessels (seen at low power in Figure 31.5G and high power in Figure 31.5H) contained no residual intralumenal lymphoma cells. Only reactive, perivascular non-neoplastic lymphocytes remained at autopsy near the infarcts (Figure 31.5H).

Intravascular lymphoma involving the brain: literature review Intravascular lymphoma (IVL), also known as angiotropic large-cell lymphoma, intravascular lymphomatosis, and even malignant angioendotheliomatosis in the older literature, is now known to be a B-cell, or occasionally T-cell, lymphoma. Lymphoma cells are confined to the lumens of capillaries, small veins, and arteries, with little or no involvement of tissue parenchyma. Although it is a systemic disorder, IVL has a distinct predilection for skin and brain. Up to one-third of cases first come to clinical attention because of their neurological symptoms and twothirds of patients will eventually develop neurological deficits over time [28].

The diagnosis can be challenging [29]. Of 64 cases with cerebral involvement found in a literature review in 1995 by Chapin and colleagues [30], only two of these 64 patients had skin involvement [30]. This statistic underscores the need for more invasive tests such as brain biopsy or autopsy in most instances for diagnosis. Patients with IVL may manifest a wide variety of findings including encephalopathy, intermittent fever seizures, and/or focal signs such as hemiparesis and myelopathy [31, 32]. The disease may mimic posterior leukoencephalopathy or demyelinating disorders [33, 34], including disseminated encephalomyelitis [32, 35]. Cases with rapidly progressive dementia and positive 14–3-3 CSF protein test (similar to occasional cases of LC (see above)) have led to mistaken clinical diagnoses of CJD [36]. Cerebrospinal fluid studies usually reveal elevated protein levels and lymphocytic pleocytosis only [30], and sometimes even brain biopsy itself fails to provide definitive diagnosis antemortem [31]. Cerebrospinal fluid cytological examination in most cases is negative [37, 38], with only rare exceptions [39]. While the recommendation is to perform MRI of the CNS in the staging work-up of IVL, neuroimaging failed to detect brain lesions in half of all patients with neurological symptoms and IVL in one large study [37]. The explanation for why lymphoma cells are confined to the lumens of vessels and fail to extend to parenchyma or meninges is elusive. Ponzoni et al. postulate that the lack of CD29 (beta 1 integrin) and CD54 (ICAM-1) adhesion molecules on lymphoma cells of IVL – two molecules important for lymphocyte trafficking and transvascular migration – may explain the unusual pattern [40]. Similar to our case, where lymphoma appeared to respond – at least initially – to chemotherapy, up to 40– 50% of patients with IVL in larger series have demonstrated response [41], especially those with the “cutaneous variant” of disease where the disease is limited to the skin [37].

Role of neuropathological assessment In this patient, both pre-mortem brain biopsy and autopsy contributed to understanding the details of the case. Brain biopsy established a diagnosis – IVL – and directed treatment. Autopsy disclosed the pathophysiology of progressive CNS dysfunction leading to death. Linking pre-mortem and post-mortem diagnoses facilitates a complete description of the effects of

495


this illness on the CNS, and permits elegant neurobehavioral clinicopathological correlation.

Conclusion In this chapter, three examples of hematopoietic tumors causing white matter dementia have been detailed: lymphomatosis cerebri (LC), mycosis fungoides of the CNS, and intravascular lymphoma (IVL). In all three cases, the white matter involvement of the cerebrum contributed significantly to prominent neurobehavioral dysfunction. Each case illustrates the potential value of neuropathological assessment – including brain biopsy, autopsy, or both – to neurobehavioral evaluation. These cases also underscore the value of neuropathological assessment in the management of challenging clinical cases and in the study of brain–behavior relationships. Finally, these cases provide specific examples of the potential contribution of neuropathology to the study of neurobehavioral disorders – whether of the uncommon types experienced by the patients described in this chapter or the highly prevalent conditions such as Alzheimer’s disease, Parkinson’s disease, and others encountered in the daily practice of BN&NP.

Acknowledgment The authors gratefully acknowledge the expert manuscript preparation by Ms. Rosalyn Griffith and Ms. Diana Doyle.

References 1. Fuller GN, Kros JM. Gliomatosis cerebri. In Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC Press; 2007, pp. 50–2. 2. Lantos PL, Bruner JM. Gliomatosis cerebri. In Kleihues P, Cavenee WK, editors. Pathology and Genetics of Tumours of the Nervous System. Lyon: IARC Press; 2000, pp. 92–3.

496

5. Filley CM, Kleinschmidt-DeMasters BK, Lillehei KO, Damek DM, Harris JG. Gliomatosis cerebri: neurobehavioral and neuropathological observations. Cogn Behav Neurol. 2003;16(3): 149–59. 6. Deckert M, Paulus W. Malignant lymphomas. In Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC Press; 2007, pp. 188–92. 7. Bakshi R, Mazziotta JC, Mischel PS et al. Lymphomatosis cerebri presenting as a rapidly progressive dementia: clinical, neuroimaging and pathologic findings. Dement Geriatr Cogn Disord. 1999;10(2):152–7. 8. Rollins KE, Kleinschmidt-DeMasters BK, Corboy JR, Damek DM, Filley CM. Lymphomatosis cerebri as a cause of white matter dementia. Hum Pathol. 2005; 36(3):282–90. 9. Weaver JD, Vinters HV, Koretz B et al. Lymphomatosis cerebri presenting as rapidly progressive dementia. Neurologist 2007;13(3):150–3. 10. Lewerenz J, Ding X, Matschke J et al. Dementia and leukoencephalopathy due to lymphomatosis cerebri. J Neurol Neurosurg Psychiatry 2007;78(7):777–8. 11. Kanai R, Shibuya M, Hata T et al. A case of ‘lymphomatosis cerebri’ diagnosed in an early phase and treated by whole brain radiation: case report and literature review. J Neurooncol. 2008;86(1):83–8. 12. Moulignier A, Galicier L, Mikol J et al. Primary cerebral lymphoma presenting as diffuse leukoencephalopathy. AIDS 2003;17(7):1111–13. 13. Thurnher MM, Rieger A, Kleibl-Popov C et al. Primary central nervous system lymphoma in AIDS: a wider spectrum of CT and MRI findings. Neuroradiology 2001;43(1):29–35. 14. Provinciali L, Signorino M, Ceravolo G, Pasquini U. Onset of primary brain T-lymphoma simulating a progressive leukoencephalopathy. Ital J Neurol Sci. 1988;9(4):377–81. 15. Carlson BA. Rapidly progressive dementia caused by nonenhancing primary lymphoma of the central nervous system. AJNR Am J Neuroradiol. 1996;17(9): 1695–7.

3. Artigas J, Cervos-Navarro J, Iglesias JR, Ebhardt G. Gliomatosis cerebri: clinical and histological findings. Clin Neuropathol. 1985;4(4):135–48.

16. Ayuso-Peralta L, Orti-Pareja M, Zurdo-Hernandez M et al. Cerebral lymphoma presenting as leukoencephalopathy. J Neurol Neurosurg Psychiatry 2001;71(2):243–6.

4. Jennings MT, Frenchman M, Shehab T et al. Gliomatosis cerebri presenting as intractable epilepsy during early childhood. J Child Neurol. 1995;10(1): 37–45.

17. Bodensteiner DC, Skikne B. Central nervous system involvement in mycosis fungoides: diagnosis, treatment and literature review. Cancer 1982;50(6): 1181–4.


18. Rappaport H, Thomas LB. Mycosis fungoides: the pathology of extracutaneous involvement. Cancer 1974;34(4):1198–229.

31. Beristain X, Azzarelli B. The neurological masquerade of intravascular lymphomatosis. Arch Neurol. 2002; 59(3):439–43.

19. Hallahan D, Griem M, Griem S, Duda E, Baron J. Mycosis fungoides involving the central nervous system. J Clin Oncol. 1986;4(11):1638–44.

32. Schwarz S, Zoubaa S, Knauth M, Sommer C, Storch-Hagenlocher B. Intravascular lymphomatosis presenting with a conus medullaris syndrome mimicking disseminated encephalomyelitis. Neuro Oncol. 2002;4(3):187–91.

20. Makepeace AR, Sebag-Montefiore D, Spittle MF, Smith NP. Mycosis fungoides of the central nervous system. J R Soc Med. 1989;82(2):116–17. 21. Tacconi L, Eccles S, Johnston FG, Symon L. Mycosis fungoides with central nervous system involvement – a case report: T-cell lymphoma of the brain. Surg Neurol. 1995;43(4):389–92. 22. Vitek JJ, Duvall ER. Cranial computed tomography in the tumorous stage of mycosis fungoides. J Comput Assist Tomogr. 1982;6(4):702–5. 23. Conrad ME, Omura GA. Mycosis fungoides: carcinogens and cerebral involvement. Am J Med Sci. 1987;293(2):122–4. 24. Zonenshayn M, Sharma S, Hymes K et al. Mycosis fungoides metastasizing to the brain parenchyma: case report. Neurosurgery 1998;42(4):933–7. 25. Li N, Kim JH, Glusac EJ. Brainstem involvement by mycosis fungoides in a patient with large-cell transformation: a case report and review of literature. J Cutan Pathol. 2003;30(5):326–31. 26. del Carpio-O’Donovan R, Freeman C. Brainstem involvement with mycosis fungoides: an unusual central nervous system complication. Am J Neuroradiol. 2002;23(4):533–4. 27. Lally A, Hollowood K, Whittaker S, Turner R. Central nervous system involvement in stage 1b mycosis fungoides. Br J Dermatol. 2007;157(4):815–16. 28. Aznar AO, Montero MA, Rovira R, Vidal FR. Intravascular large B-cell lymphoma presenting with neurological syndromes: clinicopathologic study. Clin Neuropathol. 2007;26(4):180–6. 29. Vieren M, Sciot R, Robberecht W. Intravascular lymphomatosis of the brain: a diagnostic problem. Clin Neurol Neurosurg. 1999;101(1):33–6. 30. Chapin JE, Davis LE, Kornfeld M, Mandler RN. Neurologic manifestations of intravascular lymphomatosis. Acta Neurol Scand. 1995;91(6):494–9.

33. Moussouttas M. Intravascular lymphomatosis presenting as posterior leukoencephalopathy. Arch Neurol. 2002;59(4):640–1. 34. Liew CL, Shyu WC, Tsao WL, Li H. Intravascular lymphomatosis mimicks a cerebral demyelinating disorder. Acta Neurol Taiwan 2006;15(4): 264–8. 35. Gaul C, Hanisch F, Neureiter D et al. Intravascular lymphomatosis mimicking disseminated encephalomyelitis and encephalomyelopathy. Clin Neurol Neurosurg. 2006;108(5):486–9. 36. Albrecht R, Krebs B, Reusche E et al. Signs of rapidly progressive dementia in a case of intravascular lymphomatosis. Eur Arch Psychiatry Clin Neurosci. 2005;255(4):232–5. 37. Ferreri AJ, Campo E, Seymour JF et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the ‘cutaneous variant’. Br J Haematol. 2004;127(2):173–83. 38. Glass J, Hochberg FH, Miller DC. Intravascular lymphomatosis. A systemic disease with neurologic manifestations. Cancer 1993;71(10):3156–64. 39. Ossege LM, Postler E, Pleger B, Muller KM, Malin JP. Neoplastic cells in the cerebrospinal fluid in intravascular lymphomatosis. J Neurol. 2000;247(8): 656–8. 40. Ponzoni M, Arrigoni G, Gould VE et al. Lack of CD 29 (beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis. Hum Pathol. 2000;31(2):220–6. 41. DiGiuseppe JA, Nelson WG, Seifter EJ, Boitnott JK, Mann RB. Intravascular lymphomatosis: a clinicopathologic study of 10 cases and assessment of response to chemotherapy. J Clin Oncol. 1994;12(12): 2573–9.

497

Section III Chapter

32

Treatments in Behavioral Neurology & Neuropsychiatry

Principles of pharmacotherapy Jonathan M. Silver

Psychopharmacologic treatment of neuropsychiatric disorders, such as traumatic brain injury (TBI), dementia, and stroke, targets a range of symptoms and clinical syndromes, including depression, mania, affective lability, anxiety, apathy, psychosis, aggression, fatigue, and sleep disturbances. These phenomena may present as independent problems but often occur as sub-syndromes and in combinations that cross conventional diagnostic boundaries. When an apparently singular and discrete psychiatric diagnosis (i.e., major depression) presents itself, it is not uncommon to encounter idiosyncratic persistence of specific symptoms despite otherwise adequate treatment. While diagnostic parsimony is desired, physicians should be prepared to “think outside the box” regarding this population as exceptions are often the rule. Individually tailored combinations of medications may be required to alleviate the atypical clinical problems physicians are more likely to confront in this patient population. For this reason, the neuropsychiatric strategy of evaluating and monitoring individual symptoms is necessary and differs from the usual syndromal approach of the conventional psychiatric paradigm. It is prudent logistically to initiate each treatment sequentially as opposed to concurrently to evaluate effectively the associated efficacy and/or side effects. The initiation of pharmacotherapy follows a thorough neuropsychiatric evaluation as well as consideration and/or trials of other potentially effective therapeutic options including psychotherapeutic, cognitive–behavioral, and environmental interventions. As has been found with treatment of some psychiatric disorders (i.e., depression, panic disorder, and obsessive-compulsive disorder), a combination of simultaneously administered therapeutic interventions is often more effective than mono-modal

treatment [1]. As described elsewhere in this volume, individual psychotherapy, cognitive rehabilitation, behavioral modification, group and family psychotherapies, environmental modification and procedural interventions all have the potential to alleviate neuropsychiatric disturbances. Pharmacotherapy therefore is but one of several possible interventions for persons with such disturbances. However, it is among the more medically complex neuropsychiatric treatments and entails risks for both patients and the clinicians providing their care. Regardless of the type of pharmacotherapy undertaken or the target of such treatment, an understanding of the principles of pharmacotherapy is an essential component of the medical knowledge for subspecialists in Behavioral Neurology & Neuropsychiatry (BN&NP). This chapter reviews the principles of pharmacotherapy for neuropsychiatric disturbances and addresses practical issues that often arise during treatment. Some of the recommendations offered here incorporate published evidence and a distillation of observations and experiences from many years of clinical practice. While the focus here is on neuropsychiatric treatment, these principles also are relevant to the psychopharmacologic treatment of common primary psychiatric and neurological disorders.

Therapeutic alliance Even when the rationale for a particular medication trial is optimal, and takes into account the patient’s past experience, the probability of a response to the agent, appropriate dosage, possible drug–drug interactions, and potential side effects, neuropsychiatric symptoms still may fail to respond to pharmacotherapy and/or the patient may experience an


498

Chapter 32: Principles of pharmacotherapy

intolerable adverse reaction to that medication. These types of events can strain the physician–patient relationship and may lead the patient to discontinue treatment in search of a “better” physician. For this reason, it is important to establish a working alliance with the patient at the onset of treatment by soliciting the patient’s input when considering new treatment options. While promoting modestly the genuine value of experience and clinical judgment, the clinician must also acknowledge the patient’s fears and concerns regarding medications and side effects, and the benefits derived from actively participating in the decisionmaking process. Reassure patients in advance that, if a particular medication fails to be effective or the side effects become intolerable, other options will be explored. Symptoms that worsen shortly after administering a new medication are likely the result of the medication; an appropriate response is to acknowledge their occurrence and offer to reduce or discontinue the medication rather than immediately increasing it (even if higher doses are necessary eventually). These approaches provide the patient with reassurance that the physician is attentive to his or her concerns and create the kind of therapeutic alliance that will be needed to manage neuropsychiatric disturbances pharmacologically.

Evaluation It is critical to conduct a thorough developmental and neurological history and examination of the patient prior to the initiation of any intervention. When considering pharmacotherapy, two issues require additional attention. First, the presenting complaints must be carefully assessed and defined. Operationalized definitions and rating scales can be used, and may help to document the severity of specific symptoms and to track the results of treatment interventions. Examples of such scales include the Neurobehavioral Rating Scale–Revised [2] and the Neuropsychiatric Inventory [3]. More symptom-specific rating scales include the Overt Aggression Scale [4, 5], Apathy Evaluation Scale [6], or scales to assess emotional lability [7]. Despite their assessment value, these instruments do not replace clinical judgment or the need to communicate directly with the patient and/or caregiver. Treatment is an active, ongoing, collaborative process and a global clinical impression is often the most accurate. If improvement is indicated through “objective” measurements, but the patient and/or caregiver perceive

no change, then the medication has not been of sufficient benefit. Second, the use and effectiveness of ongoing treatments must be reevaluated continually, including pharmacologic and non-pharmacologic therapies (prescribed and self-administered). When reviewing the patient’s current medication regimen, four key issues should be addressed: (1) the indications for prescribed medications; (2) potential side effects and interactions with other medications; (3) the necessity of other prescribed medications; and (4) the patient’s (and/or caregiver’s) treatment priorities. Consultation with the patient’s treatment team may be needed to determine whether a prescribed medication is required and/or a new medication might be helpful. In some cases, a treatment has not been applied properly, was predicated on misdiagnosis of the problem, or was introduced as a result of poor communication among treating professionals regarding the problem in question. A potentially effective medication may not have been beneficial because it was prescribed at too low a dose or for too brief a period of time. In other instances, the most appropriate pharmacologic recommendation may be to eliminate one or more ongoing treatments or to discontinue medication altogether while investigating the use of other, possibly non-pharmacologic, therapeutic approaches. Patients also sometimes receive medications that either produce or exacerbate psychiatric symptoms such as depression, mania, hallucinations, insomnia, nightmares, cognitive impairments, restlessness, paranoia, or aggression. When such medications complicate the assessment of neuropsychiatric status or may be contributing to a patient’s neuropsychiatric problems, a carefully planned withdrawal of such agents precedes additional pharmacologic interventions. This becomes complicated when there are many physicians prescribing medications to the patient. It is important to assign one physician in such a group the task of reviewing and coordinating all ongoing treatments; in some cases, this task is most appropriately assigned to a subspecialist in BN&NP while in others it may be a neurologist, psychiatrist, physiatrist, or internist. Prioritizing treatment is necessary when patients have multiple neuropsychiatric symptoms. For example, treatment of a seizure disorder typically takes priority over the treatment of depression and

499

Section III: Treatments in Behavioral Neurology & Neuropsychiatry

cognitive impairment due to the complications brought on by uncontrolled seizures. Properly chosen, some anticonvulsants have the potential to ameliorate several such comorbid symptoms. Conversely, for patients with post-TBI or post-stroke mood and cognitive disorders, priority is given to the treatment of depression since this problem exacerbates cognitive problems [8, 9].

Medication selection There are controlled clinical trials assessing the effects of medications on neuropsychiatric symptoms among neurodegenerative dementias (e.g. Alzheimer’s disease, Parkinson’s disease). However, studies of the effects of psychotropic medications on neuropsychiatric symptoms experienced by patients with other neurological disorders are few, and rigorously designed, double-blind, placebo-controlled studies in these populations are rare (e.g., see [10]). Therefore, decisions regarding medication selection are generally based on: research regarding treatment of a particular symptom or syndrome in the specific neuropsychiatric condition whenever available; current knowledge of the efficacy of medications in other psychiatric disorders; current knowledge of the efficacy of medications in analogous psychiatric disorders (e.g., TBI-related attentional problems may be analogous to attention-deficit hyperactivity disorder); hypotheses regarding the neurochemical pathophysiology of the disorder may contribute to the medication selection based on its putative mechanism of action; side effect profiles of the medication; a medication’s ease of use by a patient; prior experience with specific patients and medications; and the advice of experts or more experienced clinicians.

Evidence-based and hypothesis-driven medication selection Unfortunately, the pathophysiologies of phenotypically similar neuropsychiatric symptoms may differ among patients with different neurological disorders. Thus, clinicians often must rely on studies of a neuropsychiatric symptom or syndrome in different populations to guide their treatment selections. For example, one might look to studies of treatment of depression in stroke to decide which medication to treat depression in TBI, or otherwise fall back on the Food

500

and Drug Administration (FDA)-approved medication for primary major depressive disorder. In lieu of population-specific studies of target symptoms, physicians may select an FDA-approved medication for the primary psychiatric disorder that most resembles a patient’s neuropsychiatric problem (e.g., major depressive disorder) or appeal to hypothesized neurochemical changes as a guide to treatment selection (i.e., if apathy is a consequence of low levels of dopamine transmission, then perhaps it can be treated with prodopaminergic medications).

Side effect profiles Side effect profiles also may guide medication selection, especially when selecting among several medications within a particular pharmacologic class. For example, when treating a patient with depression in which insomnia is a concomitant problem, physicians may avoid prescribing antidepressant medications that produce daytime sedation and instead consider agents that might facilitate sleep. Physicians may avoid medications within a class that have more anticholinergic properties, which can adversely affect cognition (e.g., use sertraline rather than paroxetine) [11]. Anticipating commonly cited side effects is appropriate (e.g., topiramate-induced cognitive impairments [12]), but it is also necessary to be vigilant for adverse neuropsychiatric side effects even when using symptomatically “clean” medications. For example, lamotrigine [13] is generally regarded as a cognitively neutral agent but can result in cognitive deficits. In one patient treated by the author of this chapter, a patient with bipolar disorder taking 300 mg of lamotrigine per day was forced to drop out of school due to medicationinduced, neuropsychologically documented cognitive problems. After the dose of this agent was decreased to 150 mg per day, the patient’s cognitive impairments resolved and she was able to return to school.

Ease of use Ease of use is an important consideration as regards treatment adherence. Medications prescribed once daily are easier to take and may increase adherence to treatment as compared with agents requiring multiple daily doses [14, 15]. The need to monitor blood levels or other parameters (white blood cell counts, liver function, etc.) is unwelcome and/or logistically problematic for some patients and therefore may interfere with adherence to treatment. The type and


natural course of side effects also influence a patient’s willingness to take a medication. For example, a patient may need to choose between taking a medication that may produce weight gain and hair loss and that requires blood tests (e.g., sodium valproate), one that may cause weight gain and sexual dysfunction (e.g., selective serotonin reuptake inhibitors (SSRIs)), or one that causes only mild transient dizziness but is often less effective than the agents with more frequent and concerning side effects (e.g., buspirone). Depending upon the perceived potency, efficacy, and severity of the clinical situation, a patient may elect as an initial medication trial an agent that is easier to use and/or tolerate over one that is more likely to be efficacious.

Prior clinical experience An individual clinician’s prior experience with the use of a particular medication to treat a specific neuropsychiatric problem (e.g., post-TBI anxiety) also influences treatment selection. While there is some merit to this practice, it entails some risks borne of selective recall as well. It is very difficult for most clinicians to recall accurately the exact number of patients they have treated with a specific medication and all of their treatments responses experienced by those patients. This is explained by response bias: the tendency to recall positive events and forget negative ones. This bias is reflected in publication of single case studies with remarkable responses to specific medications, the absence of published single case studies describing an absence of treatment effect (see [16, 17] for a useful discussion of publication biases).

Expert opinion Finally, seek expert opinion and the advice of colleagues, whose actual or perceived experience treating a specific neuropsychiatric problem may inform treatment selection, especially in the absence of other published literature on the problem requiring treatment. The development of expert-consensus guidelines can offer practical guidance in such circumstances and may guide the clinical trial development. However, there are several caveats regarding the use of expert opinion as a guide to treatment selection. Expert opinions may be inconsistent and sometimes are simply wrong (even if they make theoretical sense),

and sometimes are demonstrated to be so once wellcontrolled studies of a particular treatment strategy are conducted (for example, see [18] about Gingko biloba and dementia). Additionally, many individuals who formulate expert guidelines receive industry support [19] and there are legitimate reasons to be concerned as payment by pharmaceutical companies can unduly influence expert opinions [20]. On the other hand, because pharmaceutical companies have not been strongly committed to neuropsychiatry, with some notable exceptions such as Alzheimer’s disease, there are relatively few paid experts for treatment of many neuropsychiatric problems.

Use of medications After selecting a medication, the general guidelines offered below are important to follow in all cases and with each medication prescribed. (1) With regard to dosing, “start low and go slow, but go.” (2) Make only one medication change at a time. (3) Frame all interventions as single-subject therapeutic trials. (4) Continuously reassess the clinical condition for which treatment is prescribed. (5) Remain vigilant for possible drug–drug interactions through treatment. (6) Anticipate the need to augment partial responses, and do so before discontinuing a partially effective treatment.

Dose escalation Some clinicians suggest that patients with neurological conditions are more sensitive to the adverse neurological and psychotropic effects of medications than are patients without such conditions, including those with phenomenologically similar primary psychiatric disorders. It is important to acknowledge that studies demonstrating this phenomenon are few. However, increasing or decreasing the dose of psychotropic medications in small increments over longer time periods than might be seen in general psychiatric services remains an acceptable and prudent practice in BN&NP. At the same time, it is important to anticipate that many patients with neuropsychiatric disorders will require and will tolerate medications reasonably at standard, or even relatively high, therapeutic

501


doses. In other words, with regard to dose escalation, “start low and go slow, but go.”

Medication changes and dose adjustments Whenever possible, medication adjustments (dose or type) are best undertaken sequentially rather than concurrently; in other words, make only one medication change at a time. This facilitates identifying the beneficial and adverse effects of each medication and increases the likelihood that the simplest, lowest dose, and most effective treatment regimen will be constructed. This approach may not be feasible to follow in emergency situations (i.e., severe acute agitation) or inpatient settings with very short lengths of stay. Appropriate timing of incremental medication changes and/or dose adjustments also requires considering the time to onset of action for the agent(s) being used. For example, the therapeutic effects of antidepressants, and the occasional development of treatment-related side effects (e.g., apathy, agitation) typically have an onset latency of 2–4 weeks. Starting or adjusting an antidepressant dose, or adding a second agent, during the first 2–4 weeks after starting an antidepressant therefore may not be the ideal time during which to add a psychostimulant or other augmenting agent to treat “residual” symptoms.

Therapeutic trials Although there is an increasingly useful literature describing the types and doses of medications used to treat neuropsychiatric conditions, there remain few studies describing optimal durations of treatment, treatment discontinuation, and relapse risk. Psychotropic medications need be prescribed in an effort to enhance the probability of benefit and reduce the possibility of adverse reactions. Medications must be given sufficient time to impart their full effects. When the decision is made to administer a medication, the patient and clinician must agree in advance on their definition of an adequate therapeutic trial. This includes identification of target symptom(s), the degree of relief from those symptoms that treatment is expected to afford, the duration of treatment needed to determine whether the medication prescribed is effective, and the types and severities of side effects that are acceptable. Inadequate therapeutic trials, both in terms of dose and duration, undermine accurate assessment of the potential therapeutic benefit and

502

tolerability of a medication used to treat a neuropsychiatric problem. Consigning a potentially useful agent to the list of “tried and failed” as a result of an inadequate therapeutic trial constitutes a major lost opportunity to a patient and may result in his condition being incorrectly regarded as “treatment resistant.”

Continuous reassessment of treatment need Continuous reassessment of treatment need is necessary whenever medications are prescribed. When a patient appears to have responded favorably to medication treatment, tapering or discontinuation of the medication should be considered and decisions toward those ends made in conjunction with the patient. Spontaneous remission of neuropsychiatric symptoms may occur, particularly during the recovery period from acute neurological insults and among patients whose disorders are inherently episodic (e.g., major depressive disorder). In such circumstances, clinicians and patients need to remain open to the possibility that a prescribed medication may have played no role in the observed improvement and may be appropriate to discontinue. Alternatively, improvement of symptoms may be treatment-related and may also entail carryover effects – i.e., therapeutic effects that persist after a medication is discontinued. The occurrence and duration of such effects varies, but their possible occurrence necessitates continuous reassessment of treatment need even after medication treatment is discontinued. The lack of published guidance regarding the treatment durations for neuropsychiatric conditions and treatment discontinuation protocols presents problems for clinicians considering such issues. Extrapolating from treatment guidelines established for analogous conditions, and especially primary psychiatric disorders, may be of some use in such medical decision-making. For example, practice guidelines published by the American Psychiatric Association [21] may offer a reasonable framework within which to develop a working treatment plan for many of the neuropsychiatric disturbances. For other neuropsychiatric conditions (e.g., post-traumatic aggression or apathy), there is little published evidence to guide treatment continuation or discontinuation decisions. In general, if a patient has responded favorably to medication treatment, the decision regarding when to taper and attempt to discontinue the medication


following TBI should be determined in conjunction with a case-specific risk–benefit determination.

Vigilance for drug–drug interactions When a new medication is initiated in combination with medications previously prescribed, vigilant observation for the development of drug–drug interactions is necessary. These interactions may be predicated on medication combination-specific alteration of pharmacokinetics that result in increased half-lives and serum levels of medications. This occurs frequently with the use of anticonvulsants or other agents that markedly affect hepatic metabolism or renal elimination. Additionally, condition-specific alterations of pharmacodynamics may develop and predispose patients to additive or synergistic adverse effects (i.e., increased sedative effects when several sedating medications are administered simultaneously).

Augmentation of partial responses If a patient does not respond favorably to the initial medication prescribed, several alternatives are available. If there has been no response to treatment, changing to a medication with a different mechanism of action is recommended. However, if there has been a partial response to a medication then addition of another medication with a different mechanism of action may prove more useful than abandoning entirely treatment with the partially effective agent. The selection of a second, supplementary or augmenting medication should be based on the possible complementary or contrary mechanisms of action of such agents, the individual and combined side effect profiles of the initial and secondary agents, and the potential pharmacokinetic and pharmacodynamic interactions.

Other practical issues in neuropsychopharmacology Generic medications The quandary of whether to rely on generic versus brand name medication occurs frequently in practice [22–27]. One important factor is the patient’s attitude toward brand names. As has been shown with wine, the belief of receiving “top shelf” is associated with preference and a better “placebo” response [28]. Anecdotal

stories of patients’ infections responding less robustly to some generic antibiotics or some generic antihypertensives and statins not performing as well have been noted. In addition, most clinicians have had patients who insist that the brand medication works better than the generic version. Muddying the waters further, there have been publicized concerns regarding the purity of some generic medications, although both brand and generic drugs are produced in facilities that have been inspected by the Food and Drug Administration. Some background information is helpful regarding the difference between generic and brand medications. According to FDA guidelines [29], generic medications must provide serum levels of ±15% of the corresponding brand name medication. In the treatment of some conditions – for example, “brittle” epilepsies or psychotic disorders – this degree of variance could be clinically important, especially when considering that two different generics could differ theoretically by as much as 30%. If a patient could be guaranteed that the same generic is always received, this does not present a problem. However, the available generic medication sometimes changes from one month to another as a function of the supplier used by the pharmacy that dispenses the medication. Are such changes always clinically relevant? In most cases, they are probably negligible. For example, for fluoxetine 20 mg/day, the blood-level variation would be equivalent to a difference of daily dosage of between 17 and 23 mg; by contrast potentially important differences have been found for diazepam and some anticonvulsants [30]. When pharmacokinetics were compared for brand and generic formulations of citalopram and venlafaxine, no difference was found for citalopram [31]. However, generic venlafaxine had 150% greater maximum concentration and 43% higher active metabolite [31]. There were three times more side effects with the generic formulation of venlafaxine. For some medications, where rapid effect/absorption is an issue (i.e., stimulants and benzodiazepines), it is plausible that a slight change in absorption could result in a different immediate response. An effective approach in practice is to have open discussions and formulate a plan: either resolve to start with brand, and if it works, try a crossover to generic at a later time, or start with generic and see how it works. Some medications are available in generic formulations, while others are available only in brand name

503


form. In cases where efficacy and side effects among several medications within a category are similar, the generic alternative is usually chosen [32]. Many insurance plans have lower co-pays for generic medications, yet some patients have a clear preference for the brand name medication, despite the possibility of incurring additional cost. A related decision is whether to use newer “longacting” formulations of medications. While some medications (e.g., bupropion) cannot be taken in the immediate release (IR) form at higher dosages, and the seizure risk may be greater with the IR form [33], other medications (e.g., paroxetine, valproate, quetiapine) can be given once a day in the older formulation. In these latter cases, scientific support for the longacting formulation is scant (although occasionally side effects may be mitigated) and the added expense is usually unjustified.

Insurance issues In BN&NP, many medications are used for “nonapproved” (i.e., “off-label”) indications. While physicians are permitted to prescribe medications for non-approved purposes, insurance carriers may not approve payment for such prescriptions. Patients incur the expense of these prescriptions, which sometimes are prohibitive. In some cases, a letter of justification, including references to supporting scientific literature, may persuade an insurance carrier to cover a portion of the medication’s cost. However, other, often underappreciated, alternatives may need to be explored. For example, a trial of modafinil may be considered for excessive fatigue in a patient with multiple sclerosis (MS) or TBI, although some studies have been inconsistent regarding its efficacy [34, 35]. Due to the expense of modafinil, insurance carriers often deny this use. Other medications with related pharmacologic properties and similar clinical benefits may be much less expensive and more readily approved by insurers; in the example of MS- or TBI-related fatigue, amantadine [36, 37] or stimulants such as methylphenidate. Another example of an underappreciated alternative pharmacotherapy comes when considering memantine for the treatment of cognitive impairment. Because there are few studies of the use of this medication in patients who do not have Alzheimer’s disease, approval may be denied by the insur-

504

ance company. However, amantadine and memantine are both moderate-affinity uncompetitive NMDA receptor antagonists. Both of these agents appear to increase dopamine release, decrease pre-synaptic dopamine reuptake, stimulate dopamine receptors, and/or enhance post-synaptic dopamine receptor sensitivity [38–45]. Given their pharmacologic similarities, treatment might be undertaken with amantadine instead of memantine and with potentially similar effects. The use of acetylcholinesterase inhibitors (AChE) may also be denied by insurance carriers for patients whose cognitive impairments are due to conditions other than Alzheimer’s disease or Parkinson’s disease. When considering treatment options for a patient with cognitive impairments due to another cause – for example, TBI or stroke – an alternative to the usual cholinesterase inhibitors (i.e., donepezil, rivastigmine, galantamine) is huperzine-A, a supplement which has a similar mechanism of action [46]. Another potential insurance-related problem with the prescription of some medications, and especially AChE inhibitors, is diagnostic “guilt by association:” although these agents are prescribed for patients without dementia, disability and life insurance companies may falsely conclude that patients receiving them have a neurodegenerative dementia. This erroneous assumption can result in a long, involved process of trying to convince the insurance company that a patient has neither a dementia nor its attendant prognosis.

Use of newly approved medications A new medication has just been approved. There are color advertisements in journals, and a gigantic display at the annual meeting. How much clinical experience is necessary before prescribing this new medication, and with which patients? First, remember that most of the new medications are “me too” drugs: they may be extended release formulations, or a new agent that has been chemically altered in some inessential way, with a mechanism of action virtually identical to older, less expensive drugs. Second, when a drug is approved, it may have been given to several thousand (at most), carefully selected study patients for several months (at most). While common side effects may manifest in that study group, these medications will eventually be prescribed for months and years to millions


of patients with more complicated conditions. In the drug development process, a compound may appear to be perfect conceptually and in early animal models, and have minor side effects in clinical trials; yet the drug’s true value only becomes apparent years after approval. It is after this experience that the benefits, risks, and cost become apparent. This author’s personal bias is to delay use of new medication unless it offers a potentially unique benefit to a patient who has not responded to established treatment. Because there is no evidence that “newer” is necessarily “better,” there is virtually no reason to use a newly approved medication for a patient who has not yet been treated with an “older” drug.

Pharmaceutical industry interactions A familiar scenario: a pharmaceutical sales representative appears in the office dragging the ubiquitous wheeled, carry-on suitcase behind. The representative is there to talk about some new or old medication, provide information, answer questions, and arrange for samples. Gone are the days of the free pen [47]. The clinician is faced with several issues: should he or she meet with the representative, and if so then for how long? Is it permissible to simply accept medication samples? And, in any case, should medication samples be given to patients? Pharmaceutical representatives can only provide information about the FDA-approved indications of medications. Representatives distribute publications demonstrating the efficacy of their medications. It is important to be mindful that the information provided by the pharmaceutical representative is designed to show preference (bias) to the medication that he or she is marketing. This information has been approved and provided by the marketing department of the pharmaceutical company. Samples can be very helpful in starting patients on new medication to determine whether it can be tolerated before filling a prescription. Pharmaceutical companies are eager to provide product samples in the hopes that doing so will lead to a prescription for that specific medication. Drug companies would not provide samples if this did not predictably lead to an increased rate of prescribing their products. Thus, the decision to prescribe a medication should not be based on whether or not samples of a specific medication are on hand in the physician’s clinic – even though it may

be difficult not to start a patient on the drug that “just happens” to be in the doctor’s office. When samples are provided to patients, the expiration date on those samples needs to be checked. Many physicians’ offices keep years’ worth of samples on hand, some of which will expire before they are offered to patients. As the end of the patent life on brand name medications approaches, samples often are no longer made available. This presents a significant problem for patients whose treatment has been predicated on their availability. It is important to consider the long-term implications of this practice before beginning a treatment with a medication that a patient will not be able to afford once it is not longer available in sample form. As an alternative to providing medications by dispensing samples, many pharmaceutical companies offer assistance programs for patients who cannot afford prescribed medications. Information regarding available programs can be obtained from the company or representative.

Off-label uses of medications Neuropsychiatrists often treat symptoms for which there are few or no approved medications (i.e., irritability, fatigue, cognitive symptoms, etc.). Off-label prescribing of medication is common. The rationale, evidence, and potential side effects of these medications should be discussed with the patient and/or caregiver, and documented in the medical record.

Alternative medications and treatment Many patients take vitamins and supplements for either “health maintenance” or to treat a neuropsychiatric condition. Certain alternative treatments have more evidence for efficacy than others, and may be beneficial, while others that appear obvious may be counterproductive (see [48] for the deleterious effects of vitamin C and E on exercise benefits). The purity of and potential for interactions from the vitamins and supplements are a concern [49]. It is helpful to have access to references that review the potential benefits of certain supplements so that physicians can discuss the information with patients (such as [50]). Other lifestyle interventions may benefit a patient’s mood, anxiety, and cognition. Regular exercise (both

505


cardio and strength training), a regular schedule, adequate sleep, relaxation techniques (e.g., slow breathing, yoga), and weight maintenance may be beneficial and can be discussed with patients.

Reluctance to take medications Adherence to or compliance with any treatment regimen is an important issue. In some instances, disagreements arise between patient and relatives as to the significance of a problem. For example, in patients with a brain injury, irritability is often more of a concern to relatives and fatigue may be more of a priority for the patient. Sometimes, a patient lacks confidence in a medical model where a medication can be used to treat a symptom. While education is important, there should be an open discussion of all potential concerns regarding the proposed treatment philosophy [51]. With some neurologic disorders, there is concern that medications can adversely affect recovery and can be a source of resistance from patients, families, and staff. The perceived bias against the use of psychiatric medications may have several sources, including the stigma associated with mental illness and psychiatry as well as past, unpleasant experiences the patient may have had with psychotropic medications. The stigma may be related to the perception that psychiatric symptoms are a sign of weakness, indolence, or even moral decline. The neuropsychiatric paradigm emphasizes neurobiological effects (without negating emotional and psychological factors), where symptoms are ascribed to alterations in neurotransmitter functions or brain circuitry that are potentially treatable with centrally active medications. Another fear regarding medication is that it will interfere with the “natural healing process.” Certain medications can produce cognitive impairments and may interfere with neuronal recovery after injury. For example, anticonvulsants such as phenytoin and carbamazepine may exacerbate cognitive impairments among persons with TBI [52, 53]. Similarly, among TBI patients, typical antipsychotic medications (e.g., haloperidol, fluphenazine, thioridazine, chlorpromazine) may exacerbate cognitive impairments [54] and may also prolong the period of posttraumatic amnesia [55]. Benzodiazepines are known to impair memory and other aspects of cognition [56]. In addition, these classes of pharmacologic agents may impede neuronal recovery after TBI [57]. Medications

506

with anticholinergic properties may impair attention, concentration, and memory [58, 59]. Experimental evidence in traumatically brain-injured rats supports this observation [60], as does common clinical experience in the treatment of patients with TBI. Such observations are consistent with the observed effects of both experimental and human TBI on cortical cholinergic function. However, these caveats must be considered and weighed against other relevant considerations. While a clinician may shy away from an anticholinergic drug like nortriptyline in patients whose conditions involve cognitive impairments (and, especially, cholinergic deficit-related cognitive impairments), comparative efficacy trials may provide evidence that outweighs (or contradicts) hypothesis-driven tolerability concerns. For example, comparative efficacy trials in stroke and Parkinson’s disease between nortriptyline and an SSRI (fluoxetine or paroxetine) revealed that nortriptyline was effective, while the SSRI was no different from placebo [61, 62]. Tricyclic antidepressants can be prescribed but only after careful consideration of potentially less problematic antidepressants. Additionally, some medications that conventional wisdom suggests are problematic to administer to persons with neurological disorders may have unexpected benefits. For example, antidepressants and lithium appear to increase hippocampal connections and brain-derived neurotrophic factor (BDNF) [63, 64]. Patients and families have natural concerns about certain medications based upon what they have read in newspapers, heard on television, or gleaned from websites. It is the clinician’s responsibility to be current about recent developments, and, where possible, review the original articles in the scientific literature to develop their own understanding and perspective on these reports. For example, there is appropriate concern for the increased mortality when elderly patients with dementia are prescribed antipsychotic medications with unclear efficacy [65, 66]. A similar analysis applies to the reports of suicide risk associated with anticonvulsant medications, where a meta-analysis of all anticonvulsants indicated a 1.8 times greater risk of suicidality (thoughts or behavior) [67]. However, a recent study suggests this is not the case, and the risk of suicide is elevated to a similar extent before and after the diagnosis of epilepsy [68]. Patients and physicians can and should obtain


up-to-date information regarding these issues through PubMed (www.pubmed.com) and other scientific literature search engines in order to address, with the best information available, pharmacotherapy concerns expressed by patients and their families.

Consultations There are three major situations where consultations arise relevant to pharmacotherapy. First, a treating clinician solicits input from another clinician to gain a different perspective and treatment strategies for a patient who has not responded favorably to treatment. Second, a clinician may be asked by a treating clinician to render a second opinion on such issues. Third, the patient and/or his family directly requests a second opinion on the pharmacotherapy of neuropsychiatric disturbances. Clinicians requesting a second opinion or performing one will find it helpful to receive the records and opinions of the other clinicians involved in the case. Reviewing such records in advance of the consultation, however, may skew the unbiased observations of the consultant. With “confirmation bias,” physicians tend to see what others have already observed. This presents some risk that a physician will substantiate the view of another clinician because of this bias. On the other hand, the consulting physician does not want to miss important facts observed by others. One solution to this dilemma is to have the initial consultation performed “blind” then obtain the patient information and see the patient for a second visit, if necessary. There is an associated risk in disagreeing with a patient’s request for a second opinion. Such requests are clear signs that something is not going well in treatment; one hopes that the treating clinician is aware of such problems before the patient makes a request for a second opinion. When such requests are made, it is useful to support the request and acknowledge that it may provide useful information – even the best clinicians sometimes miss things that are diagnostically or therapeutically important. However, the second opinion should be obtained from someone that both the clinician and patient believe has sufficient expertise to be of value as a consultant. At other times, a patient will seek a second opinion consultation without the knowledge of the treating physician. This needs to be discussed, although the decision to notify the other doctor or alter treatment is ultimately one made by the patient.

Medications for improving life without disease A recent area of discussion and controversy is the use of medications to enhance cognitive function in individuals who do not have a specific disorder. This has been termed “cosmetic neurology” or “neuroenhancement” [69–72]. One example is the use of stimulants to improve concentration in students studying for an examination. This is a frequent practice in college, although all too often it is done with drugs prescribed for others. Certainly, individuals engage in activities to enhance normal capabilities. These can range from exercise and weight loss to “anti-aging” strategies and the use of supplements (legal and banned). The ethics and future role, if any, of subspecialists in BN&NP performing “plastic surgery of the mind” through cosmetic pharmacotherapy are not fully elaborated and current practices of this type should be subjects of concern for the field.

Conclusion The prescription of a medication, while superficially appearing easy, involves many layers of decisionmaking. It is an active collaborative process between doctor, patient, and caregiver that goes far beyond simply calling the pharmacy. The decision about which medication, if any, to prescribe is determined by multiple factors: symptom, disease, ease of use, cost, insurance, etc. In the era of instant information, physicians need to be mindful that patients and families are aware of the potential problems with some medications. It is a physician’s responsibility to be prepared to actively address concerns and place them in the proper perspective. While physicians strive to prescribe medications rationally, sometimes things that do not make sense seem to work. For example, a patient with depression and anxiety may respond best to a combination of paroxetine 10 mg and escitalopram 10 mg after experiencing paroxetine 20 mg as too stimulating and escitalopram 20 mg as too sedating; the opposite of what “common sense” would lead one to believe. Similarly, some patients find methylphenidate more stimulating than dextroamphetamine despite the usual clinical experience to the contrary. A medication with an absence of support for or even negative studies in the literature may prove to be beneficial for some patients. If experience teaches anything, it is that physicians

507


must maintain a humble perspective on the enormous amount of information they do not know about the effects of the prescribed medications.

References 1. Mitchell PH, Veith RC, Becker KJ et al. Brief psychosocial-behavioral intervention with antidepressant reduces poststroke depression significantly more than usual care with antidepressant: living well with stroke: randomized, controlled trial. Stroke 2009;40(9):3073–8. 2. McCauley SR, Levin HS, Vanier M et al. The neurobehavioural rating scale-revised: sensitivity and validity in closed head injury assessment. J Neurol Neurosurg Psychiatry 2001;71(5):643–51. 3. Cummings JL, Mega M, Gray K et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44(12):2308–14. 4. Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D. The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986;143(1):35–9. 5. Silver JM, Yudofsky SC. The Overt Aggression Scale: overview and guiding principles. J Neuropsychiatry Clin Neurosci. 1991;3(2):S22–9. 6. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 1991;38(2):143–62. 7. Smith RA, Berg JE, Pope LE et al. Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients. Multiple Sclerosis 2004;10(6): 679–85. 8. Silver JM, McAllister TW, Arciniegas DB. Depression and cognitive complaints following mild traumatic brain injury. Am J Psychiatry 2009;166(6):653–61. 9. Narushima K, Paradiso S, Moser DJ, Jorge R, Robinson RG. Effect of antidepressant therapy on executive function after stroke. Br J Psychiatry 2007;190:260–5.

13. Meador KJ, Loring DW, Vahle VJ et al. Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology 2005;64(12):2108–14. 14. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23(8): 1296–310. 15. Zeller A, Ramseier E, Teagtmeyer A, Battegay E. Patients’ self-reported adherence to cardiovascular medication using electronic monitors as comparators. Hypertens Res. 2008;31(11):2037–43. 16. Baker CB, Johnsrud MT, Crismon ML, Rosenheck RA, Woods SW. Quantitative analysis of sponsorship bias in economic studies of antidepressants. Br J Psychiatry 2003;183:498–506. 17. Perlis RH, Perlis CS, Wu Y et al. Industry sponsorship and financial conflict of interest in the reporting of clinical trials in psychiatry. Am J Psychiatry 2005; 162(10):1957–60. 18. DeKosky ST, Williamson JD, Fitzpatrick AL et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. J Am Med Assoc. 2008; 300(19):2253–62. 19. Cosgrove L, Bursztajn HJ, Krimsky S, Anaya M, Walker J. Conflicts of interest and disclosure in the American Psychiatric Association’s Clinical Practice Guidelines. Psychother Psychosom. 2009;78(4): 228–32. 20. Moynihan R. Key opinion leaders: independent experts or drug representatives in disguise? Br Med J. 2008;336(7658):1402–3. 21. American Psychiatric Association. APA Practice Guidelines. Available from: http://www.psychiatryonline.com/pracGuide/ pracGuideHome.aspx. 22. Berg MJ, Gross RA, Tomaszewski KJ, Zingaro WM, Haskins LS. Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology 2008;71(7):525–30. 23. Bolton S. Bioequivalence studies for levothyroxine. AAPS J. 2005;7(1):E47–53.

10. Warden DL, Gordon B, McAllister TW et al. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma 2006;23(10):1468–501.

24. Barone JA, Byerly WG. Determination of bioequivalence of psychotropic drugs and concerns involving product interchange. J Clin Psychiatry 1986;47(Suppl.):28–32.

11. Schmitt JA, Kruizinga MJ, Riedel WJ. Non-serotonergic pharmacological profiles and associated cognitive effects of serotonin reuptake inhibitors. J Psychopharmacol. 2001;15(3):173–9.

25. Diamond BI, Albrecht JW. Medical and psychiatric implications of generic drugs. Psychopathology 1987; 20(Suppl. 1):92–8.

12. Salinsky MC, Storzbach D, Spencer DC et al. Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers. Neurology 2005;64(5):792–8.

508

26. Kesselheim AS, Misono AS, Lee JL et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and metaanalysis. J Am Med Assoc. 2008;300(21):2514–26.


27. Van Wijk BL, Klungel OH, Heerdink ER, de Boer A. Generic substitution of antihypertensive drugs: does it affect adherence? Ann Pharmacother. 2006;40(1): 15–20. 28. Plassmann H, O’Doherty J, Shiv B, Rangel A. Marketing actions can modulate neural representations of experienced pleasantness. Proc Natl Acad Sci USA 2008;105(3):1050–4. 29. US Food and Drug Administration. Guidances (Drugs). Available from: http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/default.htm.

dopaminergic transmission by amantadine. Eur J Neurosci. 2004;19(8):2212–20. 41. Peeters M, Maloteaux JM, Hermans E. Distinct effects of amantadine and memantine on dopaminergic transmission in the rat striatum. Neurosci Lett. 2003; 343(3):205–9. 42. Quack G, Hesselink M, Danysz W, Spanagel R. Microdialysis studies with amantadine and memantine on pharmacokinetics and effects on dopamine turnover. J Neural Transm Suppl. 1995;46: 97–105.

30. Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003;25(6):1578–92.

43. Spanagel R, Eilbacher B, Wilke R. Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat – a pharmacokinetic microdialysis study. Eur J Pharmacol. 1994;262(1–2):21–6.

31. Chenu F, Batten LA, Zernig G et al. Comparison of pharmacokinetic profiles of brand-name and generic formulations of citalopram and venlafaxine: a crossover study. J Clin Psychiatry 2009;70(7): 958–66.

44. Smialowska M. The influence of 1,3-dimethyl-5-adamantanamine (D-145) on catecholaminergic neurons of the rat brain, histofluorescence studies. Pol J Pharmacol Pharm. 1976;28(3):259–67.

32. Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373(9665):746–58.

45. Clement HW, Grote C, Svensson L et al. In vivo studies on the effects of memantine on dopamine metabolism in the striatum and n. accumbens of the rat. J Neural Transm Suppl. 1995;46:107–15.

33. Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry 2007;62(4):345–54.

46. Wang BS, Wang H, Wei ZH et al. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer’s disease: an updated meta-analysis. J Neural Transm. 2009;116(4): 457–65.

34. Lange R, Volkmer M, Heesen C, Liepert J. Modafinil effects in multiple sclerosis patients with fatigue. J Neurol. 2009;256(4):645–50.

47. Wazana A. Physicians and the pharmaceutical industry: is a gift ever just a gift? J Am Med Assoc. 2000;283(3):373–80.

35. Stankoff B, Waubant E, Confavreux C et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology 2005;64(7):1139–43.

48. Ristow M, Zarse K, Oberbach A et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci USA 2009;106(21): 8665–70.

36. Krupp LB, Coyle PK, Doscher C et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995;45(11):1956–61. 37. Pucci E, Branas P, D’Amico R et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2007;1:CD002818. 38. Kornhuber J, Weller M, Schoppmeyer K, Riederer P. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl. 1994;43:91–104. 39. Page G, Peeters M, Maloteaux JM, Hermans E. Increased dopamine uptake in striatal synaptosomes after treatment of rats with amantadine. Eur J Pharmacol. 2000;403(1–2):75–80. 40. Peeters M, Romieu P, Maurice T et al. Involvement of the sigma 1 receptor in the modulation of

49. ConsumerLab.com. ConsumerLab.com. Available from: http://www.consumerlab.com. 50. Brown RP, Gerbarg PL, Muskin PR. How to use Herbs, Nutrients & Yoga in Mental Health Care. 1st edition. New York, NY: W.W. Norton; 2009. 51. Blackwell B. Treatment adherence. Br J Psychiatry 1976;129:513–31. 52. Dikmen SS, Temkin NR, Miller B, Machamer J, Winn HR. Neurobehavioral effects of phenytoin prophylaxis of posttraumatic seizures. J Am Med Assoc. 1991; 265(10):1271–7. 53. Smith KR, Jr., Goulding PM, Wilderman D et al. Neurobehavioral effects of phenytoin and carbamazepine in patients recovering from brain trauma: a comparative study. Arch Neurol. 1994;51(7):653–60.

509


54. Stanislav SW. Cognitive effects of antipsychotic agents in persons with traumatic brain injury. Brain Inj. 1997;11(5):335–41. 55. Rao N, Jellinek HM, Woolston DC. Agitation in closed head injury: haloperidol effects on rehabilitation outcome. Arch Phys Med Rehabil. 1985;66(1):30–4. 56. Buffett-Jerrott SE, Stewart SH. Cognitive and sedative effects of benzodiazepine use. Curr Pharm Des. 2002;8(1):45–58. 57. Goldstein LB. Neuropharmacology of TBI-induced plasticity. Brain Inj. 2003;17(8):685–94. 58. de Smet Y, Ruberg M, Serdaru M et al. Confusion, dementia and anticholinergics in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1982;45(12): 1161–4. 59. Dubois B, Pilon B, Lhermitte F, Agid Y. Cholinergic deficiency and frontal dysfunction in Parkinson’s disease. Ann Neurol. 1990;28(2):117–21. 60. Dixon CE, Liu SJ, Jenkins LW et al. Time course of increased vulnerability of cholinergic neurotransmission following traumatic brain injury in the rat. Behav Brain Res. 1995;70(2):125–31. 61. Menza M, Dobkin RD, Marin H et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009;72(10): 886–92. 62. Robinson RG, Schultz SK, Castillo C et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry 2000;157(3):351–9. 63. Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated with

510

antidepressant medication. Biol Psychiatry 2001; 50(4):260–5. 64. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of hippocampal neurogenesis by lithium. J Neurochem. 2000;75(4):1729–34. 65. Jeste DV, Blazer D, Casey D et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008; 33(5):957–70. 66. Salzman C, Jeste DV, Meyer RE et al. Elderly patients with dementia-related symptoms of severe agitation and aggression: consensus statement on treatment options, clinical trials methodology, and policy. J Clin Psychiatry 2008;69(6):889–98. 67. Hesdorffer DC, Kanner AM. The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia 2009;50(5):978–86. 68. Hesdorffer DC, Ishihara L, Mynepalli L et al. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol 2012 (Epub ahead of print). 69. Chatterjee A. Cosmetic neurology: the controversy over enhancing movement, mentation, and mood. Neurology 2004;63(6):968–74. 70. Greely H, Sahakian B, Harris J et al. Towards responsible use of cognitive-enhancing drugs by the healthy. Nature 2008;456(7223):702–5. 71. Cakic V. Smart drugs for cognitive enhancement: ethical and pragmatic considerations in the era of cosmetic neurology. J Med Ethics 2009;35(10):611–15. 72. Larriviere D, Williams MA, Rizzo M, Bonnie RJ. Responding to requests from adult patients for neuroenhancements: guidance of the Ethics, Law and Humanities Committee. Neurology 2009;73(17): 1406–12.

Section III Chapter

33


Rehabilitation and pharmacotherapy of cognitive impairments David B. Arciniegas, Hal S. Wortzel, and Kimberly L. Frey

Cognitive impairments define some neuropsychiatric syndromes (e.g., dementia, delirium) [1] and are prominent features of many primary psychiatric disorders [2–5] and neurological conditions [6–9]. Regardless of the clinical condition in which they develop, cognitive impairments are substantial sources of disability and of distress for affected individuals and their families [10, 11]. The evaluation and treatment of cognitive impairments therefore is a core component of the practice of Behavioral Neurology & Neuropsychiatry (BN&NP). Neuropsychiatric function comprises a diverse set of information-processing abilities that operate within a hierarchy of relative neuroanatomic and functional complexity [12, 13] (Box 33.1). Between the lower and higher ends of this hierarchy are multiple psychologically distinct, neurobiologically interactive, and functionally important cognitive domains: attention, perception, recognition, working memory, implicit (procedural) memory, explicit (declarative) memory, language, prosody, praxis, visuospatial function, and executive function. Each of these cognitive domains is predicated on relatively specific, albeit highly interconnected, sets of neural structures and networks [14]. Increasingly complex cognitive functions rely on, and often incorporate, the neuroanatomic structures and functional processes supporting relatively basic cognitive functions. Impairments at the lower end of the cognitive hierarchy also may compromise information processing not only at those levels but also at higher ones (e.g., executive function), even when the neuroanatomic substrates of the latter are intact [15, 16]. Similarly, disturbances of emotional generation, whether excessive (e.g., sadness, fearfulness, irritability) or deficient

Box 33.1. A hierarchy of neuropsychiatric function, with relatively more basic functions at the bottom of this list and relatively more complex functions at its top. Personality Emotional regulation Comportment Executive function (including executive control functions) Visuospatial function Melokinetic and ideomotor praxis Language and prosody Memory, generation of emotion Perception and recognition (gnosis) Processing speed Sustained attention, motivation Selective attention Arousal and sleep

(e.g., affective placidity), color attention and perception, may aberrantly direct (or entirely fail to direct) information-processing resources, and thereby often interfere with cognition [16–21]. Impairments at the upper end of the hierarchy (i.e., executive dysfunction) include deficits of “intrinsic” executive functions (e.g., abstraction, judgment, problem solving) as well as impairments of “executive control functions” [22]. The latter compromise effective use of relatively intact cognitive functions at the lower end of the hierarchy, including executive control of attention, memory, language, praxis, and visuospatial function. This heuristic simplifies cognitive and noncognitive neuropsychiatric functions, and it is by


511


Box 33.2. Elements of the pre-treatment evaluation of cognitive impairments. Detailed history-taking, emphasizing the nature, course, and functional relevance of cognitive complaints and/or impairments Identification of cognitive and non-cognitive strengths and weaknesses Developmental, medical, neurological, psychiatric, substance use, occupational, social, and family histories Current and past medications and substance use General physical and neurological examinations Mental status examinations, including “bedside” cognitive examinations Formal neuropsychological testing (if needed) Neurodiagnostic studies Structural brain imaging, preferably with magnetic resonance imaging (MRI) Electroencephalography (EEG) (when clinically indicated) Serum, urine, and cerebrospinal fluid studies (when clinically indicated)

no means the only schema by which these phenomena may be understood usefully. Nonetheless, it offers a clinically practical guide to the clinical evaluation, differential diagnosis, and treatment of cognitive impairments and will be used to organize the presentation of this material in this chapter. This chapter first reviews several essential pretreatment considerations. The principles of neuropsychiatric treatment are discussed in Chapter 32, and only a few of these are reiterated briefly here. The general principles of cognitive rehabilitation and pharmacotherapy are then reviewed, followed by considerations of the evaluation and management of domainspecific cognitive impairments.

Pre-treatment evaluation Cognitive complaints and/or impairments are common reasons for consultation with BN&NP subspecialists. The assessment of patients with such problems includes the elements presented in Box 33.2. As noted above, the evaluation of cognition begins by determining whether the presenting problem is a subjective concern (i.e., cognitive complaint), an objectively demonstrable cognitive impairment, or both. Concurrently, the specific types and course(s) of cognitive

512

problems also are clarified. Patients, or the individuals requesting their evaluation, often voice concerns about “memory” problems; however, the intended referent of “memory” is sometimes a disturbance in an entirely different cognitive domain (e.g., inattention, word-finding deficits, ideational apraxia, dyscalculia). The temporal features of the presenting problem also require similarly careful clarification – i.e., sudden vs. rapid vs. insidious onset; intermittent vs. persistent impairment; static vs. progressive decline. Cognitive examination follows a detailed general physical and neurological examination in which assessment for focal, lateralizing, or elementary neurological findings, and subtle neurological signs are identified and used to refine the differential diagnosis. Cognitive performance and the process by which performance is achieved are incorporated into the clinical assessment in the manner described in Chapter 23 (Mental status examination). At a minimum, “bedside” cognitive assessments are used to characterize the patient’s cognitive difficulties and are normatively interpreted in order to ascertain the severity of those problems [23]. Neuropsychological testing may be useful when bedside cognitive assessments fail to identify impairments in the cognitive domains suggested by patient complaints or history, or when the pattern of impairment on these assessments is inconsistent with the diagnosis otherwise suggested by history and examination. Incorporating tests of effort and validity, as well as assessments of psychiatric/psychological processes (e.g., anxiety, depression) known to adversely affect cognitive performance also informs the evaluation and may direct initial treatment efforts toward noncognitive targets. Formal neuropsychological testing also may clarify cognitive strengths and weaknesses and thereby informs rehabilitative treatment planning, including compensatory strategy development. Collectively, these assessments clarify the clinical presentation, identify treatment targets, and establish a baseline to which the effects of treatment can be compared. Additional neurodiagnostic assessments may be appropriate to perform in some clinical contexts. Among persons with dementia, the American Academy of Neurology practice parameter for the diagnosis of dementia [24] recommends performing serum laboratory assessments for common reversible causes of cognitive impairment and additional assessments only when the clinical history supports their performance. When seizure-related (i.e., post-ictal)

Chapter 33: Rehabilitation and pharmacotherapy of cognitive impairments

cognitive impairments or delirium are suspected, electroencephalography (EEG) may inform the diagnostic assessment. Consistent with the recommendations of the American Academy of Neurology [24], structural brain imaging, usually magnetic resonance imaging (MRI), is appropriate to obtain as part of the evaluation of patients with cognitive impairment, including those with suspected dementia.

General treatment considerations Patient and family education, supportive therapy, environmental and behavioral interventions, and compensatory strategy development are the cornerstones of treatment for persons with cognitive impairments. Some patients also may benefit from formal cognitive rehabilitation and/or pharmacotherapy; however, these also will usually be provided as adjuncts to educational, supportive, environmental and behavioral, and office-based compensatory strategy interventions.

Education In the context of treating cognitive impairments, education includes discussion of the types, severities, causes, functional implications, and prognosis of those impairments with patients and their families/caregivers. Although patients and caregivers often expect subspecialists in BN&NP to prescribe medications for cognitive impairments, these are best regarded as adjuncts to other interventions and their anticipated benefits often will be modest; this element of patient and caregiver education needs to be provided unambiguously before initiating any cognitiondirected treatments and often requires reiteration after treatment is begun. Education establishes realistic treatment expectations and defines treatment duration and outcome goals (see Chapter 32). For example, appropriate cognitive treatment goals for patients with progressive neurodegenerative or neurological disorders (e.g., Alzheimer’s disease (AD), Parkinson’s disease, etc.), include supporting everyday function, delaying progression of cognitive symptoms and functional decline, and improving patient and caregiver quality of life despite persistent and/or progressive symptoms [25]. In this context, temporarily stabilizing cognitive impairment is a more realistic treatment expectation than is improving cognition. For patients with potentially reversible causes of cognitive impairment, education about time-limited treatment and the need to

focus treatment on the condition causing cognitive impairments (to the extent possible) is essential. Concurrently, supportive measures, symptomtargeted rehabilitative interventions, and, in some cases, pharmacotherapies are provided. Since spontaneous recovery often contributes to cognitive improvement in these contexts, treatment-related education should help patients and caregivers anticipate treatment discontinuation trials following a plateau in cognitive and functional recovery. When cognitive impairments are chronic problems – including those due to neurological conditions, primary psychiatric disorders (e.g., schizophrenia, bipolar disorder), and neurodevelopmental disorders – additional cognitive rehabilitation and pharmacotherapeutic interventions may be considered. Realistic treatment expectations in this context include developing adaptive or compensatory strategies that both limit the adverse functional consequences of chronic cognitive impairments and also improve patient and/or caregiver quality of life. Less often, rehabilitative and pharmacologic treatments may remediate cognitive impairments. However, such treatment responses are neither invariable nor entirely predictable. Cognitive remediation therefore may be a laudable treatment goal but not a routine treatment expectation.

Supportive therapy Supportive therapy focuses on the personal, social/occupational, and functional challenges presented by cognitive impairments as well as their underlying causes. It is appropriate to provide such therapy to patients and their caregivers/families. The purposes of supportive therapy are to acknowledge the experience of cognitive problems, to work collaboratively to identify solutions to those problems and their consequences, and to foster adaptation if they prove intractable or progressive. In addition to these direct purposes, providing supportive therapy also promotes adherence to other prescribed treatments via the enhanced therapeutic alliance its provision creates. When patients are aware of and troubled by cognitive difficulties, focusing educational and supportive efforts on the patient is necessary and appropriate. When patients are not fully aware of their impairments, functional limitations, or treatment needs, engaging caregivers/families in these aspects of treatment is essential.

513


Environmental, behavioral, and compensatory interventions Environmental modification, behavioral management, and compensatory strategy development are also essential elements of any treatment plan targeting cognitive impairments and their functional consequences. Successful cognitive remediation or rehabilitation interventions generally include a mix of stimulus modalities, complexity, and response demands, and necessitate active involvement of the therapist in performance monitoring, feedback, and skills/strategy training. Critical to the effectiveness of such interventions is matching them to the functional limitations and functional goals of the patient and/or caregivers/family. In other words, useful interventions are patient- and family-centered: they address realworld problems in ways that are within the abilities of the patient and caregivers. Additionally, these interventions succeed to the extent that they generalize beyond the context of treatment and focus on improving not only performance on office-based tasks involved but also in everyday settings. It therefore is important to understand the contexts in which cognitive problems present functional challenges, recognize the relationship between perceived cognitive failures and affective/behavioral problems, and encourage the use of a proactive, rather than purely reactive, approach to these issues. This approach, in turn, facilitates improvements in the functional use of cognition, mitigates cognitive impairment-related disability, and alleviates patient and caregiver distress. For example, outlining daily events and challenges and scheduling them to coincide with periods when the individual is well rested and refreshed may limit the adverse effects of physical and/or cognitive fatigue on the patient’s function. Performance on everyday tasks and interpersonal interactions may also be improved substantially simply by adjusting patient and family expectations: i.e., waiting longer for verbal responses, teaching others not to respond or perform immediately for the individual, allowing longer intervals to accomplish tasks, and so forth. Encouraging the use of “cognitive prosthetics” such as memory notebooks, timers with alarms and messages, task lists, verbal and/or non-verbal cues from others (or by signage posted in the patient’s environment) is often quite helpful for impairments in attention, working memory, declarative memory, and executive function. Use of cognitive prosthetics may also reduce performance

514

failure- or frustration-related affective responses (e.g., anxiety, crying, anger/agitation, etc.). Similarly, assistive technologies such as communication devices, “smart phones,” global positioning devices, and so forth also may permit compensation for impairments in language, topographical orientation, and executive function.

Cognitive rehabilitation Consultation and/or collaboration with a cognitive rehabilitation specialist may refine these interventions, but is not a prerequisite to their provision by subspecialists in BN&NP. When formal cognitive rehabilitation is undertaken, applying an evidence-based approach to treatment selection and administration is encouraged. The American Congress of Rehabilitation Medicine (ACRM) [26–28] and the European Federation of Neurological Societies (EFNS) [29, 30] developed evidence-based recommendations for the rehabilitation of cognitive deficits associated with stroke and traumatic brain injury (TBI). General cognitive rehabilitation interventions commented upon by these groups, the level of evidence supporting them, as well as comments on their use, are presented in Table 33.1. Information of this type regarding domain-specific cognitive rehabilitation interventions is presented in Table 33.2. Although the recommendations offered by the ACRM and EFNS are intended to apply to TBI and stroke specifically, the interventions they describe are used to treat cognitive impairments associated with other neuropsychiatric disorders as well [31]. Cognitive rehabilitative interventions also are used to assist patients and families with neurodegenerative disorders; compensatory strategy development, functional adaptation by caregivers, and improved quality of life, rather than cognitive remediation, are appropriate treatment goals in such contexts. Similarly, cognitive rehabilitation interventions may be used to improve functional independence among patients with cognitive impairments due to primary psychiatric disorders such as schizophrenia or bipolar disorder. Before referring a patient for cognitive rehabilitation, we recommend reviewing the literature to ascertain the intervention types, if any, for which there is evidence of benefit for the treatment of cognitive impairments associated with that patient’s specific neurological condition. Discussing the evidence


Table 33.1. Evidence-based recommendations for the general approach to cognitive rehabilitation for persons with traumatic brain injury (TBI) and/or stroke. The recommendation levels offered by the American Congress of Rehabilitation Medicine (ACRM) are framed as Standard ⬎ Guideline ⬎ Option, whereas the European Federation of Neurological Societies (EFNS) framed evidence-based recommendations as Definite ⬎ Probable ⬎ Possible. For the purpose of presentation in this table, these recommendations are presented as levels A (Standard/Definite), B (Guideline/Probable), and C (Option/Possible), NR (not recommended). The EFNS reviews do not yet specifically address these interventions; blank cells therefore reflect the absence of specific comment on the intervention described.

Evidence-based recommendations Intervention

ACRM

EFNS

Comment

Comprehensive-holistic neuropsychologic rehabilitation

A

Recommended during post-acute rehabilitation to reduce cognitive and functional disability for persons with moderate to severe TBI

B

In the context of a comprehensive neuropsychologic rehabilitation program, integrated treatment of individualized and group psychotherapies (emphasizing emotional, behavioral, and interpersonal function) are recommended and may facilitate success of cognition-specific interventions

Compensatory strategy training

B

Recommended for persons with severe memory impairment only if applied to functional activities; likely to be most useful when offered after emergence from post-traumatic amnesia (include the late post-injury period)

Self-regulation and self-monitoring instruction

C

May be helpful for persons with impairments of executive function, attention (including neglect states), memory, and/or emotional regulation

Computer-based tasks without therapist involvement

NR

Rote practice on computer without clinician involvement is not recommended

supporting any proposed cognitive rehabilitation interventions with the patient, his or her caregiver/family, and the cognitive rehabilitation specialist to whom the patient is referred is an essential element of treatment planning – especially since the cost of cognitive rehabilitation often will be borne entirely by the patient and his or her family. Thereafter, coordinating the development, implementation, and evaluation of a time-limited, goal-directed, and functionally relevant cognitive rehabilitation treatment plan by engaging the ongoing input of all parties to it also is required.

Pharmacotherapy As noted earlier, pharmacotherapy is best regarded as an adjunct to non-pharmacologic treatments of cognitive impairment. Nonetheless, common clinical experience suggests that the tendency among most physicians, including some subspecialists in BN&NP, is to prescribe medications as first-line interventions for cognitive impairments and to undervalue, or sometimes ignore entirely, non-pharmacologic interventions of the sorts described in this chapter. Although pharmacotherapy may be useful, individual responses to medications aimed at improving or stabilizing cognitive performance are highly variable and, when used

in isolation, of modest value at best. In general, we suggest that medications be regarded as interventions intended to support brain functioning in a manner that enhances the effectiveness of non-pharmacologic treatments. Even where there are regulatory agency-approved or generally accepted uses of pharmacologic treatments for specific cognitive disorders (e.g., dementia due to AD), individual treatment selection remains a matter of clinical judgment and empiric trial. The published literature should be used as an initial guide to treatment planning. When there are no published reports that are directly relevant to the condition of the patient for whom treatment is being planned, selecting medications that have been used in pathophysiologically and/or phenomenologically similar conditions is encouraged – recognizing that these types of comparisons are relatively weak foundations for treatment selection. It is essential to engage patients or their medical decision-makers in the treatment selection process, and to obtain informed consent to treatment before prescribing cognition-specific pharmacotherapies. At a minimum, the elements of that process include: discussion of the published evidence for treatment and/or the rationale for treatment-by-analogy; whether treatment is regulatory agency-approved, an

515


Table 33.2. Evidence-based recommendations for the domain-specific rehabilitation of cognitive impairments following traumatic brain injury (TBI) and/or stroke. The recommendation levels offered by the American Congress of Rehabilitation Medicine (ACRM) are framed as Standard ⬎ Guideline ⬎ Option, whereas the European Federation of Neurological Societies (EFNS) framed evidence-based recommendations as Definite ⬎ Probable ⬎ Possible. For the purpose of presentation in this table, these recommendations are presented as levels A (Standard/Definite), B (Guideline/Probable), and C (Option/Possible), NR (not recommended); blank cells indicate the absence of specific comment on the intervention described.

Cognitive

Evidence-based recommendations

domain

ACRM

EFNS

Comment

Attention

A

A

Attention training is recommended during the post-acute rehabilitation period, and includes direct attention training as well as metacognitive training directed at compensatory strategy development and improved real-world function. The evidence available does not permit distinguishing between the effects of specific attention training during acute recovery and early rehabilitation periods from spontaneous recovery or from more general cognitive interventions

B

Memory

Language

516

A

Clinician-guided computer-based attention training may be used as an adjunct to other cognitive rehabilitation interventions for attention; however, this adjunctive strategy should not consist solely of repeated exposure to computer-based training tasks B

For individuals with mild memory impairments, memory strategy training is recommended; this training includes internalized strategies (e.g., visual imagery) and external memory compensations (e.g., notebooks).

B

For individuals with severe memory impairments, functionally relevant external memory compensations (e.g., notebooks) may be useful

C

For individuals with severe memory impairments, errorless learning may facilitate learning specific skills or knowledge; however, transfer of this training to novel tasks or functional use of memory is limited

C

Group-based interventions may be useful for the treatment of persons with memory impairments following TBI

A

B

Cognitive-linguistic therapies are recommended during acute and post-acute rehabilitation following left-hemisphere stroke

A

Specific interventions for functional communication deficits, including pragmatic conversational skills, are recommended as rehabilitation interventions for social communication deficits following TBI

B

Treatment of specific language impairments (e.g., reading comprehension and language formulation) is recommended; treatment intensity should be considered a key factor for effective language rehabilitation

C

Group-based interventions may be useful for the treatment of post-stroke language impairments

C

Group-based interventions may be useful for the rehabilitation of social communication skills after TBI

C

Computer-based interventions may be an adjunct to clinician-guided treatment for cognitive-linguistic deficits, but are not appropriately used without therapist involvement or in a manner that relies solely on repeated exposure and practice

Praxis

A

Specific gestural or strategy training is recommended as an acute rehabilitation intervention for apraxia following left hemisphere stroke

Vision and visuospatial function

A

A/B

Interventions for hemispatial (left) neglect after right (non-dominant) hemisphere stroke are recommended. The best evidence supports visual scanning as well as visuo-spatio-motor training; there also is evidence that reading, copying and figure description, video feedback, trunk orientation, forced use of left eye, and prism goggles also may be helpful

C

C

In the treatment of hemispatial neglect, there is modest evidence supporting the use of alertness and sustained attention training, caloric or galvanic vestibular stimulations, transcutaneous electrical stimulation of neck muscles, or limb activation technologies


Table 33.2. (cont.)

Cognitive

Evidence-based recommendations

domain

ACRM

Comment

C

For visual perceptual deficits (without left neglect) after right hemisphere stroke, systematic training of visuospatial deficits and visual organization skills may be useful during acute rehabilitation

C

Computer-based interventions to extend visual fields may be considered, and is most useful when combined with other rehabilitative interventions (e.g., paper/pencil tasks, positioning, neck vibration, forced use of left eye, and prism goggles)

NR Executive function

EFNS

NR

Computer-based exercises to treat left neglect after stroke do not appear to be effective

A

Metacognitive strategy training (i.e., self-monitoring and self-regulation, including emotional self-regulation) is recommended for treating executive dysfunction

A

Metacognitive strategy training is recommended as a component of interventions for attention and memory impairments, as well as visuospatial dysfunction (neglect)

B

Training in problem-solving strategies is recommended during the post-acute rehabilitation phase; this approach is most useful directed at strategies that apply directly to personally relevant everyday situations and functional activities.

C

Group-based interventions may be useful treatments for executive dysfunction, including problem-solving skills, after TBI

“off-label” treatment (i.e., lacking regulatory agency approval for the proposed use) that is generally accepted in the medical community, or an entirely novel “off-label” treatment; the indications for and possible benefits of treatment; the side effects and possible risks of treatment; and the likely costs of treatment, especially for “off-label” treatment for which third-party payers are unlikely to provide coverage. When medications are used to treat cognitive impairments, it is important to consider the principles of pharmacotherapy described in Chapter 32. In short, a “start-low, go-slow, but go” approach is encouraged. Assessing and documenting the effects of treatment (whether beneficial, adverse, or absent) is strongly encouraged; this entails pre-treatment assessment of the target cognitive impairment(s) using standardized assessments (including “bedside” cognitive measures) as well as cognitive impairment-related functional limitations. Accurate recording of the response to treatment, whether non-pharmacologic or pharmacologic, and sharing those results with the patient and his or her caregivers may facilitate engagement in and adherence to prescribed treatment. When treatment response is documented assiduously, it also decreases the likelihood that unsuccessful treatments will be continued or repeated. In the following sections of this chapter, cognitive domain-specific treatments are reviewed. Where

they inform treatment, the phenomena captured within each cognitive domain as well as relevant neuroanatomic and/or neurochemical considerations are considered briefly. This area of clinical practice is evolving, and new treatments and meta-analyses of treatment types are published frequently. For this reason, emphasis is placed on approaches that apply to the broadest possible range of conditions treated by BN&NP subspecialists.

Arousal Arousal denotes a state of wakefulness that occurs along a continuum with pathological extremes at both ends. Coma is the extreme end of the hypoarousal end of that continuum, and manic excitement, severe anxiety (including the hypervigilance and heightened reactivity of post-traumatic stress disorder), and agitated delirium represents conditions along the hyperarousal side of that continuum. Conditions producing hyperarousal and their management are addressed in Chapters 34 and 35, leaving the focus here on the evaluation and treatment of hypoarousal. Hypoarousal is a consequence of many conditions, including TBI, hypoxic-ischemic brain injury, cerebrovascular events, metabolic disturbances, medication or substance intoxication, cerebral neoplasms, advanced neurodegenerative conditions, and

517


congenital/developmental disorders, among others. Specific impairments of arousal are often grouped together as disorders of consciousness, and include coma, vegetative states (VS) – whether transient or persistent (i.e., PVS) – and the minimally conscious state (MCS). Hypoarousal reflects structural and/or functional impairment of the arousal system, which is comprised by several selective distributed reticulothalamic, thalamocortical, and reticulocortical networks. These networks include: reticulothalamic cholinergic projections arising from the pendunculopontine and laterodorsal tegmental; glutamatergic projections from the thalamus to the cortex (i.e., thalamocortical projections), which activate cortex and prepare it for information processing; and reticulocortical dopaminergic, noradrenergic, serotonergic, and cholinergic projections. The balance of activity within and between reticulothalamic, thalamocortical, and reticulocortical systems influences level of arousal. Injury to or dysfunction of these components impairs arousal and, therefore, cognition in general. The evaluation of the hypoaroused patient is described in Chapter 6. Based on a systematic review of the content validity, reliability, diagnostic validity, and prognostic value of the scales used most commonly to assess disorders of consciousness, the American Congress of Rehabilitation Medicine [32] recommends using the Coma Recovery Scale–Revised [33] for this purpose. Laboratory assessments directed at the identification of metabolic, endocrine, toxic, and other potential medical contributors to hypoarousal are essential elements of the diagnostic evaluation, and direct treatments toward the underlying causes of these conditions. Structural neuroimaging is recommended as an element of the diagnostic and prognostic evaluation of persons with disorders of consciousness; computed tomography (CT) and/or MRI may be required depending on the suspected underlying condition (see Chapter 26). Neuroimaging findings also may inform treatment response expectations; the absence of brain tissue targeted by medications bodes poorly for treatment response, whereas relatively preserved anatomy suggests otherwise. Functional MRI is emerging as an additional aid to the evaluation of disorders of consciousness [34], and may become an important element of both evaluation and treatment in the near future. EEG and evoked potentials, particularly somatosensory

518

evoked potentials, can also be useful as a method of identifying causes of, or contributors to, hypoarousal (e.g., seizures) and for making prognostic determinations. When causative or contributory medical conditions are present, treatment directed at such conditions is a prerequisite to any other intervention for patients with impaired arousal. Concurrently, providing supportive care and actively preventing additional medical complications is essential. Environmental interventions are directed toward providing cues that encourage adaptive engagement and limit distractions and overstimulation, including pain and medical assessments/procedures (i.e., venipuncture for “routine” serum laboratory assessments that are unlikely to yield management-directing information). Facilitating the entrainment of sleep–wake cycles by regulating lighting schedules and, as much as is feasible, providing feedings at typical mealtimes rather than continuously also may be useful environmental methods of entraining circadian rhythms needed to establish and maintain arousal. Coma stimulation protocols involve structured sensory stimulation, which their proponents suggest may promote recovery of sensory awareness and emergence from coma. The value of coma stimulation protocols remains uncertain [35, 36], but such interventions are unlikely to cause harm. If provided at all, doing so in the context of time-limited trials of coma stimulation with assiduous, serial, pre- and posttreatment structure assessments to evaluate the effects of their provision is encouraged. There are no FDA-approved pharmacologic options for the treatment of coma, PVS, or MCS. Based on the neurochemistry of arousal systems, glutamate-modulating, catecholamine augmenting, and/or pro-cholinergic agents might be useful. Among agents with such properties, amantadine – an uncompetitive N-methyl-D-aspartate (NMDA) antagonist that also indirectly facilitates dopaminergic function – is presently regarded as the first-line treatment for disorders of consciousness [37–39]. There are reports describing improvements of these disorders in response to treatment with bromocriptine [40], levodopa [41], pramipexole [41], methylphenidate [42, 43], lamotrigine [44], modafinil [45], and zolpidem [46–48], among others. The evidence supporting the use of these agents is limited, and the benefits and risks attendant to their use among persons with


disorders of consciousness are uncertain. Nonetheless, these medications may be treatment options when amantadine is ineffective or when amantadineinduced side effects are intolerable.

Attention and processing speed Attention refers to the ability to select and sustain information processing on an internal or external stimulus and, with executive control of attention, to alternate between information processing targets. Processing speed denotes the rate at which an individual processes and reacts to stimuli or information, and is manifested clinically as reaction time or response latency. Impaired attention and processing speed are features of many neurological and neuropsychiatric conditions; because they often co-occur and are addressed therapeutically in similar manners, their treatments are considered together in this chapter. Attention is not a unitary cognitive function but instead a set of processes that direct information processing [14]. The neuroanatomic bases of attention therefore are several, and include large-scale neural networks linking arousal centers, primary and secondary association cortices, heteromodal (parietal and frontal) cortical areas, limbic and paralimbic structures (including the amygdala and anterior cingulate cortex), thalamus, and the white matter structures connecting these areas. The distributed nature of the neuroanatomy of attention renders this set of cognitive abilities vulnerable to disruption by many neurological disorders. Spatial attention is generally regarded as a function that is lateralized to the non-dominant (usually the right) hemisphere. Processing speed is a similarly complex construct, involving not only the speed of information transfer within the brain but also the efficiency of information processing in and across cognitive domain-specific neural networks. In clinical practice, however, processing speed impairments are most frequently associated with conditions that disrupt the structure and/or function of cerebral white matter [49]. Attention and processing speed are modulated by multiple neurotransmitter systems, including glutamate, gamma-aminobutyric acid (GABA), acetylcholine, dopamine, norepinephrine, and serotonin [14, 50], as well as the interactions between these systems and genetically mediated variations in the receptors at which they act and the enzymes responsible for

their metabolism [51–53]. Modulation of any of these neurotransmitter systems may alter attention and processing speed. Clinical observation alone may suffice as evaluation of severe impairments in attention or processing speed. Less severe disturbances of attention and processing speed are more challenging to identify, and may not be readily apparent in the quiet, nondistracting, controlled environment in which many clinical examinations are performed. Few bedside cognitive screening measures include timed tasks and challenging tasks of attention and/or processing speed. Accordingly, the clinical examination of persons complaining of problems with attention and processing speed often requires formal neuropsychological evaluation, the results of which may be used to guide treatment selection and monitoring. Environmental and/or lifestyle adjustments for attention and processing speed impairments are directed at identifying and minimizing sources of distraction and overstimulation. Helping patients, caregivers, and others (e.g., employers, teachers) set realistic expectations about the pace and time required for task completion is essential; concurrently, it is important to provide supportive counseling about these impairments and their effects on perceived selfefficacy or self-worth. These interventions facilitate the development of reasonable expectations about level of productivity (or, conversely, need for functional support) at home and/or at work. In addition to allotting an appropriate amount of time and support for daily tasks, building defined periods of rest and recovery into the patient’s schedule may further enhance their function. Cognitive rehabilitation focused specifically on remediation of attentional impairments and/or compensatory strategy development may be useful [26– 30] (see Table 33.2). These interventions are most useful when provided to highly motivated patients with relatively mild impairments, during periods of relative clinical stability (e.g., late, rather than acute, post-injury or post-stroke periods), and in a manner that addresses specific, real-world functional limitations. As noted earlier, most pharmacotherapies for attention and/or processing speed impairments augment catecholaminergic function, cholinergic function, or both. Catecholamines quadratically modulate signal-to-noise ratio in information processing

519


systems. Mid-range cerebral catecholamine levels allow information processing networks to optimize processing of “signal” (information to which attention is directed) and, through active inhibition at the neural level, to minimize “noise” (information to which attention is not directed, i.e., potential distractors). When cerebral catecholamine levels are low, signal-tonoise ratio is reduced as a result of inadequate “signal” generation; when levels of cerebral catecholamines are high, signal-to-noise ratio is low as a result of excessive “noise” (i.e., information processing circuits that should be inhibited remain active and compete for information processing resources). Methylphenidate augments cerebral catecholamine levels and is commonly used to treat attention and processing speed impairments [54–60]. Despite commonly expressed concerns regarding the cardiovascular safety of methylphenidate, use of this agent among adults with brain injuries [61–64] or adult attention-deficit hyperactivity disorder (ADHD) [65–68] is generally well tolerated and safe. The effect of this medication on seizure threshold also appears to be modest, and its use does not appear to alter seizure frequency even among persons at risk for or with established epilepsies [61, 62, 69, 70]. It is prudent to perform baseline cardiovascular assessments, evaluate seizure risk, and monitor assiduously for adverse events when treatment with methylphenidate or similar medications is undertaken. Clinicians and patients commonly voice concerns for tachyphylaxis and the development of methylphenidate abuse/dependence; however, these problems are uncommon, even among persons with histories of substance use disorders [71, 72]. Nonetheless, it is important to remain vigilant for signs of drug abuse, dependence, and/or diversion when this or any other stimulant medication is used to treat attention and/or processing speed impairments. When methylphenidate is ineffective or tolerated poorly, other catecholamine-augmenting agents may be considered. These agents include dextroamphetamine, amantadine, bromocriptine, levodopa, bupropion (sustained-release formulation), atomoxetine, and modafinil [58–60]. The literature describing their effects on attention and related problems among persons with neurological disorders suggests that these agents tend to be more beneficial for processing speed impairments than attention (vigilance), but there is substantial inter-individual treatment-response variability.

520

Acetylcholine improves the efficiency of signaling across many neurobehaviorally salient networks [50], and supports cognition quite broadly. The effects of acetylcholine on cognition follow an inverted-U curve, and either deficits or excesses of acetylcholine compromise the cognitive functions supported by this neurotransmitter. Treatment of patients with cerebral cholinergic deficits using pro-cholinergic agents – most commonly one of the acetylcholinesterase inhibitors – may at least partially remediate those deficits and thereby improve cognition, including attention. In the absence of in vivo markers of cerebral cholinergic function, however, the empiric use of such agents poses at least some risk of impairing attention and other cognitive functions: patients whose cognitive impairments occur in the setting of either normal or excessive cerebral acetylcholine levels may be made worse by the administration of agents that increase those levels [73, 74]. As discussed later in this chapter, the acetylcholinesterase inhibitors are used primarily to treat declarative memory impairments. These agents also appear to improve sustained attention and processing speed impairments in some patients as well, and particularly among persons with comorbid, prominent declarative memory impairments [58, 75–77]. Among the acetylcholinesterase inhibitors, donepezil is used most commonly in light of its relative ease of use (once-daily dosing, one-step titration to maximal dose), favorable side effect profile, and limited drug–drug interactions. Galantamine, particularly in its extended-release formulation, and transdermal rivastigmine appear favorable in these regards as well, but published reports of their use for the treatment of conditions other than the neurodegenerative dementias (or mild cognitive impairment preceding them) are relatively few, and the findings with regard to their effects on attention are mixed [76–82]. In general, these agents are regarded as second-line interventions (at best) for impaired attention and/or processing speed. In principle, agents that normalize glutamatergic signaling (e.g., uncompetitive NMDA receptor antagonists, sigma-1 agonists) also may improve attention and processsing speed. As with dopamine and acetylcholine, either hypo- or hyperfunction of the glutamatergic system will produce neuronal dysfunction and, consequently, a broad range of cognitive impairments [59, 83–89]. The uncompetitive NMDA receptor antagonists memantine and amantadine are not


generally used as first-line treatments for attention and processing speed impairments, but they appear to be of some benefit for these problems [58, 90, 91], especially among persons with TBI [58–60, 92]. Their effects on attention and processing speed may reflect direct influences on glutamatergic signaling, indirect facilitation of dopaminergic function, or both of these and/or other mechanisms [59]. In contexts where hyperarousal interferes with attention (e.g., severe anxiety), augmentation of GABA function (e.g., with benzodiazepines) attenuates the activity of a broad range of neurobehaviorally salient networks and neurotransmitter systems, thereby reducing hyperarousal and secondarily improving selective and sustained attention. Similarly, serotonergic augmentation may modulate attention and processing speed via alterations of emotional, motivational, and social cognition as well as through modulatory influences on other neurotransmitter systems [93–95]. Agents that influence cerebral serotonergic systems, either through global increases in serotonin or receptor subtype-specific effects, thereby indirectly alter attention and processing speed through a variety of mechanisms. At present, however, attention and processing speed impairments usually are not primary targets of serotonergic pharmacotherapies; exceptions to this rule are depressive, anxiety, or other psychiatric disorders for which agents of these types are used to treat emotional or behavioral symptoms and secondarily improve cognitive disturbances. Partial responses to pharmacologic monotherapy of attention and processing speed are not uncommon, and are reasonably addressed by augmentation with a second attention- or processing speed-enhancer. Given that the principal beneficial effects of most of the non-stimulant medications are attributable (directly or indirectly) to the augmentation of cerebral catecholaminergic function, however, rational pharmacotherapy suggests that augmentation of a stimulant be undertaken using an agent with a complementary (rather than redundant) mechanism of action (e.g., complementing a catecholaminergic treatment with a pro-cholinergic or a glutamate-stabilizing treatment). When an augmentation strategy of this sort is undertaken, and maximally tolerated and beneficial doses established, it is important to taper the dose of primary medication in order to determine the necessity of its continued use (to reduce or eliminate polypharmacy whenever possible).

Recognition (gnosis) Agnosia describes a sensory domain-specific inability to recognize objects that is the result of impaired integration of sensory information at a cortical level (cortically based perception), impaired attachment of meaning to those percepts (association), or both. Patients with agnosia typically present with this problem in a single sensory domain (i.e., visual, auditory, tactile and, at least theoretically, olfactory and gustatory) and with neuroanatomical lesions to the cortical processing streams serving the sensory domain in which the agnosia occurs. The sensory domain-specific presentation allows for distinguishing agnosias clinically from impaired naming (anomia): patients with agnosia are unable to recognize a stimulus presented in the affected domain (e.g., visual) but remain able to recognize (and name) it when it is presented in an unaffected domain (e.g., auditory or tactile). Since intact primary sensory function is a required element of the agnosias, the evaluation for agnosia begins with a thorough examination of elementary sensory function. Additionally, since agnosia must be distinguished from anomia (alone or as part of another aphasia), a detailed language examination is required. Formal neuropsychological testing also may facilitate identification of the type and severity of agnosia. Identifying preserved recognition abilities in other sensory modalities also is needed, and contributes importantly to the development of compensatory strategies for specific agnosias. Unfortunately, formal cognitive rehabilitative interventions for agnosia lack robust evidentiary support [96, 97]. There also are no well-established pharmacotherapies for any of the agnosias. Educational, supportive, and environmental/behavioral interventions are likely to be the interventions that subspecialists in BN&NP are best able to offer, and will focus on helping patients and families adapt to agnosia-related functional limitations. Individually tailored compensatory strategies that capitalize on preserved cognitive abilities also may be worthwhile to attempt to develop. However, it will be prudent to maintain modest expectations of the likelihood that such strategies will improve daily function substantially. Consultation with a speech-language and/or occupational therapist experienced in the management of patients with agnosias may be very useful in such circumstances.

521


Memory Memory refers to the ability to learn, store, and retrieve information. Memory is not a unitary cognitive function; it comprises multiple cognitive processes that are supported by multiple neuroanatomical networks and neurochemical processes. These processes are described in detail in Chapter 11 of this volume. In clinical practice, the evaluation and treatment of memory disturbances is simplified by dividing them into working memory, declarative memory, and procedural memory types.

Working memory Working memory refers to the process of holding information in mind, or “on-line,” for a brief period immediately after that stimulus leaves the sensory field. Working memory overlaps with and extends the process of sustained attention, and depends on a complex set of bihemispheric cortical (especially frontoparietal) and subcortical structures that are supported by multiple neurotransmitter systems [98– 101]. The cortical, subcortical, and/or white matter elements of these networks are susceptible to disruption by a wide range of neurological and psychiatric disorders. Consequently, working memory impairments are common features of many conditions for which subspecialists in BN&NP are consulted. Working memory impairments are often difficult to distinguish from other attention and memory impairments at the bedside. Additionally, the neuroanatomies of working memory and executive function overlap substantially, and impairments in these domains often co-occur. Consequently, formal neuropsychological testing may be needed to distinguish between these problems and to identify their respective contributions to problems with everyday function. Treatment of working memory impairments follows the general principles outlined in Table 33.1 as well as the educational, supportive, behavioral, and environmental interventions discussed in the attention and processing speed impairment section of this chapter. There is emerging evidence that formal cognitive rehabilitation interventions specifically targeting working memory also may be useful [102]. These interventions are of two general types: strategy training, which is intended to promote the use of supplemental domain-specific techniques (e.g., mnemonic devices, information “chunking”) with which to improve a patient’s ability to hold in mind auditory and/or

522

visual information [102, 103]; and core training, which involves repetition of demanding working memory tasks designed to target domain-general working memory mechanisms [102, 104]. Although both approaches may be useful, selecting patients for these treatments and providing the structured intervention needed to obtain benefits from them is best undertaken by a cognitive rehabilitation specialist experienced in their administration. Pharmacologic treatments of working memory impairments include augmentation of cerebral catecholaminergic function, cholinergic function, or both. The initial approach employed often depends on the types of comorbid cognitive problems. For example, co-occurring working memory, attention, and/or processing speed impairments suggest that augmenting cerebral catecholaminergic function may be the most useful initial approach. Stimulant medications (e.g., methylphenidate, dextroamphetamine, mixed amphetamine salts) are often used for this purpose, although guanfacine (an agonist at adrenergic ␣2A receptors) [105], atomoxetine [106], and bromocriptine (an agonist at dopamine D2 receptors) [107] also may improve working memory. Pre-clinical evidence suggests that agonism of nicotinic ␣4␤2 and/or ␣7 receptors also may be useful treatments for these types of impairments, especially among persons with schizophrenia and related conditions [108, 109]. Pre-clinical studies also suggest that antagonists of histamine H3 receptors, which secondarily increase cerebral catecholamines, acetylcholine, and histamine, may become useful treatments for these types of cognitive impairments as well [110]. These and other receptor subtype-specific interventions may emerge as next-generation cognitionenhancing medications if multi-center randomized clinical trials support their effectiveness. As discussed more fully in the next subsection of this chapter, acetylcholinesterase inhibitors are used to treat declarative memory impairments associated with a broad range of neuropsychiatric conditions [111, 112]. When used for this purpose, some patients will experience secondary improvements in working memory as well [76, 77]. However, these agents do not appear to be particularly useful first-line treatments of working memory impairments, especially among persons with schizophrenia and related conditions [113– 115]. Working memory impairments are not the primary targets of serotonergic pharmacotherapies.


However, when medications that augment cerebral serotonin function are used to treat depressive, anxiety, and other psychiatric disorders, working memory and other cognitive disturbances associated with these conditions may improve secondarily [116].

Declarative memory Declarative memory describes the learning, storage, and retrieval of semantic (facts), episodic (events), and autobiographical (personal) information. Information acquisition requires intact sensory-to-cortical pathways, primary and secondary association cortices, parietal heteromodal association cortices, entorhinal-hippocampal complex, frontal cortices, and white matter connections between these areas. When this distributed representational network activates, and especially when accompanied by robust motivational/emotional, or “survival-related,” limbicparalimbic signaling, long-term potentiation (LTP) within the network processing that information is initiated. Long-term potentiation is a glutamatergically mediated and cholinergically dependent process [117, 118] that is necessary for the development of stable large-scale representational networks – i.e., the neural bases of “memory.” Impaired declarative new learning is generally associated with dysfunction of the hippocampal-forniceal-mammillothalamic pathway, whereas impaired volitional retrieval of declarative information is associated with dysfunction of the frontal-subcortical systems necessary for reactivation of the neural network in which such information is represented (see Chapter 11). While this description oversimplifies declarative memory, it offers a foundation for identifying declarative memory impairments and upon which to develop clinical interventions. History-taking from patients (and/or their caregivers) with memory complaints focuses on determining whether that patient is experiencing difficulty acquiring new information (i.e., facts, daily events, or other personally relevant information) and/or retrieving previously (including recently) learned information. As noted earlier in this chapter, patients and their families/caregivers frequently use the term “memory problems” as the chief complaint for many initial clinical encounters. Careful history and examination is needed to clarify the referent of such complaints before undertaking treatments designed to improve or compensate for disturbances of declarative memory.

Sensory impairments (e.g., vision loss, hearing deficits) sometimes interfere with or are responsible for difficulties with new learning. When present, it is prudent to treat the impairments to the greatest extent possible in order to minimize their possible contributions to problems with declarative new learning. Provided that such deficits are not present or do not substantively interfere with information acquisition, information yielded by bedside assessments and/or formal neuropsychological testing of declarative memory may be used to assess declarative memory and to guide treatment planning. Treatment of declarative memory impairments includes the educational, supportive, environmental, behavioral, and compensatory strategy interventions described earlier in this chapter. In general, interventions are most useful when they are offered not only to the patient but also the patient’s family/caregivers. Sources of overstimulation and distraction should be reduced as much as possible so as not to interfere with information acquisition or to distract while a patient is attempting to recall information. Encouraging rehearsal of new information may assist with encoding, and using written, verbal, and/or other environmental cues to facilitate retrieval may improve daily function despite persistent memory problems. Patients with declarative memory impairments often experience effort-related fatigue. Encouraging patients to anticipate the need to include cognitive rest periods in their daily schedules may mitigate the adverse effects of this type of fatigue on daily function. Additionally, it is often useful to identify occupational, academic, or interpersonal contexts in which memory impairments are functionally limiting and to engage individuals in those contexts with whom the patient interacts in the design and implementation of memory impairments compensation strategies. These approaches tend to be particularly useful for highly motivated patients with relatively mild impairments and when the interventions address specific, real-world, and personally meaningful functional limitations. Patients with relatively mild declarative memory impairments may benefit from formal cognitive rehabilitation employing memory strategy training [26– 30]. This type of training includes internalized strategies (e.g., visual imagery) and external memory compensation tools (e.g., notebooks, day planners, alarms, and other “cognitive prosthetics”). In clinical practice, these approaches tend to be used most easily by

523


patients whose declarative memory impairments are dominated by difficulties with retrieval rather than encoding; in other words, patients whose ability to learn new information extends to remembering to use these strategies and in who strategy training seeks to improve executive control of declarative memory. Among patients with relatively more severe memory impairments, functionally relevant external memory compensations (e.g., notebooks) also may be useful but it often requires substantial and intensive clinician- or caregiver-guided practice to make their use habitual. Errorless learning is a technique in which correct information is provided to the patient before he or she is permitted to “recall” and subsequently learn incorrect information, and its use may facilitate learning specific skills or knowledge. However, its principal benefits are likely to be avoidance of cognitive failures and the affective and/or behavioral responses they engender rather that functional improvements per se. In most cases, engaging caregivers, families, and others with whom the patient interacts will be necessary to develop compensatory and other rehabilitative interventions that minimize the negative effects of declarative memory impairments on functional abilities and quality of life, especially when these problems are progressive. Augmentation of cerebral cholinergic function, usually with acetylcholinesterase inhibitors, is widely regarded as the first-line pharmacologic intervention for declarative memory impairments associated with many neurological disorders [58–60, 111, 119, 120]. In clinical practice, the benefits of these agents do not appear to differ substantively as a function of the type of declarative memory impairment (i.e., encoding deficits, retrieval problems, or both). Reports suggesting that these agents also may lessen declarative memory disturbances associated with primary psychiatric disorders (e.g., schizophrenia, major depressive disorder, bipolar disorder, alcohol use disorders) are mixed [121, 122]. However, their use for these purposes is best reserved for the treatment of residual, medication-induced, or procedure-related cognitive impairments among persons receiving maximally tolerable and effective treatments of their primary psychiatric disorders. Uncompetitive NMDA receptor antagonists (i.e., memantine or amantadine) also improve declarative memory function associated with many neurological and psychiatric conditions [90, 123–129]. Memantine is used commonly as an adjunct to acetylcholinesterase

524

inhibitors for the treatment of the neurodegenerative dementias and cerebrovascular disease-related cognitive disorders [130–132]. Analyses of the specific effects of memantine on cognition in these contexts consistently demonstrate improvements in declarative memory across the spectrum of dementia severity [125, 126, 128, 129], although the clinical relevance of such improvements among persons with mild dementia is controversial [133]. There is emerging evidence of a potential benefit of memantine on cognitive impairments following TBI [92], although the limited evidence suggests that the improvements afforded by this treatment are predominantly in the domains of attention and language rather than declarative memory. Memantine and amantadine also are being studied as treatments for schizophrenia-associated cognitive impairments, including declarative memory disturbances [134, 135]. However, reports of the benefits of these agents in this context are mixed [134, 136– 138] and associated with a non-trivial rate of clinically important adverse effects [137]. Additional evidence demonstrating the safety and tolerability of NMDA receptor antagonists is needed before recommending them as treatments for schizophrenia-associated memory impairments. There is a limited literature suggesting that catecholamine augmentation using methylphenidate or neurochemically similar compounds may improve declarative memory among persons with TBI and other acquired brain injuries [58, 60, 139]. In light of the neurochemistry of declarative memory reviewed earlier in this section, it seems likely that the effect of catecholamine augmentation on declarative memory is indirect and related to primary improvements in arousal, sustained attention, processing speed, working memory, depression and/or other affective disturbances. Although it is possible that these agents might more directly improve declarative memory, the neurochemical mechanisms explaining such an effect are not clear or well established experimentally. As noted earlier in this chapter, pre-clinical reports suggest that nicotinic ␣4␤2 and/or ␣7 receptor agonists [108, 109] or histamine H3 receptor antagonists [110] also may be useful treatments for declarative memory impairments associated with a broad range of neurological and neuropsychiatric disorders, including AD and schizophrenia. However, additional clinical studies are needed to determine the role, if any, of these agents for this purpose.


There also is evidence that citicholine (CDPcholine) may improve declarative memory impairments associated with neurological and psychiatric conditions [140–143]. The available evidence suggests that this is a relatively safe agent, even among the elderly and patients with chronic neurological disorders. However, the minimal regulatory oversight of the production of citicholine and the limited data regarding its efficacy and safety suggest that any use of this agent be undertaken cautiously.

Procedural memory Procedural memory, a type of implicit memory, refers to the learning, storing, and retrieval of motor sequences (i.e., “how” to do tasks). Conceptually, procedural learning is related to praxis, which describes the performance of skilled purposeful movement on demand. The acquisition of new skills (i.e., procedural learning) is demonstrated at a later date by contextually relevant use of those skills (i.e., recall of previously learned procedures) on the on-demand request for their demonstration (i.e., praxis, or when impaired, apraxia). Procedural memory relies on the development and fine-tuning of sensorimotor-frontal-subcorticalcerebellar networks involved in the skill acquisition (including rehearsal) and later performance. Procedural memory impairments are common among patients with conditions that affect these structures, especially the striatum and the cerebellum. Unlike declarative memory, procedural memory is not hippocampally dependent and is dissociable from declarative memory. This dissociation is therapeutically relevant: declarative memory impairments that occur in the setting of relatively preserved procedural memory may find the latter an avenue of compensation for the former. For example, repeated, systematized, and structured procedures for daily routines or use of cognitive prosthetics might allow individuals to compensate for declarative memory deficits [144]. However, the evidence supporting this suggestion is mixed [144–147]. This variability may reflect two important features of procedural memory. First, although procedural memory is not hippocampally dependent it nonetheless may be adversely affected by structural or functional abnormalities in the systems supporting declarative memory. Recent evidence [148] suggests that episodic memory and executive function are involved in the

learning phase of procedural memory. Accordingly, severe disturbances and/or comorbid impairments in all three of these cognitive domains may attenuate the benefits of compensatory strategies that rely on intact procedural memory. Second, consolidation of procedural learning is facilitated by intensive, rather than temporally distributed, rehearsal [148, 149] and by sleep (especially rapid eye movement, or REM, sleep) [150]. Rehabilitation approaches that rely on procedural memory but fail to provide adequately intensive treatment or to ensure the development of the type of sleep necessary for procedural memory consolidation are likely to be suboptimally effective. Procedural memory is not generally assessed by BN&NP subspecialists, but is an important function about which to obtain information – particularly in patients with impaired declarative memory. When impairments in this cognitive domain are suspected or when rehabilitation plans that depend upon intact procedural memory are considered, formal neuropsychological testing of procedural memory is encouraged. As many neuropsychologists do not routinely include procedural memory in their assessment batteries [23], specifically requesting testing of this function using tasks such as rotary pursuit, serial reaction time, mirror tracing, and/or the weather prediction task [151– 153] may be necessary. The non-pharmacologic treatments of procedural memory impairments are not well established. As noted above, intensive initial rehearsal, relatively normal sleep (or at least adequate periods of REM sleep), as well as declarative memory and executive function contribute importantly to procedural learning. When treatment is directed specifically at procedural memory impairments, or when procedural memory is used to compensate for declarative memory impairments, intensive repetition of the procedures on which training occurs is essential. The intensity of treatment requires task repetitions sufficient to produce withinsession learning plateaus (saturation) [149] as well as a frequency of training sessions that maintains performance at or near those plateaus [148]. The pharmacologic treatment of procedural memory impairments is underdeveloped as well. It is plausible that medications that improve the functioning of the sensorimotor-frontal-subcorticalcerebellar networks involved in the skill acquisition and performance might facilitate improvements in procedural memory – i.e., agents that augment cerebral catecholamine and/or acetylcholine levels

525


or that normalize glutamatergic signaling. However, the effects of medications with these properties on procedural memory impairments are not yet demonstrated and any such treatment should be regarded as investigational.

Language Language refers to any system of symbolic communication, and includes the use of verbal, written, gestural or other symbols to effect information transfer. Syntax describes the way in which linguistic elements (e.g., words) are organized into strings (e.g., phrases or clauses) used when communicating. Semantics refers to the relation between words, phrases, signs, and symbols (e.g., signifiers), their meanings, and their interpretations. In most adults, the left hemisphere is dominant for the syntactic and semantic aspects of language. Injury to language-related areas of the brain disturbs syntax and/or semantics, producing clinical problems that are described as aphasias. Aphasia generally involves impairments of object naming and at least one other core aspect of language: fluency, repetition, and/or comprehension. There are many types of aphasias (see Chapter 12), most of which are acquired in adult life through vascular injury or neurodegenerative disease involving neural networks of the dominant (usually left) hemisphere, and particularly the perisylvian areas, that support the syntactic and semantic aspects of language. The evaluation of language requires consideration of careful examination of naming, fluency, comprehension, and repetition. Consultation with a speechlanguage pathologist and/or neuropsychologist may be required to characterize language deficits and to formulate a language rehabilitation plan. When such consultation is impractical, subspecialists in BN&NP may consider using the Mississippi Aphasia Screening Test for these purposes [154]. Treatment of aphasia includes the educational, supportive, environmental, behavioral, and compensatory strategy interventions described earlier in this chapter. In general, interventions are most useful when they are offered not only to the patient but also the patient’s family/caregivers. Engaging patients and their caregivers in the National Aphasia Association (www. aphasia.org/) and their network of community-based aphasia support groups is encouraged. Involvement in such groups may offer patients and caregivers advice and assistance derived from the first-hand experience

526

of living and coping with aphasia, and may contribute usefully to improving their quality of life [155, 156]. Aphasias and non-aphasic functional communication impairments may be improved through languagespecific rehabilitation [26–30]. The evidence supporting these interventions is developed most fully for the post-stroke aphasias, and supports both individual and group-based treatments (see Table 33.2). When aphasia rehabilitation is undertaken, referral to and collaboration with a speech-language pathologist with training and experience in provision of evidence-based aphasia treatments is encouraged. Intensity of treatment appears to be an important contributor to effectiveness, and suggests that traditional once- or twice-weekly 1-hour treatment sessions may be insufficient to effect maximal improvements in language impairments. In response to observations documenting the importance of treatment intensity, constraint-induced aphasia therapy (CIAT) and other forms of intensive aphasia treatment have been developed [157, 158]. In CIAT, treatment is provided for several hours daily over a 2- to 4-week treatment period, and is organized around a therapy task that forces verbal communication (i.e., constrains nonverbal and non-productive communication attempts) and that requires active engagement with the therapist. This approach appears to benefit patients with chronic and severe aphasias. Additional research is needed to refine the treatment and to better define the specific additional clinical characteristics of the populations for which CIAT is most beneficial. The role, if any, of language rehabilitation in the management of persons with progressive aphasias (e.g., non-fluent primary progressive aphasia, frontotemporal dementias, AD) is not well established. There are case reports suggesting that rehabilitationbased language interventions, including the development of alternative communication strategies, may be of some benefit in this context [159–162]. Controlled studies are needed to evaluate the possible benefits of language rehabilitation on progressive aphasias. Pharmacotherapies for non-progressive aphasia are underdeveloped. Several studies suggest that agents augmenting cerebral dopaminergic function and/or cholinergic function may improve acute and chronic post-stroke aphasias [163]. Catecholaminergic augmentation strategies for post-stroke aphasia, including bromocriptine and dexamphetamine, are most useful for the treatment of non-fluent aphasias. The benefits conferred by these agents are relatively


modest, occur in a limited subset of patients, and may be attributable to concurrent effects on motor function and/or motivational systems. Among the acetylcholinesterase inhibitors, only donepezil has been studied as a treatment for post-stroke aphasia [164, 165]. Language improvements are not maintained after donepezil discontinuation, suggesting a symptomatic rather than restorative pharmacologic effect. Acetylcholinesterase inhibitors also appear promising as treatments for adults with neurodevelopmental disorder-associated language disturbances, including Down syndrome [166, 167] and autism [168]. Combined memantine and CIAT improved chronic post-stroke aphasia in a single-site, randomized, double-blind, placebo-controlled study [169]. The memantine-treated groups in this study maintained improvements after study drug discontinuation, raising the possibility that combined memantine-CIAT may afford more than purely symptomatic improvements. Combining piracetam [170, 171], mixed amphetamine salts [172], and, perhaps, bromocriptine [173, 174] with post-stroke language rehabilitation also improves outcomes over rehabilitation or pharmacotherapies alone. The progressive aphasias also may be amenable to treatment using pharmacotherapies. Among persons with primary progressive aphasia, bromocriptine [175], galantamine [176], and memantine [177, 178] appear to afford modest improvements in language function and/or slow symptom progression. Among persons whose aphasia is a component of dementia, memantine may improve language [125, 126, 128, 129]. These observations, derived from pooled studies of memantine in dementia, suggest that the presence or development of aphasia in this context may be a reason to consider the addition of memantine to other ongoing therapies. There also is emerging evidence that transcranial magnetic stimulation may be useful for the treatment of non-progressive (usually post-stroke) [179– 181] and progressive aphasias [182]. However, the role of this intervention, alone or as an adjunct to language rehabilitation and/or pharmacotherapy, requires further investigation before its routine use in aphasia rehabilitation can be recommended.

Prosody Prosody refers to the melodic, affective, and kinesic components of language that add meaning and

enhance communication. Analogous to syntactic and semantic communication, fluency, comprehension, and repetition characterize prosody. Aprosodia results from injury to or dysfunction of areas in the nondominant hemisphere neuroanatomic homologs of the language areas of the dominant hemisphere. Like aphasia, aprosodia may present as an isolated problem (e.g., post-stroke) or as an element of a broader set of co-occurring cognitive impairments (e.g., in AD). The evaluation of prosody is described in detail in Chapter 13, to which readers are referred for additional information. There are no established treatments for the aprosodias. However, identifying these problems and educating patients and families about them may improve functional communication. Among patients with motor aprosodias, encouraging them to communicate affect directly (i.e., verbalizing feelings such as sadness, happiness, anger, etc.) is essential. Education is aimed at making patients and those with whom they interact aware that aprosodia renders inference about feeling states from facial expression and gestures unreliable. Among patients with sensory aprosodias, education directed at those with whom patients interact encourages direct communication of feelings (i.e., by describing them) and avoidance of sarcasms, double entendre, or other subtle prosodic devices that change the meaning of spoken utterances.

Praxis Praxis is the process by which a skill is enacted. Although this term has other meanings in other fields, in medicine its use is generally limited to its negative forms, apraxia (without praxis) or dyspraxia (poor praxis) and to describe impaired ability to perform skilled purposeful movements that is not attributable to sensory, motor, or language deficits (see Chapter 14). Apraxia may involve axial, limb, and/or whole-body movements and includes three major subtypes: limb-kinetic (or melokinetic), ideomotor, and ideational. Ideomotor and/or ideational apraxia are common features of many neurodevelopmental, neurodegenerative, and other neurological conditions [1, 183–191]. Apraxia may interfere with activities of daily living (ADLs), adversely affect the effective use of other cognitive functions (e.g., verbal apraxia limiting use of intact language functions), and diminish patient and caregiver quality of life [188].

527


The neuroanatomy of praxis closely approximates the neuroanatomy of language. The core deficits of ideomotor apraxia reflect defects in movement representations coded for in pre-motor association areas of the dominant hemisphere, thereby explaining the frequent co-occurrence of ideomotor apraxia and non-fluent aphasia [192]. Ideational praxis engages neural systems involved in routine movements and requires their sequencing into more complex routines; as such, this form of praxis requires executive control of complex motor programming [193] and often is comorbid with other forms of executive dysfunction. The evaluation of apraxia is predicated on assessment of sensorimotor function and language comprehension; as reflected in the definition of apraxia, if deficits in these domains are present then they cannot be of a severity sufficient to account for problems performing skilled purposeful movements on demand. Several bedside assessments of praxis are available and may be a useful guide to such evaluations [185, 194, 195]. Additional assessment of praxis, as well as associated cognitive and functional problems, by a speech-language pathologist, occupational therapist, and/or neuropsychologist also may provide information that is useful diagnostically and therapeutically. Education, supportive therapy, behavioral and environmental interventions, and compensatory strategy training are important elements of any treatment plan for persons with apraxia. As this type of impairment is not in common parlance outside BN&NP and related disciplines, ensuring that patients, their caregivers, and other clinicians understand the problem and its implications is a prerequisite to other interventions. Among patients with progressive conditions in which apraxia is likely to become more severe and functionally limiting, caregiver education and training is especially important. As apraxia worsens, caregivers often are required to provide increasingly “hands on” assistance to patients – in other words, facilitating movements and task performance with manual initiation and/or facilitation rather than verbal cues and encouragement. Caregivers, and especially spouses and adult offspring, sometimes are not emotionally prepared to provide this level of support when it becomes necessary. Some caregivers initially regard providing “hands on” assistance with ADLs – especially feeding, bathing, and toileting – as intrusive or demeaning to those for whom they are

528

caring. Unfortunately, such reactions and resistance to providing assistance with these tasks may put at risk the health and safety of patients with apraxia. Providing caregivers and patients with supportive therapy focused on these issues may allow them to accept the necessity of such interventions, identify alternate providers when such are necessary, and cope with the change in roles and relationship entailed by this and related cognitive disabilities. Compensatory strategy training for task- and/or gesture-related post-stroke apraxia may improve everyday function [26–28, 196], although consensus is lacking on the effectiveness of these interventions [197]. The evidence regarding the rehabilitation of apraxia associated with other conditions, especially neurodegenerative and/or vascular dementias, is less well developed. While acknowledging that the evidence for the effectiveness of apraxia-focused rehabilitation is meager, patients and caregivers nonetheless often benefit from training provided by rehabilitation therapists on methods of reducing the complexity of tasks with which apraxia interferes. This training focuses on setting up task elements (e.g., objects, their locations, their order) in a manner that facilitates performance despite apraxia, as well as identifying verbal and/or physical cues that facilitate appropriate limb or body positioning during task execution [198]. For example, patients with relatively preserved language and executive function may benefit from training to use self-talk as a means of guiding and reinforcing task performance. Errorless learning, in which task performance is guided by imitative cues, also may be helpful for some patients [199]; however, improvements are task-specific and tend not to generalize to untrained tasks. When language is compromised but visual and visuospatial skills are relatively preserved, pictures may be useful task performance cues. When such interventions are not successful, elimination of some tasks (e.g., stovetop cooking), manual facilitation of tasks, or performance of tasks by a caregiver may be necessary. The pharmacotherapy of apraxia is underdeveloped. There are case reports describing lessening of isolated apraxic impairments during treatment with levodopa [200], amantadine [201], or donepezil [202]. Among patients with dementias, apraxia tends to respond to treatment with acetylcholinesterase inhibitors [203, 204] and/or memantine [125, 126, 129]. The available evidence therefore suggests that


apraxia may be a treatment-responsive target of pharmacotherapy among persons with dementias. If pharmacotherapy is provided for apraxia following stroke or other focal brain injuries, time-limited empiric trials of catecholamine-augmenting agents (including indirect augmentation with amantadine or memantine) or acetylcholinesterase inhibitors also may be considered.

Visuospatial function Visuospatial function denotes a set of complex visual processing abilities that include spatial awareness and attention, awareness of self-other and self-object spatial relationships, visuospatial memory, and the ability to interpret and navigate the extrapersonal space (see Chapter 15). Disorders of visuospatial function are common features of many neurological disorders, particularly those affecting the structure and/or function of the right hemisphere through lesion or neurodegeneration. Visuospatial function is supported by a distributed neural network involving the reticular system, thalamus, superior colliculus, striatum, parietal cortex, and frontal eye fields [14]. As suggested above, right hemispheric specialization for this cognitive function is typical, and the right parietal cortex appears to be a critical node in the extended network supporting spatial attention. Visuospatial memory also is relatively lateralized to the right hemisphere, and the parahippocampal gyrus is a key element of the visuospatial memory network [205, 206]. Catecholamines and acetylcholine appear to modulate visuospatial function [126, 203, 207–209], although statements regarding the influences of these neurotransmitter systems on visuospatial function are based on inferences drawn from the effects of pharmacotherapies in neurodegenerative dementias. The evaluation for visuospatial dysfunction requires careful assessment of sensory and motor function as well as memory, language, recognition, praxis, and executive function; deficits in any of these may lead to impairments on tasks that ostensibly assess visuospatial function. Notwithstanding these and other confounds on the assessment of visuospatial function, line bisection, target cancellation tasks, and reading tasks are commonly used to assess this cognitive domain. Construction tasks (such as figure copy or clock drawing tasks) and self-dressing may reveal unilateral neglect and other disturbances

of visuospatial function. Testing for extinction to bilateral simultaneous stimulation may reveal hemiinattention. Visuospatial memory is assessed usefully by object location-learning and recall tests (i.e., the patient watches the examiner hide objects and then is asked to recall their location and/or retrieve those objects after a brief delay). Supportive, educational, behavioral, environmental, and compensatory strategy trainings are appropriate elements of the treatment for visuospatial impairments. The supportive and educational interventions are important to offer to patients and their caregivers. When anosognosia commonly accompanies severe hemispatial inattention, caregivers often become the principal recipients and beneficiaries of supportive and education interventions. In general, behavioral and environmental modifications for visuospatial dysfunction are provided by cognitive rehabilitation specialists and are most useful when anchored to evidence-based interventions (see Table 33.2) [26–30]. At their simplest, these interventions include modification of tasks such that their performance capitalizes on preserved function (usually in the unaffected hemispace) while concurrently providing training on visual scanning and visuospatial-motor training. Cues to draw attention to the affected hemispace may be useful as well. Encouraging caregivers to remove or reduce safety hazards in the neglected hemispace is essential, particularly when rehabilitation is ongoing and/or proves ineffective. Alertness and sustained attention training may secondarily benefit visuospatial function, as may a wide variety of assistive devices (e.g., prism goggles, caloric or galvanic vestibular stimulators, transcutaneous electrical stimulators applied to neck muscles, limb activation technologies). However, computer-based exercises alone are not effective treatments of hemispatial neglect and their use is not recommended. Clinical reports and expert opinions suggest that acetylcholinesterase inhibitors and uncompetitive NMDA receptor antagonists may improve visuospatial function among persons with neurodegenerative dementias [126, 203, 207–214]. Although these agents are usually prescribed in these contexts for problems other than visuospatial function, these studies suggest a possible role for their use among persons presenting with focal lesions or degeneration producing impairments in this cognitive domain [202, 215].

529


However, the pharmacotherapy of post-stroke hemispatial neglect historically focuses on catecholamine augmentation. Several studies suggest that bromocriptine or methylphenidate may improve post-stroke hemispatial neglect [216–218], although there are reports of this approach exacerbating hemispatial neglect as well [219–221]. Acetylcholinesterase inhibitors may be an alternative approach to the pharmacotherapy of post-stroke unilateral neglect [215]. If a medication is added to other rehabilitative interventions, assiduous monitoring of treatment effects is essential – these agents may improve attention in the affected hemispace or instead exacerbate neglect by redirecting attention to the unaffected hemispace [219–221].

Executive function Executive function refers to cognitive processes that manage and control “basic” aspects of cognition (i.e., executive control functions) as well as complex cognitive skills such as categorization and abstraction, problem solving, behavioral planning and organization, and set shifting (“intrinsic” executive functions). Executive dysfunction is a common feature of many neurological and psychiatric disorders [222– 228], and contributes substantially to functional disability, quality of life, and caregiver burden [10, 226, 228–235]. Executive function is predicated on the integrity of the dorsolateral prefrontal-subcortical circuits in both cerebral hemispheres and their connections to brain areas serving other sensory, motor, cognitive, emotional, and behavioral functions (see Chapter 5). The dorsolateral prefrontal-subcortical circuit also interacts with other prefrontal-subcortical circuits and limbic-subcortical circuits; these interactions facilitate executive control of motivation, social cognition, and emotion. All of these circuits are influenced by multiple neurotransmitters, including glutamate, GABA, acetylcholine, dopamine, norepinephrine, serotonin, and histamine. Impairments in this cognitive domain therefore may result from injury to or dysfunction of these circuits, their open-loop elements, a broad range of neurotransmitter disturbances, or a combination of these factors. Patients with mild executive dysfunction (and preserved insight) may present independently for evaluation and treatment of this problem. In many cases, however, executive dysfunction is accompanied by

530

(and contributes to) impaired insight, leading others to bring the patient for evaluation and treatment. Since executive function is not a term in common use outside the clinical neurosciences, problems in this cognitive domain are often described by patients and caregivers as difficulties with attention (alternating or divided), memory (retrieval), language (word-finding, fluency), or other basic cognitive functions. The history therefore must clarify the nature of the presenting problem as executive dysfunction, impairments in basic cognitive functions, or both. Obtaining descriptions of cognitive and functional performance from reliable informants (e.g., caregivers, family, employers) familiar with the patient’s pre-morbid and current daily function is a particularly important element of the evaluation for executive dysfunction. Bedside assessments such as the Frontal Assessment Battery [236], Executive Interview [237], or similar measures [22] are essential components of the evaluation for executive dysfunction. In light of the high prevalence and functional relevance of executive dysfunction among persons evaluated by subspecialists in BN&NP [10, 22, 238], including an assessment of this cognitive domain in routine clinical practice and normatively interpreting performance on that assessment [10, 239, 240] are encouraged. When there are concerns about the validity of bedside assessment of executive function, or when the examination findings and clinical history are discordant, formal neuropsychological testing and performance-based functional evaluations may be appropriate. Education, support, behavioral and environmental modifications, and compensatory strategy training are important elements of the treatment of executive dysfunction. It sometimes is useful to explain executive function to patients and caregivers using an adaptation of William H. Calvin’s description of consciousness [241] – that is, executive function is the “conductor” of the “cerebral symphony,” selecting the piece to be performed, setting the pace of the performance, calling to the various sections of the orchestra to play or to rest as needed, and harmoniously organizing, coordinating, monitoring, and modifying their performance. Others with a business or administrative background find similarly useful the analogy of executive function as the Chief Executive Officer of the corporation that is the brain. With these or other similar analogies in mind, the substantial functional implications of executive dysfunction on occupational, academic, financial, medical, relational, and other aspects


of daily life may be apprehended easily [10, 230– 232]. Patients and caregivers require supportive therapy, at a minimum, in order to understand and cope effectively with executive dysfunction and its consequences. When the functional consequences of executive dysfunction are severe – for example, job loss, major family role changes, and impairments of the ability to drive, manage finances, make medical decisions, or live independently – patients and/or their caregivers may need and benefit from additional formal psychotherapeutic interventions (see Chapter 36). The behavioral/environmental interventions and compensatory strategies described in the preceding sections of this chapter are likely to be useful for persons with executive dysfunction, and especially impaired executive control of basic cognitive function (e.g., attention, memory, language, praxis, visuospatial function). These include analyzing and reducing the complexity of tasks, using verbal, visual, and other cues (e.g., day planners, electronic organizers with alarms, other cognitive prosthetics) to guide the timing and performance of tasks, establishing structures and routines for tasks, and minimizing sources of overstimulation and distraction. In general, these strategies are most likely to be adopted successfully by patients with relatively preserved motivation, mild impairments, and preserved insight. Among patients with severely impaired executive function, and especially those who are unaware of their deficits, ensuring that interventions are provided not only to the patient but also to his or her caregiver(s) may be most productive. As noted in Table 33.2, there is evidence supporting formal cognitive rehabilitation of executive function among persons with neurological injuries [26– 28]. There is emerging evidence that such approaches also may be useful for persons with schizophrenia, other primary psychiatric disorders, and neurodegenerative disorders [31, 242–248]. When cognitive rehabilitation of executive function is undertaken, subspecialists in BN&NP are encouraged to seek the assistance of a speech-language pathologist, occupational therapist, and/or neuropsychologist with both experience in this field and skill in the provision of evidencebased cognitive rehabilitation. Despite the common occurrence of executive dysfunction among persons with neurological and psychiatric disorders, few studies are available to guide the

pharmacotherapy of this problem. In general, pharmacotherapy of executive dysfunction is adjunctive to cognitive rehabilitation, and it is prudent to maintain relatively modest expectations of medication-related improvements in this cognitive function. The neuroanatomy and neurochemistry of executive function predict that problems in the cognitive domain are likely to be accompanied by other neuropsychiatric disturbances, including other cognitive impairments, emotional and behavioral disturbances, motor dysfunction, and movement disorders. As a general principle, identifying and treating such problems should precede attempts to pharmacologically remediate executive dysfunction specifically [22]. For example, when executive dysfunction is comorbid with impairments of arousal, attention, or processing speed, catecholaminergic augmentation (e.g., methylphenidate) may improve this entire constellation of cognitive impairments [22]. As suggested in the section of this chapter on attention and processing speed, uncompetitive NMDA receptor antagonists and/or acetylcholinesterase inhibitors also may be useful for the set of comorbid cognitive impairments [58, 75, 90, 91]. If executive dysfunction accompanies declarative memory impairments (e.g., among patients with AD and other dementias), then treatment with acetylcholinesterase inhibitors and/or an uncompetitive NMDA receptor antagonism also may improve executive function [249]. This approach also appears to be useful among persons with vascular dementia, including those in whom executive dysfunction is accompanied by relatively mild (and predominantly dysexecutive) memory impairments [250]. When executive dysfunction accompanies affective or behavioral symptoms (e.g., depression, anxiety, psychosis), medications targeting the latter symptoms should be selected so as to avoid exacerbating executive dysfunction and, possibly, to concurrently enhance this and other cognitive functions [22]. For example, it is prudent to avoid prescribing agents that robustly antagonize dopamine type-2 receptors or post-synaptic muscarinic acetylcholine receptors as well as agents that are sedating (e.g., benzodiazepines). Treatment of depressive or anxiety disorders with selective serotonin reuptake inhibitors (SSRIs) may secondarily improve cognition, including executive dysfunction [225, 251, 252]. The atypical antipsychotics, as a class, also appear to modestly improve cognition, including executive dysfunction, among

531


patients with schizophrenia receiving such agents for the treatment of psychotic symptoms [253, 254]. The effects of these agents on cognition when used to treat the mood or behavioral symptoms of bipolar disorder and other psychiatric conditions is uncertain [255–257], and suggests the possibility that these agents may adversely affect cognition in a non-trivial subset of these patients. As suggested in Chapters 34 and 35, the treatment of emotional and behavioral disturbances among patients with comorbid cognitive problems – and, in light of its functional importance, executive dysfunction more specifically – is best undertaken using agents with the lowest likelihood of adversely affecting cognition. There is a limited literature suggesting that vascular dementia-related executive dysfunction may improve during treatment with sertraline, independent of emotional or behavioral disturbances [258]. Agents that target the serotonergic system, as well as those with receptor subtype-specific effects, may prove useful treatments for executive dysfunction. However, additional study of these possibilities is needed before the use of such agents for this purpose can be recommended.

Conclusion Cognitive complaints and/or impairments are common reasons for consultation with BN&NP subspecialists. This chapter outlined an approach to the evaluation and management of these problems. This approach emphasizes the importance of comprehensive neuropsychiatric assessment prior to undertaking cognition-specific treatments, and the need to consider the contribution of non-cognitive problems to cognitive complaints and/or impairments. It uses supportive, educational, behavioral, and environmental interventions in the treatment of cognitive disorders, and encourages their provision to patients and caregivers. Compensatory strategies are used to allow patients and/or their caregivers to improve everyday function despite persistent or progressive cognitive impairments. Where the evidence supports the usefulness of cognitive rehabilitation, referral to a specialist with training and experience in the provision of these interventions also is encouraged. Medications also may be useful in the treatment of persons with cognitive impairments. With few exceptions, pharmacotherapy alone affords relatively modest improvements in cognition. Medications

532

therefore are more appropriately regarded as adjunctive, rather than primary, interventions for cognitive impairments. Pharmacotherapy may alter the cerebral physiologic milieu in a manner that facilitates engagement in and response to non-pharmacologic interventions, with emerging evidence supporting this suggestion. There is preliminary evidence that other procedural interventions, including transcranial magnetic stimulation, may have a similar role in the treatment of cognitive impairments. In summary, the treatment of cognitive impairments is a multimodal, multidisciplinary undertaking. Useful treatments address real-world functional challenges experienced by patients and caregivers, incorporate realistic treatment-response expectations, and ensure that patients and families are provided with the support and resources needed to cope effectively with cognitive impairments and their consequences.

References 1. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision: DSM–IV–TR. Washington, DC: American Psychiatric Association; 2000. 2. Kalkstein S, Hurford I, Gur RC. Neurocognition in schizophrenia. Curr Top Behav Neurosci. 2010;4: 373–90. 3. Green MF, Nuechterlein KH, Gold JM et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry 2004;56(5):301–7. 4. Yatham LN, Torres IJ, Malhi GS et al. The International Society for Bipolar Disorders–Battery for Assessment of Neurocognition (ISBD–BANC). Bipolar Disord. 2010;12(4):351–63. 5. Hasselbalch BJ, Knorr U, Kessing LV. Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review. J Affect Disord. 2011;134(1–3):20–31. 6. Dikmen SS, Corrigan JD, Levin HS et al. Cognitive outcome following traumatic brain injury. J Head Trauma Rehabil. 2009;24(6):430–8. 7. Seidel GA, Giovannetti T, Libon DJ. Cerebrovascular disease and cognition in older adults. Curr Top Behav Neurosci. 2012;10:213–41. 8. Langdon DW. Cognition in multiple sclerosis. Curr Opin Neurol. 2011;24(3):244–9. 9. Berg AT. Epilepsy, cognition, and behavior: the clinical picture. Epilepsia 2011;52(Suppl. 1):7–12.


Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56(9):1143–53.

10. Royall DR, Lauterbach EC, Kaufer D et al. The cognitive correlates of functional status: a review from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2007;19(3):249–65.

25. Geldmacher DS, Frolich L, Doody RS et al. Realistic expectations for treatment success in Alzheimer’s disease. J Nutr Health Aging 2006;10(5):417–29.

11. Matza LS, Buchanan R, Purdon S et al. Measuring changes in functional status among patients with schizophrenia: the link with cognitive impairment. Schizophr Bull. 2006;32(4):666–78.

26. Cicerone KD, Dahlberg C, Kalmar K et al. Evidence-based cognitive rehabilitation: recommendations for clinical practice. Arch Phys Med Rehabil. 2000;81(12):1596–615.

12. Mesulam MM. Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000.

27. Cicerone KD, Dahlberg C, Malec JF et al. Evidence-based cognitive rehabilitation: updated review of the literature from 1998 through 2002. Arch Phys Med Rehabil. 2005;86(8):1681–92.

13. Arciniegas DB, Beresford TP. Neuropsychiatry: An Introductory Approach. Cambridge: Cambridge University Press; 2001.

28. Cicerone KD, Langenbahn DM, Braden C et al. Evidence-based cognitive rehabilitation: updated review of the literature from 2003 through 2008. Arch Phys Med Rehabil. 2011;92(4):519–30.

14. Mesulam MM, editor. Attentional networks, confusional states, and neglect syndromes. In Principles of Behavioral and Cognitive Neurology. 2nd edition. Oxford: Oxford University Press; 2000, pp. 174–256.

29. Cappa SF, Benke T, Clarke S et al. EFNS guidelines on cognitive rehabilitation: report of an EFNS task force. Eur J Neurol. 2003;10(1):11–23.

15. Gazzaley A. Influence of early attentional modulation on working memory. Neuropsychologia 2011;49(6): 1410–24.

30. Cappa SF, Benke T, Clarke S et al. EFNS guidelines on cognitive rehabilitation: report of an EFNS task force. Eur J Neurol. 2005;12(9):665–80.

16. Barsalou LW, Breazeal C, Smith LB. Cognition as coordinated non-cognition. Cogn Process 2007;8(2): 79–91.

31. Lovell MR, Franzen MD. Cognitive rehabilitation and behavior therapy for patients with neuropsychiatric disorders. In Yudofsky SC, Hales RE, editors. Essentials of Neuropsychiatry and Behavioral Neurosciences. 2nd edition. Washington, DC: American Psychiatric Publishing; 2010, pp. 531–50.

17. Bourke C, Douglas K, Porter R. Processing of facial emotion expression in major depression: a review. Aust N Z J Psychiatry 2010;44(8):681–96. 18. Staugaard SR. Threatening faces and social anxiety: a literature review. Clin Psychol Rev. 2010;30(6):669–90. 19. Damasio AR. Descartes’ Error: Emotion, Reason, and the Human Brain. New York, NY: Putnam; 1994. 20. Dunn BD, Dalgleish T, Lawrence AD. The somatic marker hypothesis: a critical evaluation. Neurosci Biobehav Rev. 2006;30(2):239–71. 21. Phelps EA. Emotion and cognition: insights from studies of the human amygdala. Annu Rev Psychol. 2006;57:27–53.

32. Seel RT, Sherer M, Whyte J et al. Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil. 2010;91(12):1795–813. 33. Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale–Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil. 2004;85(12):2020–9. 34. Owen AM, Coleman MR. Functional neuroimaging of the vegetative state. Nat Rev Neurosci. 2008;9(3): 235–43.

22. Royall DR, Lauterbach EC, Cummings JL et al. Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2002;14(4):377–405.

35. Lombardi F, Taricco M, De Tanti A, Telaro E, Liberati A. Sensory stimulation of brain-injured individuals in coma or vegetative state: results of a Cochrane systematic review. Clin Rehabil. 2002;16(5): 464–72.

23. Strauss E, Sherman EMS, Spreen O. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. 3rd edition. Oxford: Oxford University Press; 2006.

36. Lombardi F, Taricco M, De Tanti A, Telaro E, Liberati A. Sensory stimulation for brain injured individuals in coma or vegetative state. Cochrane Database Syst Rev. 2002;2:CD001427.

24. Knopman DS, DeKosky ST, Cummings JL et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality

37. Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot

533


double-blind randomized trial. J Head Trauma Rehabil. 2002;17(4):300–13. 38. Giacino JT, Whyte J. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil. 2003;18(1):4–5; author reply 5–6. 39. Whyte J, Katz D, Long D et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: a multicenter study. Arch Phys Med Rehabil. 2005;86(3):453–62. 40. Passler MA, Riggs RV. Positive outcomes in traumatic brain injury-vegetative state: patients treated with bromocriptine. Arch Phys Med Rehabil. 2001;82(3): 311–15. 41. Patrick PD, Buck ML, Conaway MR, Blackman JA. The use of dopamine enhancing medications with children in low response states following brain injury. Brain Inj. 2003;17(6):497–506. 42. Hornyak JE, Nelson VS, Hurvitz EA. The use of methylphenidate in paediatric traumatic brain injury. Pediatr Rehabil. 1997;1(1):15–17.

53. Tharoor H, Lobos EA, Todd RD, Reiersen AM. Association of dopamine, serotonin, and nicotinic gene polymorphisms with methylphenidate response in ADHD. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(4):527–30. 54. Sivan M, Neumann V, Kent R, Stroud A, Bhakta BB. Pharmacotherapy for treatment of attention deficits after non-progressive acquired brain injury. A systematic review. Clin Rehabil. 2010;24(2):110–21. 55. Biederman J, Spencer T, Wilens T. Evidence-based pharmacotherapy for attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol. 2004;7(1): 77–97. 56. Faraone SV, Spencer T, Aleardi M, Pagano C, Biederman J. Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2004;24(1):24–9.

43. Worzniak M, Fetters MD, Comfort M. Methylphenidate in the treatment of coma. J Fam Pract. 1997;44(5):495–8.

57. Jadad AR, Boyle M, Cunningham C, Kim M, Schachar R. Treatment of attention-deficit/hyperactivity disorder. Evid Rep Technol Assess (Summ). 1999; 11:i–viii, 1–341.

44. Showalter PE, Kimmel DN. Stimulating consciousness and cognition following severe brain injury: a new potential clinical use for lamotrigine. Brain Inj. 2000;14(11):997–1001.

58. Warden DL, Gordon B, McAllister TW et al. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma 2006;23(10):1468–501.

45. Rivera VM. Modafinil for the treatment of diminished responsiveness in a patient recovering from brain surgery. Brain Inj. 2005;19(9):725–7.

59. Arciniegas DB, Silver JM. Pharmacotherapy of posttraumatic cognitive impairments. Behav Neurol. 2006;17(1):25–42.

46. Clauss RP, Nel WH. Effect of zolpidem on brain injury and diaschisis as detected by 99mTc HMPAO brain SPECT in humans. Arzneimittelforschung. 2004;54(10):641–6.

60. Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury – a state-of-the-art review. J Rehabil Res Dev. 2009;46(6):851–79.

47. Cohen SI, Duong TT. Increased arousal in a patient with anoxic brain injury after administration of zolpidem. Am J Phys Med Rehabil. 2008;87(3):229–31.

61. Willmott C, Ponsford J. Efficacy of methylphenidate in the rehabilitation of attention following traumatic brain injury: a randomised, crossover, double blind, placebo controlled inpatient trial. J Neurol Neurosurg Psychiatry 2009;80(5):552–7.

48. Whyte J, Myers R. Incidence of clinically significant responses to zolpidem among patients with disorders of consciousness: a preliminary placebo controlled trial. Am J Phys Med Rehabil. 2009;88(5):410–18. 49. Filley CM. White matter: organization and functional relevance. Neuropsychol Rev. 2010;20(2):158–73. 50. Arciniegas DB. Cholinergic dysfunction and cognitive impairment after traumatic brain injury. Part 1: the structure and function of cerebral cholinergic systems. J Head Trauma Rehabil. 2011;26(1):98–101. 51. Froehlich TE, McGough JJ, Stein MA. Progress and promise of attention-deficit hyperactivity disorder pharmacogenetics. CNS Drugs 2010;24(2):99–117.

534

52. Kieling C, Genro JP, Hutz MH, Rohde LA. A current update on ADHD pharmacogenomics. Pharmacogenomics 2010;11(3):407–19.

62. Willmott C, Ponsford J, Olver J, Ponsford M. Safety of methylphenidate following traumatic brain injury: impact on vital signs and side-effects during inpatient rehabilitation. J Rehabil Med. 2009;41(7):585–7. 63. Alban JP, Hopson MM, Ly V, Whyte J. Effect of methylphenidate on vital signs and adverse effects in adults with traumatic brain injury. Am J Phys Med Rehabil. 2004;83(2):131–7; quiz 8–41, 67. 64. Burke DT, Glenn MB, Vesali F et al. Effects of methylphenidate on heart rate and blood pressure among inpatients with acquired brain injury. Am J Phys Med Rehabil. 2003;82(7):493–7.


65. Castells X, Ramos-Quiroga JA, Rigau D et al. Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression analysis. CNS Drugs 2011;25(2):157–69. 66. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother. 2009;7(1):34–59. 67. Adler LA, Spencer T, McGough JJ, Jiang H, Muniz R. Long-term effectiveness and safety of dexmethylphenidate extended-release capsules in adult ADHD. J Atten Disord. 2009;12(5):449–59. 68. Adler LA, Zimmerman B, Starr HL et al. Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose-escalation study. J Clin Psychopharmacol. 2009;29(3):239–47. 69. Wroblewski BA, Leary JM, Phelan AM, Whyte J, Manning K. Methylphenidate and seizure frequency in brain injured patients with seizure disorders. J Clin Psychiatry 1992;53(3):86–9. 70. Feldman H, Crumrine P, Handen BL, Alvin R, Teodori J. Methylphenidate in children with seizures and attention-deficit disorder. Am J Dis Child. 1989;143(9):1081–6. 71. Castells X, Casas M, Perez-Mana C et al. Efficacy of psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev. 2010;2:CD007380. 72. Castells X, Casas M, Vidal X et al. Efficacy of central nervous system stimulant treatment for cocaine dependence: a systematic review and meta-analysis of randomized controlled clinical trials. Addiction 2007;102(12):1871–87. 73. Beglinger LJ, Gaydos B, Tangphao-Daniels O et al. Practice effects and the use of alternate forms in serial neuropsychological testing. Arch Clin Neuropsychol. 2005;20(4):517–29. 74. Beglinger LJ, Gaydos BL, Kareken DA et al. Neuropsychological test performance in healthy volunteers before and after donepezil administration. J Psychopharmacol. 2004;18(1):102–8. 75. Zhang L, Plotkin RC, Wang G, Sandel ME, Lee S. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil. 2004;85(7):1050–5. 76. Silver JM, Koumaras B, Chen M et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology 2006;67(5):748–55. 77. Silver JM, Koumaras B, Meng X et al. Long-term effects of rivastigmine capsules in patients with traumatic brain injury. Brain Inj. 2009;23(2):123–32.

78. Tenovuo O. Central acetylcholinesterase inhibitors in the treatment of chronic traumatic brain injury – clinical experience in 111 patients. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(1): 61–7. 79. Tenovuo O, Alin J, Helenius H. A randomized controlled trial of rivastigmine for chronic sequels of traumatic brain injury – what it showed and taught? Brain Inj. 2009;23(6):548–58. 80. Christodoulou C, Melville P, Scherl WF et al. Effects of donepezil on memory and cognition in multiple sclerosis. J Neurol Sci. 2006;245(1–2):127–36. 81. Krupp LB, Christodoulou C, Melville P et al. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004;63(9): 1579–85. 82. Krupp LB, Christodoulou C, Melville P et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology 2011;76(17):1500–7. 83. Rammsayer TH. Effects of pharmacologically induced changes in NMDA-receptor activity on long-term memory in humans. Learn Mem. 2001;8(1):20–5. 84. Rammsayer TH. Effects of pharmacologically induced changes in NMDA receptor activity on human timing and sensorimotor performance. Brain Res. 2006; 1073–1074:407–16. 85. Parsons CG, Stoffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system – too little activation is bad, too much is even worse. Neuropharmacology 2007;53(6): 699–723. 86. Wroolie TE, Kenna HA, Williams KE et al. Cognitive effects of memantine in postmenopausal women at risk of dementia: a pilot study. Acta Neurol Scand. 2009;119(3):172–9. 87. Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003;9(3): 275–308. 88. van Wageningen H, Jorgensen HA, Specht K, Hugdahl K. Evidence for glutamatergic neurotransmission in cognitive control in an auditory attention task. Neurosci Lett. 2009;454(3):171–5. 89. Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol. 2007;78:69–108. 90. Ambrozi L, Danielczyk W. Treatment of impaired cerebral function in psychogeriatric patients with memantine – results of a phase II double-blind study. Pharmacopsychiatry 1988;21(3):144–6.

535


91. Ferris S, Schneider L, Farmer M, Kay G, Crook T. A double-blind, placebo-controlled trial of memantine in age-associated memory impairment (memantine in AAMI). Int J Geriatr Psychiatry 2007;22(5):448–55.

106. Hazell PL, Kohn MR, Dickson R et al. Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis. J Atten Disord. 2011;15(8):674–83.

92. Kim YW, Shin JC, An YS. Changes in cerebral glucose metabolism in patients with posttraumatic cognitive impairment after memantine therapy: a preliminary study. Ann Nucl Med. 2010;24(5):363–9.

107. Wallace DL, Vytlacil JJ, Nomura EM, Gibbs SE, D’Esposito M. The dopamine agonist bromocriptine differentially affects fronto-striatal functional connectivity during working memory. Front Hum Neurosci. 2011;5:32.

93. Fink KB, Gothert M. 5-HT receptor regulation of neurotransmitter release. Pharmacol Rev. 2007; 59(4):360–417. 94. Canli T, Lesch KP. Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci. 2007;10(9):1103–9. 95. Canli T, Omura K, Haas BW et al. Beyond affect: a role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task. Proc Natl Acad Sci USA 2005;102(34):12,224–9. 96. Behrmann M, Marotta J, Gauthier I, Tarr MJ, McKeeff TJ. Behavioral change and its neural correlates in visual agnosia after expertise training. J Cogn Neurosci. 2005;17(4):554–68. 97. Burns MS. Clinical management of agnosia. Top Stroke Rehabil. 2004;11(1):1–9. 98. Budson AE. Understanding memory dysfunction. Neurologist 2009;15(2):71–9. 99. Ricciardi E, Bonino D, Gentili C et al. Neural correlates of spatial working memory in humans: a functional magnetic resonance imaging study comparing visual and tactile processes. Neuroscience 2006;139(1):339–49. 100. Schlosser RG, Wagner G, Sauer H. Assessing the working memory network: studies with functional magnetic resonance imaging and structural equation modeling. Neuroscience 2006;139(1):91–103. 101. Cabeza R, Nyberg L. Imaging cognition II: an empirical review of 275 PET and fMRI studies. J Cogn Neurosci. 2000;12(1):1–47. 102. Morrison AB, Chein JM. Does working memory training work? The promise and challenges of enhancing cognition by training working memory. Psychon Bull Rev. 2011;18(1):46–60. 103. McNamara DS, Scott JL. Working memory capacity and strategy use. Mem Cognit. 2001;29(1): 10–17. 104. Klingberg T, Forssberg H, Westerberg H. Training of working memory in children with ADHD. J Clin Exp Neuropsychol. 2002;24(6):781–91. 105. Gamo NJ, Arnsten AF. Molecular modulation of prefrontal cortex: rational development of treatments for psychiatric disorders. Behav Neurosci. 2011; 125(3):282–96.

536

108. D’Souza MS, Markou A. Schizophrenia and tobacco smoking comorbidity: nAChR agonists in the treatment of schizophrenia-associated cognitive deficits. Neuropharmacology 2012;62(3): 1564–73. 109. Wallace TL, Porter RH. Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease. Biochem Pharmacol. 2011;82(8):891–903. 110. Brioni JD, Esbenshade TA, Garrison TR, Bitner SR, Cowart MD. Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer’s disease. J Pharmacol Exp Ther. 2011; 336(1):38–46. 111. Devi G, Silver J. Approaches to memory loss in neuropsychiatric disorders. Semin Clin Neuropsychiatry 2000;5(4):259–65. 112. Coffey CE, McAllister TW, Silver JM. Guide to Neuropsychiatric Therapeutics. Philadelphia, PA: Lippincott Williams & Wilkins; 2007. 113. Sharma T, Reed C, Aasen I, Kumari V. Cognitive effects of adjunctive 24-weeks Rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation. Schizophr Res. 2006;85(1–3):73–83. 114. Stip E, Sepehry AA, Chouinard S. Add-on therapy with acetylcholinesterase inhibitors for memory dysfunction in schizophrenia: a systematic quantitative review, part 2. Clin Neuropharmacol. 2007;30(4): 218–29. 115. Dyer MA, Freudenreich O, Culhane MA et al. High-dose galantamine augmentation inferior to placebo on attention, inhibitory control and working memory performance in nonsmokers with schizophrenia. Schizophr Res. 2008;102(1–3): 88–95. 116. Silver JM, McAllister TW, Arciniegas DB. Depression and cognitive complaints following mild traumatic brain injury. Am J Psychiatry 2009;166(6):653–61. 117. Giovannini MG. The role of the extracellular signal-regulated kinase pathway in memory encoding. Rev Neurosci. 2006;17(6):619–34. 118. Kullmann DM, Lamsa KP. Long-term synaptic plasticity in hippocampal interneurons. Nat Rev Neurosci. 2007;8(9):687–99.


119. Doody RS, Stevens JC, Beck C et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56(9):1154–66. 120. Martorana A, Esposito Z, Koch G. Beyond the cholinergic hypothesis: do current drugs work in Alzheimer’s disease? CNS Neurosci Ther. 2010; 16(4):235–45. 121. Ribeiz SR, Bassitt DP, Arrais JA et al. Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs 2010;24(4):303–17. 122. Ago Y, Koda K, Takuma K, Matsuda T. Pharmacological aspects of the acetylcholinesterase inhibitor galantamine. J Pharmacol Sci. 2011; 116(1):6–17. 123. Battista MA, Hierholzer R, Khouzam HR, Barlow A, O’Toole S. Pilot trial of memantine in the treatment of posttraumatic stress disorder. Psychiatry 2007; 70(2):167–74. 124. Brown ES, Vazquez M, Nakamura A. Randomized, placebo-controlled, crossover trial of memantine for cognitive changes with corticosteroid therapy. Biol Psychiatry 2008;64(8):727–9. 125. Emre M, Mecocci P, Stender K. Pooled analyses on cognitive effects of memantine in patients with moderate to severe Alzheimer’s disease. J Alzheimers Dis. 2008;14(2):193–9. 126. Mecocci P, Bladstrom A, Stender K. Effects of memantine on cognition in patients with moderate to severe Alzheimer’s disease: post-hoc analyses of ADAS-cog and SIB total and single-item scores from six randomized, double-blind, placebo-controlled studies. Int J Geriatr Psychiatry 2009;24(5):532–8. 127. Owley T, Salt J, Guter S et al. A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2006;16(5):517–24. 128. Pomara N, Ott BR, Peskind E, Resnick EM. Memantine treatment of cognitive symptoms in mild to moderate Alzheimer disease: secondary analyses from a placebo-controlled randomized trial. Alzheimer Dis Assoc Disord. 2007;21(1):60–4. 129. Schmitt FA, van Dyck CH, Wichems CH, Olin JT. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Dis Assoc Disord. 2006;20(4):255–62. 130. Erkinjuntti T, Roman G, Gauthier S, Feldman H, Rockwood K. Emerging therapies for vascular

dementia and vascular cognitive impairment. Stroke 2004;35(4):1010–17. 131. Raina P, Santaguida P, Ismaila A et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379–97. 132. Smith M, Wells J, Borrie M. Treatment effect size of memantine therapy in Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord. 2006;20(3): 133–7. 133. Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011;68(8):991–8. 134. de Lucena D, Fernandes BS, Berk M et al. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. J Clin Psychiatry 2009;70(10):1416–23. 135. Gama CS, Lucena DD, Cruz C, Lobato MI, Belmonte-de-Abreu PS. Improvement of schizophrenia negative and positive symptoms with amantadine as add-on therapy to antipsychotics: a case series. Rev Bras Psiquiatr. 2010;32(2):193–4. 136. Zdanys K, Tampi RR. A systematic review of off-label uses of memantine for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2008;32(6): 1362–74. 137. Lieberman JA, Papadakis K, Csernansky J et al. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology 2009;34(5):1322–9. 138. Silver H, Goodman C, Isakov V, Knoll G, Modai I. A double-blind, cross-over comparison of the effects of amantadine or placebo on visuomotor and cognitive function in medicated schizophrenia patients. Int Clin Psychopharmacol. 2005;20(6):319–26. 139. Arciniegas DB, Topkoff J, Silver JM. Neuropsychiatric aspects of traumatic brain injury. Curr Treat Options Neurol. 2000;2(2):169–86. 140. Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005;2:CD000269. 141. Levin HS. Treatment of postconcussional symptoms with CDP-choline. J Neurol Sci. 1991;103(Suppl.): S39–42. 142. Brown ES, Gorman AR, Hynan LS. A randomized, placebo-controlled trial of citicoline add-on therapy in outpatients with bipolar disorder and cocaine dependence. J Clin Psychopharmacol. 2007;27(5): 498–502.

537


143. Zafonte R, Friedewald WT, Lee SM et al. The citicoline brain injury treatment (COBRIT) trial: design and methods. J Neurotrauma 2009;26(12): 2207–16. 144. van Halteren-van Tilborg IA, Scherder EJ, Hulstijn W. Motor-skill learning in Alzheimer’s disease: a review with an eye to the clinical practice. Neuropsychol Rev. 2007;17(3):203–12. 145. Kime SK, Lamb DG, Wilson BA. Use of a comprehensive programme of external cueing to enhance procedural memory in a patient with dense amnesia. Brain Inj. 1996;10(1):17–25. 146. Donaghy S, Williams W. A new protocol for training severely impaired patients in the usage of memory journals. Brain Inj. 1998;12(12):1061–76. 147. Kessels RP, van Loon E, Wester AJ. Route learning in amnesia: a comparison of trial-and-error and errorless learning in patients with the Korsakoff syndrome. Clin Rehabil. 2007;21(10):905–11. 148. Beaunieux H, Hubert V, Witkowski T et al. Which processes are involved in cognitive procedural learning? Memory 2006;14(5):521–39. 149. Hauptmann B, Reinhart E, Brandt SA, Karni A. The predictive value of the leveling off of within session performance for procedural memory consolidation. Brain Res Cogn Brain Res. 2005;24(2):181–9. 150. Walker MP, Brakefield T, Morgan A, Hobson JA, Stickgold R. Practice with sleep makes perfect: sleep-dependent motor skill learning. Neuron 2002;35(1):205–11. 151. Gabrieli JD, Corkin S, Mickel SF, Growdon JH. Intact acquisition and long-term retention of mirror-tracing skill in Alzheimer’s disease and in global amnesia. Behav Neurosci. 1993;107(6):899–910. 152. Ferraro FR, Balota DA, Connor LT. Implicit memory and the formation of new associations in nondemented Parkinson’s disease individuals and individuals with senile dementia of the Alzheimer type: a serial reaction time (SRT) investigation. Brain Cogn. 1993;21(2):163–80. 153. Cavaco S, Anderson SW, Allen JS, Castro-Caldas A, Damasio H. The scope of preserved procedural memory in amnesia. Brain 2004;127(Pt 8):1853–67. 154. Nakase-Thompson R, Manning E, Sherer M et al. Brief assessment of severe language impairments: initial validation of the Mississippi aphasia screening test. Brain Inj. 2005;19(9):685–91. 155. van der Gaag A, Smith L, Davis S et al. Therapy and support services for people with long-term stroke and aphasia and their relatives: a six-month follow-up study. Clin Rehabil. 2005;19(4):372–80. 156. Simmons-Mackie N, Raymer A, Armstrong E, Holland A, Cherney LR. Communication partner training in

538

aphasia: a systematic review. Arch Phys Med Rehabil. 2010;91(12):1814–37. 157. Cherney LR, Patterson JP, Raymer A, Frymark T, Schooling T. Evidence-based systematic review: effects of intensity of treatment and constraint-induced language therapy for individuals with stroke-induced aphasia. J Speech Lang Hear Res. 2008;51(5):1282–99. 158. Meinzer M, Elbert T, Djundja D, Taub E, Rockstroh B. Extending the constraint-induced movement therapy (CIMT) approach to cognitive functions: constraint-induced aphasia therapy (CIAT) of chronic aphasia. NeuroRehabilitation 2007;22(4):311–18. 159. Pattee C, Von Berg S, Ghezzi P. Effects of alternative communication on the communicative effectiveness of an individual with a progressive language disorder. Int J Rehabil Res. 2006;29(2):151–3. 160. Louis M, Espesser R, Rey V et al. Intensive training of phonological skills in progressive aphasia: a model of brain plasticity in neurodegenerative disease. Brain Cogn. 2001;46(1–2):197–201. 161. Beeson PM, King RM, Bonakdarpour B et al. Positive effects of language treatment for the logopenic variant of primary progressive aphasia. J Mol Neurosci. 2011;45:724–36. 162. Rapp B, Glucroft B. The benefits and protective effects of behavioural treatment for dysgraphia in a case of primary progressive aphasia. Aphasiology 2009;23(2):236–65. 163. Berthier ML. Poststroke aphasia: epidemiology, pathophysiology and treatment. Drugs Aging 2005; 22(2):163–82. 164. Berthier ML, Green C, Higueras C et al. A randomized, placebo-controlled study of donepezil in poststroke aphasia. Neurology 2006;67(9):1687–9. 165. Berthier ML, Hinojosa J, Martin Mdel C, Fernandez I. Open-label study of donepezil in chronic poststroke aphasia. Neurology 2003;60(7):1218–19. 166. Johnson N, Fahey C, Chicoine B, Chong G, Gitelman D. Effects of donepezil on cognitive functioning in Down syndrome. Am J Ment Retard. 2003;108(6): 367–72. 167. Heller JH, Spiridigliozzi GA, Doraiswamy PM et al. Donepezil effects on language in children with Down syndrome: results of the first 22-week pilot clinical trial. Am J Med Genet A. 2004;130A(3):325–6. 168. Hertzman M. Galantamine in the treatment of adult autism: a report of three clinical cases. Int J Psychiatry Med. 2003;33(4):395–8. 169. Berthier ML, Green C, Lara JP et al. Memantine and constraint-induced aphasia therapy in chronic poststroke aphasia. Ann Neurol. 2009;65(5): 577–85.


170. Enderby P, Broeckx J, Hospers W, Schildermans F, Deberdt W. Effect of piracetam on recovery and rehabilitation after stroke: a double-blind, placebo-controlled study. Clin Neuropharmacol. 1994;17(4):320–31.

183. Donkervoort M, Dekker J, van den Ende E, Stehmann-Saris JC, Deelman BG. Prevalence of apraxia among patients with a first left hemisphere stroke in rehabilitation centres and nursing homes. Clin Rehabil. 2000;14(2):130–6.

171. Huber W. The role of piracetam in the treatment of acute and chronic aphasia. Pharmacopsychiatry 1999;32(Suppl. 1):38–43.

184. Pedersen PM, Jorgensen HS, Kammersgaard LP et al. Manual and oral apraxia in acute stroke, frequency and influence on functional outcome: The Copenhagen Stroke Study. Am J Phys Med Rehabil. 2001;80(9):685–92.

172. Spiegel DR, Alexander G. A case of nonfluent aphasia treated successfully with speech therapy and adjunctive mixed amphetamine salts. J Neuropsychiatry Clin Neurosci. 2011;23(1):E24. 173. Bragoni M, Altieri M, Di Piero V et al. Bromocriptine and speech therapy in non-fluent chronic aphasia after stroke. Neurol Sci. 2000;21(1):19–22. 174. Ashtary F, Janghorbani M, Chitsaz A, Reisi M, Bahrami A. A randomized, double-blind trial of bromocriptine efficacy in nonfluent aphasia after stroke. Neurology 2006;66(6):914–16. 175. Reed DA, Johnson NA, Thompson C, Weintraub S, Mesulam MM. A clinical trial of bromocriptine for treatment of primary progressive aphasia. Ann Neurol. 2004;56(5):750. 176. Kertesz A, Morlog D, Light M et al. Galantamine in frontotemporal dementia and primary progressive aphasia. Dement Geriatr Cogn Disord. 2008; 25(2):178–85. 177. Boxer AL, Lipton AM, Womack K et al. An open-label study of memantine treatment in 3 subtypes of frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord. 2009;23(3):211–17. 178. Johnson NA, Rademaker A, Weintraub S et al. Pilot trial of memantine in primary progressive aphasia. Alzheimer Dis Assoc Disord. 2010;24(3):308. 179. Szaflarski JP, Vannest J, Wu SW et al. Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia. Med Sci Monit. 2011;17(3):CR132–9. 180. Barwood CH, Murdoch BE, Whelan BM et al. The effects of low frequency Repetitive Transcranial Magnetic Stimulation (rTMS) and sham condition rTMS on behavioural language in chronic non-fluent aphasia: short term outcomes. NeuroRehabilitation 2011;28(2):113–28. 181. Barwood CH, Murdoch BE, Whelan BM et al. Improved language performance subsequent to low-frequency rTMS in patients with chronic non-fluent aphasia post-stroke. Eur J Neurol. 2011;18(7):935–43. 182. Finocchiaro C, Maimone M, Brighina F et al. A case study of Primary Progressive Aphasia: improvement on verbs after rTMS treatment. Neurocase 2006;12(6):317–21.

185. Zwinkels A, Geusgens C, van de Sande P, Van Heugten C. Assessment of apraxia: inter-rater reliability of a new apraxia test, association between apraxia and other cognitive deficits and prevalence of apraxia in a rehabilitation setting. Clin Rehabil. 2004;18(7): 819–27. 186. McKenna K, Cooke DM, Fleming J, Jefferson A, Ogden S. The incidence of visual perceptual impairment in patients with severe traumatic brain injury. Brain Inj. 2006;20(5):507–18. 187. O’Suilleabhain P, Dewey RB, Jr. Movement disorders after head injury: diagnosis and management. J Head Trauma Rehabil. 2004;19(4):305–13. 188. Vanbellingen T, Bohlhalter S. Apraxia in neurorehabilitation: classification, assessment and treatment. NeuroRehabilitation 2011;28(2):91–8. 189. Stieglitz Ham H, Bartolo A, Corley M et al. Exploring the relationship between gestural recognition and imitation: evidence of dyspraxia in autism spectrum disorders. J Autism Dev Disord. 2011;41(1):1–12. 190. Bunn L, Roy EA, Elliott D. Speech perception and motor control in children with Down syndrome. Child Neuropsychol. 2007;13(3):262–75. 191. Zoia S, Pelamatti G, Rumiati RI. Praxic skills in Down and mentally retarded adults: evidence for multiple action routes. Brain Cogn. 2004;54(1):7–17. 192. Leiguarda R. Limb apraxia: cortical or subcortical. Neuroimage 2001;14(1 Pt 2):S137–41. 193. Shallice T. Fractionation of the supervisory system. In Stuss DT, Knight RT, editors. Principles of Frontal Lobe Function. Oxford: Oxford University Press; 2002, pp. 261–77. 194. Almeida QJ, Black SE, Roy EA. Screening for apraxia: a short assessment for stroke patients. Brain Cogn. 2002;48(2–3):253–8. 195. Power E, Code C, Croot K, Sheard C, Gonzalez Rothi LJ. Florida Apraxia Battery – Extended and Revised Sydney (FABERS): design, description, and a healthy control sample. J Clin Exp Neuropsychol. 2010; 32(1):1–18. 196. Pomeroy V, Aglioti SM, Mark VW et al. Neurological principles and rehabilitation of action disorders:

539


rehabilitation interventions. Neurorehabil Neural Repair 2011;25(5 Suppl.):33S–43S. 197. West C, Bowen A, Hesketh A, Vail A. Interventions for motor apraxia following stroke. Cochrane Database Syst Rev. 2008;1:CD004132. 198. Smania N, Aglioti SM, Girardi F et al. Rehabilitation of limb apraxia improves daily life activities in patients with stroke. Neurology 2006;67(11):2050–2. 199. Buxbaum LJ, Haaland KY, Hallett M et al. Treatment of limb apraxia: moving forward to improved action. Am J Phys Med Rehabil. 2008;87(2):149–61. 200. Yamada S, Matsuo K, Hirayama M, Sobue G. The effects of levodopa on apraxia of lid opening: a case report. Neurology 2004;62(5):830–1. 201. Yasuoka T, Ikeda M, Maki N et al. [A case of corticobasal degeneration of which movemental disturbances were improved by administration of amantadine]. No To Shinkei 2001;53(8):781–5. 202. Kim E, Lee Y, Lee J, Han SH. A case with cholinesterase inhibitor responsive asymmetric posterior cortical atrophy. Clin Neurol Neurosurg. 2005;108(1):97–101. 203. Burns A, Bernabei R, Bullock R et al. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol. 2009;8(1):39–47. 204. Levy ML, Cummings JL, Kahn-Rose R. Neuropsychiatric symptoms and cholinergic therapy for Alzheimer’s disease. Gerontology 1999;45(Suppl. 1):15–22. 205. Epstein R, Deyoe EA, Press DZ, Rosen AC, Kanwisher N. Neuropsychological evidence for a topographical learning mechanism in parahippocampal cortex. Cogn Neuropsychol. 2001;18(6):481–508. 206. Epstein R, Kanwisher N. A cortical representation of the local visual environment. Nature 1998;392(6676): 598–601.

memory following low-dose scopolamine challenge in healthy older adults. Neuropsychologia 2008;46(10): 2476–84. 211. Snyder PJ, Bednar MM, Cromer JR, Maruff P. Reversal of scopolamine-induced deficits with a single dose of donepezil, an acetylcholinesterase inhibitor. Alzheimers Dement. 2005;1(2):126–35. 212. Wezenberg E, Verkes RJ, Sabbe BG, Ruigt GS, Hulstijn W. Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects. Psychopharmacology (Berlin). 2005;181(3): 582–94. 213. Darreh-Shori T, Kadir A, Almkvist O et al. Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine. Neurobiol Aging 2008;29(2): 168–84. 214. Kulisevsky J, Garcia-Sanchez C, Berthier ML et al. Chronic effects of dopaminergic replacement on cognitive function in Parkinson’s disease: a two-year follow-up study of previously untreated patients. Mov Disord. 2000;15(4):613–26. 215. Paolucci S, Bureca I, Multari M, Nocentini U, Matano A. An open-label pilot study of the use of rivastigmine to promote functional recovery in patients with unilateral spatial neglect due to first ischemic stroke. Funct Neurol. 2010;25(4):195–200. 216. Fleet WS, Valenstein E, Watson RT, Heilman KM. Dopamine agonist therapy for neglect in humans. Neurology 1987;37(11):1765–70. 217. Hurford P, Stringer AY, Jann B. Neuropharmacologic treatment of hemineglect: a case report comparing bromocriptine and methylphenidate. Arch Phys Med Rehabil. 1998;79(3):346–9. 218. Mukand JA, Guilmette TJ, Allen DG et al. Dopaminergic therapy with carbidopa L-dopa for left neglect after stroke: a case series. Arch Phys Med Rehabil. 2001;82(9):1279–82.

207. Chamberlain SR, Muller U, Robbins TW, Sahakian BJ. Neuropharmacological modulation of cognition. Curr Opin Neurol. 2006;19(6):607–12.

219. Grujic Z, Mapstone M, Gitelman DR et al. Dopamine agonists reorient visual exploration away from the neglected hemispace. Neurology 1998;51(5): 1395–8.

208. Dujardin K, Laurent B. Dysfunction of the human memory systems: role of the dopaminergic transmission. Curr Opin Neurol. 2003;16(Suppl. 2):S11–16.

220. Barrett AM. Dopamine agonists reorient visual exploration away from the neglected hemispace. Neurology 1999;53(7):1610; author reply –11.

209. Freo U, Pizzolato G, Dam M, Ori C, Battistin L. A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials. J Neural Transm. 2002; 109(5–6):857–70. 210. Thomas E, Snyder PJ, Pietrzak RH et al. Specific impairments in visuospatial working and short-term

540

221. Barrett AM, Crucian GP, Schwartz RL, Heilman KM. Adverse effect of dopamine agonist therapy in a patient with motor-intentional neglect. Arch Phys Med Rehabil. 1999;80(5):600–3. 222. Schillerstrom JE, Deuter MS, Wyatt R, Stern SL, Royall DR. Prevalence of executive impairment in patients seen by a psychiatry consultation service. Psychosomatics 2003;44(4):290–7.


223. Royall DR. Executive cognitive impairment: a novel perspective on dementia. Neuroepidemiology 2000;19(6):293–9.

236. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment Battery at bedside. Neurology 2000;55(11):1621–6.

224. Roman GC, Royall DR. Executive control function: a rational basis for the diagnosis of vascular dementia. Alzheimer Dis Assoc Disord. 1999;13(Suppl. 3):S69–80.

237. Royall DR, Mahurin RK, Gray KF. Bedside assessment of executive cognitive impairment: the executive interview. J Am Geriatr Soc. 1992;40(12):1221–6.

225. DeBattista C. Executive dysfunction in major depressive disorder. Expert Rev Neurother. 2005; 5(1):79–83.

238. Lewis MW, Babbage DR, Leathem JM. Assessing executive performance during cognitive rehabilitation. Neuropsychol Rehabil. 2011;21(2):145–63.

226. Harvey PD, Wingo AP, Burdick KE, Baldessarini RJ. Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord. 2010;12(4):364–75.

239. Appollonio I, Leone M, Isella V et al. The Frontal Assessment Battery (FAB): normative values in an Italian population sample. Neurol Sci. 2005;26(2): 108–16.

227. Krishnadas R, Moore BP, Nayak A, Patel RR. Relationship of cognitive function in patients with schizophrenia in remission to disability: a cross-sectional study in an Indian sample. Ann Gen Psychiatry. 2007;6:19.

240. Royall DR, Palmer R, Chiodo LK, Polk MJ. Declining executive control in normal aging predicts change in functional status: the Freedom House Study. J Am Geriatr Soc. 2004;52(3):346–52.

228. Bowie CR, Leung WW, Reichenberg A et al. Predicting schizophrenia patients’ real-world behavior with specific neuropsychological and functional capacity measures. Biol Psychiatry 2008;63(5):505–11.

241. Calvin WH. The Cerebral Symphony: Seashore Reflections on the Structure of Consciousness. New York, NY: Bantam Books; 1990. 242. Kurtz MM. Neurocognitive rehabilitation for schizophrenia. Curr Psychiatry Rep. 2003;5(4):303–10.

229. Alptekin K, Akvardar Y, Kivircik Akdede BB et al. Is quality of life associated with cognitive impairment in schizophrenia? Prog Neuropsychopharmacol Biol Psychiatry 2005;29(2):239–44.

243. Velligan DI, Kern RS, Gold JM. Cognitive rehabilitation for schizophrenia and the putative role of motivation and expectancies. Schizophr Bull. 2006;32(3):474–85.

230. Schillerstrom JE, Salazar R, Regwan H, Bonugli RJ, Royall DR. Executive function in self-neglecting adult protective services referrals compared with elder psychiatric outpatients. Am J Geriatr Psychiatry 2009;17(10):907–10.

244. Eack SM, Pogue-Geile MF, Greenwald DP, Hogarty SS, Keshavan MS. Mechanisms of functional improvement in a 2-year trial of cognitive enhancement therapy for early schizophrenia. Psychol Med. 2010;Sep 22:1–9.

231. Royall DR, Chiodo LK, Polk MJ. Correlates of disability among elderly retirees with “subclinical” cognitive impairment. J Gerontol A Biol Sci Med Sci. 2000;55(9):M541–6.

245. Avila R, Carvalho IA, Bottino CM, Miotto EC. Neuropsychological rehabilitation in mild and moderate Alzheimer’s disease patients. Behav Neurol. 2007;18(4):225–33.

232. Royall DR, Cabello M, Polk MJ. Executive dyscontrol: an important factor affecting the level of care received by older retirees. J Am Geriatr Soc. 1998;46(12):1519–24.

246. Giordano M, Dominguez LJ, Vitrano T et al. Combination of intensive cognitive rehabilitation and donepezil therapy in Alzheimer’s disease (AD). Arch Gerontol Geriatr. 2010;51(3):245–9.

233. Hjarthag F, Helldin L, Karilampi U, Norlander T. Illness-related components for the family burden of relatives to patients with psychotic illness. Soc Psychiatry Psychiatr Epidemiol. 2010;45(2):275–83.

247. Rozzini L, Costardi D, Chilovi BV et al. Efficacy of cognitive rehabilitation in patients with mild cognitive impairment treated with cholinesterase inhibitors. Int J Geriatr Psychiatry 2007;22(4):356–60.

234. Marshall GA, Rentz DM, Frey MT et al. Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer’s disease. Alzheimers Dement. 2011;7(3):300–8.

248. Clare L, Linden DE, Woods RT et al. Goal-oriented cognitive rehabilitation for people with early-stage Alzheimer disease: a single-blind randomized controlled trial of clinical efficacy. Am J Geriatr Psychiatry 2010;18(10):928–39.

235. Brown TE, Landgraf JM. Improvements in executive function correlate with enhanced performance and functioning and health-related quality of life: evidence from 2 large, double-blind, randomized, placebo-controlled trials in ADHD. Postgrad Med. 2010;122(5):42–51.

249. Riepe MW, Adler G, Ibach B et al. Domain-specific improvement of cognition on memantine in patients with Alzheimer’s disease treated with rivastigmine. Dement Geriatr Cogn Disord. 2007;23(5):301–6.

541


250. Schneck MJ. Vascular dementia. Top Stroke Rehabil. 2008;15(1):22–6. 251. Bragin V, Chemodanova M, Dzhafarova N et al. Integrated treatment approach improves cognitive function in demented and clinically depressed patients. Am J Alzheimers Dis Other Demen. 2005;20(1):21–6. 252. McLennan SN, Mathias JL. The depression-executive dysfunction (DED) syndrome and response to antidepressants: a meta-analytic review. Int J Geriatr Psychiatry 2010;25(10):933–44. 253. O’Grada C, Dinan T. Executive function in schizophrenia: what impact do antipsychotics have? Hum Psychopharmacol. 2007;22(6):397–406. 254. Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull. 1999;25(2):233–55.

542

255. Frangou S, Donaldson S, Hadjulis M, Landau S, Goldstein LH. The Maudsley Bipolar Disorder Project: executive dysfunction in bipolar disorder I and its clinical correlates. Biol Psychiatry 2005;58(11): 859–64. 256. Torrent C, Martinez-Aran A, Daban C et al. Effects of atypical antipsychotics on neurocognition in euthymic bipolar patients. Compr Psychiatry. 2011;52: 613–22. 257. Vieta E. The influence of medications on neurocognition in bipolar disorder. Acta Psychiatr Scand. 2009;120(6):414–15. 258. Royall DR, Cordes JA, Roman G et al. Sertraline improves executive function in patients with vascular cognitive impairment. J Neuropsychiatry Clin Neurosci. 2009;21(4):445–54.

Section III Chapter

34


Pharmacotherapy of emotional disturbances Steven L. Dubovsky

Disorders of emotional expression, experience, and/or regulation may be direct manifestations of neurological illness or side effects of its treatment, or they may be caused by primary alterations of the neural systems subserving these neuro-psychiatric functions Regardless of cause, disorders of mood and affect are among the most common problems encountered in the practice of Behavioral Neurology & Neuropsychiatry (BN&NP). Several types of emotional disturbance occur in patients with neurological disease. Much of the time, emotional changes are symptoms of a comorbid mood disorder, which may be expressed directly as depressed, elated, irritable, or anxious mood or which may be altered by right-sided brain disease (i.e., aprosodia). This chapter provides an overview of the principles of pharmacotherapy for disorders of mood and affect. The typical clinical features and differential diagnoses of these disturbances are described briefly. Thereafter, the pharmacologic treatments of the conditions are outlined.

Primary mood disorders Major depressive disorder Major depressive disorder is the most common primary mood disorder, and is characterized by the occurrence of one or more major depressive episodes (Box 34.1) without a history of hypomanic, manic, or mixed mood episodes [1, 2]. Although this mood disorder may begin at any age, the average age of onset is in the middle of the third decade of life. The lifetime risk for major depressive disorder is 10–25% among women and 5–12% among men, and the point prevalences in women and men are 5–9% and 2–3%,

Box 34.1. Features of a major depressive episode. Five or more symptoms present most of the day nearly every day for at least 2 weeks Symptoms must include depressed mood and/or loss of interest or pleasure (i.e., anhedonia) Additional symptoms: Feeling sad or empty or appearing tearful Decreased interest or pleasure Weight loss or gain of at least 5% or daily loss of appetite Insomnia or hypersomnia Observable psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness or excessive or inappropriate guilt Indecisiveness or decreased ability to think or concentrate Recurrent thoughts of death or suicide

respectively [2]. Major depressive disorder is 1.5–3 times more common among first-degree relatives of persons with this condition than in the general population. The course of the illness is highly variable, but isolated major depressive episodes with an interepisode latency of many years, increasing frequency of major depressive episodes (i.e., decreasing interepisode interval) with increasing age, and clusters of frequent major depressive episodes are typical patterns [2]. The number of prior episodes predicts the likelihood of subsequent episodes: 60% of people with one major depressive episode experience a second one, 70% of those with two such episodes experience a third, and 90% of those with three episodes experience a fourth [2]. Additionally, a relatively small number of people (5–10%) who present initially with a major


543


depressive episode subsequently develop a hypomanic or manic episode. The clinical presentation of major depressive episodes may be obscured by neurological conditions. Changes in weight, sleep, and activity, difficulty thinking and fatigue are common symptoms of many neurological conditions; when present, it is not uncommon for these symptoms to be dismissed as relevant to the diagnosis of depression. However, the diagnosis of depression is best made without regard to the possible attributions of such symptoms, especially among patients experiencing persistent excessive sadness and/or anhedonia. Even when a primary neurological disorder (e.g., traumatic brain injury (TBI), stroke) causes cognitive, behavioral, or somatic problems like those of depression, comorbid depression increases their number, perceived severity, and functional importance – and treatment of depression improves not only mood but also these other problems as well [3–8]. As such, using the DSM–IV–TR criteria for depression to diagnose major depressive episodes whether they occur as a primary psychiatric disorder or in the context of a neurological condition is appropriate. Major depression also is an important consideration when patients are non-adherent with treatment, become disinterested or uninvolved in treatment, fail to improve, or exhibited unexpected clinical declines. Although these problems may have other causes (e.g., apathy, worsening of a progressive neurological disorder, psychosocial or caregiving problems), depression often is a remediable issue and its effective treatment may allow patients to re-engage more effectively in their own care. Additionally, a personal or family history of depression should heighten vigilance for the development of this problem during the treatment of any other condition for which a patient seeks care.

Bipolar disorder Bipolar disorder is a chronic disorder defined by the occurrence of at least one manic or hypomanic episode (Box 34.2) or at least one mixed mood episode; many individuals with bipolar disorder also experience major depressive episodes [2]. The average age of onset for bipolar disorder is 20 years of age; onset after age 40 years is unusual and raises concerns for a non-primary (i.e., medically or neurologically related, substance-induced) form of this disorder or other conditions with similar symptoms [2, 9]. The lifetime

544

Box 34.2. Typical symptoms of mania and hypomania. Abnormally and persistently elevated, expansive or irritable mood lasting one week (or any duration if hospitalization is necessary) for mania or 4 days for hypomania Three or more additional symptoms are required if mood is elevated; four or more additional symptoms are required if mood is only irritable Additional symptoms: Inflated self-esteem or grandiosity Decreased need for sleep Increased or pressured speech Flight of ideas or racing thoughts Distractibility Increase in goal-directed behavior Excessive involvement in pleasurable activities with high potential for painful consequences

prevalence of bipolar disorder is relatively low (0.4– 1.6%) but it is a highly heritable condition, with twin studies demonstrating heritability estimates among monozygotic twins of 0.8 or higher [10–12]. Unlike major depressive disorder, bipolar disorder is equally common in men and women. However, gender tends to influence initial presentation, with mania being more likely in men and depression in women. The course of bipolar disorder is recurrent, with more than 90% of individuals experiencing more than one episode of mania. In the majority of patients, manic episodes immediately precede or follow depressive episodes; the pattern of such episodes tends to be characteristic in an individual patient. The interval between episodes tends to decrease with advancing age and a substantial minority (20–30%) of patients continue to experience residual mood and affective symptoms as well as functional impairment between episodes [2, 13]. Over the course of the illness, men tend to experience approximately equal numbers of manic and depressive episodes, whereas in women depressive episodes often dominate the clinical course of the disorder. Mania is characterized by elation in about 50% of men and 30% of women. Much of the time, a manic or hypomanic mood is manifested by irritability or dysphoric overstimulation, which can be mistaken for panic attacks. Hypomania can be confused with the expansiveness that is sometimes associated with multiple sclerosis (MS) and some central nervous system (CNS) infections such as neurosyphilis and human

Chapter 34: Pharmacotherapy of emotional disturbances

Box 34.3. Behaviors that suggest depression. Withdrawal Loss of interest Failure to improve as expected Negativism Cognitive dysfunction out of proportion to neurological disease Failure to thrive Box 34.4. Behaviors that suggest hypomania or mania despite aprosodia. Agitation Hyperactivity Decreased sleep Sleep–wake cycle reversal Rapid and/or incoherent speech Overstimulated by interpersonal interactions

immunodeficiency virus (HIV) disease, but those conditions are not accompanied by decreased need for sleep or grandiosity.

Aprosodia comorbid with primary mood disorders Aprosodia, a disturbance of the ability to understand or impart affect normally into language (including its gestural and kinesic aspects), is associated with dysfunction of the non-dominant (usually right) hemisphere (see Chapter 13) [14, 15]. In the presence of aprosodia, patients may appear affectively flat, and their speech and related communications may be deficient in emotional content. In the presence of aprosodia, disturbances of mood often are less obvious than are behavioral derivatives of depression (Box 34.3) or mania (Box 34.4) [16]. When these behavioral derivatives are present in a patient with aprosodia (especially of the motor type), empiric treatment of a possible mood disorder is reasonable. Conversely, the absence of these behavioral derivatives in a patient with aprosodia argues against interpreting flat facial expressions and emotionally deficient communication as signs of a mood disorder, and prompts caution against an empirical medication trial.

Mood disorders caused by neurological disease Depression is common among persons with neurological disorders such as cerebrovascular disease

Box 34.5. Examples of neurological conditions with which depression or mania are associated. Alzheimer’s disease Parkinson’s disease Diffuse Lewy body disease Frontotemporal lobar degeneration Huntington’s disease Traumatic brain injury Cerebrovascular disease (e.g., stroke, vascular dementia) Multiple sclerosis Systemic lupus erythematosus Epilepsy Human immunodeficiency virus infection Neurosyphilis Cerebral toxoplasmosis Cerebral neoplasms Central nervous system paraneoplastic syndromes Amyotrophic lateral sclerosis Myasthenia gravis Wilson’s disease

(including stroke and vascular dementia), TBI, epilepsy, MS, Alzheimer’s disease (AD), and Parkinson’s disease (PD), among others, and depression in these patients worsens the outcome of the neurological illness [17, 18]. These and other neurological conditions that commonly cause depression or mania are summarized in Box 34.5 [1, 4, 8, 19–25]. For example, as many as 40% of patients with PD and half of those with left-sided strokes develop major depression as a result of the impact of those illnesses on the neurobiology of mood [26]. In a study of all new cases of PD over 22 months, depression, apathy, disturbed sleep, and anxiety were observed in 37%, 27%, 18%, and 17% of patients, respectively [27]. Systemic lupus erythematosus has been associated with depression and cognitive impairment [28], both of which may be manifestations of CNS involvement. Importantly, depression is not necessarily associated with immunological evidence of disease exacerbation [29]. Myasthenia gravis is frequently associated with depression and anxiety; it is not yet known how frequently these are reactions to the illness as opposed to effects of the inflammatory response associated with this and similar diseases [30, 31]. The extent to which fatigue in myasthenia is a function of depression versus the underlying illness is a common clinical question that may be answered by an empirical antidepressant trial, initially with one of the more activating preparations such as bupropion.

545


Box 34.6. Clinical features of pathological laughing and crying. Brief, frequent, uncontrollable episodes of laughing and/or crying The episodes of pathological affect are excessively intense with respect to their inciting stimuli The valence of feelings experienced may or may not be congruent with the valence of the display of affect The valence of the displays of affect may be incongruent with those expected in the context of their occurrence (i.e., laughing when crying would be expected or vice versa) The episodes of pathological affect do not produce a persistent change in the prevailing mood The episodes of pathological affect are the result of a neurological condition other than dacrystic or gelastic epilepsy and represent a clinically significant change in the patient’s customary affects The condition produces subjective distressing and/or impairs social, occupational, or other important aspects of everyday function

Possibly because its genome contains hydroxylases that can alter dopamine and serotonin biosynthesis, toxoplasma gondii infection has been associated with depression as well as behavioral changes [32]. Secondary mania is associated with righthemispheric stroke, trauma, and tumor, and particularly with focal lesions of right basoventral, anterior temporal, orbitofrontal, caudate, and thalamic areas [33–37]. In contrast to primary mania (i.e., idiopathic bipolar disorder), secondary mania is not clearly associated with a family history of bipolar disorder in first-degree relatives of the affected individual. The potential severity of the neurological conditions underlying late-onset mania is indicated by a retrospective study in which half of 50 elderly manic patients were dead from neurological causes after 6 years of follow-up [38].

Disorders of affect Pathological laughing and crying (PLC, also known as pseudobulbar affect (PBA), involuntary emotional expression disorder (IEED), and emotional incontinence, among other names) describes a syndrome of affect dysregulation characterized by brief, intense, frequent episodes of uncontrollable laughing and/or crying that are provoked by non-sentimental or trivially sentimental stimuli [39] (Box 34.6). These episodes are

546

not manifestations of a mood disorder such as depression or mania, may be incongruent with the valence of a patient’s prevailing mood, and do not represent ictal displays of affect; instead, PLC reflects a disruption of the structure and/or function of the neural networks involved in the moment-to-moment regulation of emotion [40–45]. Pathological laughing and crying is often embarrassing to patients and their families and may interfere with the patient’s performance of activities of daily living as well as interpersonal interactions [44, 46, 47]. It also is a source of confusion for affected patients and their families: frequent episodes of crying and/or laughter often lead families and clinicians to misunderstand them as signs of a mood disorder, despite patients’ protestations to the contrary. The neuroanatomy and neurochemistry of PLC are complex, but generally involve disturbances of the structure and/or function of the ventral paralimbic (emotional generation), dorsal prefrontal (emotional regulation), and pontocerebellar (emotional modulation) networks as well as multiple neurotransmitter systems (serotonin, dopamine, and their interactions with glutamate) that functionally modulate these networks [39, 40, 42, 48] (see also Chapter 18). Lesions that disturb voluntary modulation of the function of the ventral network and its connections to autonomic and brainstem motor effectors of emotional expression produce contextually inappropriate and disinhibited affect [39, 42, 48]. Pathological laughing and crying is produced by many neurological disorders (Box 34.7) [39], but estimates of the frequency of PLC are available only for the most common of these. The frequency of post-stroke PLC ranges from 11–34% [49–51], with most patients experiencing this syndrome in the first year after stroke. During the first year following TBI, approximately 5–11% develop PLC [52, 53]. The frequencies of PLC in the late periods after stroke or TBI have not been established clearly. As many as 50% of persons with amyotrophic lateral sclerosis (ALS) develop PLC [54]; this condition is more common among persons with bulbar involvement, and rarely (∼2% of cases) may be the presenting symptom of ALS [55]. Approximately 10% of patients with MS develop PLC [56], and usually during the latter stages of this disease. The frequency of PLC among patients with AD is a matter of controversy; the most carefully conducted study of this subject [57] observed PLC in 39% of subjects with AD, 25% of which presented with crying alone and 14% with laughing or mixed laughing and crying episodes.


Box 34.7. Conditions associated with pathological laughing and crying. Strokes (subcortical, brainstem) Traumatic brain injury Alzheimer’s disease Parkinson’s disease Progressive supranuclear palsy Corticobasal degeneration Olivopontine cerebellar atrophy Frontotemporal dementia Complex partial epilepsy Amyotrophic lateral sclerosis Primary lateral sclerosis Herpes encephalitis Neurosyphilis Multiple sclerosis Kuru (a prion disease) Central pontine myelinolysis Wilson’s disease Central nervous system lipid storage diseases Brainstem arteriovenous malformation or aneurysm Cerebral tumors Brainstem or cerebellar tumors Cerebellar cyst Normal pressure hydrocephalus Third ventricle arteriovenous malformation or aneurysm

After excluding persons with comorbid mood disorders and PLC, the frequency of PLC alone in AD was 18%.

Anxiety disorders Anxiety disorders, including generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, and/or post-traumatic stress disorder (PTSD) are common in the general population [2] as well as persons with neurological disorders [58–65]. When these conditions develop, they often are chronic conditions that wax and wane in severity. Both in the primary and secondary forms, anxiety disorders are sources of substantial morbidity and disability, and may be very distressing and difficult for caregivers of persons with severe neurological conditions to manage effectively. Some anxiety disorders involve persistent excessive anxiety, fear, and/or worry (apprehensive expectation) analogous to the persistent mood disturbances of major depressive, hypomanic, and manic episodes. When present in this manner, the experience of

anxiety is usually accompanied by several additional symptoms, including other disturbances of emotion (e.g., irritability) as well as cognitive (e.g., difficulty concentrating, “mind going blank”), behavioral (e.g., restlessness, feeling “keyed up” or “on edge”), and physical (e.g., fatigue, muscle tension, sleep disturbance). Generalized anxiety disorder is the prototypic form of this problem. Alternatively, anxiety disorders may involve paroxysms of intense anxiety and fear, analogous to the episodic disturbances of affect that characterize PLC. Also similar to PLC, paroxysmal episodes of anxiety – i.e., panic attacks – begin abruptly, may or may not be provoked by relevant environmental (including interpersonal) stimuli, and are accompanied by brief anxiety-related disturbances of cognition (e.g., fear of losing control, going crazy, or dying, feelings of derealization or depersonalization) and physical function (e.g., shortness of breath, sensation of choking, palpitations, tachycardia, chest pain or discomfort, paresthesias, diaphoresis, trembling or shaking, nausea or abdominal distress, chills or hot flushes, dizziness, or lightheadedness). Recurrent episodes of panic may lead to chronic anticipatory anxiety (i.e., fear of additional panic attacks) and behavioral changes intended to avoid places or situations in which help might not be available in the event of an unexpected or situationally predisposed panic attack. Psychological and neurobiological factors contribute to the development of anxiety disorders, and there is no single theory of these conditions that accounts fully for their development [66–68]. In most neurobiological theories of persistent and paroxysmal anxiety disorders, however, the amygdala is featured prominently. The central nucleus of the amygdala influences the function of multiple other neural structures that serve as somatic effectors, including the lateral hypothalamus (activation of sympathetic nervous system), paraventricular nucleus of the thalamus (activation of corticotrophin-releasing factor stress axis), parabrachial nucleus (influence on respiration, leading to dyspnea), locus coeruleus (increase of heart rate, blood pressure, and enhancement of fearrelated learning), nucleus reticularis pontis caudalis (enhancement of somatic reflexes), and the periaqueductal gray (inducement of freezing behavior) [68]. It has been suggested that the bed nucleus of the stria terminalis may mediate the more diffuse and persistent symptoms of generalized anxiety disorder. Whether anxiety disorders represent aberrant and excessive

547


signal generation by the amygdala and related feargenerating systems, inadequate regulation of these systems by top-down (i.e., prefrontal cortical) modulators, or some combination of these processes is not clear. However, disturbances in these systems are commonly compromised by neurological injury or disease, leading to their relatively high frequencies in these contexts. When any form of anxiety disorder is present, clinicians must carefully assess patients for comorbid conditions (medical, psychiatric, substance-related, etc.) and environmental factors that may be driving the anxiety symptoms, and, when possible, treat such conditions before specifically targeting anxiety symptoms. Depression, in particular, is commonly comorbid with anxiety disorders among persons with either the primary or secondary forms of these conditions. Many of the treatments for depression (e.g., antidepressants) also improve persistent and paroxysmal anxiety; these are mentioned together in the following sections of this chapter. In general, however, psychotherapeutic interventions directed at the patient, caregivers, and/or family and systems in which the patient lives (Chapter 37) are essential components of treatment; anxiolytic medications are best regarded as potentially useful adjuncts to psychotherapeutic interventions.

Medication-induced affective symptoms Depression, anxiety and to a lesser extent mania are common side effects of medications used in neurological practice. For example, 50% of patients treated with interferon alpha become depressed [69]. Medications that may induce disturbances of mood and affect are presented in Table 34.1 [1, 70]. Medications used commonly for emotional disturbances include antidepressants, antipsychotics, and mood stabilizers. These medications are effective for primary mood disorders that are comorbid with neurological illness, and may be useful treatments of emotional disturbances resulting from neurological disorders. An exhaustive review of treatment options for depression, mania, and disorders of affect associated with all neurological conditions is beyond the scope of this chapter; readers are referred elsewhere for such reviews [39, 58–63, 71–73]. The remainder of this chapter described general approaches to the

548

Table 34.1. Examples of medications that may produce disturbances of mood and affect.

Medication

Emotional symptom

Acyclovir

Depression

Amantadine

Depression, mania

Baclofen

Depression, mania

Bromocriptine

Mania, depression

Chloroquine

Mania

Corticosteroids

Depression, mania

Cyclobenzaprine

Mania

Cycloserine

Depression

Interferon alpha

Depression, mania

Levodopa

Mania, depression, anxiety

Pergolide

Mania; depression on withdrawal

Quinacrine

Mania

Vinblastine, vincristine

Depression

Zidovudine

Mania

pharmacotherapy of emotional disturbances, and particularly those likely to be encountered in the practice of BN&NP. This discussion is organized primarily by medication type, and considers their use for the treatment of primary and secondary disturbances of emotion as well as other uses among persons with neurological disorders.

Antidepressants Antidepressants are indicated for the treatment of unipolar depression, depression associated with neurological conditions, and secondary depressive disorders [74–76]. Antidepressants other than bupropion are also effective for most anxiety disorders. Several antidepressant classes are available: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), third-generation antidepressants with mixed actions (including serotonin 5HT2 receptor antagonists such as trazodone and nefazodone, mixed receptor antagonists such as mirtazepine and serotonin/norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine), and monoamine oxidase inhibitors (MAOIs). It has been thought for some time that the therapeutic effect of antidepressants is related to their capacity to enhance neurotransmission with norepinephrine, serotonin and/or dopamine by decreasing degradation (MAOIs) or inhibiting uptake of monoamine neurotransmitters (TCAs, SSRIs, third-generation antidepressants).


More recent data implicate multiple actions on intracellular signaling as well as actions on glucocorticoids, excitatory amino acids, neurotrophic factors, and epigenetic mechanisms, among others, in the therapeutic mechanism of antidepressants [77, 78]. The SSRIs are a diverse group of compounds that share interference with the serotonin transporter, resulting in increased serotonergic neurotransmission. The SSRIs have variable potencies in blocking serotonin reuptake, but they are all equally effective with similar side effect profiles. An exception to this is paroxetine; this agent has anticholinergic properties that are comparable to those of the new TCAs [79], making it a less favorable choice for patients with conditions in which cerebral cholinergic reserve is reduced and medication-induced cognitive and/or neurobehavioral impairments more likely (e.g., AD, TBI). Although some neurological patients may not tolerate the anticholinergic and hypotensive effects of the TCAs, these agents remain important elements of the pharmacotherapeutic repertoire of subspecialists in BN&NP. Third-generation antidepressants comprise a heterogeneous group of medications with different actions that also may have useful applications for the treatment of depression among persons with specific neurological conditions. For example, the modest prodopaminergic effects of bupropion may improve and extend its therapeutic benefits among persons with PD. Similarly, striatal release of dopamine is mediated by 5HT2 heteroreceptors on dopaminergic neurons; 5HT2 antagonists (e.g., trazodone, nefazodone, and atypical antipsychotics) therefore may have properties that improve their usefulness as treatments (primary or adjunctive) for depression in PD. At the same time, increased activity of 5HT2 receptors resulting from SSRI administration may explain the tendency of a subgroup of patients with PD to tolerate SSRIs (i.e., that subgroup in which increased serotonergic tone results in decreased striatal release of dopamine mediated by 5HT2 heteroreceptors on dopaminergic neurons) [80]. Agents that augment cerebral catecholaminergic function are sometimes useful treatments for depression among persons with neurological conditions, either as part of an augmentation strategy for persons taking an SSRI or TCA or, in some cases, as a primary treatment of depression. For example, low doses of psychostimulants (e.g., methylphenidate 5–10 mg three times daily) can be helpful for depression associated with fatigue and cognitive dysfunction,

especially in the context of an illness that is expected to improve (e.g., TBI, stroke). Similarly, the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist memantine, which indirectly augments cerebral catecholaminergic function, may be useful for the treatment of primary (including treatmentresistant) depression [81]. However, its use for such purposes in primary and secondary depressive syndromes remains underexplored. A related medication, riluzole, is approved for the treatment of ALS and also may have antidepressant properties [82]. Additional antidepressant choices in specific neurological disorders are considered in Table 34.2 [26]. Most MAOIs inhibit both isoforms of the enzyme MAO, which degrades monoamines such as the catecholamines and the indoleamines. MAO-A is present in the gastrointestinal tract and the brain, whereas MAO-B is present in the brain and blood platelets but not in the gastrointestinal tract. Inhibition of gastrointestinal MAO results in increased absorption of tyramine, a substrate for the enzyme that acts as a pressor agent resulting in the need for restriction of foods high in tyramine content. Selegiline and its newer congener, rasagiline, are selective inhibitors of MAO-B used to treat PD. Selegiline, but not rasagiline, is metabolized to amphetamine and methamphetamine [83], and both of these medications appear to have neuroprotective properties. The reversible inhibitor of MAO-A (RIMA) meclobemide, which is available in many countries but not the USA, avoids dietary tyramine interactions because the drug is displaced by tyramine so that it can be metabolized normally. Although all of these agents are potentially useful treatments for depression among persons with neurological conditions, safety and tolerability concerns are generally discouraging of their use in these contexts. In addition to their benefits on depression, some antidepressants may be useful for concurrent physical symptoms. For example, TCAs are effective for chronic pain, with a number needed to treat (NNT) for at least moderate pain relief of 3.6 [84]. Less extensive data suggest that venlafaxine is also effective (NNT = 3.1) [84]. The greatest effectiveness has been found for diabetic neuropathy (NNT = 1.3), for which duloxetine is also used. However, TCAs do not appear to be effective for HIV-related neuropathy. In the treatment of chronic pain, the number needed to harm (NNH) for adverse effects causing withdrawal of medication is 28 for amitriptyline and

549


Table 34.2. Commonly used pharmacotherapies for primary, comorbid, and secondary depressive syndromes. Abbreviations: SSRI – selective serotonin reuptake inhibitor; SR – sustained release; XL – extended release; TCA – tricyclic antidepressant; ECT – electroconvulsive therapy; MAOI – monoamine oxidase inhibitor.

550

Clinical state

Treatment options

Uncomplicated unipolar depression

SSRI Bupropion SR/XL

Severe depression

Venlafaxine Mirtazapine TCA ECT (combined with medication)

Depression and anxiety

Initial treatment with benzodiazepine, when necessary SSRI Venlafaxine Mirtazapine MAOI Antidepressant and buspirone

Depression with dementia or impaired cognition

SSRI other than paroxetine Bupropion Stimulant (primary or adjunctive) Venlafaxine Duloxetine Selegiline

Depression with Parkinson’s disease

TCA SSRI Selegiline Bupropion ECT

Depression with stroke

SSRI TCA (nortriptyline) Stimulant (primary or adjunctive) Bupropion SR/XL

Depression with traumatic brain injury

SSRI other than paroxetine Stimulant (primary or adjunctive) Bupropion SR/XL Third-generation antidepressants

Depression with multiple sclerosis

SSRI TCA Stimulant (primary or adjunctive)

Depression with epilepsy

SSRI Pregabalin Gabapentin MAOI

Depression with migraine

Trazodone Mirtazapine TCA

Depression with cancer

Mirtazapine SSRI Bupropion

Depression with inanition or nausea

Chewable mirtazapine

16 for venlafaxine [84], making the TCAs, venlafaxine, and probably duloxetine appropriate first-line treatments. Nefazodone has been found effective for pain associated with fibromyalgia, as has pregabalin. Despite the involvement of serotonin in nociception, the SSRIs do not appear to be particularly useful in the treatment of chronic pain unless it is a symptom of depression. Similarly, first-line treatments for migraine prophylaxis in adults include the TCA amitriptyline in addition to beta-blockers, with valproate and topiramate considered second-line treatments along with calcium channel blockers. Low doses of amitriptyline were found to be effective for chronic daily migraines [85]. Consensus recommendations in the absence of controlled trials suggest that MAOIs are also useful for migraine prevention and nimodipine and verapamil (discussed below) have some randomized trials supporting efficacy although more research is needed [86]. SSRIs are sometimes helpful for migraine headaches, but in some patients these medications make migraine headaches worse.

Neurological side effects and interactions Potential neurological side effects of antidepressants and interactions with neurological medications influence treatment choice. Some common examples of antidepressant side effects and interactions are summarized in Tables 34.3 and 34.4 [26, 80]. All antidepressants have the potential to lower the seizure threshold, but the dose at which this occurs is usually higher than the therapeutic dose. However, this level overlaps the therapeutic dose and the seizure risk increases up to tenfold (e.g., from 0.4% to 4–5%) with maprotiline, clomipramine, and bupropion at doses above 225 mg, 250 mg, and 450 mg daily, respectively. At lower therapeutic doses, these medications do not adversely affect the treatment of epilepsy. Overdose of amoxapine, a medication used for the treatment of some cases of psychotic depression, has been associated with a higher risk of mortality than other antidepressants because of intractable seizures, but this has not been an issue at therapeutic doses. All SSRIs inhibit striatal release of dopamine and exacerbate the effect of dopamine D2 receptor blockade by other medications such as antipsychotic drugs. As a result, these medications can cause myoclonus, nocturnal leg movement, and extrapyramidal syndromes, especially akathisia [87]. For the same reason, the SSRIs increase postural sway, predisposing to falls.


Table 34.3. Some common neurological side effects of antidepressants. Abbreviations: TCA – tricyclic antidepressant; SSRI – selective serotonin reuptake inhibitor; MAOI – monoamine oxidase inhibitor; SIADH – syndrome of inappropriate antidiuretic hormone secretion.

Side effect

Comment

Sedation, ataxia

Tertiary amine TCA Mirtazapine Trazodone

Anticholinergic effects

TCA Paroxetine Phenelzine

Akathisia, parkinsonism

Amoxapine SSRI

Tremor

TCA SSRI Venlafaxine Duloxetine Bupropion

Problems with word finding, cognitive dulling

SSRI

Yawning

SSRI Clomipramine

Hyponatremia (SIADH-related)

SSRI Venlafaxine

Neuroleptic malignant syndrome

Amoxapine

Myoclonus, including nocturnal myoclonus

Amoxapine SSRIs

Paresthesias

MAOI

Diaphoresis

TCA Bupropion Venlafaxine SSRI

Seizures

Clomipramine Maprotiline Bupropion (at high doses) Amoxapine (in overdose)

Falls

SSRI TCA

A few cases of tardive dyskinesia have been reported as well [88]. All TCAs have anticholinergic and antihistaminergic side effects that can impair cognition. The tertiary amine TCAs such as amitriptyline and imipramine are the most sedating and anticholinergic of the group and generally should be avoided in demented and brain-damaged patients. The secondary amine TCAs (desipramine and nortriptyline) are better tolerated and have the additional advantage of an established correlation between serum level and clinical response. Sedation and postural hypotension caused by TCAs

can increase the risk of falls in patients with impaired motor function. Monoamine oxidase inhibitors can interfere with pyridoxine metabolism, causing peripheral neuropathy, which can also be the result of direct neurotoxicity; manifestations may include paresthesias, numbness, gait disturbances, and falls. Supplementation with vitamin B6 may ameliorate these side effects. Myoclonus, especially nocturnal myoclonus, occurs in up to 15% of patients taking phenelzine.

Mood stabilizers Mood stabilizers are used to treat bipolar disorder [89, 90]. Technically, a mood stabilizer treats both mania and depression and prevents recurrences of both, but lithium is the only medication for which data clearly support all of these actions [91]; electroconvulsive therapy (ECT) is also effective for all dimensions of bipolar disorder. Anticonvulsants have been used extensively in bipolar mood disorders, especially for treatment and prophylaxis of mania, with mixed results. All antipsychotic drugs are effective for mania (discussed in the next section of this chapter), and some second-generation atypical antipsychotics are used for maintenance treatment of bipolar disorders [90]. Some calcium channel blocking agents have antimanic and possible mood-stabilizing properties, although data on this issue are not as extensive as for some other medication classes. Lithium appears to be the most reliably effective drug in patients with discrete episodes of primary mania and depression. Anticonvulsants are appropriate initial choices for bipolar mood disorder accompanied by an abnormal electroencephalogram (EEG). Carbamazepine is useful for mixed and rapidly cycling bipolar states and possibly PTSD. Sedating and GABAergic properties of valproate (divalproex) make it an early choice for bipolar disorder accompanied by anxiety, agitation, and insomnia; it is more effective for mania than depression. Lamotrigine is approved as “maintenance treatment” in bipolar disorder; however, in industry-sponsored trials [92, 93] it lengthened the time to recurrence of depression but not mania, with only a 9% difference in recurrence rates between lamotrigine and placebo. Lamotrigine is probably most appropriately used in combination with a standard mood stabilizer for bipolar depression. In a few small open trials, oxcarbazepine, used generally as an adjunct to a standard mood stabilizer,

551


Table 34.4. Examples of interactions between antidepressants and other medications used commonly in Behavioral Neurology & Neuropsychiatry. Abbreviations: TCA – tricyclic antidepressant; SSRI – selective serotonin reuptake inhibitor; MAOI – monoamine oxidase inhibitor.

Antidepressant(s)

Other medication(s)

Drug–drug interactions of concern

TCA

Sedating medications

Additive sedation

TCA

Cyclobenzaprine

Additive quinidine-like effects

TCA

Levodopa

Decreased absorption of TCA Reduced effect of levodopa

TCA, venlafaxine, SSRI

Stimulants

Increased antidepressant levels

Desipramine, fluoxetine

Methadone

Increased antidepressant levels

SSRI

Antipsychotic drugs

Additive EPS

SSRI, TCA, venlafaxine, duloxetine

Valproate

Increased free antidepressant levels

SSRI

Dextromethorphan

Serotonin syndrome

SSRI

Calcium channel blockers (CCB)

Increased CCB effect

TCA, SSRI, venlafaxine, duloxetine, bupropion

Carbamazepine; phenytoin

Decreased antidepressant effect due to enzyme induction Increased carbamazepine levels with fluoxetine and fluvoxamine due to 3A4 inhibition

Most antidepressants

Phenytoin, carbamazepine

Reduced antidepressant levels

SSRI, SNRI

Triptans

Rare serotonin syndrome caused either by inhibition of antidepressant metabolism or additive receptor effects

MAOI

SSRI, clomipramine, imipramine, meperidine, dextromethorphan, ziprasidone

Severe serotonin syndrome

MAOI

Levodopa

Hypertension (reduced with co-administration of carbidopa)

MAOI

Central nervous system (CNS) depressants, anesthetics

Potentiation of CNS depression caused by inhibition of hepatic metabolism

MAOI

Aspartamine

Headache Diaphoresis

appeared to be beneficial for about half of patients with mania [94]. Some patients with bipolar disorder who do not respond well to carbamazepine have a better response to oxcarbazepine, and vice versa. Open studies suggested that topiramate might have mood-stabilizing properties, but controlled research has not supported this contention, and a Cochrane Review concluded that there is insufficient evidence to support the use of topiramate in any phase of bipolar disorder [95]. The risk of cognitive impairment and mood destabilization with long-term treatment raises concerns about the use of topiramate to promote weight loss in patients taking mood stabilizers. Topiramate was effective in PTSD for re-experiencing, but not total symptom scores in one study [96]; however, in another study dropout rates due to adverse effects were so high that benefit as an adjunct for PTSD could not be demonstrated [97].

552

Levetiracetam reduced mania scores in an openlabel 5-week trial, although it did not produce additional benefit when combined with valproate [98]. Other open-label experience suggests that levetiracetam may not have any mood-stabilizing properties [99]. An open-label 6-month study of zonisamide in obese, remitted bipolar patients demonstrated significant weight loss, but almost three-quarters of the patients dropped out due to adverse effects on mood [100]. The risk–benefit ratio for zonisamide to promote weight loss in bipolar disorder therefore seems unacceptably high. The phenylalkylamine calcium channel blocker (CCB) verapamil also has antimanic properties in most but not all controlled studies; however, negative studies of this agent used lower doses and shorter durations of treatment, suggesting study design (rather than the medication itself) accounts for the lack of observed treatment effects [101]. Because it does not


cause sedation or cognitive or psychomotor impairment, verapamil is well tolerated by demented patients, although, because the sustained release form is not as effective in mood disorders as the immediate release form, frequent dosing may be difficult for these patients to remember. The dihydropyidine CCB nimodipine, which is approved for the treatment of stroke, has been effective in a few studies of complex bipolar mood disorders [102]. The medication is better tolerated than verapamil but requires very frequent dosing because of the short elimination half-life.

antipsychotics tend to be associated with a lower frequency of adverse motor effects than typical (first-generation) antipsychotics. Among these agents, clozapine and quetiapine are least likely to induce extrapyramidal side effects [105, 106]. Quetiapine, olanzapine, and risperidone, alone or as adjuncts to valproate, may be useful treatments for secondary mania [37, 107–109]. Among patients with mania in PD, quetiapine or clozapine are less likely to exacerbate motor impairments and therefore are preferred treatments when antipsychotics are used [72].

Mood stabilizers for secondary mania

Other uses of mood stabilizers in neurological conditions

Secondary mania is a relatively uncommon problem and its treatments are underdeveloped. Much of what is known about treating secondary mania is derived from case reports and small case series of persons with mania following TBI or stroke. As reviewed elsewhere [37, 103], lithium, carbamazepine, valproate, haloperidol (with or without benzodiapines), and combinations of these agents are reported treatments for secondary mania. Valproate is relatively neutral with respect to its effects on cognition and motor function, and is generally regarded as the first-line treatment of secondary mania [104]. Although other agents may be effective treatments of secondary mania, cognitive and motor side effects may limit their usefulness. Carbamazepine, lithium, and benzodiazepines may adversely affect cognition and motor performance, especially during the early period following TBI, stroke, or other acute neurological events to which the secondary mania is related. Additionally, the effect of these conditions on lithium therapeutic index, and particularly the risk of lithium toxicity and/or lithium-induced seizure, is unknown. Dosing adjustments (using the “start low, go slow, but go” approach described in Chapter 32) and vigilance for treatment-induced cognitive and motor side effects is essential. Haloperidol and other typical antipsychotics with potent type-2 dopamine receptor antagonism may interfere with neuronal recovery, cognition, and motor function, especially when administered chronically. Nonetheless, these medications may be useful treatments of secondary mania when valproate is ineffective or tolerated poorly. As discussed further in the next section of this chapter, atypical (second-generation) antipsychotics also are used to treat mania, including secondary mania. In general, the second-generation

Lithium has been used to treat a number of recurrent disorders including cluster headache and cyclical neutropenia. Induction of leukocytosis by lithium can improve leukopenia caused by chemotherapy for cancer and autoimmune disease. Because it interferes with antidiuretic hormone (ADH; vasopressin) signaling in the renal tubule, lithium counteracts the syndrome of inappropriate ADH secretion (SIADH). Lithium has occasionally been used to treat spasmodic torticollis and Huntington’s disease. Lithium has multiple neuroprotective effects that may provide mechanisms for amelioration of dementing disorders such as AD [110]. A Danish database comparison of 16,238 people who purchased lithium and almost 1.5 million people who did not found that patients who continued to fill prescriptions for lithium had a decreased risk of all forms of dementia, and for AD in particular [111]. A magnetic resonance imaging (MRI) study of 12 untreated bipolar patients, 17 lithium-treated bipolar patients, and 46 controls found that total gray matter volumes were significantly greater in lithium-treated patients than the other groups [112]. The potential application of lithium as a neuroprotective agent is complicated by the frequent occurrence of cognitive impairment as a side effect. Carbamazepine has been used to treat chronic pain. An anti-excitotoxin effect of lamotrigine could be helpful in degenerative disorders, although this has not been studied. Nimodipine is approved for the acute treatment of subarachnoid hemorrhage, although its effectiveness for this condition is not robust. Verapamil is a second-line treatment for migraine headache prophylaxis. Because they do not impair cognition, the CCBs are generally well tolerated

553


by demented patients, but the need for frequent dosing can be a problem if a caretaker is not available to monitor medications.

Neurological side effects and drug–drug interactions Most mood stabilizers have the potential for side effects in multiple systems, especially cognitive dysfunction with lithium and anticonvulsants; examples of such problems are presented in Table 34.5. The most important interactions with medications used to treat primary neurological conditions involve neurotoxicity, necessitating caution in adjusting doses of both classes of medication; examples of these concerns are presented in Table 34.6.

Antipsychotics Antipsychotic drugs are usually necessary adjuncts to antidepressants in the treatment of psychotic depression. Studies with first-generation antipsychotics suggested that high doses were needed for remission; it is not yet clear whether lower doses of atypical antipsychotics are effective. It also has been suggested that relapse is common when these agents are discontinued; however, common clinical experience suggests that it may be possible to withdraw them safely within a few months of remission of psychotic depression. Industry-sponsored studies suggest that olanzapine [113] and quetiapine [114] may be useful adjuncts in the maintenance treatment of bipolar disorder. Controlled trials demonstrated reduced depression rating scale scores in bipolar depression with quetiapine [115], leading to approval by the FDA for this indication. However, differences between placebo and quetiapine groups in these studies were modest, and the data analyses performed did not control for the effects of quetiapine-induced sedation and improved sleep on depression rating scale scores. All industry-sponsored studies used enriched samples and excluded patients with complex and comorbid conditions, leaving uncertain the clinical effectiveness of these medications in the treatment of persons with bipolar disorder. Atypical antipsychotics (especially quetiapine) are commonly used to treat anxiety and insomnia. However, the neurological side effects of these medications warrant careful consideration of risks and benefits, especially in neurologically impaired patients. As with studies of new anticonvulsants, studies of

554

atypical antipsychotic drugs in all phases of bipolar disorder have excluded patients with medical or neurological comorbidity, so the role of antipsychotic drugs in the maintenance treatment of neurologically ill patients with mood instability remains to be demonstrated.

Neurological side effects and drug–drug interactions Common acute extrapyramidal side effects of all antipsychotic drugs include Parkinsonism, dystonia, akathisia, and bradykinesia, which are most common with high-potency first-generation antipsychotics (neuroleptics) but can occur with any antipsychotic drug. If akathisia is confused with agitation and bradykinesia is confused with depression, the medication may be continued or even increased in dose rather than withdrawn. Anticholinergic antiparkinsonian medications such as benztropine and trihexyphenidyl are usually used to treat Parkinsonism, and intramuscular diphenhydramine is used for acute dystonia, but unless there is a past history of significant extrapyramidal symptoms with antipsychotic drugs, pre-treatment with anticholinergic medications is not recommended, especially for neurological patients, who tolerate these medications poorly. Benzodiazepines are more effective than anticholinergic drugs for akathisia. Extrapyramidal and hypotensive side effects of antipsychotic drugs are particularly troublesome for patients with movement and gait disorders. These side effects are least severe with quetiapine and clozapine, making these the preferred antipsychotics for patients with PD [72]. However, the use of clozapine is complicated by sedation, weight gain, and the need for regular blood tests. Low-potency first-generation antipsychotics like chlorpromazine lower the seizure threshold more than high-potency first-generation antipsychotics. Clozapine also causes dose-dependent lowering of the seizure threshold, with a 5% incidence of seizures at doses above 600 mg/day. The effect of the atypical antipsychotics on seizure threshold is not well established; however, there is evidence suggesting that olanzapine is more epileptogenic than risperidone [116]. The incidence of neuroleptic malignant syndrome (NMS) is only 0.01–0.02%, but the mortality rate is as high as 10% when it does develop [117]. All of the atypical (second-generation) antipsychotic drugs


Table 34.5. Adverse effects of the most commonly used mood-stabilizing medications. Abbreviations: EEG – electroencephalography; CNS – central nervous system; SIADH – syndrome of inappropriate antidiuretic hormone secretion.

Medication

Effects

Lithium

Affective Cognitive

Affective blunting Memory impairment, cognitive dulling, “dazed” feeling, difficulty with word finding, confusion, occurrence of such problems requires evaluation of serum lithium levels and for treatment-induced hypothyroidism and/or hypercalcemia Extrapyramidal Parkinsonism; may also produce intolerance of antiparkinsonian drugs Neuromuscular Tremor, ataxia, dysarthria, incoordination, myoclonus; falls may result from ataxia and incoordination, and myoclonus; tremor may improve with beta-blocker or consolidating lithium into a single dose administered at bedtime Intracranial Pseudotumor cerebri, in which headache may not be present; elevated intracranial pressure may pressure not remit after lithium discontinuation Electrophysiologic Generalized slowing, disorganization of background rhythm, suppression of rapid eye movement sleep, seizures Endocrine Hyperparathyroidism common; hypercalcemia can cause confusion, depression, mania, weakness; hypothyroidism in 20% of adults; interference with insulin signaling may impair diabetes control Renal Polyuria and polydipsia caused by interference with vasopressin signaling. Nephrogenic diabetes insipidus may be reduced by amiloride, which reduces lithium transport into collecting duct; interstitial nephrosis and tubular and glomerular atrophy have been reported Developmental Use during pregnancy is associated with an increased risk of cardiac and other developmental anomalies, including Ebstein’s anomaly; lithium is excreted in breast milk, and nursing during treatment with this agent is not recommended

Carbamazepine, CNS oxcarbazepine Neuroendocrine Dermatologic

Hematologic Cardiac Developmental

Valproate

Comments

CNS Neuroendocrine Dermatologic Hepatic

Pancreatic Metabolic Hematologic Reproductive Developmental

Ataxia, tremor, sedation, lethargy, diplopia, cognitive impairment, irritability, confusion, restlessness, seizures SIADH; hyponatremia may cause confusion, delirium, myoclonus, or seizures Rash in 10% of patients, which remits in approximately half of these; rare but serious, and sometime fatal, toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) may develop in approximately 1–6/10,000 newly treated patients; the risk of TEN/SJS is approximately ten times higher among patients with HLA-B∗ 1502, which is most commonly present in patients of Asian ancestry and for whom pre-treatment screening for this allele is recommended Agranulocytosis risk is 2/525,000; routine complete blood counts do not predict bone marrow suppression; no bone marrow suppression with oxcarbazepine Second- and third-degree atrioventricular block may occur, generally among patients with underlying cardiac (including conduction) disturbances Use during pregnancy may increase the risk for fetal malformations, including spina bifida, craniofacial defects, cardiovascular malformations, and hypospadias, among other anomalies; carbamazepine and its epoxide metabolite are excreted into breast milk, and nursing during treatment with this agent is not recommended Sedation, ataxia, tremor, impaired memory Weight gain; polycystic ovaries; polycystic ovarian syndrome in a minority with polycystic ovaries Rash; alopecia Hepatotoxicity in 1/50,000 adults, the risk of which decreases with advancing age; higher rate of hepatotoxicity in children, especially those taking multiple other anticonvulsant medications, congenital metabolic disorders, and severe seizure disorders associated with mental retardation Pancreatitis may develop during treatment, and is potentially life-threatening Use is contraindicated in patients with urea cycle disorders (i.e., ornithine transcarbamylase deficiency), in whom valproate administration may produce a potentially fatal hyperammonemic encephalopathy Thrombocytopenia is relatively common, and often transient despite continued valproate administration; may be a treatment-limiting problem in some patients Menstrual disturbances, polycystic ovaries, and hyperandrogenism may develop; may increase the risk for developing polycystic ovarian syndrome Crosses the placenta; first trimester exposure may affect fetal neural tube development and increase risk for associated birth defects (anencephaly, meningomyelocele, and spina bifida)

555


Table 34.6. Common interactions between mood stabilizers and other medications used commonly in Behavioral Neurology & Neuropsychiatry. Abbreviations: ACE – angiotensin converting enzyme; NSAID – non-steroid anti-inflammatory drug.

Mood stabilizer

Other medication(s)


Lithium

Antipsychotics Clonazepam Tetracycline ACE inhibitors Calcium channel blockers Carbamazepine Ketamine NSAID Valproate

Neurotoxicity, increased extrapyramidal side effects Occasional neurotoxicity Increased lithium toxicity Increased lithium levels Additive cardiac slowing, neurotoxicity Neurotoxicity Lithium toxicity Increased lithium level Neurotoxicity

Carbamazepine

Valproate Phenytoin, phenobarbital Benzodiazepines Corticosteroids Oral contraceptives Verapamil

Increased carbamazepine level; decreased valproate level Decreased levels of all medications Decreased levels of alprazolam and clonazepam Decreased corticosteroid levels; false positive dexamethasone suppression test Decreased contraceptive efficacy Increased carbamazepine levels; neurotoxicity

Valproate

Benzodiazepines Ethosuximide, felbamate, phenobarbital, primidone, phenytoin Salicylates Warfarin

Increased diazepam levels; absence seizures with clonazepam Increased anticonvulsant levels

Carbamazepine, phenytoin, topiramate, phenobarbital, estrogen, lithium, fluoxetine Valproate

Decreased lamotrigine levels

Lamotrigine

Increased unbound valproate; prolonged bleeding time, bruising Increased unbound warfarin

Increased lamotrigine levels

have been associated with NMS (in juvenile as well as adult patients) [118], although at a lower rate than the older neuroleptics. Other dopamine antagonists such as metoclopramide, amoxapine, and prochlorperazine can also cause NMS, as may abrupt withdrawal of dopaminergic medications such as amantadine and L-dopa. Combining SSRIs with antipsychotic drugs increases the risk of NMS because of an additive antidopaminergic effect and increased antipsychotic drug levels by fluoxetine and paroxetine [119]. The risk of recurrence of NMS with reintroduction of an antipsychotic drug is 30%, so these medications should be restarted cautiously at low initial doses of preparations that are less potent at D2 receptor blockade. Other interactions of antipsychotic drugs with medications commonly used in neurological practice are addressed in Table 34.7. Extrapyramidal syndromes that may be caused by chronic use of any antipsychotic drug include tardive dyskinesia (TD), tardive dystonia, and tardive akathisia. The risk of TD is around 5–10% per year with the neuroleptics and about 0.5%/year with the atypical antipsychotics. TD often does not progress, especially if it is mild, and it remits about half the time

556

with medication discontinuation, although it may take three years to resolve completely. Medications that have been used to treat TD with mixed results include vitamin E, acetazolamide (combined with thiamine to reduce the risk of kidney stones), cholinergic agonists, and verapamil. Clozapine may also ameliorate TD, although in rare cases it has been thought to cause TD. Tardive dystonia, which is more disabling, has been treated with anticholinergic medications, benzodiazepines, clozapine, tetrabenazine, and botulinum toxin. Tardive akathisia is treated in the same manner as acute akathisia. A review of Medicaid records of 44,218 patients taking first-generation neuroleptics, 46,089 patients taking atypical antipsychotic drugs, and 186,600 matched controls found that, compared with controls, the incidence of sudden cardiac death was increased about twofold with both classes of medication corrected for behavioral and cardiac risk factors [120]. The risk was evident in patients taking antipsychotic drugs for less than a year, indicating that chronic metabolic effects of the medication did not explain it. A presumed mechanism involves inhibition of potassium efflux channels to prolong cardiac depolarization,


Table 34.7. Drug–drug interactions of concern in relation to co-administration of antipsychotics with other medications used commonly in Behavioral Neurology & Neuropsychiatry.

Antipsychotic(s)

Other medication(s)


First-generation antipsychotics, quetiapine, olanzapine, clozapine

Anticholinergic drugs

Additive anticholinergic effect Anticholinergic drug may impair absorption of antipsychotic drug and may increase risk of tardive dyskinesia

First-generation antipsychotics

Lithium

Increased risk of extrapyramidal symptoms

All antipsychotics

Opiates

Additive sedation

All antipsychotics

Selective serotonin reuptake inhibitors

Increased extrapyramidal symptoms

All antipsychotics

Phenytoin

Increased free phenytoin levels due to displacement from binding protein Decreased antipsychotic levels

All antipsychotics

Valproate

Increased free antipsychotic levels

Aripiprazole

Carbamazepine

Decreased antipsychotic levels

Clozapine

Carbamazepine

Contraindicated combination due to increased risk of treatment-induced agranulocytosis

Clozapine

Benzodiazepines

Additive sedation Risk of respiratory arrest

All antipsychotics

Barbiturates

Decreased antipsychotic effect Increased barbiturate levels Additive sedation

predisposing to re-entry arrhythmias, the most dangerous of which is torsades de pointes. This effect is marked with thioridazine, which has been associated with sudden cardiac death [121]. A few case reports of torsades de pointes have been associated with quetiapine, risperidone, and ziprasidone [120]. In 2005, a black box warning was added to atypical antipsychotic drugs concerning an increased risk of cerebrovascular events and death in older patients [122]. The FDA warning was based on a meta-analysis of 17 randomized controlled trials of olanzapine, risperidone, aripiprazole, and quetiapine for agitation in elderly demented patients that found a hazard risk of 1.6–1.7 for cerebrovascular events with these drugs [123], while another meta-analysis found that the odds ratios of cerebrovascular adverse events were 2.13 for the atypicals as a group and 3.43 for risperidone [124]. The warning was extended to ziprasidone and clozapine based on a presumed class effect although there were fewer extensive data on those medications [122]. Cohort studies of the neuroleptics have led to extension of the warning to neuroleptics as well as atypicals [122]. In a sample of 10,615 Veterans Affairs patients over age 65 with a diagnosis of dementia, there was a significant difference between the overall one-year mortality rate (18%) and the rates for patients taking first-generation antipsychotics

(25.2%), second-generation antipsychotics (22.6%), or both classes (29.1%), while the risk of death with other psychotropic medications was the same as with no psychiatric medications [125]. The conclusion from these studies is that while they are not contraindicated, there is evidence of significant risk using the atypicals in elderly neurologically impaired patients [122]. There is no reason to think that this risk would be mitigated in younger neurological patients. Antipsychotics also are reported to accelerate cognitive decline in cognitively impaired patients, even when other factors that affect cognition are controlled [126]. Atypical antipsychotics, especially olanzapine and risperidone, can also increase confusion, agitation, and delirium in demented patients [122, 126].

Treatment of pathological laughing and crying In many respects, treatment of PLC is similar to the treatment of secondary depressive syndromes. Systematic reviews [39, 45, 127–129] and comprehensive literature surveys suggest that SSRIs and TCAs are effective treatments of PLC, and often improve this condition within 2–3 days of treatment initiation, usually in doses lower than those used to treat

557


depression. Several large, placebo-controlled studies of dextromethorphan-quinidine also suggest that this agent may be a useful treatment for PLC [39]. The quinidine component of this combination is present in order to inhibit metabolism via the hepatic enzyme CYP450 2D6, which allows dextromethorphan (rather than its metabolite, dextrorphan) to enter the CNS at the levels required to produce its therapeutic effect. Unfortunately, potent inhibition of CYP450 2D6 may also raise levels of other concurrent administered medications and limit the usefulness of this medication in patients in whom such medications are necessary. Single case reports and case series suggest that stimulants, other catecholamine-augmenting agents, and lamotrigine also may be useful treatments for this problem. Treatments for PLC, as well as comments on their uses and drug–drug interactions, are presented in Table 34.8. In general, other mood-stabilizing agents are ineffective treatments of PLC. Their ineffectiveness highlights the need to distinguish between PLC and secondary hypomanic, manic, or mixed mood states (i.e., bipolar disorder).

Treatment of emotional outbursts Unpredictable outbursts of crying, anger, and shouting – unrelated to PLC – are common manifestations of agitation among persons with dementia and other severe neurological disorders. Antipsychotic drugs are used to treat these behaviors, but they are no more effective than placebo for chronic intermittent agitation [130]. Since the risk of antipsychotic medicationinduced neurological side effects is increased among persons with dementia and other neurological disorders, high-potency first-generation antipsychotics (e.g., haloperidol) generally are not appropriately used for these purposes. Cardiovascular side effect risks as well as anticholinergic-related side effects also make low-potency first-generation antipsychotics (e.g., thioridazine, chlorpromazine) very poor choices in this population. Industry-sponsored studies suggested that atypical antipsychotics such as risperidone, olanzapine, and quetiapine are superior to placebo for the treatment of behavioral disturbances in dementia. However, the National Institutes of Health (NIH)-funded Clinical Antipsychotic Trials of Intervention Effectiveness in AD (CATIE-AD) study of 421 AD patients with agitation and/or psychosis who were randomly

558

assigned for 36 weeks to atypical antipsychotic drugs or placebo suggests otherwise. While there was no significant difference in discontinuation for any reason (the primary end-point) in demented outpatients for risperidone, olanzapine, quetiapine, and placebo, any apparent benefit because of a slightly but statistically significantly longer time to discontinuation for olanzapine was outweighed by time to discontinuation for adverse effects – which favored placebo over olanzapine [131]. Olanzapine and risperidone produced significantly greater reduction of Neuropsychiatric Inventory (NPI) scores than placebo, but the total difference between these drugs and placebo was 3.5– 7.6 points out of an average initial score of 37, suggesting that the statistically significant difference may have been clinically trivial [132]. Aside from worsening of functioning with olanzapine, there were no differences between active treatments and placebo in cognition, quality of life, care needs, or functioning. Similarly, use of antipsychotic drugs was not found to reduce anxiety, depression, agitation, or psychosis in 933 Norwegian nursing home residents [133]. Atypical antipsychotic drugs therefore do not appear to be preferable for chronic treatment of outbursts of emotion or agitation among persons with dementia [122]. When these symptoms are treated with an atypical antipsychotic, using the lowest effective dose for the shortest time period is recommended and carefully monitoring the patient for the development of adverse effects and objectively assessing treatment response is essential. A number of other medication classes have varying levels of empirical support for treatment of chronic emotional outbursts in neurologically impaired patients. The greatest experience is with the beta-adrenergic blocking agents, especially propranolol [134]. Some patients respond well to relatively low doses of this medication, but others need 500 mg/day or more to treat chronic emotional outbursts effectively. There is a popular misconception that propranolol causes depression, but the data in these populations do not support this notion. However, sedation, hypotension, and sexual dysfunction can be treatment-limiting side effects [135]. Citalopram [136] and probably the other SSRIs [137] appear at least as useful as antipsychotic drugs for psychosis as well as affective outbursts in neurological patients. Buspirone also reduces agitation and emotional outbursts; however, doses of this agent in excess of 60 mg daily administered for several weeks (or longer)


Table 34.8. Medications that may be used to treat pathological laughing and crying (PLC). Selective serotonin reuptake inhibitors (SSRIs) with short half-lives and relatively few drug–drug interactions are the safest and usually most effective therapies for PLC. Other agents may be considered if SSRIs are ineffective or tolerated poorly. TCA – tricyclic antidepressants.

Dose

Special considerations

Citalopram

5–40 mg daily

Relatively short half-life; few drug–drug interactions

Escitalopram

5–20 mg daily

Relatively short half-life; few drug–drug interactions; may be modestly more anxiolytic than citalopram

Sertraline

25–200 mg daily

Relatively short half-life; modest sexual dysfunction; may increase the sedating effects of carbamazepine

Fluoxetine

5–40 mg daily

Long half-life of primary active metabolite, norfluoxetine; inhibits multiple CYP450 enzymes, which may increase the risk of problematic drug–drug interactions

Paroxetine

5–40 mg daily

Anticholinergic properties may be treatment limiting for some patients, especially those with cognitive impairments; discontinuation syndrome may be problematic for some patients; weight gain; inhibition of CYP450 2C19 and 2D6 increases the risk of problematic drug–drug interactions

Nortriptyline

10–150 mg daily

Relatively less anticholinergic than older TCAs; inhibition of CYP450 2D6 increases the risk of problematic drug–drug interactions

Imipramine

10–300 mg daily

Anticholinergic side effects and cardiac disease-related contraindications may limit the use of this agent, especially in older patients; inhibition of CYP450 1A2, 2C19 and 2D6 increases the risk of problematic drug-drug interactions

Amitriptyline

10–300 mg daily

Anticholinergic side effects and cardiac disease-related contraindications may limit the use of this agent, especially in older patients; inhibition of CYP450 1A2, 2C19 and 2D6 increases the risk of problematic drug-drug interactions

Methylphenidate

5–30 mg twice daily

Low but non-trivial risk of anorexia, insomnia, and dependence/abuse; may usefully augment partial responses to SSRIs

Dextroamphetamine


Low but non-trivial risk of anorexia, insomnia, and dependence/abuse; may usefully augment partial responses to SSRIs

Carbidopa-levodopa

25–100 tablet, 1–2 tablets up to four times daily

Tablets include carbidopa 25 mg and levodopa 100 mg; carbidopa doses of less than 75 mg are associated with nausea and vomiting; postural hypotension may occur when co-administered with antihypertensive agents; dose-related hallucinations and paranoia, dyskinesias

Mirtazapine

15–45 mg daily

Initial dose may be sedating, and usually is administered prior to sleep; may usefully augment partial responses to SSRIs

Venlafaxine XR

37.5–225 mg daily

Hypertension may be treatment-limiting for some patients; usual neurological symptoms (“twitching” or “shock-like” sensations) are sometimes reported; potentially difficult discontinuation syndrome

Lamotrigine

25–100 mg daily

Initial dose is maintained for 2 weeks, then increased to 50 mg daily for 2 weeks, then increased by 50 mg daily every 1–2 weeks to effective dose; co-administration of valproate necessitates slower titration (see manufacturer’s product information sheet); co-administration of other anticonvulsants also alters rate of dose escalation; the risk of severe, potentially life-threatening rash may increased by co-administration with valproate or by exceeding either the recommended initial dose or rate of dose escalation

Amantadine


The effects of anticholinergic agents and psychostimulants may be potentiated by amantadine; risk of treatment-related seizures is uncertain, and monitoring for their development is essential; psychosis and confusion may occur at high doses

Dextromethorphanquinidine (DMQ)

20–10 capsule, once or twice daily

Treatment is initiated as DMQ/20–10 capsule once daily; after 7 days, dose may be advanced to DMQ/20–10 capsule twice daily; quinidine inhibits cyP450 2D6, necessitating dose adjustment of medications also metabolized through this pathway

are needed to afford relief from these problems [122, 138]. Valproate, carbamazepine, and lithium have been used to reduce severe affective dysregulation with agitation, but controlled studies demonstrating such effects are lacking [122].

Conclusion The types, severities, and causes of emotional disorders that subspecialists in BN&NP will encounter in their patients are many, varied, and complex. Persons

559


with neurological disorders may experience primary mood disorders, and the expression of those disorders may be altered by their neurological conditions. Secondary mood disorders, anxiety disorders, and disorders of affect also develop among persons with neurological disorders, and may occur concurrently. In some circumstances, the emotional disturbance may present in a typical manner and in others (especially among persons with advanced progressive neurological disorders or severe acquired brain injuries, or severe neurodevelopmental disorders) may present as apparently non-specific emotional symptoms or behavioral disturbances (Chapter 35). These problems may respond to appropriate medications. However, their use poses risks of neurological side effects and adverse drug–drug interactions that may adversely affect the neurological illness producing emotional disturbances. Mood disorders caused by neurological disorders may also respond to psychotropic medications, as may some affective side effects of medications that cannot be discontinued. Knowledge of interactions of psychotropic and neurological medications is essential when prescribing treatments for emotional disturbances among patients with neurological conditions. For patients with unipolar or bipolar mood disorders who cannot tolerate antidepressants or mood stabilizers, electroconvulsive therapy (ECT) is an option even in the presence of dementia, and it may be preferable for patients with refractory PD (see Chapter 38). Electroconvulsive therapy is risky in patients with space-occupying lesions, but with very careful management it may be possible to administer it in some circumstances. Chronic intermittent emotional dysregulation among patients with neurological disorders may be a manifestation of PLC, or it may be a component of more generalized agitation. Considering the balance of risks and benefits, SSRIs are appropriate initial choices for either condition. Beta-blockers, anticonvulsants, and lithium are preferable to antipsychotic drugs for chronic agitation, although the risks of their use in these populations are not trivial. Firstgeneration antipsychotics are generally poor choices for any form of chronic agitation, and the newer atypical antipsychotics have not consistently been found to be superior to placebo for this indication. The risks of these drugs often outweigh the benefits in agitated non-psychotic patients with neurological conditions.

560

References 1. Dubovsky SL, Dubovsky AN. Concise Guide to Mood Disorders. 1st edition. Washington, DC: American Psychiatric Publishing; 2002. 2. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision: DSM–IV–TR. Washington, DC: American Psychiatric Association; 2000. 3. Cook KF, Bombardier CH, Bamer AM et al. Do somatic and cognitive symptoms of traumatic brain injury confound depression screening? Arch Phys Med Rehabil. 2011;92(5):818–23. 4. Bombardier CH, Fann JR, Temkin NR et al. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. J Am Med Assoc 2010;303(19):1938–45. 5. Fann JR, Uomoto JM, Katon WJ. Sertraline in the treatment of major depression following mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2000;12(2):226–32. 6. Fann JR, Uomoto JM, Katon WJ. Cognitive improvement with treatment of depression following mild traumatic brain injury. Psychosomatics 2001; 42(1):48–54. 7. Cumming TB, Churilov L, Skoog I, Blomstrand C, Linden T. Little evidence for different phenomenology in poststroke depression. Acta Psychiatr Scand. 2010; 121(6):424–30. 8. Spalletta G, Robinson RG. How should depression be diagnosed in patients with stroke? Acta Psychiatr Scand. 2010;121(6):401–3. 9. Arciniegas DB. New-onset bipolar disorder in late life: a case of mistaken identity. Am J Psychiatry 2006; 163(2):198–203. 10. Cardno AG, Marshall EJ, Coid B et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999;56(2): 162–8. 11. Kendler KS, Pedersen NL, Neale MC, Mathe AA. A pilot Swedish twin study of affective illness including hospital- and population-ascertained subsamples: results of model fitting. Behav Genet. 1995;25(3): 217–32. 12. Kieseppa T, Partonen T, Haukka J, Kaprio J, Lonnqvist J. High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry 2004; 161(10):1814–21. 13. Henry C, Van den Bulke D, Bellivier F et al. Affective lability and affect intensity as core dimensions of bipolar disorders during euthymic period. Psychiatry Res. 2008;159(1–2):1–6.


14. Ramasubbu R, Kennedy SH. Factors complicating the diagnosis of depression in cerebrovascular disease, Part II – Neurological deficits and various assessment methods. Can J Psychiatry 1994;39(10):601–7. 15. Ross ED. The aprosodias. Functional-anatomic organization of the affective components of language in the right hemisphere. Arch Neurol. 1981;38(9): 561–9. 16. Dubovsky SL. Using electroconvulsive therapy for patients with neurological disease. Hosp Community Psychiatry 1986;37(8):819–25. 17. Kanner AM. Should neurologists be trained to recognize and treat comorbid depression of neurologic disorders? Yes. Epilepsy Behav. 2005;6: 303–11. 18. Nilsson FM, Kessing LV, Sorensen TM, Andersen PK, Bolwig TG. Affective disorders in neurological diseases: a case register-based study. Acta Psychiatr Scand. 2003;108(1):41–50. 19. Taylor L, Wicks P, Leigh PN, Goldstein LH. Prevalence of depression in amyotrophic lateral sclerosis and other motor disorders. Eur J Neurol. 2010;17(8):1047–53.

28. Kozora E, Arciniegas DB, Filley CM et al. Cognitive and neurologic status in patients with systemic lupus erythematosus without major neuropsychiatric syndromes. Arthritis Rheum. 2008;59(11): 1639–46. 29. Harel L, Sandborg C, Lee T, von Scheven E. Neuropsychiatric manifestations in pediatric systemic lupus erythematosus and association with antiphospholipid antibodies. J Rheumatol. 2003; 33(9):1873–7. 30. Kulaksizoglu IB. Mood and anxiety disorders in patients with myasthenia gravis: aetiology, diagnosis and treatment. CNS Drugs 2007;21(6):473–81. 31. Greim B, Engel C, Apel A, Zettl UK. Fatigue in neuroimmunological diseases. J Neurol. 2007; 254(Suppl. 2):II102–6. 32. Henriquez SA, Brett R, Alexander J, Pratt J, Roberts CW. Neuropsychiatric disease and Toxoplasma gondii infection. Neuroimmunomodulation. 2009;16(2): 122–33.

20. Atassi N, Cook A, Pineda CM et al. Depression in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2011;12(2):109–12.

33. Berthier ML, Kulisevsky J, Gironell A, Fernandez Benitez JA. Poststroke bipolar affective disorder: clinical subtypes, concurrent movement disorders, and anatomical correlates. J Neuropsychiatry Clin Neurosci. 1996;8(2):160–7.

21. Patten SB, Berzins S, Metz LM. Challenges in screening for depression in multiple sclerosis. Mult Scler. 2010;16(11):1406–11.

34. Starkstein SE, Mayberg HS, Berthier ML et al. Mania after brain injury: neuroradiological and metabolic findings. Ann Neurol. 1990;27(6):652–9.

22. Starkstein SE, Dragovic M, Jorge R, Brockman S, Robinson RG. Diagnostic criteria for depression in Alzheimer disease: a study of symptom patterns using latent class analysis. Am J Geriatr Psychiatry 2011; 19(6):551–8.

35. Starkstein SE, Robinson RG. Mood disorders in neurodegenerative diseases. Semin Clin Neuropsychiatry 1996;1(4):272–81.

23. Marsh L, McDonald WM, Cummings J, Ravina B. Provisional diagnostic criteria for depression in Parkinson’s disease: report of an NINDS/NIMH Work Group. Mov Disord. 2006;21(2):148–58. 24. Ottman R, Lipton RB, Ettinger AB et al. Comorbidities of epilepsy: results from the Epilepsy Comorbidities and Health (EPIC) survey. Epilepsia 2011;52(2): 308–15. 25. Blass DM, Rabins PV. Depression in frontotemporal dementia. Psychosomatics 2009;50(3):239–47.

36. Starkstein SE, Robinson RG. Mechanism of disinhibition after brain lesions. J Nerv Ment Dis. 1997;185(2):108–14. 37. Oster TJ, Anderson CA, Filley CM, Wortzel HS, Arciniegas DB. Quetiapine for mania due to traumatic brain injury. CNS Spectr. 2007;12(10): 764–9. 38. Shulman KI, Tohen M, Satlin A, Mallya G, Kalunian D. Mania compared with unipolar depression in old age. Am J Psychiatry 1992;149(3):341–5. 39. Wortzel HS, Oster TJ, Anderson CA, Arciniegas DB. Pathological laughing and crying: epidemiology, pathophysiology and treatment. CNS Drugs 2008; 22(7):531–45.

26. Dubovsky SL, Dubovsky AN. Geriatric neuropsychopharmacology. In Coffey CE, Cummings JL, editors. The American Psychiatric Press Textbook of Geriatric Neuropsychiatry. 3rd edition. Washington, DC: American Psychiatric Press; 2010.

40. Parvizi J, Anderson SW, Martin CO, Damasio H, Damasio AR. Pathological laughter and crying: a link to the cerebellum. Brain 2001;124(Pt 9):1708–19.

27. Aarsland D, Bronnick K, Alves G et al. The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease. J Neurol Neurosurg Psychiatry 2009;80(8):928–30.

41. Arciniegas DB, Topkoff J. The neuropsychiatry of pathologic affect: an approach to evaluation and treatment. Semin Clin Neuropsychiatry 2000;5(4): 290–306.

561


42. Wilson SA. Original papers: some problems in neurology. J Neurol Psychopathol. 1924;4(16): 299–333.

58. Robinson RG. The Clinical Neuropsychiatry of Stroke. 2nd edition. Cambridge: Cambridge University Press; 2006.

43. Schiffer RB, Herndon RM, Rudick RA. Treatment of pathologic laughing and weeping with amitriptyline. N Engl J Med. 1985;312(23):1480–2.

59. Trimble MR, Schmitz B. The Neuropsychiatry of Epilepsy. 2nd edition. Cambridge: Cambridge University Press; 2011.

44. Cummings JL, Arciniegas DB, Brooks BR et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr. 2006;11(6):1–7.

60. Coffey CE, McAllister TW, Silver JM. Guide to Neuropsychiatric Therapeutics. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.

45. Parvizi J, Arciniegas DB, Bernardini GL et al. Diagnosis and management of pathological laughter and crying. Mayo Clin Proc. 2006;81(11):1482–6.

61. Yudofsky SC, Hales RE, American Psychiatric Publishing. The American Psychiatric Publishing Textbook of Neuropsychiatry And Behavioral Neurosciences. 5th edition. Washington, DC: American Psychiatric Publishing; 2008.

46. Brooks BR. Involuntary emotional expression disorder: treating the untreated. CNS Spectr. 2007; 12(4 Suppl. 5):23–7. 47. Calvert T, Knapp P, House A. Psychological associations with emotionalism after stroke. J Neurol Neurosurg Psychiatry 1998;65(6):928–9. 48. Rabins PV, Arciniegas DB. Pathophysiology of involuntary emotional expression disorder. CNS Spectr. 2007;12(4 Suppl. 5):17–22. 49. House A, Dennis M, Molyneux A, Warlow C, Hawton K. Emotionalism after stroke. Br Med J. 1989; 298(6679):991–4. 50. Kim JS. Pathological laughter and crying in unilateral stroke. Stroke 1997;28(11):2321. 51. Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150(2):286–93. 52. Zeilig G, Drubach DA, Katz-Zeilig M, Karatinos J. Pathological laughter and crying in patients with closed traumatic brain injury. Brain Inj. 1996;10(8): 591–7. 53. Tateno A, Jorge RE, Robinson RG. Pathological laughing and crying following traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2004;16(4):426–34. 54. Gallagher JP. Pathologic laughter and crying in ALS: a search for their origin. Acta Neurol Scand. 1989;80(2): 114–17. 55. Gubbay SS, Kahana E, Zilber N et al. Amyotrophic lateral sclerosis. A study of its presentation and prognosis. J Neurol. 1985;232(5):295–300. 56. Feinstein A, Feinstein K, Gray T, O’Connor P. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol. 1997;54(9):1116–21. 57. Starkstein SE, Migliorelli R, Teson A et al. Prevalence and clinical correlates of pathological affective display in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1995;59(1):55–60.

562

62. Silver JM, McAllister TW, Yudofsky SC. Textbook of Traumatic Brain Injury. 2nd edition. Arlington, VA: American Psychiatric Publishing; 2011. 63. Krishnamoorthy ES, Prince M, Cummings JL. Dementia: A Global Approach. Cambridge: Cambridge University Press; 2010. 64. Lauterbach EC. Psychiatric Management in Neurological Disease. 1st edition. Washington, DC: American Psychiatric Press; 2000. 65. Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord. 2009; 24(15):2175–86. 66. Jetty PV, Charney DS, Goddard AW. Neurobiology of generalized anxiety disorder. Psychiatr Clin North Am. 2001;24(1):75–97. 67. Martin EI, Ressler KJ, Binder E, Nemeroff CB. The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Psychiatr Clin North Am. 2009;32(3):549–75. 68. Ninan PT, Dunlop BW. Neurobiology and etiology of panic disorder. J Clin Psychiatry 2005;66(Suppl. 4): 3–7. 69. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24–31. 70. Kulisevsky J, Pascual-Sedano B, Barbanoj M et al. Acute effects of immediate and controlled-release levodopa on mood in Parkinson’s disease: a double-blind study. Mov Disord. 2007;22(1):62–7. 71. Zafonte R, Hammond F, Dennison A, Chew E. Pharmacotherapy to enhance arousal: what is known and what is not. Prog Brain Res. 2009;177:293–316. 72. Miyasaki JM, Shannon K, Voon V et al. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66(7):996–1002.


73. Doody RS, Stevens JC, Beck C et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56(9):1154–66. 74. American Psychiatric Association. Treatment of Patients with Major Depressive Disorder. Washington, DC: American Psychiatric Publishing; 2011. 75. Sinyor M, Schaffer A, Levitt A. The sequenced treatment alternatives to relieve depression (STAR∗ D) trial: a review. Can J Psychiatry 2010;55(3):126–35. 76. Price A, Rayner L, Okon-Rocha E et al. Antidepressants for the treatment of depression in neurological disorders: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry 2011;82(8):914–23. 77. Shelton RC. Intracellular mechanisms of antidepressant drug action. Harv Rev Psychiatry 2000;8(4):161–74. 78. Tardito D, Perez J, Tiraboschi E et al. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev. 2006;58(1):115–34. 79. Schmitt JA, Kruizinga MJ, Riedel WJ. Non-serotonergic pharmacological profiles and associated cognitive effects of serotonin reuptake inhibitors. J Psychopharmacol. 2001;15(3):173–9. 80. Dubovsky SL. Beyond the serotonin reuptake inhibitors: rationales for the development of new serotonergic agents. J Clin Psychiatry 1994;55(Suppl.): 34–44. 81. Zarate CA, Jr, Singh JB, Carlson PJ et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63(8):856–64. 82. Pittenger C, Coric V, Banasr M et al. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs 2008;22(9):761–86.

87. Gerber PE, Lynd LD. Selective serotonin-reuptake inhibitor-induced movement disorders. Ann Pharmacother. 1998;32(6):692–8. 88. Dubovsky SL, Thomas M. Tardive dyskinesia associated with fluoxetine. Psychiatr Serv. 1996;47(9): 991–3. 89. American Psychiatric Association. Treatment of Patients with Bipolar Disorder. Washington, DC: American Psychiatric Publishing; 2002. Available from: http://www.psychiatryonline.com/pracGuide/ pracGuideChapToc 8.aspx. 90. Derry S, Moore RA. Atypical antipsychotics in bipolar disorder: systematic review of randomised trials. BMC Psychiatry 2007;7:40. 91. Bauer MS, Mitchner L. What is a “mood stabilizer”? An evidence-based response. Am J Psychiatry 2004; 161(1):3–18. 92. Calabrese JR, Bowden CL, Sachs G et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003;64(9):1013–24. 93. Bowden CL, Calabrese JR, Sachs G et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003;60(4):392–400. 94. Conway CR, Chibnall JT, Nelson LA et al. An open-label trial of adjunctive oxcarbazepine for bipolar disorder. J Clin Psychopharmacol. 2006;26(1):95–7. 95. Vasudev K, Macritchie K, Geddes J, Watson S, Young A. Topiramate for acute affective episodes in bipolar disorder. Cochrane Database Syst Rev. 2006;1: CD003384. 96. Tucker P, Trautman RP, Wyatt DB et al. Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2007;68(2):201–6.

84. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;4:CD005454.

97. Lindley SE, Carlson EB, Hill K. A randomized, double-blind, placebo-controlled trial of augmentation topiramate for chronic combat-related posttraumatic stress disorder. J Clin Psychopharmacol. 2007;27(6): 677–81.

85. Krymchantowski AV, Silva MT, Barbosa JS, Alves LA. Amitriptyline versus amitriptyline combined with fluoxetine in the preventative treatment of transformed migraine: a double-blind study. Headache 2002;42(6):510–14.

98. Kruger S, Sarkar R, Pietsch R, Hasenclever D, Braunig P. Levetiracetam as monotherapy or add-on to valproate in the treatment of acute mania – a randomized open-label study. Psychopharmacology (Berlin) 2008;198(2):297–9.

86. Loj J, Solomon GD. Migraine prophylaxis: who, why, and how. Cleve Clin J Med. 2006;73(9):793–4, 7, 800–1 passim.

99. Post RM, Altshuler LL, Frye MA et al. Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder. J Clin Psychiatry 2005;66(3):370–4.

83. Guay DR. Rasagiline (TVP-1012): a new selective monoamine oxidase inhibitor for Parkinson’s disease. Am J Geriatr Pharmacother. 2006;4(4):330–46.

563


100. Wang PW, Yang YS, Chandler RA et al. Adjunctive zonisamide for weight loss in euthymic bipolar disorder patients: a pilot study. J Psychiatr Res. 2008;42(6):451–7. 101. Dubovsky SL. Calcium channel antagonists as novel agents for manic-depressive disorder. In Schatzberg AF, Nemeroff CB, editors. The American Psychiatric Press Textbook of Psychopharmacology. 1st edition. Washington, DC: American Psychiatric Press; 1995, pp. 377–88. 102. Post RM, Pazzaglia P, Ketter TA et al. Carbamazepine and nimodipine in refractory bipolar illness: efficacy and mechanisms. In Halbreich U, Montgomery SA, editors. Pharmacotherapy for Mood, Anxiety, and Cognitive Disorders. Washington, DC: American Psychiatric Press; 2000, pp. 77–110. 103. Warden DL, Gordon B, McAllister TW et al. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma 2006;23(10):1468–501. 104. Evans DL, Byerly MJ, Greer RA. Secondary mania: diagnosis and treatment. J Clin Psychiatry 1995; 56(Suppl. 3):31–7. 105. Cole P, Rabasseda X. Quetiapine in bipolar disorder: increasing evidence of efficacy and tolerability. Drugs Today (Barcelona) 2004;40(10):837–52. 106. Serretti A, De Ronchi D, Lorenzi C, Berardi D. New antipsychotics and schizophrenia: a review on efficacy and side effects. Curr Med Chem. 2004;11(3):343–58. 107. Daniels JP, Felde A. Quetiapine treatment for mania secondary to brain injury in 2 patients. J Clin Psychiatry 2008;69(3):497–8. 108. Dervaux A, Levasseur M. Risperidone and valproate for mania following stroke. J Neuropsychiatry Clin Neurosci. 2008;20(2):247. 109. Goyal R, Sameer M, Chandrasekaran R. Mania secondary to right-sided stroke – responsive to olanzapine. Gen Hosp Psychiatry 2006;28(3):262–3. 110. Yeh HL, Tsai SJ. Lithium may be useful in the prevention of Alzheimer’s disease in individuals at risk of presenile familial Alzheimer’s disease. Med Hypotheses 2008;71(6):948–51.

to acute treatment with olanzapine. Am J Psychiatry 2006;163(2):247–56. 114. Vieta E, Suppes T, Eggens I et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord. 2008; 109(3):251–63. 115. Thase ME, Macfadden W, Weisler RH et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006; 26(6):600–9. 116. Brodtkorb E, Mula M. Optimizing therapy of seizures in adult patients with psychiatric comorbidity. Neurology 2006;67(12 Suppl. 4):S39–44. 117. Strawn JR, Keck PE, Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry 2007;164(6): 870–6. 118. Croarkin PE, Emslie GJ, Mayes TL. Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases. J Clin Psychiatry 2008;69(7): 1157–65. 119. Stevens DL. Association between selective serotonin-reuptake inhibitors, second-generation antipsychotics, and neuroleptic malignant syndrome. Ann Pharmacother. 2008;42(9):1290–7. 120. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360(3):225–35. 121. Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SH. Thioridazine and sudden unexplained death in psychiatric in-patients. Br J Psychiatry 2002;180: 515–22. 122. Passmore MJ, Gardner DM, Polak Y, Rabheru K. Alternatives to atypical antipsychotics for the management of dementia-related agitation. Drugs Aging 2008;25(5):381–98. 123. Friedman JH. Atypical antipsychotics in the elderly with Parkinson disease and the “black box” warning. Neurology 2006;67(4):564–6.

111. Kessing LV, Sondergard L, Forman JL, Andersen PK. Lithium treatment and risk of dementia. Arch Gen Psychiatry 2008;65(11):1331–5.

124. Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 2006;14(3):191–210.

112. Sassi RB, Nicoletti M, Brambilla P et al. Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett. 2002;329(2): 243–5.

125. Kales HC, Valenstein M, Kim HM et al. Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry 2007;164(10):1568–76; quiz 623.

113. Tohen M, Calabrese JR, Sachs GS et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding

126. Brooks JO, Hoblyn JC. Neurocognitive costs and benefits of psychotropic medications in older adults. J Geriatr Psychiatry Neurol. 2007;20(4):199–214.

564


127. Hackett ML, Yang M, Anderson CS, Horrocks JA, House A. Pharmaceutical interventions for emotionalism after stroke. Cochrane Database Syst Rev. 2010;2:CD003690. 128. House AO, Hackett MI, Anderson CS, Horricks JA. Pharmaceutical interventions for emotionalism after stroke: the Cochrane Stroke Group. Stroke 2004;35(6): E218-E. 129. Wortzel HS, Anderson CA, Arciniegas DB. Treatment of pathologic laughing and crying. Curr Treat Options Neurol. 2007;9(5):371–80. 130. Dubovsky SL. Clinical Guide to Psychotropic Medications. 1st edition. New York, NY: Norton; 2005. 131. Schneider LS, Tariot PN, Dagerman KS et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525–38. 132. Sultzer DL, Davis SM, Tariot PN et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer’s disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry 2008;165(7):844–54. 133. Selbaek G, Kirkevold O, Engedal K. The course of psychiatric and behavioral symptoms and the use of

psychotropic medication in patients with dementia in Norwegian nursing homes – a 12-month follow-up study. Am J Geriatr Psychiatry 2008;16(7):528–36. 134. Brooke MM, Patterson DR, Questad KA, Cardenas D, Farrel-Roberts L. The treatment of agitation during initial hospitalization after traumatic brain injury. Arch Phys Med Rehabil. 1992;73(10):917–21. 135. Yudofsky SC. Beta-blockers and depression. The clinician’s dilemma. J Am Med Assoc. 1992;267(13): 1826–7. 136. Pollock BG, Mulsant BH, Rosen J et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry 2007;15(11):942–52. 137. Dubovsky SL, Thomas M. Beyond specificity: effects of serotonin and serotonergic treatments on psychobiological dysfunction. J Psychosom Res. 1995; 39(4):429–44. 138. Cantillon M, Brunswick R, Molina D, Bahro M. Buspirone vs haloperidol – a double-blind trial for agitation in a nursing home population with Alzheimer’s disease. Am J Geriat Psychiatry 1996; 4(3):263–7.

565

Section III Chapter

35


Pharmacotherapy of behavioral disturbances Thomas W. McAllister and David B. Arciniegas

Challenging behavior is a major source of distress and disability in individuals with neuropsychiatric disorders. Such behaviors are frequently the proximate cause cited for seeking institutional care and add significant burden to families and caregivers [1, 2]. The evaluation and treatment of such behavioral disturbances is among the most frequent reasons for consultation with a subspecialist in Behavioral Neurology & Neuropsychiatry (BN&NP). Successful treatment of challenging behaviors most commonly involves a multimodal approach that makes use of cognitive, behavioral, environmental, and pharmacologic interventions. Medications often will be ineffective or incompletely effective if a principal contributor to the challenging behaviors is a recurrent and unaddressed precipitating stimulus in the environment. Similarly, behavioral or environmental interventions will not be successful if the target behaviors are driven by a poorly controlled medical illness, an active psychiatric disorder, or some other disturbance in the patient’s internal neurochemical milieu. Although this chapter focuses on medication approaches to the management of challenging behaviors, their consideration necessitates careful attention to the overall psychosocial environment of the individual, with careful thought given to other interventions that will maximize benefits conferred by pharmacotherapy. Additional information on behavioral and environmental approaches to challenging behaviors can be found in Chapter 37. This chapter first presents a discussion of the components and typology of challenging behavior. General principles in the use of medications to address these behaviors follow. The next section describes specific behavioral problems commonly encountered in the clinical practice of BN&NP; particular attention

is given to their prevalence in neuropsychiatric disorders, the manner in which the underlying neuropsychiatric illness may alter presentation of the behavior, and differential diagnostic issues. Treatment approaches are then discussed, and evidence of efficacy in specific neuropsychiatric disorders, where such is available, is reviewed. Additionally, guidance is offered regarding alterations of the doses of medication necessitated by some neuropsychiatric disorders. Consistent with the intent of this volume and the scope of this chapter, emphasis is placed on the principles and approach to treatment rather than on exhaustively cataloguing the behavioral neuropharmacology literature.

Dimensions and types of challenging behaviors Clarifying what is meant by terms such as “challenging” or “disturbed” behavior requires first establishing to whom the behavior is challenging or disturbing and why it is regarded as such. The behaviors of many individuals with neuropsychiatric disorders are upsetting to those around them, but often those behaviors present no risk to the individual or to others. The individual also may neither be concerned about the behaviors nor aware that the behavior is of concern to others. In the former instance, the clinician must determine whether the behavior should be treated or the response of others in the individual’s system of care requires intervention. In the latter instance, providing the patient with pharmacotherapy is not the appropriate management approach. In some cases, a patient’s behaviors present a threat to himself or to others, are functionally impairing, curtail their activities, and/or reduce quality of life. For


566

Chapter 35: Pharmacotherapy of behavioral disturbances

example, loud threatening outbursts or public displays of sexual behavior may not be overtly harmful, yet may result in atrophy of the social network, increased turnover of staff, or reluctance on the part of staff to take the individual to community outings for fear of creating a scene. In such circumstances, the behaviors threaten the patient’s quality of life. Once a behavior becomes a physical, functional, or other type of threat to an individual or those with whom he or she interacts, several features of the behavior require assessment. These include the nature of the behavior, as well as its frequency, intensity (severity), and the context in which it occurs. Additionally, it is important to consider whether there is a compelling rationale for treating the behavior pharmacologically. For example, the clinician should ask whether the behavior is within the range of normal but occurring at an abnormal frequency (e.g., too much or too little sexual behavior) or whether the behavior is “abnormal” to such a degree that even very infrequent occurrences may be a legitimate concern (e.g., command hallucinations to assault someone). Abnormalities in the frequency domain may be of at least two types: abnormal frequency for the individual (i.e., a change in the baseline frequency of the behavior) or abnormal frequency for the environment (i.e., occurring at a frequency that is above or below cultural, environmental, or community standards). Often careful analysis of the presenting concern suggests that it is not the frequency of the behavior per se but rather the intensity of the problematic behavior(s) that is of concern. For example, an individual who historically became irritable but maintained behavior control when his desires were frustrated now begins responding to frustration with physical aggression. Although the behavioral events of concern are not necessarily occurring more frequently, the severity of those events are judged to be more serious and entails a greater threat to the individual and others. In such a case, the perceived need to treat such a patient likely would be increased. In some cases, both the frequency and intensity of the problematic behaviors may be increased. Alternatively the frequency and intensity of a behavior may not change but instead begin occurring in a context that is problematic. For example, yelling may be tolerable when alone or in a private setting but less so when it occurs in public or in a group residential setting. In any of these circumstances, the perceived need to treat escalating behavioral problems becomes compelling. All of these considerations may inform

on the underlying cause of the problematic behaviors as well as the most useful and effective management approach – pharmacotherapeutic, behavioral, environmental, or some combination thereof.

Importance of diagnosis Challenging behaviors are a ubiquitous component of neuropsychiatric disorders. On the one hand, it is tempting to attribute the cause of the challenging behavior to the underlying illness (e.g., “the patient’s aggressive outbursts are due to his Alzheimer’s disease”). While such attributions may not be entirely inaccurate, they usually offer little guidance with regard to the management of challenging behaviors. There are many potential, and sometimes co-occurring, causes for challenging behaviors among persons with neuropsychiatric disorders. Treatment of these behaviors – particularly when pharmacologic interventions are used – necessitates careful appraisal and consideration of their possible causes (Table 35.1). A full discussion of all of these factors is beyond the scope of this chapter but a brief review of the roles of co-occurring cognitive and emotional disturbances, the development of psychiatric illness, disease-related damage to strategic neural circuitry, and diseasespecific alterations in neurotransmitters is warranted.

Co-occurring cognitive impairments Cognitive problems can play an important role in the development and presentation of challenging behaviors. For example, some individuals with limited attention capacity may display other challenging behaviors when placed in environments with multiple stimuli (i.e., environments that are over-stimulating with regard to an individual’s information-processing capacities). Individuals with memory impairment may respond angrily or aggressively when confronted about (or by evidence of) their impairments. Memory impairments also may contribute to the development of paranoid ideation (e.g., delusions of theft) and related behavioral disturbances among persons with dementias or other amnestic disorders. There is evidence that cholinesterase-inhibitor treatment of persons with neurodegenerative dementias (e.g., dementia due to Alzheimer’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies, vascular dementia) [3, 4], traumatic brain injury (TBI) [5] and, possibly, other neuropsychiatric conditions (e.g., autism, attention-deficit hyperactivity

567


Table 35.1. Possible causes of and contributors to challenging behavior in neuropsychiatric disorders.

Etiological category

Example(s)

Treatment implications

Disease-specific dysfunction of neural circuits

Traumatic brain injury; frontotemporal dementia; obsessive-compulsive disorder

Interventions directed at restoring function in these circuits

Disease-specific alteration in neurotransmitter systems

Destruction of dopamine neurons in Parkinson’s disease; loss of cholinergic neurons in Alzheimer’s disease

Pharmacotherapy targeting that neurotransmitter alteration

Co-occurring cognitive impairments

Delusions of theft and/or jealousy in Alzheimer’s disease; paranoia in post-stroke Wernicke’s aphasia

Treat cognitive impairments and thereby mitigate their contributions to behavioral disturbances

Comorbid psychiatric disorders

Depression following stroke; mania due to traumatic brain injury; depression in Down syndrome

Interventions (pharmacologic and non-pharmacologic) targeting the comorbid psychiatric disorder

Abnormal responses to environmental stimuli and stimulus-bound behaviors

Lateral orbitofrontal dysfunction due to ¨ traumatic brain injury; Kluver–Bucy-like syndrome following herpes simplex-1 encephalitis

Manage exposure to stimulus (e.g., behavioral and environmental interventions; see Chapter 37)

Iatrogenic factors

Medication-induced agitation and aggression; steroid-induced mania

Eliminate or reduce the doses of offending medications or other iatrogenic contributors to behavioral disturbances

Other medical disorders

Delirium-related agitation and aggression; inadequately treated pain

Treat underlying medical disorder; if necessary, concurrently manage behavioral disturbances pharmacologically and non-pharmacologically

disorder, schizophrenia) [6] may improve neuropsychiatric symptoms, including behavioral disturbances. Similar effects are reported in response to treatment with agents that directly or indirectly augment catecholaminergic function among persons with neurodegenerative dementias [7], vascular dementia [8], TBI [9], and attention-deficit hyperactivity disorder [10], among other conditions. Whether such effects reflect the effect of such agents on cognition, independent effects of these agents on behavior, or some combination of these effects remains uncertain. Nonetheless, this evidence suggests the potential usefulness of both ascertaining the role that cognitive status plays in the etiology of challenging behaviors and also applying pharmacotherapies that concurrently target cognition and behavior – in other words, attempting to mitigate behavioral disturbances via improving cognition.

Comorbid psychiatric disorders Many neuropsychiatric disorders are associated with an increased relative risk of psychiatric disorders, including mood, anxiety, and psychotic disorders [11–18]. For example, Koponen et al. [19] studied 60 individuals 30 years after TBI and observed new postTBI Axis I (i.e., major psychiatric) disorders among

568

almost half (48%) of that sample. The most common psychiatric diagnoses were depression, substance abuse, and anxiety disorders. Rates of lifetime and current depression (26%, 10%), panic disorder (8%, 6%), and psychotic disorders (8%, 8%) also were significantly higher than community base rates. Hibbard et al. [16] studied 100 adults who, on average, were eight years post-TBI. Although some subjects had Axis I disorders prior to injury, these and other psychiatric disorders were common post-TBI. The most frequent post-TBI Axis I diagnoses were major depression and anxiety disorders (i.e., post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and panic disorder), and almost half (44%) of individuals had two or more disorders. Individuals without pre-TBI Axis I disorders were most likely to develop post-TBI major depressive and substance use disorders. They also noted that post-TBI major depression and substance use disorders were more likely to remit than were anxiety disorders. More recently, this group [12] reported a longitudinal study of 188 individuals enrolled within 4 years of injury and assessed at yearly intervals on at least two occasions. They observed elevated rates (relative to population base rates) of psychiatric disorders, and particularly depression and substance abuse, prior to injury. They also noted an elevated frequency of depression, substance


abuse, and post-traumatic stress disorder during the first post-TBI assessment and that the frequencies of these disorders declined over time. Increased frequencies of psychiatric disorders are also observed among persons with stroke [20, 21], Alzheimer’s disease [22], Parkinson’s disease [13, 23], or intellectual disabilities [14], among many other neuropsychiatric disorders. Clinicians should be alert to the possibility that challenging behavior, including aggression [24], may be related to – or be the presenting symptom of – comorbid psychiatric disorders in these populations.

Diagnostic and labeling issues Individuals with neuropsychiatric conditions may report symptoms in a variety of domains (e.g., discouragement, frustration, fatigue, anxiety), but not all of these symptoms merit description as psychiatric disorders. Psychiatric symptoms that are consistent and sustained over time (usually weeks), and that are of sufficient severity to interfere with social or occupational function or quality of life, may be described collectively and legitimately as psychiatric disorders. In the studies cited in the preceding section of this chapter, standard diagnostic criteria employing this principle were used, and their findings suggest strongly that TBI, stroke, Alzheimer’s disease, Parkinson’s disease, and other neurological conditions act in some fashion to facilitate the development of psychiatric disorders. While scientifically reasonable, application of this principle in clinical practice is confounded by current diagnostic schemes, especially those anchored to the Diagnostic and Statistical Manual of Mental Disorders (DSM) [25]. The DSM approach to psychiatric diagnosis relies on standardized phenomenological criteria and is less helpful when evaluating persons with neuropsychiatric disorders for psychiatric conditions. Perhaps most importantly, the DSM-based approach to psychiatric diagnosis does not recognize or allow for the alteration of syndromic presentations in the presence of other brain disease. For example, the manner in which the approach to diagnosing depression might be altered to accommodate a non-verbal individual is not addressed in the DSM. The idea that depression can be expressed in other ways is not reflected directly in the menu of symptom options. For example, so-called “depressive equivalents” must be inferred by creative clinicians. Thus, diagnostic schemes for the identification of psychiatric diagnoses among persons with neuropsychiatric conditions that alter their

presentation or confound their evaluation require consideration and refinement in future editions of the DSM.

Damage to strategic neural circuitry Behavior occurs along a continuum, from reflexive to motivated or purposeful. There are three general components to motivated behaviors: initiation, procurement, and self-monitoring. These components, along with decision-making and mental flexibility, are often regarded as elements of executive function. Critical to executive function are several frontal-subcortical circuits [26, 27], which are discussed at length in Chapter 5. Each circuit follows a similar path starting from frontal cortex to striatum, to globus pallidus, to thalamus, and back to frontal cortex. Although each of the major frontal-subcortical circuits is discrete, they operate in parallel and are reciprocally interconnected both with each other and with other brain regions. These circuits and the brain areas to which they are connected are subject to disruption by a vast array of brain disorders. Consequently, many neuropsychiatric disorders entail impairments in executive functions. Those involving the dorsolateral prefrontalsubcortical circuit (and/or areas to which it is connected) impair executive functions such as decisionmaking, problem solving and mental flexibility as well as executive control over other aspects of cognition (e.g., attention, working memory, declarative memory, language, praxis, visuospatial function). Conditions affecting the lateral orbitofrontal-subcortical circuit and related nodal points impair intuitive, nuanced social behaviors and the capacity to selfmonitor and self-correct in real time within a social context. Conditions affecting the anterior cingulatesubcortical circuit and related areas impair motivated and reward-related behaviors. As such, much of the altered behavior and/or personality changes exhibited by persons with many neuropsychiatric disorders may be understood most usefully as elements of the “dysexecutive syndrome” produced by these disorders.

Disease-specific alteration in neurotransmitter systems Disruption of specific neurotransmitter systems also may contribute to the development of challenging

569


behaviors. For example, apathy, psychomotor slowing, and cognitive deficits in Parkinson’s disease are contributed to by destruction of mesencephalic dopamine neurons of the substantia nigra and ventral tegmental area dopaminergic neurons and subsequent functional deficits in the mesostriatal and mesocortical dopaminergic pathways [28]. Conversely, compensatory increases in dopamine receptor sensitivity within reward circuitry induced by Parkinson’s disease [29], combined with the use of dopamine agonists or deep brain stimulation (DBS) to treat this condition, may contribute to some of the sexually compulsive, gambling-related, and other behavioral excesses (i.e., “hedonistic homeostatic dysregulation” [30]) that develop in some persons with Parkinson’s disease [31].

General psychopharmacological principles Several factors should be considered prior to prescribing medications for challenging behaviors. These issues are considered in greater detail in Chapter 32.

Heightened vulnerability to medication side effects Individuals with neuropsychiatric disorders often manifest an increased sensitivity to psychotropic side effects (see [32] for review), and this sensitivity may take several forms. The first is a tendency to develop typical side effects associated with the given medication at a lower than usual dose. The second is a lowered threshold at which the individual develops a medication-induced delirium (i.e., toxic encephalopathy). The third is a worsening of the neurological deficits associated with the underlying disorder. For example, it is not uncommon to observe worsening of tremor or gait problems, increased emotional lability, or increased slowing of speed of information processing associated with psychotropic drug use. In other words, other problems experienced by the patient are susceptible to being made worse by the medications prescribed for behavioral problems. This highlights the need to evaluate medication history and current medications, as well as responses to those agents, before prescribing additional medications for behavioral or other neuropsychiatric problems. In that context, it is important to clarify whether a history of a medicine

570

that “didn’t help” reflects a true lack of response or instead the heightened vulnerability to side effects just described.

Evaluation of treatment effects Choosing an agent should be a thoughtful process based on a careful differential diagnosis (see above). The result of this process should be a therapeutic trial of adequate duration with clear target symptoms. It is critical to know the baseline frequency and intensity of the target symptoms and to monitor change in these indices over time in a systematic fashion. Therapeutic trials should have a clear end-point at which time a decision must be made whether the intervention has helped, and more importantly whether it has afforded adequate improvement (although not necessarily elimination) of the target symptom. Qualitative judgments (e.g., “he seems better”) should be avoided in favor of quantitative measures of the target symptom’s frequency and intensity using standard and reliable behavioral metrics; these include the several versions of the Neuropsychiatric Inventory (NPI) [33– 35] for broad-ranging psychiatric symptom assessments or symptom-specific scales targeting agitation [36], aggression [36, 37], psychosis [38, 39], apathy [40], impaired self-awareness [41], or other specific problems. A determination also must be made of the functional significance of any observed change. A reduction in the frequency and/or severity of a behavior that does not result in functional improvement necessitates re-evaluation of the merits of continued treatment with the medication used to treat that behavior. This type of disciplined approach to the evaluation of the targets of treatment and their responses to pharmacotherapy is essential. When less assiduous approaches to behavioral pharmacotherapy are used, patients are likely to acquire medication lists that include agents without clear benefits, to accumulate health risks associated with each agent, and to increase their risks of adverse drug–drug interactions.

Role of behavioral metaphors There are times, especially when clinical data are difficult to obtain or when the patient’s neurological condition is advanced or severe, that the etiology of a given behavior or set of behaviors will not be clear and


Table 35.2. Examples of behavioral metaphors.

Type

Behavior

Initial treatment

Depressive Negativistic, lack of interest in activities, weepy, aggressive or self-injurious behavior

SSRIs or other antidepressants

Manic

Increased level of arousal and activity, irritability, decreased need for sleep, increased sexual activity

Mood stabilizers (e.g., anticonvulsants, lithium)

Psychotic

Consistent misinterpretation Antipsychotics (e.g., of environment in a low-dose paranoid fashion, apparent risperidone) response to internal stimuli, aggression that “comes out of nowhere” but may flow out of paranoid misinterpretation of events

Anxiety

Challenging behaviors most Anxiolytics apparent in setting of anticipation of events, change in routine, consistently difficult or novel situations

the optimal treatment strategy will not be immediately apparent. In such circumstances, it may be useful to regard the behavior(s) as a syndrome in their own right or, as Tariot et al. [42–44] suggest, to employ a “behavioral metaphor.” For example, and as described in Table 35.2, an individual expressing increased negativism, loss of interest in activities, and/or self-destructive or selfinjurious behavior might be conceptualized as having a depressive syndrome and thus could reasonably be prescribed an antidepressant. An individual with increased irritability, increased arousal and activation, and a significant reduction in sleep might be conceptualized as having an irritable manic-like syndrome and thus reasonably started on a mood-stabilizing medication. When employing behavioral metaphors of these sorts, it is important that they lead to testable clinical hypotheses and that they remain understood as metaphors (i.e., having the value of illustrations only) when any treatment is used. The target behaviors and their baseline frequencies and severities require clear identification and description prior to treatment. The intended goal and end-point of treatment are best established prior to initiating treatment. When a medication is used, it is essential to perform an adequate but time-limited trial of that medication in which the effect

of treatment on target symptoms and functional status are serially re-evaluated. If pre-established treatment goals are not attained, the medication used in that time-limited trial should be discontinued and an alternative treatment and/or conceptual scheme for the target behavior should be considered. As suggested by the preceding review, behavioral disturbances – whether singly or in behavioral clusters – are common and often functionally limiting among persons with neuropsychiatric disorders. When they occur, they produce substantial suffering for persons with these problems as well as those with whom they interact. The remainder of this chapter identifies some of the most common behavioral disturbances encountered in the practice of BN&NP and outlines their pharmacologic treatments.

Impulsive and disinhibited behavior One of the more common concerns of patients and family/caregivers alike is a change in impulse control (i.e., disinhibition). This may manifest as verbal utterances, physical actions, snap decisions, and/or poor judgment flowing from the failure to fully consider the implications of a given action. There are many factors that may contribute to impulsivity. Among the most common of these is the phenomenon of stimulus-boundedness, in which an individual responds to the most salient cue in the environment or attaches exaggerated salience to a particular cue without regard to previous foci of attention or priorities. Another common cause of apparently “impulsive” behavior is clinician failure to recognize precipitating external or internal (including somatic) stimuli. All too often, little attention is paid to the antecedents of “impulsive” behavior. With careful analysis of the overall context in which a behavior is manifested it is frequently possible to understand “random” acts as, in fact, highly predictable events. This requires careful observation of the behaviors across a variety of contexts and use of applied behavioral analysis (see Chapter 37 for discussion). It also is often the case that psychiatric disorders contribute to impulsivity. Psychomotor hyperactivity associated with manic or hypomanic states can be associated with impulsive behavior. Individuals with psychotic symptoms, particularly in association with speech and language deficits that limit the ability to describe hallucinations or delusions, may appear to be impulsive when in fact they are responding to internal

571


stimuli (e.g., command hallucinations or paranoid delusions). It is also important to distinguish impulsive from compulsive behavior. The impulsive utterances, touching behavior, or other rituals of individuals with undiagnosed obsessive-compulsive disorder (OCD), especially those with limited verbal capacity, are easily misunderstood as impulsivity or disinhibition. Additionally, cognitive deficits, particularly in the domain of attention, also may contribute to impulsive behavior (analogous to the impulsivity associated with attention-deficit hyperactivity disorder). The treatment of impulsive or disinhibited behavior is determined by the diagnostic formulation. Stimulus-boundedness is best managed by environmental interventions such as limiting exposure to the precipitating stimulus. In situations where stimulus control is not feasible or modification of iatrogenic factors is intolerable (e.g., reducing the dose of dopamine agonists or manipulation of the DBS parameters), pharmacotherapy may be appropriate. In the event that psychiatric illness may be driving the target behaviors then treatment should be directed at mitigating that disorder (i.e., antidepressants, antipsychotics, anticycling agents, selective serotonin reuptake inhibitors (SSRIs) for OCD, etc.). If attentional deficits are believed to be contributing factors then the use of stimulants such as methylphenidate is reasonable. In the absence of other contributing neuropsychiatric conditions, the reduction in behavioral drive that often accompanies the use of SSRIs may make them useful for initial treatments of impulsive behavior [45, 46]. In the event that the behavior is sexually impulsive or highly aggressive, anti-androgen agents may be useful (see [47] for review of options); however, this approach is often ineffective and must be done with full consent of the individual and/or his legally authorized medical decision-maker. Lowdose atypical antipsychotic agents, particularly risperidone and olanzapine, also may be helpful in some circumstances, including as treatments of chronic impulsive behaviors among individuals with autistic spectrum disorders or dementing disorders [48]. However, clinicians need to be alert to increased risk of sudden death in the elderly population, and the risk of metabolic syndrome in individuals of all ages. As a last resort, lowering arousal levels with antipsychotics may be tried though this is typically not very successful and carries with it the risks associated with these agents.

572

Agitation, aggression, and self-injurious behaviors Aggressive, agitated, and self-injurious behaviors are common causes for concern among patients and family/caregivers. Some individuals with such behaviors develop them as a response to neuropsychiatric condition-related irritability or anger. Although a particular cue might be perceived as a legitimate aggravation of some sort, this type of behavioral response is out of proportion to the quality of the precipitating stimulus. Aggressive behaviors range from verbal outbursts to physically assaultive behaviors, and they may be directed at objects, others, or the patient him- or herself. The neurobiology of aggression is complex [49]. Several key brain regions have been identified as playing important roles in the modulation and manifestation of aggression including the orbitofrontal cortex, cingulate, the hypothalamus, and the limbic system [49]. Thus brain diseases are frequently associated with changes in the set point for displays of aggression. Rarely complex partial seizures can be associated with aggression, although in the vast majority of instances the displays are non-purposeful and occur during the period of post-ictal confusion [50]. The link between depression and aggression is well described and similar links have been noted in individuals with intellectual disability and TBI [14, 16, 51, 52]. Mania or maniclike presentations (usually involving irritable, rather than euphoric, mood) are less common than depression among persons with neurological disorders, but occur with sufficient frequency to merit consideration as a possible cause of agitated, aggressive, and/or self-injurious behavior [53]. Psychotic syndromes are important to consider as well; in this context, agitated, aggressive, or self-injurious behaviors may be responses to internal stimuli or be delusionally driven. A multimodal, multidisciplinary, collaborative approach to treatment is essential, and the nonpharmacologic treatments described earlier in this chapter are the first-line interventions. As suggested above, diagnosis also must precede treatment: identifying co-occurring medical, neurological, psychiatric (including pain), and substance-use disorders and establishing the mental status of the patient at the time the problematic behavior occurs (e.g., screening for disturbances of consciousness) are essential. Treatment is preceded by thorough characterization of these behaviors, the contexts in which they develop,


and their possible reinforcers. When medications are used, treatment of comorbid neuropsychiatric conditions (depression, psychosis, insomnia, anxiety, delirium), when present, also takes precedence over the prescription of medications specifically targeting agitation, aggression, or self-injurious behaviors. Pharmacologic treatment of these behaviors specifically follows from the above differential diagnostic process as well as hypotheses regarding the neural bases of the agitation, aggressive, or self-injurious behavior. For example, disinhibited temporolimbic activity resulting from loss of “topdown” modulation after prefrontal injury may result in these challenging behaviors; in such circumstances, reduction of “hyperactive” limbic monoaminergic neurotransmission with ␤-adrenergic receptor antagonists (i.e., propranolol), anticonvulsants (e.g., valproate, carbamazepine, lamotrigine), type 2A serotonin receptor antagonists (e.g., atypical antipsychotics), and/or dopamine receptor antagonists (e.g., haloperidol, fluphenazine) may be beneficial [54]. Alternatively, among patients with relatively intact orbitofrontal and/or dorsolateral prefrontal networks (i.e., “top-down” modulators of limbically driven behaviors), augmenting the function of those networks with monoaminergic agonists (i.e., amantadine, methylphenidate, and perhaps buspirone) or modulating the interactions between prefrontal and limbic networks by augmenting serotonergic activity (e.g., SSRIs, buspirone) might be useful [54]. However, the neurochemistry of aggression in this or any other clinical context is not understood completely, and any hypotheses about the neurobiological bases of agitation, aggression, and/or self-injurious behaviors must be regarded as entirely preliminary. Clinicians often will be unsure about the drivers of the behavior. Consequently, the pharmacologic treatment of these problems often entails a trial-and-error approach to find a medication that is both effective and tolerable. Patients may not respond to a single medication and not infrequently will require combinations of agents to treat these behaviors effectively. Finally, it often is useful to consider separately the treatment options for acute and chronic agitation, aggression, and/or self-injurious behaviors. The following discussion of pharmacologic options assumes that a careful differential diagnostic assessment has been unrevealing and that the clinician is left with a series of empiric medication trials as the most reasonable option.

Acute agitation, aggression, and/or self-injurious behaviors Antipsychotics and benzodiazepines are the most commonly used medications in the treatment of acute aggressive, agitated, and self-injurious behaviors among persons with neuropsychiatric disorders [55–59]. When an antipsychotic agent is used, atypical antipsychotics are generally recommended given their relatively low risk of acute extrapyramidal side effects [56, 60–62]. Starting doses should be low and repeated at frequent intervals until control of the target behavior is achieved. If the target behavior persists after several low-dose administrations of such agents, dose escalation and increased frequency of administration – to the point of acute sedation – may be necessary. If an atypical antipsychotic is not effective, initiating treatment with low-dose haloperidol and following a similar dose-escalation protocol is a reasonable alternative. Unfortunately, tolerance to the sedative effects of these agents is not uncommon, and its development often leads to dose escalation. In addition to the risk of adverse effects in general associated with these agents, dose-related akathisia and extrapyramidal side effects may become very problematic. When they occur, these dose-related side effects are easily misunderstood as (and contribute to) worsening agitation, restlessness, and self-injurious behaviors, setting in motion a cycle of continued dose escalation and further behavioral deterioration. Increasing agitated, aggressive, or selfinjurious behaviors in response to treatment with an antipsychotic agent therefore should prompt consideration of the possible initiations of this cycle and the use of a different class of medication. If the treatment of acute behavioral dyscontrol is effective, then decreasing the daily dose of the medication used is performed with the goal of determining the minimally effective dose that will suffice for shortterm management of these behavior(s). In some cases, chronic treatment with the agents used to achieve acute behavioral stabilization may be necessary, especially among patients with psychotic symptoms or disorders. Although this may be appropriate and effective, long-term use of any antipsychotic requires vigilance for treatment-related adverse events including metabolic syndrome, late-onset (tardive) movement disorders, seizures, and neuroleptic malignant syndrome. The sedative properties of benzodiazepines also may be helpful in the management of acute agitation

573


and aggression [55, 62]. However, benzodiazepines predictably impair memory, motor function, coordination and balance, all of which are common problems among persons with many neuropsychiatric disorders. Rarely do benzodiazepines produce paradoxical agitation; however, this adverse event may set in motion the same type of dose escalation–behavioral worsening cycle described above. For these reasons, it is best to avoid or temporally limit the use of benzodiazepines for agitation, aggression, and self-injurious behaviors. When agents in this medication class are used to treat these behaviors, using benzodiazepines with short- or moderate-duration half-lives, serum metabolism (i.e., glucuronidation), few drug–drug interactions, and no active metabolites (e.g., lorazepam, oxazepam) are recommended.

Chronic agitation, aggression, and/or self-injurious behaviors The treatment of chronic aggression, agitation, and/or self-injurious behaviors often necessitates chronic pharmacotherapy; this approach is analogous to the treatment of intractable epilepsy in that its goal is reducing the risk of recurrent problematic behaviors and not necessarily their elimination. As noted earlier in this section, treatment selection is guided first by comorbid neuropsychiatric symptoms or syndromes (i.e., depression, mania, anxiety) for which pharmacotherapies are prescribed (i.e., antidepressants, antimanic agents, anxiolytics, etc.). This approach limits, but does not necessarily obviate, polypharmacy. When chronic aggression, agitation, and/or self-injurious behaviors are not clearly related to another neuropsychiatric symptom or syndrome, or when these behaviors are so severe that symptom-targeted treatment is required, treatment selection is likely to require serial empirical trials in order to find the optimal agent (or agents). In general, it is prudent to initiate treatment agents with the most favorable risk–benefit profiles. If these agents are ineffective or partially effective, subsequent serial empirical trials of medications from different pharmacologic classes – independently or, for partial responders, as augmentation strategies – may be required. Serotonergically active antidepressants may improve aggressive, agitated, and self-injurious behaviors and do so with relatively few adverse effects [9, 63–68]. The SSRIs are the first-line agents of these

574

types and generally are prescribed at doses similar to those used to treat depressive disorders. Some patients may respond more favorably to one SSRI than another, and some patients respond better to trazodone or a tricyclic antidepressant (TCA). It therefore is reasonable to consider serial empirical trials within this general class of medication before initiating treatment with a different type of medication. When adjunctive or primary treatment with another medication is required, anticonvulsants are generally the next most appropriate class of drug to consider [69–76]. Valproate often is used as a first-line treatment given its effectiveness, tolerability, and relatively limited set of drug–drug interactions. Carbamazepine may be effective, but its side effect profile and effect on hepatic function (including induction of its own metabolism) may complicate its use for these purposes. Other anticonvulsants such as oxcarbazepine, gabapentin, and lamotrigine are commonly used in clinical practice to reduce agitated, aggressive, and/or self-injurious behaviors [77–82]; however, their uses for these purposes are less well studied than either carbamazepine or valproate. If serotonergically active antidepressants and/or anticonvulsants do not effect sufficient improvement in aggressive, agitated, or self-injurious behaviors, then treatment with an atypical antipsychotic may be considered [60–62]. When used as an adjunctive intervention, low doses of these agents may be effective; if so, then an empirical trial of atypical antipsychotic monotherapy should be undertaken in order to determine whether this treatment alone effectively reduces these behavioral disturbances. Although clozapine is included in this class of agent and may be useful as a treatment for aggressive, agitated, or self-injurious behaviors [60, 83–85], its cumbersome administration and monitoring requirements, tendency to lower seizure threshold, and associated risk of potentially life-threatening blood dycrasias render it a treatment of last resort. When any of the atypical antipsychotics are used long-term either as monotherapy or an augmentation agent, baseline and serial reassessment for cardiac, metabolic, and other antipsychotic-induced adverse effects are necessary. Lithium [63, 86, 87], ␤-adrenergic receptor antagonists [63, 76, 88–91], buspirone [92–95], longacting benzodiazepines such as clonazepam [64, 96], and, among persons with preserved ventral frontalsubcortical systems, even catecholamine-augmenting agents such as methylphenidate [97] and amantadine


[64, 98] may improve chronic agitation, aggression, and self-injurious behaviors. Among these, lithium and ␤-adrenergic receptor antagonists are generally regarded as the most effective agents, but their use may be complicated by adverse systemic and neurological side effects in these populations. Lithium, like clozapine, reduces suicide risk, possibly via reductions of cooccurring impulsivity, aggression, and affective symptoms [99]. Naltrexone, a long-acting opioid receptor antagonist, may reduce self-injurious behaviors, particularly among persons with developmental disabilities [100]; its use for this purpose is predicated on the supposition that these behaviors may be selfreinforcing and that opioid receptor antagonism may reduce the reward reinforcement associated with their performance. All of the medications used to treat chronic agitation, aggression, and self-injurious behaviors entail potentially complex administration and monitoring procedures, and their use does entail potential risks of harm. Nonetheless, the behaviors for which they are prescribed are substantial sources of suffering and potential harm to patients and those with whom they interact. Accordingly, they are important and appropriate considerations – whether as primary treatments or augmentation strategies – when other interventions prove ineffective, partially effective, intolerable, or logistically impractical.

Psychosis Hallucinations and delusions (i.e., psychotic symptoms) occur among persons with a broad range of neurological disorders and are the defining feature of schizophrenia (Table 35.3) [101]. A hallucination is a sensory perception (visual, auditory, tactile, olfactory, gustatory) that occurs in the absence of a relevant external stimulus for that perception. In contrast, an illusion is a misperception of an actual external stimulus. Delusions are fixed false beliefs: that is, ideas that are maintained consistently and that are not amenable to revision when evidence refuting them is presented. Delusions sometimes derive from ordinary life experience (e.g., concerns regarding theft, betrayal, power, wealth, or love), whereas others are bizarre and logically impossible (e.g., thought broadcasting, thought insertion, thought control). Delusions are contrasted with confabulation, which refers to incorrect ideas that are not fixed (i.e., temporally transient), usually associated with (and reflecting)

profound memory impairments, and for the purposes of pharmacotherapy are regarded as cognitive, not psychotic, symptoms. Among persons with relatively intact communication skills, patient self-report and/or clinical interview may reveal such symptoms readily. However, identifying psychotic symptoms among patients with severe cognitive and communicative impairments often is very challenging. In such patients, behavioral disturbances (such as those described in the preceding section) may reflect underlying psychosis, and careful evaluations using the methods described earlier in this chapter may be needed to so identify them. The neurologic conditions associated with psychotic symptoms vary both with regard to etiology and with regard to the amount of pathologic involvement in different cortical, subcortical, and white matter structures. As illustrated by the examples provided in Table 35.3, there are commonalities to neuroanatomic substrates of psychosis across these conditions [102– 105]. Delusions are most commonly associated with unilateral (often right-hemispheric) temporoparietal involvement whereas frank schizophreniform psychosis is more closely associated with involvement of the left or bilateral temporoparietal areas. Damage to medial temporal structures (hippocampus and amygdala), to the white matter projections connecting these structures to other limbic and frontal areas, and to the subcortical elements of limbic-subcortical and frontalsubcortical circuits also are common among patients with neurological disorders who develop psychosis. The networks into which these structures are incorporated govern processing of sensory percepts, assignment of affective valence to such information, and integration of emotional and social information. Their dysfunction predictably impairs accurate interpretation of sensory information, self-environment interactions, and affect regulation. Impaired assessment of environmental information or misattribution of internal information to the environment (hallucinations, illusions) may produce incorrect assignment of danger to this information (delusions) and/or foster inappropriate fear and threatened behavior (paranoia). The neurochemistry of psychosis in neurologic disease is as varied and complex as its structural pathologic underpinnings. Disturbances of glutamatergic function [106], dopamine [107, 108], acetylcholine [109, 110] and interactions between these and other neurotransmitters in the neuroanatomic systems described above appear to be important in the

575


Table 35.3. Examples of neurological conditions associated with the development of psychotic symptoms. Childhood disorders, and in particular mental retardation, pervasive developmental disorder, autism, and other congenital conditions may also carry an increased risk of psychosis, but are not included here. Schizophreniform psychosis connotes a condition in which hallucinations, delusions, and thought disorder occurs simultaneously and in a fashion that closely resembles schizophrenia. When delusions, hallucinations, or thought disorder may arise as independent symptoms, these terms are listed separately in the third column of this table. Adapted with permission from Arciniegas DB, Topkoff J, Held K, Frey L. Psychosis due to neurologic conditions. Curr Treat Options Neurol. 2001;3(4):347–366.

576

Condition

Site associated with psychosis

Typical symptoms

Comment

Adrenoleukodystrophy

Temporoparietal white matter

Delusions, including paranoia Hallucinations, including auditory

There are few cases of this disorder, and even fewer with psychosis, but this may be a presenting feature of the disorder


Medial temporal and temporoparietal areas, basal forebrain cholinergic nuclei leading to cortical cholinergic deficit

Delusions, including About 25% of mildly affected patients and 50% misidentification of severely affected patients develop syndromes, are the most psychotic symptoms common symptoms Misidentification syndromes may be an Hallucinations (visual ⬎ extension of a variety of cognitive auditory ⬎ olfactory) impairments such as anosagnosia, visuospatial dysfunction, or memory impairment, but the quality of such problems may in some cases take on a psychotic quality

Cortical or subcortical stroke

Temporoparietal cortex and/or subcortical gray matter

Delusions Hallucinations (visual ⬎ auditory), including release hallucinations

Psychosis appears to be more common with right temporo-parieto-occipital junction lesions; however, left-sided lesions also producing Wernicke’s aphasia may be associated with psychosis Risk of psychosis following stroke may be increased by cerebral atrophy and/or ischemic white matter disease

Diffuse Lewy body dementia

Anterior frontal and temporal cortices, including amygdalae; basal forebrain cholinergic nuclei, leading to cortical cholinergic deficit

Hallucinations, predominantly visual but auditory, olfactory, and tactile may occur Delusions

Visual hallucinations may be a prominent early feature, in contrast to Alzheimer’s disease (in which such features are late and less common than delusions) and Parkinson’s disease (in which such features are late and/or related to dopaminergic therapy)

Epilepsy

Deep, medial temporal lobe

Delusions Hallucinations Schizophreniform psychosis

Psychosis appears to be more common with left-sided foci Although psychosis is typically an interictal (or subacute post-ictal) problem, partial complex status and absence status may be mistaken for psychosis

Fahr’s disease (idiopathic basal ganglia calcification)

Caudate nucleus, especially Delusions, including medial aspect of the head of paranoid delusions this nucleus Hallucinations, including auditory (sometimes musical) and complex visual illusions Thought disorder Schizophreniform psychosis

The relationship between basal ganglia calcification (either idiopathic or secondary) is contentious: while paranoia is more common in patients with basal ganglia calcifications, the presence of calcifications is not more frequent than expected in the population of patients with neuropsychiatric disorders

Frontotemporal dementia

Disproportionate temporal lobe atrophy (“temporal lobe variant”)

Delusions

Asymmetric (right-sided) involvement is more strongly associated with delusions

Ischemic white matter disease

Frontal white matter of the frontal-subcortical circuits or temporo-parieto-occipital areas involving auditory or visual pathways

Delusions

More common with extensive and bilateral disease than with single lesions


Table 35.3. (cont.)

Condition

Site associated with psychosis

Typical symptoms

Comment

Hexosaminidase deficiencies (HEX A: Tay Sachs disease, or HEX A and B: Sandhoff’s disease)

Subcortical gray matter and cerebellum, as well as a lesser degree of diffuse cerebral involvement

Schizophreniform psychosis

In adult-onset Tay Sachs disease, psychosis occurs in 30–50% of affected individuals and may be the presenting feature of this condition


Caudate nucleus, especially medial aspect of the head of this nucleus

Hallucinations Delusions Schizophreniform psychosis

Psychiatric symptoms may precede onset of motor symptoms, but delusions are more commonly a late feature of the disease Delusions and hallucinations commonly co-occur with depression

Metachromatic leukodystrophy

Temporolimbic, frontal, and periventricular white matter


A rare feature of a rare disease

Multiple sclerosis

Temporoparietal white matter, frontal white matter, and/or subcortical white matter

Hallucinations Delusions Thought disorder

Tends to be a relatively late feature of the disease, and is related to increased plaque burden in the areas noted May wax and wane with acute lesion formation, inflammation, and resolution in the relevant areas

Neoplasm

Pituitary or suprasellar area; temporal lobe; limbic-paralimbic regions; diencephalon and tissue surrounding the third ventricle; and frontal lobes


May result from a range of tumors, including those listed; laterality of tumor location and onset of psychosis does not appear as highly correlated as in some of the other conditions listed here Neurodevelopmental tumors appear to confer higher risk of psychosis


Cortical atrophy, basal forebrain cholinergic atrophy resulting in cortical cholinergic deficit

Delusions (paranoid) Hallucinations, including formed visual hallucinations

May be an idiopathic, although uncommon, manifestation of late disease – more likely in patients of advanced age and with dementia or a premorbid history of schizophrenia. In patients with psychosis early in the disease or with relatively more minor motor symptoms, consider diffuse Lewy body disease In these patients, psychotic symptoms may result from dopaminomimetic medications used to treat motor symptoms

Dopaminomimetic therapy for Parkinson’s disease (PD) and Parkinson’s plus syndromes

Mesolimbic dopaminergic target sites

Paranoia or frank paranoid delusions Visual hallucinations

Is a common problem following administration of these agents, particularly among patients with relatively advanced disease; note, however, that psychotic symptoms may develop as an intrinsic feature of PD and the PD plus syndromes

Traumatic brain injury

Temporal or frontal lobes


More commonly associated with left-sided temporal lobe injuries; frontal lesions may be less strongly associated with psychosis due to TBI

Right hemisphere, including temporoparietal and frontal areas

Delusions and paranoia Visual hallucinations

Psychotic symptoms due to right hemispheric injury may be more specific (e.g., delusions alone) and therefore less “schizophreniform”

Putamen; possibly also globus pallidus, thalamus, cortex, and intervening white matter

Hallucinations Delusions Schizophreniform psychosis

Psychosis may be the presenting sign of Wilson’s disease. The association between putaminal copper deposition and psychosis is contentious, but may be understood as being similar to the frontal-subcortical and limbic-subcortical aberrations of schizophrenia

Wilson’s disease (progressive hepatolenticular degeneration)

577


genesis of psychotic symptoms. The role of other neurotransmitters in psychosis due to neurological disease is less fully established, although decreases in cortical serotonin, increased norepinephrine levels, and alterations of the modulatory systems responsible for regulating the function of these neurotransmitter systems also may be important [101]. The literature describing the use of typical (first-generation) and atypical (second-generation) antipsychotics, whether as treatments for primary psychiatric disorders or psychotic symptoms associated with neurological disorders, is as complex and contentious as the literature describing the neurobiological bases of psychosis [111–113]. Recent reviews of this literature, as well as analyses and commentaries on the UK’s Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), and the National Institute of Mental Health-initiated Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, suggest that firstand second-generation antipsychotics are similarly effective treatments of schizophrenia [113]. An exception to this rule is clozapine, a second-generation antipsychotic, which appears superior to most others for treatment-resistant psychosis and, as noted above, also reduces suicide risk [99, 113]. Since the advent of second-generation antipsychotics, typical antipsychotics are used less frequently to treat psychotic symptoms associated with neurologic disorders. However, the relative benefits and risks of antipsychotics (first- or second-generation) for the treatment of psychosis associated with neurologic conditions other than Alzheimer’s disease have not been studied extensively. There are concerns about both the effectiveness and safety (i.e., stroke, mortality) risks of these medications as treatments for psychosis associated with neurodegenerative dementias [57, 111, 114]. Importantly, these risks appear similar for both the typical and atypical antipsychotics [114]. Outside the neurodegenerative dementias literature, there are few reports with which to guide selection among the atypical antipsychotic agents in these populations. While acknowledging these concerns and the limitations of the literature, individual patients with psychosis associated with neurological conditions may benefit from judicious administration of these medications, especially when other, less potentially problematic, agents and/or non-pharmacologic interventions fail [57, 114, 115]. Additionally, when patients and families are offered the choice between living with intractable and

578

functionally disruptive psychotic symptoms or accepting the treatment-associated medical (including cerebrovascular) risks and low rate of treatment effectiveness, common clinical experience suggests that many will elect to undertake an empiric trial of an antipsychotic in the hope that the affected patient will be a member of the subgroup for whom these treatments are effective and well tolerated. When any of these agents are used, clinicians are strongly encouraged to perform a brief review of the literature, and to identify relevant systematic reviews, comparative efficacy trials, or professional society and/or governmental practice parameters. The results of that review then should be used to guide the selection of an antipsychotic that is well suited to the treatment of psychosis in the context of the specific neurological condition with which it is associated. At the time of this writing, atypical antipsychotics are generally preferred as treatments for psychotic symptoms and related behavioral disturbances among persons with acquired brain injuries or developmental disabilities in light of their relatively lower risks of extrapyramidal symptoms and akathisia [101, 116, 117]. Regardless of the agent selected, starting doses of antipsychotic medications in these contexts generally are one-third to one-half of those used among persons with primary psychotic disorders. Gradual titration to doses similar to those used in other contexts may be required to effect improvement in psychosis and related behavior disturbances. Baseline assessment of and periodic monitoring for cardiac problems (i.e., prolonged QTc) and also metabolic syndrome during treatment with any atypical antipsychotic medication is recommended. Additionally, vigilance for the development of treatment-emergent movement disorders such as dystonias, dyskinesias, and akathisia, neuroleptic malignant syndrome, and seizures is particularly important in these populations.

Apathy and related disorders of motivation Apathy denotes a decrease in goal-directed cognition, emotion, and behavior [118], and is the prototypic disorder of diminished motivation [119] (see also Chapter 9). Apathy is quite common in many neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Huntington’s disease, frontotemporal dementia,


stroke, vascular dementia, traumatic and acquired brain injuries, and schizophrenia [120–125]. Although apathy and disorders of diminished motivation may not appear to be as imminently dangerous as some of the other behaviors described in the preceding sections of this chapter, they often are sources of substantial concern and frustration to family/caregivers. In milder forms, apathy frequently is misinterpreted as “laziness” or “depression.” The latter is particularly concerning given that many treatments for depression – including the serotonergically active antidepressants – may produce mild forms of apathy, creating a situation in which misdiagnosis-based treatment of depression exacerbates apathy. In their most extreme forms (e.g., abulia, akinetic mutism), apathy is disabling and risks malnutrition- and immobilityinduced physical injury (e.g., dehydration, decubitus and other stasis ulcers, deep vein thromboses and pulmonary emboli). Disorders of diminished motivation also may be linked paradoxically to impulsivity or aggression. In some cases, patients may not engage spontaneously in goal-directed behavior but may automatically react impulsively or aggressively in response to a stimulus with very high motivational salience (e.g., pain, food, sexual imagery, fear). Individuals should not attempt to engage patients in activities in which they have little interest but which can precipitate assaultive behavior [126]. Disorders of motivation occur in association with injury to or dysfunction of the anterior cingulatesubcortical circuit, reward circuitry, and their connections to and interactions with specific hypothalamic centers (thirst, sex, hunger) [29, 126] and the brainstem reticular formation. Key nodal points in this circuitry include the amygdala, hippocampus, caudate, entorhinal and cingulate cortices, the ventral tegmental area and the medial forebrain bundle. Catecholaminergic systems, particularly the mesolimbic dopaminergic system, appear to play critical roles in the modulation of the reward system [29, 126]. As noted above, distinguishing between apathy and depression is an essential pre-treatment task. Although the psychomotor retardation and anhedonia of depression can be mistaken for apathy, depression definitionally involves persistent and excessive sadness and/or anhedonia. Patients with apathy may appear affectively flat, but they neither endorse nor appear to be persistently and excessively sad; in contrast, they are more likely to endorse, and their caregivers describe them,

as experiencing a relative absence of emotion [127, 128]. Additionally, persons with apathy – when they can be engaged in high preference activities – generally find them pleasurable. In other words, and unlike patients with depression, apathetic patients generally are not anhedonic. It is possible for patients to experience depression and apathy; although differentiating between these conditions when they co-occur may be challenging, careful evaluation usually permits making this distinction with reasonable clinical confidence [40, 128–130]. Use of standardized measures of apathy (e.g., the Apathy Evaluation Scale [40] or the apathy subscales of the Neuropsychiatric Inventory [34] or Frontal Systems Behavior Scale [131]) and comparison of scores on these measures with those on standardized depression scales (e.g., Beck Depression Inventory – II [132]) also may facilitate making such distinctions [128]. Apathy is a difficult symptom to treat, with limited benefits afforded by environmental, behavioral, or pharmacologic interventions [133]. Nonpharmacologic interventions are essential elements of treatment [133–136], including caregiver education and direct (i.e., “hands-on”) facilitation of necessary activities. Medications are best regarded as adjuncts to these interventions. These typically include agents that directly or indirectly augment cerebral catecholaminergic function (e.g., methylphenidate, dextroamphetamine, amantadine, bromocriptine) and medications used to augment cerebral cholinergic function (e.g., donepezil, rivastigmine, galantamine) [3, 4, 133, 136, 137]. The available evidence suggests that either approach may be useful regardless of the neuropsychiatric disorder in which apathy develops. In clinical practice, however, cholinesterase inhibitors are used most commonly for the treatment of apathy associated with neurodegenerative or vascular dementias whereas catecholaminergic agents or combinations of these and cholinesterase inhibitors are more commonly used to treat apathy following TBI or stroke.

Self-awareness deficits Sometimes complicating the presence of challenging behaviors is a surprising lack of awareness of the significance of the behaviors (see [138] for review). Individuals with such impairments may be unable to appreciate that their behavior has changed subsequent to developing a neurological or psychiatric disorder. Their unawareness often is contrasted starkly by

579


family/caregivers and providers who are painfully aware of these changes and often provide detailed lists of specific concerns. Alternatively, an individual may have a vague sense that he or she is different (“not who I used to be”) and yet struggle to define or even deny the specific ways in which their behavior differs. Awareness of deficits occur in a broad range of neuropsychiatric disorders, including Alzheimer’s disease [139] and schizophrenia [140, 141]. However, awareness is not a unitary concept [138]. It therefore is important to characterize the nature and extent to which an individual suffers from this problem. In general, lack of awareness of illness is not simply a reflection of global cognitive deficits; instead, it is more closely related to frontal-executive dysfunction [142–148]. Consistent with this formulation of impaired self-awareness, patients often are less aware of changes in behavior and executive function than changes in motor function (e.g., [149]). Additionally, studies of the neuroanatomical correlates of illness awareness deficits, and in overlapping syndromes such as anosagnosia, suggest that injury to certain brain regions carries a heightened vulnerability to awareness deficits. Stuss [150, 151] suggests that frontal systems generate self-awareness, self-reflectiveness, and self-monitoring. Lack of awareness in schizophrenia is associated with selective structural brain changes, including smaller brain size and selective atrophy of certain subregions of the frontal lobes [152, 153]. Because frontal systems also play a critical role in the modulation of key social skills and behaviors (e.g., initiation, motivation, problem solving, and affective modulation), frontal lobe damage can affect the ability to understand the impact that deficits have on day-to-day function and future function and how to apply that knowledge to a current situation. In some disorders (e.g., TBI), the degree of awareness also correlates with functional and vocational outcome [154–157], although this finding is not invariant [158]. The major issue with awareness in a given individual is the determination of whether it is a “psychological denial” or is more reasonably considered a result of the underlying neuropathology. These distinctions are at times difficult [141]. However, a structured interview using measures designed specifically for these purposes, including the Scale to Assess Unawareness of Mental Disorders [159], the Self-Awareness of Deficits Interview [41], or the Awareness Questionnaire [160], may facilitate identification of this problem when it is a subject of clinician or caregiver/family concern.

580

Treatments of self-awareness deficits rely principally on behavioral and psychoeducational interventions [161–163]. At this time there are no known pharmacologic treatments for awareness deficits. As the neuroanatomic and neurochemical substrates of this very challenging behavioral deficit are characterized more completely, however, impaired self-awareness may become a target of pharmacotherapy.

Conclusion Challenging behaviors are associated with many neuropsychiatric disorders. The excess disability they produce is significant and can only be mitigated by careful attention and well-informed treatment by clinicians working with persons with these problems and their caregivers and families. Successful treatment of problematic behaviors entails the integration of environmental, behavioral, and pharmacologic strategies predicated on a careful assessment of their causes and reinforcers. The pharmacologic component of this holistic treatment approach requires that the frequency, intensity, and context of challenging behaviors be characterized carefully prior to treatment. Relationship of the behaviors to premorbid traits must be understood. Information about what makes the behaviors challenging and for whom it is a challenge is essential. Comorbid cognitive, psychiatric, medical, and iatrogenic conditions to problematic behaviors need to be identified, and their contributions to and/or interactions with the direct behavioral consequences of neurological disease or injury need to be considered. Strict adherence to conventional diagnostic schemes such as the DSM–IV may impede diagnosis, and a “relaxed fit” criteria coupled with the use of behavioral metaphors may be a more appropriate approach. In combination with these assessments, understanding the neuroanatomy and neurochemistry of the problematic behavior and the condition in which it occurs, including disease-specific alterations in strategic neurotransmitter systems, informs treatment selection. There are several general principles to consider when using medications to treat challenging behaviors. These include awareness of the heightened sensitivity of individuals with neuropsychiatric disorders to the common side effects of psychotropic agents and the implications for dosing strategies, as well as the perils of polypharmacy. Medication selection follows logically from careful characterization of the behaviors,


thorough consideration of differential diagnosis of the behaviors in the context of the individual, and the neurobiology of the neuropsychiatric disorder with which the behaviors are associated. Therapeutic trials of medications are hypothesis-driven, time limited, and predicated on clearly defined outcome measures – including metrics of the change in frequency and intensity of behaviors as well as functional significance of these changes. Medications that improve challenging behaviors should be administered at the lowest effective doses and discontinued as soon as is clinically feasible. Similarly, agents that do not clearly improve challenging behaviors should be discontinued. Under the best of circumstances, pharmacotherapy may afford some relief from challenging behaviors to patients and those with whom they interact. This treatment approach is no panacea, however, and it is not appropriately regarded as the best or sole intervention for such problems. Used judiciously and integrated into a comprehensive and holistic treatment plan, behavioral pharmacotherapy is an important element of the BN&NP subspecialist’s therapeutic repertoire.

References 1. McKeith I, Cummings J. Behavioural changes and psychological symptoms in dementia disorders. Lancet Neurol. 2005;4(11):735–42. 2. Ballard C, Day S, Sharp S, Wing G, Sorensen S. Neuropsychiatric symptoms in dementia: importance and treatment considerations. Int Rev Psychiatry 2008; 20(4):396–404. 3. Figiel G, Sadowsky C. A systematic review of the effectiveness of rivastigmine for the treatment of behavioral disturbances in dementia and other neurological disorders. Curr Med Res Opin. 2008; 24(1):157–66. 4. Cummings JL, Mackell J, Kaufer D. Behavioral effects of current Alzheimer’s disease treatments: a descriptive review. Alzheimers Dement. 2008;4(1): 49–60.

8. Kavirajan H. Memantine: a comprehensive review of safety and efficacy. Expert Opin Drug Saf. 2009;8(1): 89–109. 9. Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury – a state-of-the-art review. J Rehabil Res Dev. 2009;46(6):851–79. 10. Swanson J, Baler RD, Volkow ND. Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress. Neuropsychopharmacology 2011;36(1): 207–26. 11. Ferro JM, Caeiro L, Santos C. Poststroke emotional and behavior impairment: a narrative review. Cerebrovasc Dis. 2009;27(Suppl. 1):197–203. 12. Ashman TA, Spielman LA, Hibbard MR et al. Psychiatric challenges in the first 6 years after traumatic brain injury: cross-sequential analyses of Axis I disorders. Arch Phys Med Rehabil. 2004; 85(4 Suppl. 2):S36–42. 13. Weintraub D, Stern MB. Psychiatric complications in Parkinson disease. Am J Geriatr Psychiatry 2005; 13(10):844–51. 14. Ferrell RB, Wolinsky EJ, Kauffman CI, Flashman LA, McAllister TW. Neuropsychiatric syndromes in adults with intellectual disability: issues in assessment and treatment. Curr Psychiatry Rep. 2004;6(5): 380–90. 15. Silver JM, Kramer R, Greenwald S, Weissman M. The association between head injuries and psychiatric disorders: findings from the New Haven NIMH Epidemiologic Catchment Area Study. Brain Inj. 2001; 15(11):935–45. 16. Hibbard MR, Uysal S, Kepler K, Bogdany J, Silver J. Axis I psychopathology in individuals with traumatic brain injury. J Head Trauma Rehabil. 1998;13(4): 24–39. 17. Fann JR, Burington B, Leonetti A et al. Psychiatric illness following traumatic brain injury in an adult health maintenance organization population. Arch Gen Psychiatry 2004;61(1):53–61.

5. Masanic CA, Bayley MT, VanReekum R, Simard M. Open-label study of donepezil in traumatic brain injury. Arch Phys Med Rehabil. 2001;82(7):896–901.

18. Wei W, Sambamoorthi U, Crystal S, Findley PA. Mental illness, traumatic brain injury, and Medicaid expenditures. Arch Phys Med Rehabil. 2005;86(5): 905–11.

6. Yoo JH, Valdovinos MG, Williams DC. Relevance of donepezil in enhancing learning and memory in special populations: a review of the literature. J Autism Dev Disord. 2007;37(10):1883–901.

19. Koponen S, Taiminen T, Portin R et al. Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study. Am J Psychiatry 2002;159(8): 1315–21.

7. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006;2:CD003154.

20. Robinson RG. Poststroke depression: prevalence, diagnosis, treatment, and disease progression. Biol Psychiatry 2003;54(3):376–87.

581


21. Morrison V, Pollard B, Johnston M, MacWalter R. Anxiety and depression 3 years following stroke: demographic, clinical, and psychological predictors. J Psychosom Res. 2005;59(4):209–13.

34. Cummings JL, Mega M, Gray K et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44(12):2308–14.

22. Starkstein SE, Mizrahi R, Power BD. Depression in Alzheimer’s disease: phenomenology, clinical correlates and treatment. Int Rev Psychiatry 2008;20(4): 382–8.

35. Wood S, Cummings JL, Hsu MA et al. The use of the neuropsychiatric inventory in nursing home residents. Characterization and measurement. Am J Geriatr Psychiatry 2000;8(1):75–83.

23. Anderson KE, Weiner WJ. Psychiatric symptoms in Parkinson’s disease. Curr Neurol Neurosci Rep. 2002; 2(4):303–9.

36. Corrigan JD. Development of a scale for assessment of agitation following traumatic brain injury. J Clin Exp Neuropsychol. 1989;11(2):261–77.

24. Chan KL, Campayo A, Moser DJ, Arndt S, Robinson RG. Aggressive behavior in patients with stroke: association with psychopathology and results of antidepressant treatment on aggression. Arch Phys Med Rehabil. 2006;87(6):793–8.

37. Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D. The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986;143(1):35–9.

25. American Psychiatric Association Task Force on DSM–IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: DSM–IV. Washington, DC: American Psychiatric Association; 1994. 26. Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol. 1993;50(8):873–80. 27. Mega MS, Cummings J. Frontal subcortical circuits. In Salloway S, Malloy P, Duffy JD, eds. The Frontal Lobes and Neuropsychiatric Illness. 1st edition. Washington, DC: American Psychiatric Publishing; 2001. p. x, 264. 28. Vernier P, Moret F, Callier S et al. The degeneration of dopamine neurons in Parkinson’s disease: insights from embryology and evolution of the mesostriatocortical system. Ann N Y Acad Sci. 2004; 1035:231–49. 29. Chau DT, Roth RM, Green AI. The neural circuitry of reward and its relevance to psychiatric disorders. Curr Psychiatry Rep. 2004;6(5):391–9. 30. Giovannoni G, O’Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000;68(4):423–8. 31. Potenza MN, Voon V, Weintraub D. Drug insight: impulse control disorders and dopamine therapies in Parkinson’s disease. Nat Clin Pract Neurol. 2007;3(12): 664–72. 32. Bernardo CG, Singh V, Thompson PM. Safety and efficacy of psychopharmacological agents used to treat the psychiatric sequelae of common neurological disorders. Expert Opin Drug Saf. 2008;7(4): 435–45. 33. Kaufer DI, Cummings JL, Ketchel P et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci. 2000;12(2):233–9.

582

38. Kay SR. Positive and Negative Syndromes in Schizophrenia: Assessment and Research. New York, NY: Brunner/Mazel; 1991. 39. Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychol Rep. 1962;10:799–812. 40. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 1991;38(2):143–62. 41. Fleming JM, Strong J, Ashton R. Self-awareness of deficits in adults with traumatic brain injury: how best to measure? Brain Inj. 1996;10(1):1–15. 42. Tariot PN. The older patient: the ongoing challenge of efficacy and tolerability. J Clin Psychiatry 1999; 60(Suppl. 23):29–33. 43. Tariot PN, Loy R, Ryan JM, Porsteinsson A, Ismail S. Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev. 2002;54(12):1567–77. 44. Ryan JM, Kidder SW, Daiello LA, Tariot PN. Psychopharmacologic interventions in nursing homes: what do we know and where should we go? Psychiatr Serv. 2002;53(11):1407–13. 45. Adi Y, Ashcroft D, Browne K et al. Clinical effectiveness and cost-consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders. Health Technol Assess. 2002;6(28): 1–66. 46. Guay DR. Inappropriate sexual behaviors in cognitively impaired older individuals. Am J Geriatr Pharmacother. 2008;6(5):269–88. 47. Guay DR. Drug treatment of paraphilic and nonparaphilic sexual disorders. Clin Ther. 2009;31(1): 1–31. 48. Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. J Am Med Assoc. 2005;293(5): 596–608.


49. Siever LJ. Neurobiology of aggression and violence. Am J Psychiatry 2008;165(4):429–42. 50. Ito M, Okazaki M, Takahashi S et al. Subacute postictal aggression in patients with epilepsy. Epilepsy Behav. 2007;10(4):611–14. 51. Fann JR, Katon WJ, Uomoto JM, Esselman PC. Psychiatric disorders and functional disability in outpatients with traumatic brain injuries. Am J Psychiatry 1995;152(10):1493–9. 52. Jorge RE, Robinson RG, Moser D et al. Major depression following traumatic brain injury. Arch Gen Psychiatry 2004;61(1):42–50. 53. Shukla S, Cook BL, Mukherjee S, Godwin C, Miller MG. Mania following head trauma. Am J Psychiatry 1987;144(1):93–6. 54. Silver JM, Yudofsky SC. Aggressive disorders. In Silver JM, Yudofsky SC, Hales RE, editors. Neuropsychiatry of Traumatic Brain Injury. 1st edition. Washington, DC: American Psychiatric Press; 1994, pp. 313–53. 55. Pabis DJ, Stanislav SW. Pharmacotherapy of aggressive behavior. Ann Pharmacother. 1996;30(3):278–87. 56. Hankin CS, Bronstone A, Koran LM. Agitation in the inpatient psychiatric setting: a review of clinical presentation, burden, and treatment. J Psychiatr Pract. 2011;17(3):170–85. 57. Ballard C, Corbett A, Chitramohan R, Aarsland D. Management of agitation and aggression associated with Alzheimer’s disease: controversies and possible solutions. Curr Opin Psychiatry 2009;22(6): 532–40. 58. Allen MH, Currier GW, Carpenter D, Ross RW, Docherty JP. The expert consensus guideline series. Treatment of behavioral emergencies 2005. J Psychiatr Pract. 2005;11(Suppl. 1):5–108; quiz 10–2. 59. National Institute for Health and Clinical Excellence (NICE). Violence: The Short-Term Management of Disturbed/Violent Behaviour in In-Patient Psychiatric Settings and Emergency Departments. London: NICE; 2006.

63. Janowsky DS, Shetty M, Barnhill J, Elamir B, Davis JM. Serotonergic antidepressant effects on aggressive, self-injurious and destructive/disruptive behaviours in intellectually disabled adults: a retrospective, open-label, naturalistic trial. Int J Neuropsychopharmacol. 2005;8(1):37–48. 64. Warden DL, Gordon B, McAllister TW et al. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma 2006;23(10):1468–501. 65. Mysiw WJ, Jackson RD, Corrigan JD. Amitriptyline for post-traumatic agitation. Am J Phys Med Rehabil. 1988;67(1):29–33. 66. Jackson RD, Corrigan JD, Arnett JA. Amitriptyline for agitation in head injury. Arch Phys Med Rehabil. 1985; 66(3):180–1. 67. Szlabowicz JW, Stewart JT. Amitriptyline treatment of agitation associated with anoxic encephalopathy. Arch Phys Med Rehabil. 1990;71(8):612–13. 68. Kant R, Smith-Seemiller L, Zeiler D. Treatment of aggression and irritability after head injury. Brain Inj. 1998;12(8):661–6. 69. Geracioti TD, Jr. Valproic acid treatment of episodic explosiveness related to brain injury. J Clin Psychiatry 1994;55(9):416–17. 70. Giakas WJ, Seibyl JP, Mazure CM. Valproate in the treatment of temper outbursts. J Clin Psychiatry 1990;51(12):525. 71. Horne M, Lindley SE. Divalproex sodium in the treatment of aggressive behavior and dysphoria in patients with organic brain syndromes. J Clin Psychiatry 1995;56(9):430–1. 72. Mattes JA. Valproic acid for nonaffective aggression in the mentally retarded. J Nerv Ment Dis. 1992;180(9): 601–2. 73. Wroblewski BA, Joseph AB, Kupfer J, Kalliel K. Effectiveness of valproic acid on destructive and aggressive behaviours in patients with acquired brain injury. Brain Inj. 1997;11(1):37–47.

60. Miyasaki JM, Shannon K, Voon V et al. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66(7):996–1002.

74. Chatham-Showalter PE. Carbamazepine for combativeness in acute traumatic brain injury. J Neuropsychiatry Clin Neurosci. 1996;8(1):96–9.

61. Friedlander R, Lazar S, Klancnik J. Atypical antipsychotic use in treating adolescents and young adults with developmental disabilities. Can J Psychiatry 2001;46(8):741–5.

76. Mattes JA. Comparative effectiveness of carbamazepine and propranolol for rage outbursts. J Neuropsychiatry Clin Neurosci. 1990;2(2):159–64.

62. Fava M. Psychopharmacologic treatment of pathologic aggression. Psychiatr Clin North Am. 1997;20(2): 427–51.

75. Patterson JF. Carbamazepine for assaultive patients with organic brain disease. Psychosomatics 1987; 28(11):579–81.

77. Davanzo PA, King BH. Open trial lamotrigine in the treatment of self-injurious behavior in an adolescent with profound mental retardation. J Child Adolesc Psychopharmacol. 1996;6(4):273–9.

583


78. Bozikas V, Bascialla F, Yulis P, Savvidou I, Karavatos A. Gabapentin for behavioral dyscontrol with mental retardation. Am J Psychiatry 2001;158(6):965–6.

93. Gualtieri CT. Buspirone for the behavior problems of patients with organic brain disorders. J Clin Psychopharmacol. 1991;11(4):280–1.

79. Pachet A, Friesen S, Winkelaar D, Gray S. Beneficial behavioural effects of lamotrigine in traumatic brain injury. Brain Inj. 2003;17(8):715–22.

94. Colella RF, Ratey JJ, Glaser AI. Paramenstrual aggression in mentally retarded adult ameliorated by buspirone. Int J Psychiatry Med. 1992;22(4): 351–6.

80. Childers MK, Holland D. Psychomotor agitation following gabapentin use in brain injury. Brain Inj. 1997;11(7):537–40. 81. Tallian KB, Nahata MC, Lo W, Tsao CY. Gabapentin associated with aggressive behavior in pediatric patients with seizures. Epilepsia 1996;37(5):501–2. 82. Khurana DS, Riviello J, Helmers S et al. Efficacy of gabapentin therapy in children with refractory partial seizures. J Pediatr. 1996;128(6):829–33. 83. Cohen SA, Underwood MT. The use of clozapine in a mentally retarded and aggressive population. J Clin Psychiatry 1994;55(10):440–4. 84. Michals ML, Crismon ML, Roberts S, Childs A. Clozapine response and adverse effects in nine brain-injured patients. J Clin Psychopharmacol. 1993; 13(3):198–203. 85. Antonacci DJ, de Groot CM. Clozapine treatment in a population of adults with mental retardation. J Clin Psychiatry 2000;61(1):22–5. 86. Bellus SB, Stewart D, Vergo JG et al. The use of lithium in the treatment of aggressive behaviours with two brain-injured individuals in a state psychiatric hospital. Brain Inj. 1996;10(11):849–60. 87. Glenn MB, Wroblewski B, Parziale J et al. Lithium carbonate for aggressive behavior or affective instability in ten brain-injured patients. Am J Phys Med Rehabil. 1989;68(5):221–6.

96. Freinhar JP, Alvarez WA. Clonazepam treatment of organic brain syndromes in three elderly patients. J Clin Psychiatry 1986;47(10):525–6. 97. Mooney GF, Haas LJ. Effect of methylphenidate on brain injury-related anger. Arch Phys Med Rehabil. 1993;74(2):153–60. 98. Nickels JL, Schneider WN, Dombovy ML, Wong TM. Clinical use of amantadine in brain injury rehabilitation. Brain Inj. 1994;8(8):709–18. 99. Saunders KE, Hawton K. The role of psychopharmacology in suicide prevention. Epidemiol Psichiatr Soc. 2009;18(3):172–8. 100. Villalba R, Harrington CJ. Repetitive self-injurious behavior: a neuropsychiatric perspective and review of pharmacologic treatments. Semin Clin Neuropsychiatry 2000;5(4):215–26. 101. Arciniegas DB, Topkoff JL, Held K, Frey L. Psychosis due to neurologic conditions. Curr Treat Options Neurol. 2001;3(4):347–66. 102. Cummings JL. Psychosis in neurologic disease: neurobiology and pathogenesis. Cogn Behav Neurol. 1992;5(2):144.

88. Greendyke RM, Kanter DR, Schuster DB, Verstreate S, Wootton J. Propranolol treatment of assaultive patients with organic brain disease. A double-blind crossover, placebo-controlled study. J Nerv Ment Dis. 1986; 174(5):290–4.

103. Edwards-Lee T, Cummings JL. Focal lesions and psychosis. In Bogousslavsky J, Cummings JL, editors. Behavior and Mood Disorders in Focal Brain Lesions. Cambridge: Cambridge University Press; 2000, pp. 419–36.

89. Silver JM, Yudofsky SC, Slater JA et al. Propranolol treatment of chronically hospitalized aggressive patients. J Neuropsychiatry Clin Neurosci. 1999;11(3):328–35.

104. Slater E, Beard AW, Glithero E. The schizophrenialike psychoses of epilepsy. Br J Psychiatry 1963;109:95–150.

90. Alpert M, Allan ER, Citrome L et al. A double-blind, placebo-controlled study of adjunctive nadolol in the management of violent psychiatric patients. Psychopharmacol Bull. 1990;26(3):367–71. 91. Brooke MM, Questad KA, Patterson DR, Bashak KJ. Agitation and restlessness after closed head injury: a prospective study of 100 consecutive admissions. Arch Phys Med Rehabil. 1992;73(4):320–3. 92. Gualtieri CT. Buspirone: neuropsychiatric effects. J Head Trauma Rehabil. 1991;6(1):90–2.

584

95. Ratey JJ, Leveroni CL, Miller AC, Komry V, Gaffar K. Low-dose buspirone to treat agitation and maladaptive behavior in brain-injured patients: two case reports. J Clin Psychopharmacol. 1992;12(5):362–4.

105. Levy ML, Cummings JL. Parkinson’s Disease. In Lauterbach EC, editor. Psychiatric Management in Neurological Disease. 1st edition. Washington, DC: American Psychiatric Press; 2000, pp. 41–70. 106. Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol. 2007;78:69–108. 107. Tost H, Alam T, Meyer-Lindenberg A. Dopamine and psychosis: theory, pathomechanisms and intermediate phenotypes. Neurosci Biobehav Rev. 2010;34(5): 689–700.


108. Factor SA, Friedman JH. The emerging role of clozapine in the treatment of movement disorders. Mov Disord. 1997;12(4):483–96.

122. van Duijn E, Reedeker N, Giltay EJ, Roos RA, van der Mast RC. Correlates of apathy in Huntington’s disease. J Neuropsychiatry Clin Neurosci. 2010;22(3):287–94.

109. de Smet Y, Ruberg M, Serdaru M et al. Confusion, dementia and anticholinergics in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1982;45(12):1161–4.

123. Okura T, Plassman BL, Steffens DC et al. Prevalence of neuropsychiatric symptoms and their association with functional limitations in older adults in the United States: the aging, demographics, and memory study. J Am Geriatr Soc. 2010;58(2):330–7.

110. McKeith IG, Galasko D, Kosaka K et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47(5):1113–24. 111. Gentile S. Second-generation antipsychotics in dementia: beyond safety concerns. A clinical, systematic review of efficacy data from randomised controlled trials. Psychopharmacology (Berlin) 2010;212(2):119–29.

124. Kant R, Duffy JD, Pivovarnik A. Prevalence of apathy following head injury. Brain Inj. 1998;12(1):87–92. 125. Andersson S, Krogstad JM, Finset A. Apathy and depressed mood in acquired brain damage: relationship to lesion localization and psychophysiological reactivity. Psychol Med. 1999; 29(2):447–56. 126. McAllister TW. Apathy. Semin Clin Neuropsychiatry 2000;5(4):275–82.

112. Lepping P, Sambhi RS, Whittington R, Lane S, Poole R. Clinical relevance of findings in trials of antipsychotics: systematic review. Br J Psychiatry 2011;198(5):341–5.

127. Marin RS, Firinciogullari S, Biedrzycki RC. The sources of convergence between measures of apathy and depression. J Affect Disord. 1993;28(1):7–14.

113. Foussias G, Remington G. Antipsychotics and schizophrenia: from efficacy and effectiveness to clinical decision-making. Can J Psychiatry 2010; 55(3):117–25.

128. Lane-Brown AT, Tate RL. Measuring apathy after traumatic brain injury: psychometric properties of the Apathy Evaluation Scale and the Frontal Systems Behavior Scale. Brain Inj. 2009;23(13–14):999–1007.

114. Mittal V, Kurup L, Williamson D, Muralee S, Tampi RR. Risk of cerebrovascular adverse events and death in elderly patients with dementia when treated with antipsychotic medications: a literature review of evidence. Am J Alzheimers Dis Other Demen. 2011; 26(1):10–28.

129. Levy ML, Cummings JL, Fairbanks LA et al. Apathy is not depression. J Neuropsychiatry Clin Neurosci. 1998;10(3):314–19.

115. Ballard C, Creese B, Corbett A, Aarsland D. Atypical antipsychotics for the treatment of behavioral and psychological symptoms in dementia, with a particular focus on longer term outcomes and mortality. Expert Opin Drug Saf. 2011;10(1):35–43. 116. Arciniegas DB, Harris SN, Brousseau KM. Psychosis following traumatic brain injury. Int Rev Psychiatry 2003;15(4):328–40. 117. Shedlack KJ, Hennen J, Magee C, Cheron DM. Assessing the utility of atypical antipsychotic medication in adults with mild mental retardation and comorbid psychiatric disorders. J Clin Psychiatry 2005;66(1):52–62.

130. Glenn MB, Burke DT, O’Neil-Pirozzi T et al. Cutoff score on the apathy evaluation scale in subjects with traumatic brain injury. Brain Inj. 2002;16(6):509–16. 131. Grace JB, Malloy PF. Frontal Systems Behavior Scale: Professional Manual. Lutz, FL: Psychological Assessment Resources; 2001. 132. Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess. 1996;67(3):588–97. 133. Drijgers RL, Aalten P, Winogrodzka A, Verhey FR, Leentjens AF. Pharmacological treatment of apathy in neurodegenerative diseases: a systematic review. Dement Geriatr Cogn Disord. 2009;28(1):13–22.

118. Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci. 1991;3(3):243–54.

134. Lane-Brown AT, Tate RL. Apathy after acquired brain impairment: a systematic review of non-pharmacological interventions. Neuropsychol Rehabil. 2009;19(4):481–516.

119. Marin RS, Wilkosz PA. Disorders of diminished motivation. J Head Trauma Rehabil. 2005;20(4): 377–88.

135. Lane-Brown A, Tate R. Interventions for apathy after traumatic brain injury. Cochrane Database Syst Rev. 2009;2:CD006341.

120. Mulin E, Leone E, Dujardin K et al. Diagnostic criteria for apathy in clinical practice. Int J Geriatr Psychiatry 2011;26(2):158–65.

136. Rodda J, Morgan S, Walker Z. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer’s disease? A systematic review of randomized, placebo-controlled trials of donepezil,

121. Jorge RE, Starkstein SE, Robinson RG. Apathy following stroke. Can J Psychiatry 2010;55(6):350–4.

585


rivastigmine and galantamine. Int Psychogeriatr. 2009;21(5):813–24. 137. Roth RM, Flashman LA, McAllister TW. Apathy and its treatment. Curr Treat Options Neurol. 2007;9(5): 363–70. 138. Flashman LA, McAllister TW. Lack of awareness and its impact in traumatic brain injury. NeuroRehabilitation. 2002;17(4):285–96. 139. Ecklund-Johnson E, Torres I. Unawareness of deficits in Alzheimer’s disease and other dementias: operational definitions and empirical findings. Neuropsychol Rev. 2005;15(3):147–66. 140. Flashman LA. Disorders of awareness in neuropsychiatric syndromes: an update. Curr Psychiatry Rep. 2002;4(5):346–53. 141. Kruck CL, Flashman LA, Roth RM et al. Lack of relationship between psychological denial and unawareness of illness in schizophrenia-spectrum disorders. Psychiatry Res. 2009;169(1):33–8. 142. Young DA, Davila R, Scher H. Unawareness of illness and neuropsychological performance in chronic schizophrenia. Schizophrenia Research 1993;10(2): 117–24. 143. Mohamed S, Fleming S, Penn DL, Spaulding W. Insight in schizophrenia: Its relationship to measures of executive functions. J Nerv Ment Dis. 1999;187(9): 525–31. 144. McEvoy JP, Apperson LJ, Appelbaum PS et al. Insight in schizophrenia. Its relationship to acute psychopathology. J Nerv Ment Dis. 1989;177(1):43–7. 145. Lysaker P, Bell M. Insight and cognitive impairment in schizophrenia – performance on repeated administrations of the Wisconsin Card Sorting Test. J Nerv Mental Dis. 1994;182(11):656–60. 146. David A, Vanos J, Jones P et al. Insight and psychotic illness – cross-sectional and longitudinal associations. Br J Psychiatry 1995;167:621–8. 147. Cuesta MJ, Peralta V, Caro F, Deleon J. Is poor insight in psychotic disorders associated with poor performance on the Wisconsin Card Sorting Test. Am J Psychiatry 1995;152(9):1380–2. 148. Cuesta MJ, Peralta V. Lack of insight in schizophrenia. Schizophrenia Bull. 1994;20(2):359–66. 149. Fahy TJ, Irving MH, Millac P. Severe head injuries. A six-year follow-up. Lancet 1967;2(7514):475–9. 150. Stuss DT. Disturbance of self-awareness after frontal system damage. In Prigatano GP, Schacter DL, editors. Awareness of Deficit after Brain Injury: Clinical and Theoretical Issues. New York, NY: Oxford University Press; 1991, pp. 63–83

586

151. Stuss DT. Self, awareness, and the frontal lobes: a neuropsychological perspective. In Strauss J, editor. The Self: Interdisciplinary Approaches. Berlin: Springer-Verlag; 1991. 152. Flashman LA, McAllister TW, Johnson SC et al. Specific frontal lobe subregions correlated with unawareness of illness in schizophrenia: a preliminary study. J Neuropsychiatry Clin Neurosci. 2001;13(2): 255–7. 153. Flashman LA, McAllister TW, Andreasen NC, Saykin AJ. Smaller brain size associated with unawareness of illness in patients with schizophrenia. Am J Psychiatry 2000;157(7):1167–9. 154. Ezrachi O, Ben-Yishay Y, Kay T, DiUer L, Rattok J. Predicting employment in traumatic brain injury following neuropsychological rehabilitation. J Head Trauma Rehabil. 1991;6(3):71–84. 155. Trudel TM, Tryon WW, Purdum CM. Closed head injury, awareness of disability and long term outcome. New Hampshire Brain Injury Association Annual Meeting. Center of New Hampshire Convention Center, Manchester, NH; 1996. 156. Sherer M, Boake C, Levin E et al. Characteristics of impaired awareness after traumatic brain injury. J Int Neuropsychol Soc. 1998;4(4):380–7. 157. Sherer M, Bergloff P, Levin E et al. Impaired awareness and employment outcome after traumatic brain injury. J Head Trauma Rehabil. 1998;13(5): 52–61. 158. Cavallo MM, Kay T, Ezrachi O. Problems and changes after traumatic brain injury: differing perceptions within and between families. Brain Inj. 1992;6(4): 327–35. 159. Amador XF, Strauss DH, Yale SA et al. Assessment of insight in psychosis. Am J Psychiatry 1993;150(6): 873–9. 160. Sherer M, Bergloff P, Boake C, High W, Jr., Levin E. The Awareness Questionnaire: factor structure and internal consistency. Brain Inj. 1998;12(1):63–8. 161. Cheng SK, Man DW. Management of impaired self-awareness in persons with traumatic brain injury. Brain Inj. 2006;20(6):621–8. 162. Fleming JM, Ownsworth T. A review of awareness interventions in brain injury rehabilitation. Neuropsychol Rehabil. 2006;16(4):474–500. 163. Flashman LA, Amador XF, McAllister TW. Awareness of deficits. In Silver JM, McAllister TW, Yudofsky SC, editors. Textbook of Traumatic Brain Injury. 1st edition. Washington, DC: American Psychiatric Publishing; 2005, pp. 353–67.

Section III Chapter

36


Psychotherapy Lynne Fenton and Robert Feinstein

Psychotherapy may alleviate symptoms and improve functioning in a wide range of psychiatric disorders such as depression, anxiety, obsessive-compulsive disorder (OCD), personality disorders, and psychiatric conditions due to medical illness [1]. The effect of psychotherapy on symptoms arising in the context of neuropsychiatric disorders is less well studied; nonetheless, clinicians providing care to persons with these disorders commonly employ psychotherapeutic interventions of many forms. An important neurobiological dimension relevant to this practice is how the putative mechanisms of action of the various psychotherapies inform the suitability and potential benefits of psychotherapy for persons with neuropsychiatric disorders. In this chapter, an overview of the major types of psychotherapy is provided. As psychotherapy in the practice of Behavioral Neurology & Neuropsychiatry (BN&NP) is provided mostly by clinicians with psychiatric training, the term “neuropsychiatric” will be used herein to describe the patient populations for which these treatments may be considered. The evidence regarding the effectiveness of psychotherapy, especially among persons with neuropsychiatric disorders, is provided. Additionally, practical advice regarding the selection of psychotherapeutic treatments for patients with neuropsychiatric populations is offered.

Psychological mechanisms of psychotherapeutic effects Many factors influence the effectiveness of psychotherapy, including the quality of the therapeutic relationship, patient variables such as readiness to change, type and degree of psychological disturbance, expectations

of the therapist, as well as specific strategies and techniques of the therapy. The relevance of each of these factors differs from patient to patient. However, factors such as patient expectations and the “goodness of fit” between the patient and therapist seem to be at least as important to outcome as the particular therapeutic technique that is used. Individual studies and meta-analyses identify common factors relevant to the effectiveness of most psychotherapies [2, 3]. The quality of the therapeutic alliance (i.e., the degree to which patient and therapist work well together) accounts for 30–50% of the variability in treatment outcome. Patient variables, including expectations for improvement through psychotherapy, account for as much as 66% of the variability in treatment outcome. In contrast, the proportion of variance in treatment outcome accounted for by specific psychotherapeutic techniques is modest (12–15%). The importance of the therapeutic alliance is also important to the effect of psychotherapy on treatment outcome among patients with neuropsychiatric conditions. In a study of 66 inpatients with traumatic brain injury (TBI), a positive therapeutic alliance with the patient correlated with a favorable outcome (r = 0.42, p ⬍ 0.001) [4]. Among 19 patients with multiple sclerosis (MS) receiving 19 weeks of cognitive– behavioral therapy (CBT) for depression, the strength of the working alliance was associated with improvements in Beck Depression Inventory scores [5].

Learning New learning appears important for psychotherapeutic effectiveness, as it is an essential element of the processes that facilitate increased self-awareness,


587


improved appraisal of problematic thoughts and behaviors, and enlargement of an individual’s repertoire of adaptive solutions and communication skills. Extinction of anxiety and fear responses also involves new learning, with input from the ventral and medial prefrontal cortices (vmPFC) acting on the amygdala to suppress fear-based responses [6]. These learning processes can involve the explicit or the implicit memory systems, or both. Through repetition, consciously learned material may be made implicit (or unconscious). Through attention and exploration, material that is (or has been made) implicit may become evident or conscious. Bringing unconscious information into conscious awareness may make it possible to develop increased freedom and choice over one’s actions. Any or all of these types of learning may contribute to improvement in psychological health by psychotherapy.

Attachment theory Since the inception of formal psychotherapy theories, the notion has prevailed that a patient’s improvement in psychotherapy is due, at least in part, to the intrinsic qualities of that patient’s relationship with the therapist. As noted earlier, the current evidence regarding the mechanisms by which psychotherapy affords benefits points to the central importance of the quality of the therapeutic relationship as a predictor of treatment outcome. Research findings in the area of attachment theory suggest the intriguing possibility that a secure attachment, in the form of the therapeutic relationship, may enhance a patient’s ability to regulate his or her affects. Patterns of relating to others, strongly influenced by interactions with parental figures and beginning in infancy, may be categorized as secure or insecure. Attachment insecurity is correlated with stress-induced bilateral increase in amygdala activity [7]. Affective states, also influenced by attachment style, affect one’s ability to learn, recall, and integrate information [8]. The mesencephalic dopaminergic reward system also appears relevant to the mechanisms of psychotherapeutic effectiveness in light of its critical role in social attachments [9]. This reward system includes the ventral tegmental area, the amygdala, nucleus accumbens, thalamus, and cingulate cortex. Oxytocin and vasopressin (the so-called social neuropeptides)

588

activate this circuit, interact with dopamine to influence the activity of this circuit, and thereby affect behavior and emotional states [10]. To the degree that this system is functionally intact and accessible through psychotherapeutic interactions, it may facilitate a patient’s attachment to his or her therapist. If so, then this system may be a relevant and important mediator of psychological improvement through psychotherapy, including that offered to patients with neuropsychiatric disorders.

Psychotherapies Psychotherapy is a form of treatment in which the therapist attempts to improve the patient’s symptoms and functioning using specialized professional dialogue. Despite their differences, most psychotherapies aim to help patients identify and understand dysfunctional but modifiable patterns of thoughts, emotions, behaviors, family, and system-of-care issues in the serving of developing new, more adaptive, ways of functioning individually, interpersonally, and socially. The various psychotherapies differ with regard to the theories of the origin of psychological distress and the strategies they advance for promoting change. Each focuses on one or more domains of difficulty: emotion, cognition, behavior, interpersonal relations, or systems (i.e., family, healthcare organization, or other contexts in individuals’ function). Beitman and Yue (2004) [11] refer to these domains using the initials ECBIS, and they suggest this approach as a model to determine which type of psychotherapy may be most appropriate for a given patient. Selecting a psychotherapy begins first by identifying the ECBIS domain that best captures a patient’s target symptom. Then, a specific type of therapy, strategy, and technique best suited to that patient’s needs is selected. An overview of this approach is summarized in Table 36.1; see also Box 36.1 for brief case examples illustrating use of this approach to select appropriate psychotherapies. The main categories of psychotherapies likely to be useful for patients with neuropsychiatric disorders include: behavioral, cognitive–behavioral, interpersonal, systems and family, motivational interviewing/stages of change, supportive, and psychodynamic, and group psychotherapy. Not surprisingly, a combination of psychotherapeutic approaches, augmented with pharmacotherapy when appropriate, often is the

Table 36.1. Selecting a psychotherapy using the ECBIS model. Abbreviations: OCD – obsessive-compulsive disorder; PTSD – post-traumatic stress disorder; GAD – generalized anxiety disorder; TBI – traumatic brain injury; ABC, antecedents, behaviors, cosequences.

Target for change

Therapy to use

Conditions treated

Description/strategies

Techniques

Emotion (e.g., depression, anxiety, anger)

Supportive psychotherapy

All

Support intrapsychic and environmental adaptation and maximize functioning

Advice Validation Bolster adaptive defenses

Psychodynamic psychotherapy

Depression, anxiety, personality disorders, relationship conflicts

Understand unconscious conflicts, moral values, beliefs, and self-esteem as revealed by interactions with therapist

Confrontation Clarification Interpretation Use of transference

Cognition (e.g., irrational, thoughts, not cognitive impairments)

Cognitive–behavioral therapy

Depression, anxiety, OCD, PTSD

Identify and modify dysfunctional automatic thoughts, beliefs, and maladaptive behaviors

Six column technique analyzing: 1. Situation 2. Emotion(s): describe and rate 3. Automatic “hot” thoughts 4. Evidence supporting thoughts 5. Evidence against thoughts 6. Re-rate emotion(s) with new, more balanced thought

Behavior (e.g., impulsivity, aggression, poor health habits, substance abuse)

Behavioral therapy

Substance abuse, impulsiveness, aggression

Define and alter maladaptive behaviors; identify trigger; reinforce or extinguish behaviors

Analyze and intervene with ABC approach: antecedents (stressors/triggers), behaviors, and consequences (reinforcers)

Relaxation training

PTSD, GAD, social phobia

Induce somatic homeostasis

Focus attention Passive attitude towards negative thoughts If neurobiofeedback is used, induce alpha waves

Motivational interviewing, Stages of Change

Substance abuse, treatment adherence, diet, exercise

Elicit patient’s motivation to change

Rate importance and confidence in the ability to change Assess readiness or stage of change Use techniques specific for motivating change

Interpersonal therapy

Depression, grief, anxiety, substance abuse, borderline personality disorder

Current interpersonal relationships affect mood; modify interpersonal conflict, roles, and interactions which affect mood

Focus on one of four areas: Grief, role transition, role dispute, social isolation

Psychodynamic psychotherapy

Depression, anxiety, personality disorders, relationship conflicts

Identify maladaptive interpersonal patterns as revealed through interactions with therapist

Confrontation Clarification Interpretation Use of transference

Group therapy

Relationship conflicts, personality disorders, family support groups, substance abuse

Promote self-understanding and improved social interactions through feedback from peers

Interactions between group members are a mechanism of change

Systemic/family therapy

TBI, Alzheimer’s disease, cognitive disorders, intra-family conflict

Intervene at system that generates problem behavior; identify and correct dysfunctional family organization; improve communication and problem solving

Psychoeducation Structural family therapy: restructure roles and rules Strategic family therapy: problem solving

Interpersonal (e.g., problematic relationships at work or in personal life)

Systems (e.g., family dysfunction, role changes due to illness)


Box 36.1. Brief case examples illustrating use of the ECBIS (emotion, cognition, behavior, interpersonal, systems) approach to psychotherapy selection. A former family breadwinner physically disabled by multiple sclerosis may find interpersonal therapy helpful for relieving depression related to loss and changing roles within his family. Cognitive deficits – minimal Target symptoms – depression, changed role in family Therapy of choice – Interpersonal psychotherapy (focus on role change) A patient with a severe traumatic brain injury whose family plans to care for her after hospital discharge will likely be helped most by behavioral therapies targeting her symptoms and family psychotherapy to help her caregivers manage the new life circumstances. Cognitive deficits – severe Target symptoms – impulsive behaviors, overwhelmed caregivers Therapies of choice – behavioral therapy (contingency management), family therapy (strategic family therapy, support group, psychoeducation)

most helpful strategy to employ – in general and in neuropsychiatry.

Behavioral therapy Behavioral therapies are based on the principles of conditioning (associating a stimulus with a behavior), operant learning (positive and negative reinforcement of behavior), and social learning (role modeling adaptive group values). Problem behaviors are examined according to their antecedents (triggers or precipitants of the maladaptive behavior), behaviors, and consequences (reinforcers of behaviors); this is referred to as the “ABC” approach to behavior therapy (Table 36.2). A common behavioral therapy technique is contingency management, which focuses on modifying the factors that reinforce or discourage behaviors. Relaxation training is another form of behavioral therapy, decreasing anxiety on cue, or as a learned response to previously anxiety-provoking stimuli. Counter-conditioning extinguishes a conditioned anxiety response by repeated exposure to the distressing stimulus. A reasonable goal of these interventions is a decrease in the frequency

590

Table 36.2. The essentials of behavioral therapy. The therapeutic focus within the ECBIS model is behavior: maladaptive behavior is the problem to be solved, not merely a symptom of an underlying issue.

Basic techniques of behavioral therapy Define the maladaptive behavior and conditions under which it occurs, including triggers and modifiers Identify specific behavioral objective such as a specific decrease in frequency or intensity of behavior Take baseline measurements of the target behavior, including precipitants, frequency and intensity of behaviors Observe patient to determine how behavior is currently rewarded, ignored, or punished Modify contingencies: specify how desired behavior will be reinforced and problem behavior ignored Monitor results by measuring and tracking behavior; change treatment if needed Counter-conditioning: systematic desensitization of conditioned anxiety response by exposure to the distressing stimulus

and/or intensity of the problem behavior. This type of therapy is described in additional detail in Chapter 37. Because behavioral therapy does not rely on the presence or development of insight into the behaviors, as well as their antecedents or consequences, it is one of the most useful forms of psychotherapy in patients with cognitive impairments. A systematic review of behavioral therapy for children and adults with TBI examined 65 studies in which a total of 172 patients were included. Interventions included various programs using positive and negative reinforcement. All studies reported significant improvements in behavioral functioning, and the authors of the systematic review concluded that behavioral interventions are appropriately regarded as treatment options in this population. Another systematic review evaluated evidence-based psychological treatments for disruptive behaviors in individuals with dementia; this review concluded that contingency management is effective for decreasing problem behaviors in that population [12]. In the general population, behavioral therapy is commonly used in the treatment of substance abuse. A meta-analysis of contingency management for treatment of substance abuse found a significantly improved abstinence rate in response to this intervention, with an effect size of 0.42 [13]. In our opinion,

Chapter 36: Psychotherapy

this treatment is likely to be similarly effective in neuropsychiatric populations.

Table 36.3. The essentials of cognitive–behavioral therapy. The therapeutic focus within the ECBIS model is cognition: focuses on “hot” thoughts as primary drivers of feelings and behaviors.

Cognitive and cognitive–behavioral therapy

Basic techniques of cognitive-behavioral therapy

In contrast to behavioral therapy, cognitive therapies, particularly CBT, emphasize the importance of distorted thinking in the development of emotional symptoms and maladaptive behaviors. In general, cognitive therapies are predicated on the hypothesis that irrational thoughts are at the root of psychological symptoms: a person encounters a stressor that interacts with a distorted world-view, which produces irrational thoughts and emotions and leads to maladaptive behaviors. Unlike psychoanalytic and psychodynamic psychotherapies, cognitive therapies do not focus on the unconscious origin of such thoughts or on transference or countertransference. Instead, this school of thought regards cognitions (rational or irrational) as the products of learning and as structures that are maintained by reinforcement. Cognitive therapies therefore seek to identify and challenge symptomproducing irrational thoughts and to facilitate reframing of those thoughts in the service of emotional and behavioral improvement. Although specific training is needed to provide CBT competently, the basic techniques employed in this form of psychotherapy are summarized in Table 36.3; additionally, an example of the six-column “thought record” – derived from these techniques – that is used to help patients identify relationships between their thoughts, beliefs, and emotions is offered in Table 36.4. Other commonly used CBT techniques include exposure with response prevention (used principally in the management of OCD) and prolonged exposure therapy (used primarily for the management of posttraumatic stress disorder, or PTSD), also described briefly in Table 36.3. Exposure with response prevention and prolonged exposure therapy are intended to decrease or extinguish conditioned anxiety responses through repeated exposure to distressing triggers. First, patients are taught relaxation and distress tolerance techniques to use during the exposure sessions. Next, stimuli are rank-ordered from least to most distressing. Exposure starts with the introduction, either imagined or actual, of a minimally upsetting stimulus, in response to which patients employ their relaxation techniques. As patients are better able to tolerate this stimulus, they proceed up their rank-order list of distressing stimuli and repeat the exposure-and-response

Thought record is used to examine the links between thoughts, feeling, and behaviors by recording and rating these elements in six columns: r Describe the situation: Who, what, when, where? r Describe and rate intensity of associated emotions(s) r Identify “hot” thoughts – automatic, distorted (i.e., irrational) thoughts that cause or maintain emotional symptoms r Test the validity of automatic thoughts: what evidence supports the “hot” thought? r Test the validity of automatic thoughts: what evidence refutes the “hot” thought? r Develop balanced, more adaptive thoughts, and re-rate emotion(s) associated with new cognitions Intervention includes exposure with response prevention (used primarily to treat obsessive-compulsive disorder): r Prepare by learning to manage discomfort with relaxation techniques r Expose, either by imagined or actual exposure, to a hierarchy of increasingly distressing stimuli r Inhibit pathological behavior (compulsions) and tolerate accompanying anxiety r Through repeated exposures, gradually extinguish stimulus-provoked emotion(s) Prolonged exposure therapy, which extinguishes anxiety responses in persons with post-traumatic stress disorder and specific phobias

procedures. Gradually, these procedures extinguish distressing emotions associated with these stimuli. The neural mechanisms by which extinction is accomplished in the forms of CBT is proposed to occur through inhibitory learning. The stimulus, which originally predicted a particular (and distressing) outcome, gradually comes to predict that the outcome in fact will not occur. The original link between the conditioned stimulus and unconditioned stimulus is not erased; instead it remains intact but is opposed by new learning about the emotional salience of that stimulus. Brain regions important for inhibitory learning include the vmPFC, the amygdala, and the hippocampus [14]. In long-term extinction, the vmPFC inhibits the amygdala (by mechanisms still under debate). It is not yet clear whether the amygdala also encodes part of the inhibitory learning, or is simply inhibited by the vmPFC. The hippocampus is not required for extinction, but it is important in the contextual modulation of extinction [15, 16]. This information suggests that therapies employing inhibitory learning, such as exposure response prevention and prolonged exposure

591


Table 36.4. Example of a thought record used in cognitive–behavioral therapy.

Situation

Emotion(s)

“Hot” thoughts

Pros

Cons

Re-rate emotion(s)

Who, what, when, and where?

Describe with one word, and rate the intensity of that mood (0–100%, not intense to extremely intense)

Which thoughts drive behaviors and symptoms?

What is the evidence that supports “hot” thought?

What is the evidence that refutes “hot” thoughts?

New, more balanced thoughts More realistic view

“My project is going to be reviewed by my manager tomorrow”

“Sad (90%), nervous (95%), afraid (97%)”

“I’m going to be fired because the project is not complete”

“I am behind on the project, and my co-worker was fired recently”

“My manager has always been reasonable with me on other projects”

“This is an opportunity to get some advice on and assistance with my project; sad (50%), nervous (60%), afraid (50%)”

therapy may be less effective in individuals with damage to the vmPFC. However, to the degree that this area is spared, even in cases with malfunctioning of other areas of the PFC, these CBT techniques may be useful in decreasing conditioned anxiety as seen in phobias and PTSD. Aaron Beck described CBT and demonstrated its usefulness as a treatment for depressive and anxiety disorders [17]. Specific CBT techniques were subsequently developed for the treatment of OCD (i.e., exposure with response prevention) [18] as well as PTSD (i.e., prolonged exposure therapy) [19, 20]. Cognitive behavior therapy also is useful as a treatment for chronic pain [21], bulimia [22], substance dependence [23], and personality disorders [24]. There also is evidence that CBT may decrease hallucinations and delusions among persons with schizophrenia [25]. However, more recent observations suggest that although there may be an effect of CBT on overall symptom severity and level of negative symptoms in this population, it does not appear particularly useful as an intervention for overall symptoms of schizophrenia or schizophrenia-associated depression. Cognitive behavior therapy has a strong evidence base and has been studied in populations with neurologic disorders such as MS, TBI, Parkinson’s disease, and stroke. A complete review of this literature is beyond the scope of the present work. For the purpose of illustration, however, a few key findings are reviewed here. Uncontrolled studies suggest that CBT may be a useful treatment for depression among persons with Parkinson’s disease [26, 27]. A Cochrane systematic review found reasonable evidence that cognitive behavioral approaches are beneficial in treatment of depression in patients with MS and in

592

helping people adjust to and cope with having this disease [28]. A systematic review identified CBT as promising with respect to the treatment of depression following TBI [29]. Additional studies in this population found that CBT may be useful for the treatment of post-TBI depression [30], including an on-line form of this psychotherapy [31]. Similar to the aforementioned studies of persons with MS, CBT (provided in a group context) also improves coping skills among persons with TBI even in the absence of clear effects on depression, anxiety, or quality of life [32]. Another Cochrane meta-analysis [33] concluded that CBT, in conjunction with neurorehabilitation, is effective for treatment of generalized anxiety in persons with mild to moderate TBI. There is also some evidence suggesting that CBT may be useful for the treatment of post-stroke depression [34, 35]. However, the evidence for the use of CBT in this context is mixed [36], and two systematic reviews of treatment of post-stroke depression failed to find convincing evidence for the efficacy of CBT in this setting [37, 38]. The patient characteristics that predict response to CBT are incompletely defined in general as well as in neuropsychiatric clinical populations. As with the use of CBT among persons with schizophrenia, it seems unlikely that CBT is likely to be a useful intervention for the management of hallucinations or delusions among persons with neuropsychiatric disorders. It also seems likely that severe cognitive impairments preclude the use of most traditional CBT techniques. However, additional work is needed to define further the level of cognitive ability required for the successful use of CBT for the management of emotional and behavioral symptoms among persons with neuropsychiatric disorder.


Table 36.5. The essentials of interpersonal therapy. The therapeutic focus within the ECBIS model is interpersonal: interpersonal stressors and conflicts influence emotion, which in turn influence relationships. The therapist and patient agree to focus efforts toward improvement on one of the four areas of interpersonal functioning presented in the table.

Area of focus

Examples

Techniques

Unresolved grief

Death of loved one

Facilitate mourning process with catharsis

Role transition

Retirement

Relinquish old roles, develop new roles

Role dispute

Division of child care

Modify unsatisfying patterns and re-negotiate new role definitions

Social isolation

Lack of interpersonal skills

Form new relationships, social networks

Interpersonal psychotherapy Interpersonal psychotherapy (IPT) is based on the principle that interpersonal tension (e.g., between patient and spouse) influences emotions, and, in turn, emotions influence relationships [39]. Interpersonal psychotherapy is generally provided as a brief (i.e., time-limited) psychotherapy that focuses on the patient’s present-day interactions with others, and how these contribute to emotional well-being. The therapist and patient select among four interpersonal issues to focus on: grief, role transition, role dispute, or social isolation, as detailed in Table 36.5. A course of IPT usually consists of 12–16 weekly sessions. Originally developed and used successfully as a treatment for major depressive disorder [40, 41], adapted forms of IPT also are used to treat social phobia [42], bulimia [43], and borderline personality disorder [44]. A variation of IPT, interpersonal and social rhythm therapy (IPSRT), appears to be a useful treatment through which to accelerate the recovery rate (i.e., decrease time to recovery) among patients with bipolar disorder [45]. In this form of IPT, patients learn how disruptions in their daily routines and interpersonal relationships aggravate bipolar disorder, and work with their IPSRT therapists to minimize these disruptions. There are few studies describing the use of IPT among persons with neuropsychiatric disorders. Early reports suggested that a version of IPT modified for use among older persons (i.e., in late-life, hence IPTLL) usefully addressed depressive symptoms in the early stage of Alzheimer’s disease (AD) [46]. However, a subsequent randomized controlled study of patients

with early-stage AD providing a six-session course of IPT did not improve affective symptoms, cognitive function, or global well-being [47]. An adapted version of IPT was developed to treat depression among older patients with depression complicated by cognitive impairment (IPT-CI) [48]. In a 2-year study of this version of IPT compared with supportive clinical management among 52 elderly subjects with depression and a range of cognitive abilities [49], IPT extended time to recurrence of major depression most effectively among subjects with greater cognitive impairments (52 weeks vs. 17 weeks for supportive clinical management). Among subjects without cognitive impairments, there was no difference in time to major depression recurrence between these interventions (38 weeks vs. 32 weeks, respectively). Contrary to conventional wisdom, these studies suggest that versions of IPT adapted for persons with cognitive impairment may be useful interventions for the treatment of depression, and possibly grief and/or role transitions, among some persons with neuropsychiatric disorders. Further clarification of the relationship between cognitive impairments and IPT effectiveness is needed to better identify patients for whom this psychotherapy is likely to be particularly useful. Additionally, adaptations and evaluations of this psychotherapy for specific neuropsychiatric populations, including stroke, TBI, Parkinson’s disease, MS, and epilepsy, among others, are needed.

Family and systems therapies Neuropsychiatric conditions frequently impact the families of affected persons, a problem that in turn influences the illness experience and coping abilities of those with the neuropsychiatric disorders. Although severe cognitive impairments may limit the participation of an individual with a neuropsychiatric disorder in psychotherapy, it nonetheless is important to offer that individual’s family education about the family member’s condition, and may be useful to provide therapy directed at facilitating adaptation to the effects of that illness on the family. At a minimum, clinicians are encouraged to support patient and family education including referral to condition-specific consumerlevel organizations (see Table 36.6). Family therapy focuses on reorganizing the family structure and roles as well as improving problem solving within the family. Consideration is given to the effect of the patient’s illness on roles within the

593


Table 36.6. Support groups and resources for patients and families affected by neurological conditions.

Condition

Organization

Web site

Traumatic brain injury

Brain Injury Association of America International Brain Injury Association

www.biausa.org www.internationalbrain.org

Stroke

National Stroke Association The Stroke Network American Stroke Association (American Heart Association)

www.stroke.org www.strokenetwork.org www.strokeassociation.org


Alzheimer’s Association

www.alz.org


National Parkinson Foundation

www.parkinson.org

Lewy body dementia

Lewy Body Dementia Association

www.lbda.org

Frontotemporal dementia

Association for Frontotemporal Dementias

www.ftd-picks.org

Creutzfeldt–Jakob disease

Creutzfeldt–Jakob Disease Foundation

www.cjdfoundation.org

Amyotrophic lateral sclerosis

ALS Association

www.alsa.org

Multiple sclerosis

MS Association of America National MS Society

www.msassociation.org www.nationalmssociety.org

Epilepsy

Epilepsy Foundation

www.epilepsyfoundation.org

Hydrocephalus

Hydrocephalus Foundation

www.hydrocephalus.org

Table 36.7. The essentials of family and systems therapy. The therapeutic focus within the ECBIS model is system: attention is given to the patient’s relational functioning within their family and healthcare system, and how those interactions affect the patient’s symptoms.

Therapy type

Focus

Intervention(s)

Psychoeducation

Teach patient, family, and involved others about the patient’s illness

Improve coping skills, access to care, adherence to prescribed treatments, knowledge of relevant resources

Strategic family therapy

Problem solving

Paradoxical intervention (prescribing the symptom) and reframing

Structural family therapy

Treat symptoms within the context of the family’s organization: roles, rules, hierarchy, alliances, and coalitions

Restructure family system to promote lasting change in symptoms

family, and efforts are directed towards developing new and adaptive interactions between family members [50]. Systems therapy is a broader application of family therapy that extends the focus of evaluation and intervention to include all systems in which the patient operates, including the community, healthcare delivery systems, and payors supporting those systems. The essential features of these therapies are presented in Table 36.7. Regardless of the level of neuropsychiatric disability experienced by patients, family and system therapies are appropriate and potentially fruitful interventions with which to address and mitigate the adverse effects of neuropsychiatric disorders on families and systems. A useful measure of the maturity and stability of relationships within a family that may inform on the need for these types of therapies is the Global Assessment of Relational Functioning (GARF) scale

594

(see Table 36.8) [51]. Developed as an analog of Global Assessment of Function (GAF) that is used to assess individual functioning, the GARF score can be recorded on DSM–IV Axis V. The GARF rates functioning of the family unit in three areas: problem solving, organization, and emotional climate. These ratings are combined for an overall score, from 1 (extremely dysfunctional) to 100 (ideal functioning). Literature discussing the use of family and systems therapy among patients and families affected by neuropsychiatric disorders is extensive and generally positive; unfortunately, few of these studies employ adequate control conditions, and therefore the conclusions drawn regarding their effects cannot be regarded as definitive. One controlled study of 42 subjects with AD and their caregivers found a significant benefit to a cognitive–behavioral family intervention. The therapy consisted of 14 sessions conducted every other


Table 36.8. Global Assessment of Relational Functioning (GARF) Scale.

Features of the GARF Scale Facilitates measurement of the maturity and stability of relationships within a family or between a couple Rates family unit in the following three areas: A. Problem solving – skills in negotiating goals, rules, and routines; adaptability to stress; communication skills; ability to resolve conflict B. Organization – maintenance of interpersonal roles and subsystem boundaries; hierarchical functioning; coalitions and distribution of power, control, and responsibility C. Emotional climate – tone and range of feelings; quality of caring, empathy, involvement, and attachment/ commitment; sharing of values; mutual affective responsiveness, respect, and regard; quality of sexual functioning Gives an overall score, from 1 (extremely dysfunctional) to 100 (ideal functioning), for the functioning of the relational unit Analogous to Global Assessment of Function scale (DSM–IV–TR Axis V) that is used to assess individual functioning

week, covering topics of caregiver education, stress management, and coping skills training. Families who received the study intervention reported decreased levels of caregiver burden as well as reduced behavioral disturbance in the subjects with AD [52]. A study of 34 subjects with Parkinson’s disease reported a correlation between dissatisfaction with social support and the severity of depression, anxiety, and stress [53], suggesting a possible opportunity for improvement through family and systems therapies. In a study of 32 children with moderate-to-severe TBI, familycentered problem-solving intervention (compared against “usual care”) decreased behavioral problems in these children [54]. A randomized controlled trial of 40 children with moderate-to-severe TBI reported improved parental adaptation in response to an on-line family problem-solving therapy when compared with the control intervention of providing only internet resources [55]. Collectively, these findings support the potential benefits of family and systems therapies for persons with neuropsychiatric disorders. Importantly, these therapies do not require individuals with neuropsychiatric disorders to engage directly in these therapies. Instead, therapies are directed at the family and systems levels. This feature makes family and systems therapies reasonable to consider in the treatment plan of most individuals with neuropsychiatric disorders.

Motivational interviewing Motivational interviewing is a brief client-centered therapy that appears useful as an intervention through which to facilitate health and lifestyle changes, including alcoholism, smoking, exercise, and treatment adherence, among others [56, 57]. Rather than trying to directly persuade a person to change unhealthy behaviors, therapists use motivational interviewing to help patients identify and resolve their ambivalence about changing their behaviors, and identifies and elicits their motivation to change. The general strategies used in motivational interviewing are described in Table 36.9. People do not change their behaviors in a single leap, but pass through a series of steps as they develop new habits. Prochaska and DiClemente (1983, 1992) [58, 59] described this process as the Stages of Change (Table 36.10). This model of change is used to facilitate an individual’s assessment of his or her readiness to change a behavior (or set of behaviors), the importance of that change, and also his or her confidence about the ability to make that change [60]. Therapeutic techniques target the patient’s readiness to change, and are adjusted as patient and therapist proceed through the stages of change [61]. These techniques include the use of open-ended questions, affirmation, reflective listening, summarizing (“OARS”) and a variety of motivation, confidence, and general change strategies (see Table 36.9). A meta-analysis of 30 controlled clinical trials in which adaptations of motivational interviewing were used reported moderate effect sizes when used in the treatment of alcohol and substance abuse as well as diet and exercise [62]. In light of the influence of substance use on TBI outcomes [63] and the high rates of preTBI substance-use disorders [64], a version of motivational interviewing (i.e., systematic motivational counseling (SMC)) is available for the treatment of substance abuse after TBI. In one study of this intervention [65], 40 participants received 12 individual sessions of SMC and 54 controls received no motivational or substance abuse treatment. In these groups, the substances of abuse included alcohol, cocaine, and marijuana. When compared with the control group, subjects receiving SMC decreased use of substances and associated negative emotions. Motivational interviewing also has been studied as a possible treatment for mood disturbances among persons with stroke [66]. An open randomized clinical

595


Table 36.9. The essentials of Motivational Interviewing. The therapeutic focus within the ECBIS model is behavior: promote behavior change by exploring and resolving ambivalence. Motivation to change is elicited from the patient, rather than attempting to persuade directly. The intervention is used to improve health behaviors, including substance abuse, diet, exercise, and treatment adherence. General strategies

Express empathy for the patient and his or her ambivalence regarding behavior change Discern discrepancy between behaviors and values or goals “Roll with the patient’s resistance” – do not confront that resistance directly Encourage the patient to state his or her reasons to change Support self-efficacy: that the patient can choose, act, and maintain change

Motivational technique

O: Open-ended questions A: Affirm R: Reflective listening S: Summarize

Measure readiness to change

Using importance and confidence rulers, address the following questions: 1. How important is it to you to change your behavior? (0 = not important, 10 = extremely important) a) b)

Why isn’t this less important? What would it take to make this change more important?

2. How confident are you that you can change your behavior? (0 = no confidence, 10 = extremely confident) a) b)

Evaluate stage of change

Why aren’t you less confident? What would it take to make you more confident?

Acknowledge that behavioral changes occur in several steps Evaluate the patient’s Stage of Change (see Table 36.10) and use counseling strategies matched to that stage

trial of 411 subjects, enrolled 5–28 days post-stroke, received four weekly motivational interviewing sessions with the goal of improving psychological and practical adaptations to the sequelae of stroke. This intervention produced mood improvements at 3-months post-stroke as well as a protective effect against the development of depression; these effects were not associated with other early post-stroke functional outcomes.

596

These reports are encouraging with respect to the potential benefits of motivational interviewing for the management of behaviors that negatively affect psychological and general health, as well as other possible problems, among persons with neuropsychiatric disorders. Because persons with severe cognitive impairments were excluded from the studies described here, the relationship between cognitive functioning (or cognitive impairment) and the effectiveness of motivational interviewing is not well established. For the present, we suggest this intervention is likely to be effective among persons with neuropsychiatric disorders provided that they are relatively intact cognitively. It may be of particular use in the management of patients with comorbid neuropsychiatric disorders and substance abuse as well as those motivated to adapt psychologically to disability.

Supportive psychotherapy Supportive psychotherapy is an intervention that reinforces adaptive psychological defenses and improves daily coping. Unlike psychodynamic and psychoanalytic psychotherapies, supportive psychotherapy does not strive to uncover intrapsychic conflicts and interpret ego defenses. Instead, the primary goal of this intervention is to help patients understand their emotional life in a manner that promotes well-being, suggests solutions for personal difficulties, or fosters adaptation to known problems. Supportive techniques are essential elements of all psychotherapies, and include reassurance, praise, advice, empathy, and encouragement (see Table 36.11). Few studies examine the effectiveness of supportive psychotherapy per se, but instead use it as a comparator to other psychotherapies given that its essential elements are also used in other psychotherapies. Despite its ubiquitous incorporation into psychotherapies, a systematic review of controlled trials of brief (i.e., comprising fewer than 20 sessions) supportive psychotherapies for depression identified a beneficial effect on depression [67]. However, supportive psychotherapy is used more commonly to help patients construct a personal narrative regarding their lives in which their symptoms and dysfunctions make sense. This use of supportive psychotherapy may be particularly applicable to the psychological care of persons with neuropsychiatric disorders, whose illnesses frequently change the course of their lives substantially. In particular, this form of psychotherapy may help patients identify


Table 36.10. The Stages of Change, as described by Prochaska and DiClemente (1983, 1992) [58, 59].

Stage

Patient’s perspective

Techniques to facilitate change

Precontemplation

No intention of changing; may be unaware of problem

Validate lack of readiness; provide psychoeducation; encourage re-evaluation of behavior

Contemplation

Aware of problem; considering addressing it within 6 months

Evaluation of pros and cons of problem behavior; provide psychoeducation; promote new positive outcome expectations

Preparation

Intending to take action within one month; making a few steps toward preparing to change

Identify obstacles and assist in problem solving; encourage small initial preparatory steps

Action

Behavioral change is occurring (considered action stage during the first 6 months of behavioral change)

Restructure cues and social support; combat feeling of loss

Maintenance

Relapse prevention; consolidate gains (considered maintenance stage when behavior change lasts beyond 6 months)

Reinforce internal rewards; discuss coping with potential relapse

Relapse

Slip back to any earlier stage

Start with new earlier stage; recall earlier success; reassure that relapse is common and not permanent

Table 36.11. The essentials of supportive psychotherapy. The therapeutic focus within the ECBIS model is emotion: bolster existing and effective psychological defenses and coping styles to support adaptive functioning. Basic techniques of supportive psychotherapy Use directive counseling, advice, encouragement, praise, and reassurance Encourage reality testing Help patient tolerate a wider range of affects Limit self-destructive behaviors and impulsiveness Minimize focus on transference

meaning in their lives in the face of illness or injury, including TBI [68] and other physical disabilities [69]. A type of supportive therapy suitable for patients with AD is reminiscence therapy, in which the therapist guides an individual or group to share memories and knowledge surrounding a theme, time in history, or time period in life. Music, photographs, and other materials are often used to prompt recall of memories. A similar intervention, life review, encourages the patient’s recounting of his or her personal history, often with the participation of loved ones and creation of a permanent historical record. In a Cochrane systematic review, both reminiscence therapy and life review therapy were found to improve mood, cognition, and general function among persons with AD [70]. Supportive psychotherapy is an important element of the management of all patients with neuropsychiatric disorders, and is an essential skill for all

subspecialists in BN&NP to master and employ in their work with patients. It often may be incorporated into routine clinical care. As with the other psychotherapies, the provision of supportive psychotherapy may be limited by severe cognitive impairment. In such circumstances, however, patients’ caregivers often need supportive psychotherapy. When a patient or caregiver requires a style or intensity of supportive psychotherapy that is more than can be practicably provided during routine clinical care, then referral to and collaborative management with a mental health provider is appropriate.

Psychodynamic psychotherapy Psychodynamic psychotherapy is a derivation of psychoanalysis and is a commonly employed therapy in modern clinical practice. Like psychoanalysis, a long-term intensive treatment that examines wishes and fears, conflicts and defenses, moral values, beliefs and ideals, self-esteem, and internal representations of relationships as revealed by the patient’s interactions with the analyst, a goal of psychodynamic psychotherapy is restructuring personality. This goal is pursued by fostering personal insight, exploring and expressing emotions, understanding internal conflicts, and elucidating unconscious motivations for behaviors. Focusing the attention of therapy on the relationship between the patient and clinician is also essential to this goal, as the patient experiences the therapist tolerating thoughts and feelings that the patient previously experienced as intolerable. The essential

597


Table 36.12. The essentials of psychodynamic psychotherapy. The therapeutic focus within the ECBIS model is emotion and interpersonal: the unconscious mind dictates many thoughts, feelings, and behaviors. Therapeutic goal Not merely behavior change, but restructuring personality Core principles

Transference: current relationships are influenced by important past (especially early childhood) relationships; patients therefore are likely to respond to and interact with the therapist in ways that reveal their mental organization regarding relationships Ego defenses (e.g., denial, projection, repression, humor) are psychological maneuvers used to deal with internal conflict Insight to internal conflicts and reasons for behaviors is required in order to achieve the therapeutic goal

Therapeutic techniques

Focus on patient–therapist relationship (transference and countertransference) Empathic listening Working alliance Verbal responses – clarification, interpretation, confrontation Identifying patterns Confront outdated or maladaptive defenses and encourage mature defenses Explore resistance Follow transference and countertransference Termination

elements of psychodynamic psychotherapy are presented in Table 36.12. Psychodynamic psychotherapy and psychoanalysis use techniques such as free association (the patient says whatever comes to mind), dream analysis, and uncovering of conflicts, defense, and core values. Both regard irrational thoughts as arising from conflicts between the patient’s wishes, defenses, core values, internalized relationships, and ideals. Psychotherapists help patients establish a meaningful and coherent sense of self and a sense of authenticity. These types of therapies are particularly useful for personality disorders, and chronic anxiety and mood disorders. Brief, time-limited, and manualized psychodynamic psychotherapies have been developed and their efficacy evaluated in randomized controlled studies. Instead of aiming for a pervasive change in personality structure, these therapies focus on making symptomatic changes by resolving intrapersonal and interpersonal conflicts. A meta-analysis of randomized

598

controlled studies of short-term psychodynamic psychotherapy [71] reports large effect sizes for target problems (1.39), general psychiatric symptoms (0.90), and social functioning (0.80). These effect sizes were stable and tended to increase at follow-up (1.57, 0.95, and 1.19, respectively). Individual randomized controlled trials suggest that short-term psychodynamic psychotherapy is useful for the treatment of depression [72, 73], post-partum depression [74], PTSD [75], bulimia [76, 77], anorexia [78], personality disorders [79–81], and opiate dependence [82]. Models for the use of psychodynamic psychotherapy in the neuropsychiatric population have been published, such as those of Drubach and colleagues (1994) on the use of a psychoanalytic framework in the treatment of persons with TBI [83], and Groswasser and Stern (1998) on a psychodynamic model of behavior after acute central nervous system damage [84]. However, there are no published outcome data on the efficacy of psychodynamic psychotherapy in neuropsychiatric patients. In general, a candidate for this type of therapy must be capable of self-observation, and of making connections between feelings for his or her therapist and past and present experiences (i.e., to recognize and explore transference). In our opinion, neuropsychiatric conditions do not preclude use of this type of psychotherapy as long as psychodynamic psychotherapy candidates with these conditions retain these abilities.

Group therapy Any of the types of psychotherapy discussed in this chapter can be delivered in a group setting. The advantages of group therapy include cost-effectiveness and the provision of peer feedback and support, as well as other potentially therapeutic factors (Table 36.13). Some groups are primarily educational, whereas others serve as a social support system for patients and families. Still others provide specific psychotherapies modified for a group setting, such as cognitive– behavioral therapy, interpersonal therapy, or psychodynamic psychotherapy. A meta-analysis of 23 studies comparing the effectiveness of individual and group therapy among persons without neuropsychiatric disorders identified no outcome difference as a function of the format in which therapy was provided [85]. Group psychotherapy is used extensively in the treatment of patients with neuropsychiatric disorders, a few


Table 36.13. The essentials of group therapy. Group therapy refers to any form of psychotherapy delivered in a group format, including cognitive–behavioral therapy, interpersonal therapy, psychodynamic psychotherapy, support groups, and psychoeducation. The therapeutic focus within the ECBIS model is interpersonal: one or more therapists treat patients as a group, using the interactions between members as the mechanism by which individual change is achieved. The table presents factors that are used in group therapy to achieve this end.

Collectively, these observations suggest that group therapy may be a therapeutically and cost-effective alternative to individual therapy. Further study of group therapy interventions among persons with neuropsychiatric disorders are needed in order to define the range of problems and the types of patients best suited to treatment in this manner.

Therapeutic factors in group therapy Universality Altruism Instillation of hope Imparting information Develop socializing techniques Imitative behavior Interpersonal learning Cohesiveness Corrective recapitulation of primary family experience Existential factors Catharsis Self-understanding

noteworthy examples of which are offered here. Group therapy is effective as a treatment for depression among persons with MS [86, 87] and also those with human immunodeficiency virus (HIV) infection [88]. Group therapy is useful for the management of frustration and substance abuse [30, 32, 89] as well as coping skills training among persons with TBI. Cognitive–behavioral group therapy for patients with epilepsy may improve emotional well-being, seizure control, and stress management [90].

Conclusion Quality of life is determined by psychological wellbeing as well as by physical functioning, and psychotherapy may be a pivotal addition to a patient’s comprehensive treatment program. When considering whether and/or which psychotherapy to recommend, the first task is to determine the domain in which the patient is experiencing the most important problem(s): emotion, cognition, behavior, interpersonal relations, or systems/family (ECBIS) – see Figure 36.1. Next, the patient’s diagnosis, prognosis, cognitive abilities, pre-morbid personality traits, the presence of substance abuse, and the family and system(s) within which he or she functions all require review. Clinicians may find Tables 36.1 and 36.14 useful guides to these considerations and to the selection of psychotherapies for a patient with a specific problem arising in association with his or her neuropsychiatric disorder. Several principles may be useful guides to psychotherapy selection for persons with neuropsychiatric disorders. In general, persons with relatively intact cognition are likely to benefit from any of the psychotherapies reviewed in this chapter, and particularly for grieving physical and functional losses, Figure 36.1. Interaction between emotion, cognition, behavior, interpersonal, and systems (the ECBIS model). Intrapersonally, the triad of emotion, cognition, and behavior interact. This triad contributes to the manner in which the individual interacts with others (i.e., interpersonal relations, represented here as the plane containing the set of large circles above each triad). The collection of individuals interacting with one another comprises a system.

599


Table 36.14. Psychotherapies that may be useful in the management of psychological and psychosocial issues among persons with neuropsychiatric disorders. Abbreviations: CBT – cognitive–behavioral therapy; IPT – interpersonal therapy.

from psychotherapy, more precise therapy prescriptions may become possible.

Target symptom(s)

Psychotherapy option(s)

Aggression, impulsivity, other disruptive behaviors

Behavioral therapy (see also Chapter 38)

References

Substance abuse

Motivational interviewing Behavioral therapy (contingency management)

Depression

Cognitively intact: psychodynamic psychotherapy, supportive psychotherapy, CBT, IPT Cognitively impaired: supportive psychotherapy

Adjustment to new role

Cognitively intact: IPT, psychodynamic psychotherapy

Grief and loss

Cognitively intact: IPT, psychodynamic psychotherapy, group therapy

Dysfunctional family structure

Structural family therapy

Problem solving required by family

Strategic family therapy

Lack of knowledge of illness and resources

Psychoeducation, support groups

Poor treatment compliance, poor diet and other harmful health behaviors

Motivational interviewing

Grief and loss

Cognitively intact: IPT, group therapy

Anxiety

CBT

changes in relationships and roles, and making sense of and adapting to their changed lives. Although cognitive impairment may limit engagement in some psychotherapies (especially psychodynamic psychotherapy), the available data suggest that it is not reasonable to regard cognitive impairments as precluding psychotherapy. Persons with cognitive impairments may benefit from behavioral therapies, modified cognitive– behavioral therapies, some interpersonal therapies, family and system therapies, and supportive psychotherapy. Group therapy is efficacious and costeffective, and has the added dimension of peer support and interaction, and motivational interviewing is particularly useful for the management of substanceuse disorders and maladaptive health behaviors. Neurobiological advances have clearly informed this field, and as more is discovered about the neural circuitry required to participate in and benefit

600

1. Roth A, Fonagy P. What Works for Whom? A Critical Review of Psychotherapy Research. 2nd edition. New York, NY: Guilford Press; 2005. 2. Lambert MJ, Ogles BM. The efficacy and effectiveness of psychotherapy. In Lambert MJ, editor. Bergin and Garfield’s Handbook of Psychotherapy and Behavior Change. 5th edition. New York, NY: Wiley; 2004, pp. 139–93. 3. Wampold BE. The Great Psychotherapy Debate: Models, Methods, and Findings. Mahwah, NJ: Lawrence Erlbaum Associates; 2001. 4. Klonoff PS, Lamb DG, Henderson SW, Shepherd J. Outcome assessment after milieu-oriented rehabilitation: new considerations. Arch Phys Med Rehabil. 1998;79(6):684–90. 5. Howard I, Turner R, Olkin R, Mohr DC. Therapeutic alliance mediates the relationship between interpersonal problems and depression outcome in a cohort of multiple sclerosis patients. J Clin Psychol. 2006;62(9):1197–204. 6. Sotres-Bayon F, Bush DE, LeDoux JE. Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction. Learn Mem. 2004;11(5):525–35. 7. Lemche E, Giampietro VP, Surguladze SA et al. Human attachment security is mediated by the amygdala: evidence from combined fMRI and psychophysiological measures. Hum Brain Mapp. 2006;27(8):623–35. 8. Fonagy P, Bateman AW. Mechanisms of change in mentalization-based treatment of BPD. J Clin Psychol. 2006;62(4):411–30. 9. Insel TR. Is social attachment an addictive disorder? Physiol Behav. 2003;79(3):351–7. 10. Insel TR, Young LJ. Neuropeptides and the evolution of social behavior. Curr Opin Neurobiol. 2000;10(6):784–9. 11. Beitman BD, Yue D. Learning Psychotherapy: A Time-Efficient, Research-Based, and Outcome-Measured Psychotherapy Training Program. 2nd edition. New York, NY: W.W. Norton; 2004. 12. Logsdon RG, McCurry SM, Teri L. Evidence-based psychological treatments for disruptive behaviors in individuals with dementia. Psychol Aging. 2007;22(1):28–36. 13. Prendergast M, Podus D, Finney J, Greenwell L, Roll J. Contingency management for treatment of substance


use disorders: a meta-analysis. Addiction 2006;101(11):1546–60.

27. Dobkin RD, Allen LA, Menza M. Cognitive-behavioral therapy for depression in Parkinson’s disease: a pilot study. Mov Disord. 2007;22(7):946–52.

14. Sotres-Bayon F, Cain CK, LeDoux JE. Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex. Biol Psychiatry 2006;60(4):329–36.

28. Thomas PW, Thomas S, Hillier C, Galvin K, Baker R. Psychological interventions for multiple sclerosis. Cochrane Database Syst Rev. 2006;1:CD004431.

15. Corcoran KA, Maren S. Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J Neurosci. 2001;21(5):1720–6.

29. Fann JR, Hart T, Schomer KG. Treatment for depression after traumatic brain injury: a systematic review. J Neurotrauma 2009;26(12):2383–402.

16. Ji J, Maren S. Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction. Learn Mem. 2005;12(3):270–6.

30. Anson K, Ponsford J. Who benefits? Outcome following a coping skills group intervention for traumatically brain injured individuals. Brain Inj. 2006;20(1):1–13.

17. Beck AT. Cognitive therapy. A 30-year retrospective. Am Psychol. 1991;46(4):368–75. 18. Lindsay M, Crino R, Andrews G. Controlled trial of exposure and response prevention in obsessive-compulsive disorder. Br J Psychiatry 1997;171:135–9.

31. Topolovec-Vranic J, Cullen N, Michalak A et al. Evaluation of an online cognitive behavioural therapy program by patients with traumatic brain injury and depression. Brain Inj. 2010;24(5):762–72. 32. Anson K, Ponsford J. Evaluation of a coping skills group following traumatic brain injury. Brain Inj. 2006;20(2):167–78.

19. Foa EB, Rothbaum BO, Riggs DS, Murdock TB. Treatment of posttraumatic stress disorder in rape victims: a comparison between cognitive-behavioral procedures and counseling. J Consult Clin Psychol. 1991;59(5):715–23.

33. Soo C, Tate R. Psychological treatment for anxiety in people with traumatic brain injury. Cochrane Database Syst Rev. 2007;3:CD005239.

20. Ballenger JC, Davidson JR, Lecrubier Y et al. Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry 2000;61(Suppl. 5):60–6.

34. Rasquin SM, Van De Sande P, Praamstra AJ, Van Heugten CM. Cognitive-behavioural intervention for depression after stroke: five single case studies on effects and feasibility. Neuropsychol Rehabil. 2009;19(2):208–22.

21. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 1999;80(1–2):1–13.

35. Lincoln NB, Flannaghan T, Sutcliffe L, Rother L. Evaluation of cognitive behavioural treatment for depression after stroke: a pilot study. Clin Rehabil. 1997;11(2):114–22.

22. Hay PJ, Bacaltchuk J, Stefano S. Psychotherapy for bulimia nervosa and binging. Cochrane Database Syst Rev. 2004;3:CD000562. 23. Assanangkornchai S, Srisurapanont M. The treatment of alcohol dependence. Curr Opin Psychiatry 2007;20(3):222–7. 24. Leichsenring F, Leibing E. The effectiveness of psychodynamic therapy and cognitive behavior therapy in the treatment of personality disorders: a meta-analysis. Am J Psychiatry 2003;160(7): 1223–32.

36. Lincoln NB, Flannaghan T. Cognitive behavioral psychotherapy for depression following stroke: a randomized controlled trial. Stroke 2003;34(1):111–15. 37. Kneebone, II, Dunmore E. Psychological management of post-stroke depression. Br J Clin Psychol. 2000;39(Pt 1):53–65. 38. Hackett ML, Anderson CS, House AO. Interventions for treating depression after stroke. Cochrane Database Syst Rev. 2004;3:CD003437. 39. Weissman MM, Markowitz JC, Klerman GL. Comprehensive Guide to Interpersonal Psychotherapy. New York, NY: Basic Books; 2000.

25. Zimmermann G, Favrod J, Trieu VH, Pomini V. The effect of cognitive behavioral treatment on the positive symptoms of schizophrenia spectrum disorders: a meta-analysis. Schizophr Res. 2005;77(1):1–9.

40. Weissman MM, Klerman GL, Paykel ES, Prusoff B, Hanson B. Treatment effects on the social adjustment of depressed patients. Arch Gen Psychiatry 1974;30(6):771–8.

26. Farabaugh A, Locascio JJ, Yap L et al. Cognitive-behavioral therapy for patients with Parkinson’s disease and comorbid major depressive disorder. Psychosomatics 2010;51(2):124–9.

41. Weissman MM, Klerman GL, Prusoff BA, Sholomskas D, Padian N. Depressed outpatients. Results one year after treatment with drugs and/or interpersonal psychotherapy. Arch Gen Psychiatry 1981;38(1):51–5.

601


42. Lipsitz JD, Markowitz JC, Cherry S, Fyer AJ. Open trial of interpersonal psychotherapy for the treatment of social phobia. Am J Psychiatry 1999;156(11):1814–16. 43. Agras WS, Walsh T, Fairburn CG, Wilson GT, Kraemer HC. A multicenter comparison of cognitive-behavioral therapy and interpersonal psychotherapy for bulimia nervosa. Arch Gen Psychiatry 2000;57(5):459–66. 44. Markowitz JC, Skodol AE, Bleiberg K. Interpersonal psychotherapy for borderline personality disorder: possible mechanisms of change. J Clin Psychol. 2006;62(4):431–44. 45. Miklowitz DJ, Otto MW, Frank E et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry 2007;64(4):419–26. 46. Bauer J. [Possibilities for psychotherapy treatment of Alzheimer disease patients in the early stage of the disease]. Nervenarzt 1997;68(5):421–4. 47. Burns A, Guthrie E, Marino-Francis F et al. Brief psychotherapy in Alzheimer’s disease: randomised controlled trial. Br J Psychiatry 2005;187:143–7. 48. Miller MD, Reynolds CF, 3rd. Expanding the usefulness of Interpersonal Psychotherapy (IPT) for depressed elders with co-morbid cognitive impairment. Int J Geriatr Psychiatry 2007;22(2):101–5. 49. Carreira K, Miller MD, Frank E et al. A controlled evaluation of monthly maintenance interpersonal psychotherapy in late-life depression with varying levels of cognitive function. Int J Geriatr Psychiatry 2008;23(11):1110–13. 50. Laroi F. The family systems approach to treating families of persons with brain injury: a potential collaboration between family therapist and brain injury professional. Brain Inj. 2003;17(2):175–87. 51. Global Assessment of Relational Functioning scale (GARF): I. Background and rationale. Group for the Advancement of Psychiatry Committee on the Family. Fam Process 1996;35(2):155–72. 52. Marriott A, Donaldson C, Tarrier N, Burns A. Effectiveness of cognitive-behavioural family intervention in reducing the burden of care in carers of patients with Alzheimer’s disease. Br J Psychiatry 2000;176:557–62. 53. Simpson J, Haines K, Lekwuwa G, Wardle J, Crawford T. Social support and psychological outcome in people with Parkinson’s disease: evidence for a specific pattern of associations. Br J Clin Psychol. 2006;45(Pt 4):585–90. 54. Wade SL, Michaud L, Brown TM. Putting the pieces together: preliminary efficacy of a family problem-solving intervention for children with traumatic brain injury. J Head Trauma Rehabil. 2006;21(1):57–67.

602

55. Wade SL, Carey J, Wolfe CR. An online family intervention to reduce parental distress following pediatric brain injury. J Consult Clin Psychol. 2006;74(3):445–54. 56. Miller WR. Motivation for treatment: a review with special emphasis on alcoholism. Psychol Bull. 1985;98(1):84–107. 57. Miller WR. Motivational interviewing: research, practice, and puzzles. Addict Behav. 1996;21(6):835–42. 58. Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol. 1983;51(3):390–5. 59. Prochaska JO, DiClemente CC. Stages of change in the modification of problem behaviors. Prog Behav Modif. 1992;28:183–218. 60. Norcross JC, Prochaska JO. Using the stages of change. Harv Ment Health Lett. 2002;18(11):5–7. 61. Miller WR, Rollnick S. Motivational Interviewing: Preparing People for Change. 2nd edition. New York, NY: Guilford Press; 2002. 62. Burke BL, Arkowitz H, Menchola M. The efficacy of motivational interviewing: a meta-analysis of controlled clinical trials. J Consult Clin Psychol. 2003;71(5):843–61. 63. Bogner JA, Corrigan JD, Mysiw WJ, Clinchot D, Fugate L. A comparison of substance abuse and violence in the prediction of long-term rehabilitation outcomes after traumatic brain injury. Arch Phys Med Rehabil. 2001;82(5):571–7. 64. Hibbard MR, Uysal S, Kepler K, Bogdany J, Silver J. Axis I psychopathology in individuals with traumatic brain injury. J Head Trauma Rehabil. 1998;13(4):24–39. 65. Cox WM, Heinemann AW, Miranti SV et al. Outcomes of systematic motivational counseling for substance use following traumatic brain injury. J Addict Dis. 2003;22(1):93–110. 66. Watkins CL, Auton MF, Deans CF et al. Motivational interviewing early after acute stroke: a randomized, controlled trial. Stroke 2007;38(3):1004–9. 67. Churchill R, Hunot V, Corney R et al. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression. Health Technol Assess. 2001;5(35):1–173. 68. Prigatano GP. Disordered mind, wounded soul: the emerging role of psychotherapy in rehabilitation after brain injury. J Head Trauma Rehabil. 1991;6(4): 1–10. 69. Oliveira RA, Milliner EK, Page R. Psychotherapy with physically disabled patients. Am J Psychother. 2004;58(4):430–41.


70. Woods B, Spector A, Jones C, Orrell M, Davies S. Reminiscence therapy for dementia. Cochrane Database Syst Rev. 2005;2:CD001120. 71. Leichsenring F, Rabung S, Leibing E. The efficacy of short-term psychodynamic psychotherapy in specific psychiatric disorders: a meta-analysis. Arch Gen Psychiatry 2004;61(12):1208–16. 72. Shapiro DA, Barkham M, Rees A et al. Effects of treatment duration and severity of depression on the effectiveness of cognitive-behavioral and psychodynamic-interpersonal psychotherapy. J Consult Clin Psychol. 1994;62(3):522–34. 73. Thompson LW, Gallagher D, Breckenridge JS. Comparative effectiveness of psychotherapies for depressed elders. J Consult Clin Psychol. 1987;55(3):385–90. 74. Cooper PJ, Murray L, Wilson A, Romaniuk H. Controlled trial of the short- and long-term effect of psychological treatment of post-partum depression. I. Impact on maternal mood. Br J Psychiatry 2003;182:412–19. 75. Brom D, Kleber RJ, Defares PB. Brief psychotherapy for posttraumatic stress disorders. J Consult Clin Psychol. 1989;57(5):607–12. 76. Fairburn CG, Jones R, Peveler RC, Hope RA, O’Connor M. Psychotherapy and bulimia nervosa. Longer-term effects of interpersonal psychotherapy, behavior therapy, and cognitive behavior therapy. Arch Gen Psychiatry 1993;50(6):419–28.

80. Svartberg M, Stiles TC, Seltzer MH. Randomized, controlled trial of the effectiveness of short-term dynamic psychotherapy and cognitive therapy for cluster C personality disorders. Am J Psychiatry 2004;161(5):810–17. 81. Winston A, Laikin M, Pollack J et al. Short-term psychotherapy of personality disorders. Am J Psychiatry 1994;151(2):190–4. 82. Woody GE, McLellan AT, Luborsky L, O’Brien CP. Psychotherapy in community methadone programs: a validation study. Am J Psychiatry 1995;152(9):1302–8. 83. Drubach D, McAlaster R, Hartman P. The use of a psychoanalytic framework in the rehabilitation of patients with traumatic brain injury. Am J Psychoanal. 1994;54(3):255–63. 84. Groswasser Z, Stern MJ. A psychodynamic model of behavior after acute central nervous system damage. J Head Trauma Rehabil. 1998;13(1):69–79. 85. McRoberts C, Burlingame GM, Hoag MJ. Comparative efficacy of individual and group psychotherapy: a meta-analytic perspective. Group Dynam. 1998;2(2):101–17. 86. Crawford JD, McIvor GP. Group psychotherapy: benefits in multiple sclerosis. Arch Phys Med Rehabil. 1985;66(12):810–13. 87. Tesar N, Baumhackl U, Kopp M, Gunther V. Effects of psychological group therapy in patients with multiple sclerosis. Acta Neurol Scand. 2003;107(6):394–9.

77. Garner DM, Rockert W, Davis R et al. Comparison of cognitive-behavioral and supportive-expressive therapy for bulimia nervosa. Am J Psychiatry 1993;150(1):37–46.

88. Himelhoch S, Medoff DR, Oyeniyi G. Efficacy of group psychotherapy to reduce depressive symptoms among HIV-infected individuals: a systematic review and meta-analysis. AIDS Patient Care STDS. 2007;21(10):732–9.

78. Gowers S, Norton K, Halek C, Crisp AH. Outcome of outpatient psychotherapy in a random allocation treatment study of anorexia nervosa. Int J Eat Disord. 1994;15(2):165–77.

89. Delmonico RL, Hanley-Peterson P, Englander J. Group psychotherapy for persons with traumatic brain injury: management of frustration and substance abuse. J Head Trauma Rehabil. 1998;13(6):10–22.

79. Hellerstein DJ, Rosenthal RN, Pinsker H et al. A randomized prospective study comparing supportive and dynamic therapies. Outcome and alliance. J Psychother Pract Res. 1998;7(4):261–71.

90. Au A, Chan F, Li K et al. Cognitive-behavioral group treatment program for adults with epilepsy in Hong Kong. Epilepsy Behav. 2003;4(4):441–6.

603

Section III Chapter

37


Environmental and behavioral interventions Laura A. Flashman and Thomas W. McAllister

A variety of behaviors can be considered challenging or problematic. In clinical practice, certain behavior clusters are common sources of concern for individuals and their caregivers, including aggression, repetitive or perseverative behaviors, vocalizations, and behaviors that are “inappropriate” to a given context. This broad array of behaviors can be seen in idiopathic psychiatric disorders and certain environmental contexts (e.g., incarcerated or institutionalized populations), and are often a core component of neuropsychiatric disorders. Regardless of neuropsychiatric diagnosis, challenging behaviors present difficulties to personal and professional caregivers by making provision of care more difficult, interfering with effective communication, and decreasing quality of life. The presence and prevalence of challenging behaviors are robust predictors of caregiver psychiatric morbidity, increased prevalence of clinical depression and anxiety, and increased use of psychotropic drugs (e.g., see [1]), as well as job stress and turnover [2]. These behaviors may ultimately result in the need for institutionalization of the individual. Historically, the view was held that little could be done to improve the functioning of individuals with neuropsychiatric illness and challenging behaviors using traditional cognitive–behavioral interventions, because many of these individuals have cognitive deficits as part of their illness that make learning new information and new behavior patterns difficult. However, a growing literature over the past several decades indicates that this view is overly pessimistic. For example, recognition that memory is not a simple unitary function but rather a complex array of different but overlapping components has led to the development of behavioral techniques designed to help modify challenging behaviors or to replace those behaviors with

more acceptable ones [3] by building on an individual’s profile of cognitive strengths and weaknesses. Further, an individual’s environment can have a significant impact on his or her functioning [4]. It is frequently observed that patients with neuropsychiatric illness with good social supports who reside in environments adapted to their functional level are less likely to express challenging behaviors. This implies that management of the environment is a critical aspect of care. It is important to note that there is not a strong evidence base for the efficacy of the behavioral and environmental interventions in a wide array of neuropsychiatric disorders. The majority of studies have been done with dementia-related challenging behaviors, traumatic brain injury (TBI), autistic-spectrum disorders, intellectual disabilities, and substance-use disorders. Nevertheless, clinical experience suggests that many of these behavioral techniques can be applied successfully across a variety of neuropsychiatric disorders. In this chapter we review first the nomenclature and concepts relevant to this field. We then outline general principles important to the development and implementation of behavioral and environmental interventions. Next, we review the literature on behavioral interventions for specific populations and problems. Lastly, we suggest approaches applicable to the use of behavioral and environmental interventions to treat challenging behaviors across the spectrum of neuropsychiatric disorders.

Common nomenclature Within this field, complex terminology is often used to describe what are actually fairly straightforward principles. We offer a brief and straightforward overview


604

Chapter 37: Environmental and behavioral interventions

of some of the common terms and concepts relevant to environmental and behavioral interventions.

Functional behavioral assessment A functional behavioral assessment is a problemsolving process that relies on a variety of techniques and strategies to identify the purposes of a specific behavior. It looks beyond the behavior itself to identify significant social, affective, cognitive, and/or environmental factors associated with the occurrence (and non-occurrence) of specific behaviors, and considers both antecedents and consequences of the challenging behaviors. This broader perspective offers a better understanding of the function or purpose motivating problematic behavior. Behavioral plans based on an understanding of “why” a person exhibits particular behaviors are extremely useful in addressing a wide range of problem behaviors.

Applied behavioral analysis This term refers to an approach that emphasizes the shaping of desired behavior by deliberately manipulating the consequences. The approach is based on the fundamental principle that behaviors increase or decrease in frequency as a result of positive or negative consequences. Although applicable to a broad array of behaviors, this approach may be less applicable to “reflexive” behaviors that are stimulus-driven rather than reward-driven (see below for further discussion of this issue).

Positive behavioral supports This term refers to an approach based on the principle that behavior is best managed and modified by organizing immediate and remote antecedent supports so that individuals are less likely to engage in problematic behavior in the first place, and with practice, acquire a repertoire of more appropriate behaviors.

Stimulus control Stimulus control is an intervention aimed at modulating the frequency of antecedent behaviors. These techniques can be particularly useful because they build upon already established components of an individual’s behavioral repertoire and do not require that the individual acquire new responses. That is, the goal of stimulus control involves learning to pay attention to aspects of the environment that provide information

about the effectiveness of behaviors: what behavior is likely to be effective or ineffective, under which conditions it is so, and whether the behavior results in reinforcement or punishment.

Behavioral data collection The collection of data is a hallmark of behavioral intervention. Without an index of a behavior’s frequency or intensity of occurrence, there is no marker against which to assess a given intervention’s success or failure. Without tracking of behaviors across the intervention, reduction in behavior cannot be monitored. When more than one person is involved with tracking of data, inter-rater reliability is important to determine how consistently target behavior is recorded.

Experimental control Many studies use single subject or case study designs. Ideally, these types of studies will include a combination of baseline and treatment conditions to demonstrate experimental control of behavior. Within such studies, typical models include baseline (A) intervention (B) reversal (e.g., ABA), multiple baseline, or changing criterion (in which behavior change that occurs in response to changes in performance criteria demonstrates control) designs.

General principles An extensive knowledge base exists related to the theoretical and practical application of behavioral principles and environmental changes that impact behavior (e.g., see [5]). It is important to point out that the underlying principles that we discuss in this chapter have been developed, practiced, and written about in a variety of diverse settings ranging from childrearing practices, management of corporate productivity, treatment of psychopathology, and management of disruptive behaviors in different settings and conditions. A full discussion of these topics is beyond the scope of this chapter, and interested readers are referred elsewhere for more detail [6–8]. We focus on the adaptation and application of this broad knowledge base to neuropsychiatric populations, and the particular challenges that this can present given the common co-occurrence of medical, neurological, and psychiatric factors that influence behavior in this population. We note where there is an evidence base for particular approaches in a given disorder or symptom

605


complex; however, we suggest that many of our remarks are understood most usefully as “general principles” of this treatment approach – both because there is a lack of literature addressing particular interventions in specific neuropsychiatric disorders and also because we find that these principles are effective across a broad range of challenging behaviors in diverse neuropsychiatric populations.

Principle 1: all behavior is behavior It is important to emphasize that many clinicians view an individual patient’s behaviors as either within or outside that patient’s conscious control. This view frequently results in dichotomous characterizations of behaviors as intentional or willful (i.e., “behavioral”) or as involuntary and uncontrollable acts (i.e., when referring to a patient’s actions, stating “he couldn’t help it”). This black-and-white view of behavior gives rise to very different views of how to approach treatment, and often is associated with splitting among treatment team members (i.e., developing subgroups within the teams whose views and interpretations of a patient’s behavior are in opposition with one another). Some behaviors in specific contexts fall closer to the intentional/willful end of the continuum (e.g., carefully planned, premeditated acts of violence) whereas others are more accurately characterized as reflexive responses (stimulus-driven behavior associated with frontal-dysexecutive syndromes). However, in clinical practice a strict dualistic view of behavior as “willful” or reflexive does not often serve well the treatment planning process. Individuals with neuropsychiatric disorders are no different than anyone else – their abilities to modulate their responses to stimuli vary with their environments and the contexts in which they find themselves. A proper evaluation of challenging behaviors provides an accurate appraisal of the point on the continuum (i.e., where between premeditated and reflexive behavior) at which a particular behavior falls. This requires taking into account pre-morbid or pre-injury behavior patterns, the profile of brain injury associated with the underlying disorder (i.e., which brain regions and circuitry are affected by the illness/injury), and the environmental context in which the behavior occurs. Stimuli associated with challenging behaviors in one context may not produce those behaviors in a different context (e.g., verbal outbursts may occur in response to limit-setting when in a

606

very busy, distracting environment but not in response to limit-setting in a quiet, low-stimulus environment). A functional behavioral assessment of challenging behaviors is most useful when it offers a clear picture of the threshold or set point that the individual has with respect to modulating behavioral responses, and how that set point is impacted by the individual’s environment; this assessment, in turn, requires reconciliation with what is known clinically about the profile of that individual’s brain disease and its severity.

Principle 2: many behaviors serve a purpose, but not all behaviors are purposeful in a specific context One of the tenets of behaviorism is that all behaviors serve a purpose. This is generally taken to mean that the target behavior is helping the individual achieve something that they want or need. Often the inference that clinicians make in the face of bewildering behavior that may not have an obvious pay-off (e.g., loud outbursts, repetitive vocalizations, aggression towards self or others) is that the behavior elicits the attention of a caregiver or staff person and this serves to maintain the behavior. In this model, it is inferred that even “bad” attention (i.e., being scolded, or restricted) is perceived by the individuals as rewarding in some way and thus serves to reinforce the behavior. While this is an important dynamic in many situations, it may not always apply in individuals with neuropsychiatric disease. We suggest modifying the aforementioned tenet to “many behaviors serve a purpose, but not all behaviors are purposeful in a specific context.” For example, a young man with severe orbitofrontal damage from TBI and impaired social comportment manifested by lascivious sexual comments and actions around women may be more accurately described as engaging in stimulus-driven behavior. Although he may also want attention, the particular target behaviors of concern – no matter how often they are repeated – do not serve the purpose for which they are intended, namely intimate contact with a woman. In this instance, the capacity to learn from the repeated observation that the behavior does not achieve the desired reward is impaired by the injury, and the behavior is more sensibly viewed as reflexive (i.e., stimulus-driven). Although one might argue that this individual may receive some gain from the negative attention that


ensues from his behavior, the behavior is likely to manifest regardless of the attention received as a result of this action. Comprehensive assessment of such challenging behaviors facilitates developing first a clear understanding of the response or consequences of the behaviors. It also then determines whether the behaviors are serving their intended purposes and whether the individual is able to learn from the experience of those behaviors failing repeatedly to elicit desired responses. If the latter capacity is absent, then the behavior is likely to be one that is along the reflexive end of the continuum. This assessment of the nature of some behaviors entails important treatment implications: although shaping consequences to the behaviors may produce, over time, some reductions in those behaviors, more progress may be achieved by limiting exposures to the stimuli producing the behaviors.

Principle 3: behavioral and environmental interventions should be part of the fabric of an integrated treatment plan, not simply a “behavior plan” Although the emphasis of this chapter is on behavioral and environmental interventions, it is important to emphasize that these interventions should not be considered sufficient management of behavioral problems in and of themselves. Multimodal treatment planning generally is the most useful approach to the management of challenging behaviors. In many instances, an effective plan will call for environmental modifications aimed at reducing the exposure to stimuli that precipitate the challenging behavior as well as behavioral interventions that are aimed at modifying the frequency and intensity of the response (challenging behavior) to the precipitating stimuli. As a general rule, the closer the target behavior is to the reflexive end of the spectrum, the greater the reliance will be on environmental interventions (without the stimulus, there is no reflex); in contrast, the closer the behavior is to the “volitional” end of the spectrum, the greater the opportunity for successful behavioral interventions. Because distinctions between reflexive and volitional behaviors often are difficult to draw, and because context contributes to establishing a behavioral set point, approaches that concurrently reduce the frequency and intensity of the exposure to the stimuli (antecedents) and modulate the behavioral response to

the stimuli (behaviors and consequences) are usually necessary. Additionally, even the most carefully conceived and executed environmental and behavioral interventions will fail when an untreated medical or psychiatric condition is driving challenging behaviors. Individuals with neuropsychiatric disorders have an increased frequency of challenging behaviors at least in part related to illness/injury-related damage to circuits that modulate nuanced human behavior. The rates of other medical conditions (such as chronic pain, sleep disorders, infections) and psychiatric illnesses (including substance-use disorders) are also high in this population, and each of these factors also may influence the frequency and severity of challenging behaviors. The repertoire of challenging behaviors may be quite limited in a given individual, particularly in those with limited speech and language capacity. Although clinicians are often told that an individual “always behaved like this,” it is important to get clear information regarding the history and current frequency and intensity of the behaviors – in some instances, changes in frequency and intensity are often associated with the development of a new or recurrent medical condition (e.g., urinary tract or sinus infections) or the onset or recurrence of a depressive disorder or some other Axis I condition. Since the synaptic neurochemical milieu plays a critical role in establishing the set point of or threshold for behavioral control (or dyscontrol), it also must be addressed. Even the best conceived behavioral or environmental intervention will be less successful if the other associated conditions are not appropriately treated. The most successful interventions are those that combine effective behavioral intervention with appropriate pharmacotherapy and environmental structuring as well as with interventions appropriate to any underlying or comorbid medical or psychiatric condition.

Principle 4: adapt behavioral interventions to the individual’s cognitive capacities Many individuals with neuropsychiatric disorders have cognitive deficits that impact directly upon the effectiveness of behavioral interventions. This may manifest itself in several ways. For example, the foundation of behavioral learning theory is that a person is able to implicitly or explicitly make a connection between stimuli (events in their environment) and responses (either their response, responses of others

607


in their environment, or both). Disorders of the brain may limit an individual’s capacity to recognize and/or learn such associations, and also may limit the period of time over which these associations can be recalled. The practical implication of this is that some individuals with cognitive deficits may not be able to make these connections easily. As a result, behavioral treatment in such individuals may require an increase in amount of repetition needed to help the individual learn these associations and/or their treatment-related modifications. Furthermore, when one attempts to shape behavior by linking a reward or reinforcer to completion of a desirable behavior, it is important to set the reinforcement schedule so that it falls within the recall time span of the individual –otherwise, the individual will fail to make the connection between their behavior and the appearance of the reinforcer (including negative reinforcers). For an individual with significant memory impairments, this time span initially may be very short (minutes, hours) and then increased gradually as the behavior-reward/reinforcer relationship is established. If, for example, the plan calls for someone to refrain from a particular behavior for seven days, at which time they will get a high preference reinforcer, but the individual does not have a clear understanding of the duration of a week, the reinforcer provided at the end of the week is unlikely to be an effective one. If the target behaviors are occurring several times an hour, and the individual has little sense of time beyond the moment, it will be ineffective to set up the original schedule so that the individual will get the positive reinforcer if he or she refrains from the behavior for 24 hours. It would be more realistic to start with 30-minute blocks and then titrate up that interval as success is achieved. The use of negative reinforcers is especially challenging in the setting of this type of cognitive impairment. For example, a behavioral plan might call for the patient to refrain from a particular behavior for seven days and to link that refrain to a high preference reinforcer. However, if that patient no longer understands the meaning of a week or if he or she is unable to recall events (or the absence of events) over that duration then this intervention is likely to fail. The initial interval of reinforcement therefore needs to be adjusted to the frequency of the target behaviors as well as the ability of the individual to understand and/or recall (i.e., to connect) the absence of the behaviors to the appearance of the reinforcer. Thus, a key to a successful behavioral intervention is knowledge of the

608

individual’s cognitive strengths and weaknesses, and developing the intervention within that framework.

Principle 5: understand the nature of reward and positive reinforcement Key to successful behavioral and environmental interventions is the choice of an individually relevant and appropriate reward. It is critical to choose reinforcers that are rewarding to the individual regardless of their value to the clinician. This requires a careful inventory of items and activities that the individual enjoys and also a careful assessment of the specific components of those items and activities that he or she enjoys (i.e., is it the activity that the individual enjoys, the company or attention associated with the activity, or some other aspect of or secondary reward related to the activity that makes it enjoyable?). Identifying an array of positive reinforcers also is necessary. Even the most potent positive reinforcer will lose some salience over time. It therefore is helpful to have a variety of options to employ as behavior reinforcers. Building in choice with regard to reinforcer also adds an important dimension to the plan, especially in that it engages the individual in his or her behavior treatment planning. When possible, reinforcers that are harmful or unhealthy (e.g., candy or other foods/drinks of questionable health value) are best avoided. Although initially it may be necessary to start with any feasible reinforcer, the success of interventions over the long term requires that the reinforcers used are readily available, practical, feasible, and generalizable across the various settings in which individual is encountered (e.g., home, residential therapeutic setting, outpatient day program, inpatient settings, workplace, etc.). Neuropsychiatric disorders also may affect the individual’s ability to benefit from positive reinforcement, especially when that disorder compromises the structure and/or function of the reward circuitry needed to attach positive valence to a stimulus and/or reward [9]. This can present special challenges to designing a successful behavioral program. Although sometimes associated with disorders of substance abuse [9], apathy can also be an associated clinical syndrome with disorders of reward circuitry and may require treatment with dopaminergic agents in order to increase the likelihood of success of a behavioral program [10].


Principle 6: consistency is important It is difficult to overemphasize the importance of consistency in the implementation of a successful behavioral or environmental intervention. In our view, inconsistent application of agreed-upon plans is the single most common reason for failure of such interventions to achieve their goals. Failure to apply an agreed-upon behavioral and environmental treatment plan across the various settings in which the individual for who that plan was developed is encountered often results in variations in behavior that are settingspecific. In fact, this can be a tip off that there is a problem in the operationalization of a plan that looks good on paper. For example, an individual may show very few target behaviors at home, but a high frequency of challenging behaviors in the workplace (or vice versa). Such differences in the frequency of challenging behaviors may reflect different family members or care providers interpreting environmental limitations differently (i.e., no access to a precipitating stimulus vs. reduced access vs. occasional access). Inconsistent application of the program across time can be another problem. Treatment teams often start implementation of a plan with a burst of enthusiasm, which can be associated with initial positive results. However, behavioral and environmental plans require intense, ongoing attention to detail and maintenance in order to ensure that all those who interact with the individual are interpreting and implementing the plan in similar ways. Real-life events such as vacations, caregiver fatigue, additional psychosocial stressors, and staff turnover all can conspire to degrade the implementation of a behavioral and environmental intervention plan. Assiduous monitoring for waning application of an intervention plan and, if it occurs, management of this problem is essential to its success. Inconsistent application of behavioral and environmental interventions can not only sabotage the goals of a management plan but also exacerbate the challenging behaviors. Variable reinforcement schedules are the most potent methods by which to maintain behaviors. Inconsistent application of a behavioral program can provide exactly that kind of reinforcement schedule, in that sometimes (“just often enough”) the challenging behavior results in a reward. This can have the unintended effect of reinforcing the very behavior patterns that one is attempting to modulate. An inconsistently applied behavioral or

environmental plan can worsen behavior in a manner analogous to medications producing problematic side effects.

Physical sequelae of neuropsychiatric disorders There are several symptom clusters associated with neuropsychiatric disorders that can be effectively treated with behavioral and environmental interventions. We present a brief review of this literature but point out that there is an absence of evidence of efficacy of these interventions in specific neuropsychiatric disorders.

Pain Pain is a frequent complication of many neuropsychiatric disorders. The role of cognitive–behavioral therapy (CBT) in the treatment of chronic pain has expanded considerably over the last several decades. Meta-analytic studies and systematic reviews have shown that CBT is effective for management of pain, and that it affects pain experience, cognitive coping and appraisal, as well as reduced behavioral expression of pain [11, 12]. A review of the NIH Technology Assessment Panel on Integration of Behavioral and Relaxation Approaches into the Treatment of Chronic Pain and Insomnia [13] reported moderate effectiveness for CBT. Biofeedback and relaxation techniques, often integrated into multimodal treatment packages, have also been used for treatment of chronic pain with considerable success. The rationale for their use is that reduction of tension and arousal levels, often reported as consequences of chronic pain, can improve the wellbeing of individuals with chronic pain [13–16].

Headache Headache is a pain syndrome of particular relevance to neuropsychiatric populations. Behavioral treatments for headaches are rooted in the conceptualization of headache as a psychophysiological disorder (i.e., a physical disorder influenced by psychosocial and environmental stressors) [17]. In general, these behavioral treatments target headache-related physiological responses, using relaxation training or biofeedback, or CBT to target behaviors, emotions, and cognitions felt to be contributing to the headache. Individuals learn

609


to identify the specific psychological or behavioral triggers that cause or aggravate their headaches. They also are provided with alternate, and more effective, strategies for coping with these stressors. These techniques have been validated for both migraine and tension headaches, with recent meta-analyses reporting a 35–55% reduction in tension headaches [18, 19].

Fatigue Fatigue is a common symptom in both the general population and in those with neuropsychiatric disorders, and negatively affects quality of life. Several non-pharmacologic behavioral interventions have been proposed for the effective management of fatigue. These include exercise, psychosocial interventions, and other integrative therapies. For example, positive effects from physical interventions such as exercise have been reported in many studies, although the majority of these studies have focused on cancer as the primary disease (during and after treatment) [20–24]. Main outcomes examined have included emotional distress (e.g., depression and anxiety), quality of life, and functional capacity, as well as more physical measures such as flexibility, muscular strength, aerobic capacity, and body composition. Overall, exercise appears to be safe and well tolerated [25–31]. Moderately intense aerobic exercise (e.g., walking and cycling) ranging in duration from 10–90 minutes, 3–7 days per week and progressive resistance training (three times per week, progressively increasing sets and repetitions) were both shown to be effective in reducing fatigue. A meta-analysis by Schmitz and colleagues [23] indicated that the evidence for exercise as an effective therapy for managing fatigue (in cancer patients) is consistently positive, although the effect size was small (weighted mean effect size = 0.13), indicating the need for more effective exercise interventions. Whether similar interventions would work in neuropsychiatric disorders has not been studied. Psychosocial treatments such as individual or group support interventions, education, stress management, and coping strategy training have been used alone, or as adjuncts to exercise programs for the management of fatigue. Randomized, controlled clinical trials in cancer patients suggest that psychosocial interventions are effective as an aid to managing fatigue regardless of whether they are provided

610

individually or in a group setting, orally or written, by a licensed professional or a trained non-professional. Benefits can last for many months following cessation of the interventions [32]. Specific options are difficult to evaluate and compare, as there are a wide variety of psychosocial interventions used, and no standard protocols. Efficacy of these interventions in neuropsychiatric populations has not been studied. Other interventions that are not typically considered part of standard western European medicine also are sometimes used to treat fatigue. The most common of these include prayer, yoga, mindfulness-based stress reduction, nutrition, and restorative therapies. Mindfulness-based stress reduction is a multimodal program focused on improving well-being and health [33]. The most widely recognized program includes one 90-minute session per week for 8 weeks, along with a 3-hour silent retreat between weeks 6 and 7. The curriculum includes three major components: Hatha yoga (including yoga stretches, poses, breathing, and meditation exercises); educational materials related to mindfulness, relaxation, meditation and yoga; and group processing and discussion.

Sleep disturbances Insomnia is a subjective complaint that can reflect poor sleep quality (i.e., lack of restful sleep), reduced sleep duration, problems falling asleep, waking repeatedly during the night, and/or one of the parasomnias. Poor sleep is one of the most common complaints in the general population, with 9–12% of adults reporting persistent sleep difficulties [34]. The prevalence is higher among persons with neuropsychiatric disorders, and the majority of individuals with insomnia remain untreated. This paucity of treatment is somewhat surprising in light of the fact that there are several meta-analyses supporting the efficacy of pharmacologic and behavioral interventions for primary insomnia. Behavioral interventions are increasingly being viewed as the treatment of choice for insomnia (e.g., [34–39]), and are successful even in the elderly population [40–42]. In general, behavioral interventions designed for treatment of insomnia can be grouped into three broad categories: omnibus CBT, relaxation-based therapy, and behavioral only. Omnibus CBT includes those interventions with both a cognitive and a behavioral component, such as true CBT, imagery training, and interventions with a behavioral component combined


with a cognitive retraining component. Cognitive therapy serves to change dysfunctional beliefs and attitudes about sleep that lead to emotional distress and further sleep problems. Sleep hygiene may also be included as part of CBT. Sleep hygiene educates individuals about the impact of lifestyle habits on sleep. Relaxation-based therapy typically focuses exclusively on progressive muscle relaxation, or may include similar strategies such as biofeedback and hypnosis. The behavioral-only therapy may include interventions focused exclusively on managing sleep behavior and sleep scheduling, such as stimulus control and sleep compression or sleep restriction. Stimulus control aims to help individuals relearn the association between bed and bedtime stimuli with sleep rather than sleep disruption. Sleep restriction limits the time spent in bed at night and controls/eliminates inappropriate sleep during the day. Gains from these various behavioral treatments are reported to last for months to years following treatment, and the empirical evidence appears to suggest comparable efficacy among treatment modalities; there is some evidence, however, that stimulus control and sleep restriction are the most effective and relaxation the least effective of these interventions [34, 43]. Behavioral interventions may be effective treatments of insomnia even when individuals have other medical conditions and/or mood disturbances [34]. Ouellet amd Morin [44] evaluated the efficacy of an 8-week CBT (including stimulus control, sleep restriction, cognitive restructuring, and sleep hygiene education) for insomnia in 11 individuals with TBI. They reported an average reduction of 54% in total waketime across participants from pre- to post-treatment, with maintenance of this effect at 1-month and 3month follow-up evaluations. Few studies have investigated sleep disturbances and their treatments among persons with neuropsychiatric disorders. Pending the results of such studies, the available evidence suggests that traditional behavioral interventions for insomnia merit consideration in this population as well.

Emotional and behavioral sequelae of neuropsychiatric disorders A variety of emotional and behavioral disorders occur with increased frequency in individuals with neuropsychiatric disorders. Some evidence suggests that behavioral interventions can be effective treatments for these problems.

Depression Both individual and group therapy, using either CBT or mutual support interventions, appear to be effective treatments of depression in the general population [45–48]. Similar strategies have been tested in a few neuropsychiatric populations. For example, Lincoln and Flannaghan [49] examined CBT for depression in stroke. They studied 123 patients in a randomized controlled trial, with outcome measures gathered for 118 patients at 3 months and 111 at 6 months. While improvement in mood was noted over time, there was no significant difference between those receiving CBT and those receiving either no intervention or an attention placebo condition (involving 10 1-hour visits for 3 months with no active intervention). The authors suggested that these results could have been due to the short duration (average 9.8 sessions) and/or the low intensity of the CBT, and it was suggested that further randomized trials in this population are needed. A study by Teri et al. [50] performed a controlled clinical investigation of two non-pharmacologic treatments of depression in patients with Alzheimer’s disease. Each treatment was designed to teach caregivers behavioral strategies to alleviate patient depression, based on the assumptions that caregivers are often directly responsible for patient activity on a daily basis and that caregiver–patient interactions can be important factors in the establishment and maintenance of patient mood. Both programs employed behavioral change strategies for effective problem management. The first program emphasized increasing pleasant events for patients and positive interactions. The second program focused on caregiver training in effective problem-solving techniques, emphasizing an active and flexible approach to problem solving by incorporating greater caregiver input into the development of treatment strategies and goals. Control conditions included an equal-duration typical care intervention and a wait-list control condition, with assessment at baseline, post-treatment, and at 6-month follow-up. Individuals in both behavior treatment conditions showed significant improvement in depression symptoms and diagnosis relative to the two control conditions at both post-treatment assessment and follow-up. Of note, caregivers also showed significant improvement in their own depressive symptoms when behavioral treatments were used, which was not observed for caregivers in the control conditions.

611


Anxiety Cognitive behavior therapy is the most commonly used non-pharmacologic treatment for a variety of anxiety disorders. Meta-analyses in young, middleaged, and older adults [51–55] support the effectiveness of combined cognitive and behavioral approaches in the treatment of anxiety disorders, including panic disorder, generalized anxiety disorder (GAD), and social phobia. Cognitive behavior therapy has been reported to be an effective treatment (effect sizes ranging from 0.31 to 0.87) relative to placebo and notreatment control groups. Concomitant albeit smaller improvements in depressive symptoms have also been reported with treatment for anxiety [52–55], and these effects are reported to persist after treatment. “Pure” behavioral interventions, using in vivo exposure methods, are also effective and appear to work as well as combined treatments for some disorders, such as agoraphobia [56, 57] and social phobia [58–61]. Obsessive-compulsive disorder appears responsive to exposure and response prevention [62– 64]. Post-traumatic stress disorder (PTSD), considered by many experts to be an anxiety disorder, is commonly treated with behavioral and cognitive treatments. Elements of these treatments include exposure, cognitive restructuring, and anxiety management skills. Exposure-based treatments emphasize confrontation with fear-evoking memories of the traumatic event (i.e., imagined exposure) as well as situations or stimuli that have come to evoke avoidance or anxiety symptoms (i.e., in vivo exposure). Stress-inoculation training [65] and cognitive processing therapy [66] involve combinations of educational, exposure, relaxation, and cognitive interventions to help the individual manage symptoms of anxiety and challenge maladaptive beliefs. Many of the therapies used for treatment of PTSD involve combinations of behavioral and cognitive procedures. A meta-analysis by Van Etten and Taylor [67] suggested that cognitive–behavioral treatments, including behavior therapy (13 trials), Eye Movement Desensitization and Reprocessing (EMDR) (using 11 trials), relaxation (one trial), hypnosis (one trial) and dynamic therapy (one trial), are all highly effective in reducing symptoms of PTSD (mean effect sizes from 0.69–1.89). A second meta-analytic review [68] compared active treatment (of many different types) to a comparison group (17 studies). The average mean

612

effect size between treatment and control conditions across all studies was 0.52 at post-treatment and 0.53 at follow-up. These findings suggest that cognitive and behavioral treatments have a moderate positive effect on symptoms of PTSD; in this study, however, there was no examination of the effects of specific treatment types (i.e., exposure therapy, EMDR, stressinoculation training, hypnosis, cognitive processing therapy). In general, pharmacotherapy appears to be more effective than behavioral interventions for the treatment of panic disorder (e.g., [69]). However, in circumstances where medications may not be appropriate due to concerns regarding drug–drug interactions, or risk for significant side effects, behavioral interventions may be the best available treatment. Unfortunately there are few studies evaluating the effectiveness of behavioral interventions for the treatment of anxiety disorders among persons with neuropsychiatric disorders. Two noteworthy exceptions are recent, and positive, reports of a pilot study of cognitive processing therapy (a form of CBT) to treat individuals with TBI and comorbid PTSD [70, 71]. In light of the high frequency of anxiety disorders in this and other neuropsychiatric populations, more research of this type is needed.

Substance-use disorders Reviews examining behavioral interventions for substance abuse [72–75] suggest that brief behavioral interventions work better than no intervention at all, and that they sometimes are more effective than more intensive treatment. Brief intervention methods have included client education, coping skills training, motivational interviewing (MI), and motivation enhancement therapy (MET). Motivational interviewing is a directive, clientcentered style of counseling than can help individuals explore and resolve their ambivalence about changing. Principles of MI include understanding the individual’s view accurately, avoiding or decreasing resistance, and increasing self-efficacy and the perceived discrepancy between an individual’s actual and ideal behaviors. As this technique requires relatively intact cognition, it may not be appropriate or effective for individuals with cognitive impairments. Motivation enhancement therapy must be matched to the patient’s stage of change in regard to addiction and behavior change (i.e., pre-contemplation,


contemplation, determination, action, maintenance, relapse). Motivation enhancement therapy interventions include strategies designed to enhance motivation for change, including counseling, assessment, multiple sessions, or brief interventions. Motivational interviewing and MET are effective in the management of alcohol and drug dependence, in individuals both with and without comorbid psychiatric diagnoses [76]. In pilot work, dual-diagnosis patients are more engaged in treatment and more compliant when brief MI is used [77]. A review by Dunn and colleagues [78] evaluated 17 studies using MI in the treatment of substance abuse. The effect sizes in 11 of these studies ranged from 0.30 [79] to 0.95 [80], and favored MI. Motivational interviewing appeared to be most effective when used to enhance more intensive substance abuse treatment. In this context, MI sessions were offered prior to treatment-as-usual and usually were performed at the treatment-as-usual site by intensively trained MI research interventionists (not clinical staff). Finally, medical management, in combination with pharmacotherapy, behavioral intervention, or both, appears to improve alcohol treatment outcomes (i.e., led to a higher percent of days abstinent) [81]. Although this and other behavioral interventions have not been investigated fully as treatments for persons with comorbid substance use and neuropsychiatric disorders, the available literature suggests that behavioral interventions are important elements of the treatment of substance-use disorders.

Social skills Social skills training (SST) is a behavioral intervention that focuses on social functioning, with an emphasis on practicing the pragmatic skills of living. Social skills training, in combination with CBT, may lead to an improvement in outcomes for a variety of challenging behaviors. Social skills training and CBT may improve functioning by: (1) reducing cognitive vulnerabilities, including inflexibility and rigid thinking, as well as self-defeating beliefs; (2) enhancing ability to cope with stressors through the development of coping skills, learning to ask for support, developing support networks; and (3) improving adherence to treatments that modify biological factors contributing to disease manifestation [82]. Social skills training interventions include pivotal response training, priming, and social stories.

Pivotal response training is a naturalistic strategy that teaches complex behaviors such as language and social responding. Motivation is a necessary component for learning these complex skills, and theoretically results in learning and generalization to other situations [83]. Provision of this intervention requires extensive time and the ongoing presence of an expert treatment provider. Priming (sometimes referred to as behavioral momentum) is an antecedent manipulation; its demands are relatively low, it provides a high level of reinforcement, and is offered immediately before an activity that is difficult or challenging for an individual. Priming has been examined using videotaped instruction to reduce disruptive behaviors during transitions [84]. Social skills training interventions have been used in the management of persons with schizophrenia [85, 86], autism [87], and TBI [88, 89]. Additional research is needed to evaluate the usefulness of this intervention among persons with other neuropsychiatric disorders.

Behavioral excesses A frequently reported behavioral problem in individuals with a variety of neuropsychiatric illnesses (e.g., dementia, TBI) can be broadly described as “agitation.” Although there is no consensus definition of this problem, agitation may be defined usefully as “inappropriate verbal, vocal, or motor activity that is not explained by needs or confusion per se” ([90], p. 712). This broad definition includes a variety of challenging behaviors, including wandering and hazardous ambulation, disruptive vocalizations, physical aggression, other agitated behaviors, and multiple behaviors. The prevalence estimates of agitation vary across neuropsychiatric populations, with the onset and severity of the neuropsychiatric condition in which this problem develops, and amongst the contexts in which agitation develops. Regardless of the exact prevalence rates, agitation is problematic for the affected individual, his or her caregivers, and others who encounter that individual. Agitation also places the affected individual at risk for physical harm, increases caregiver stress, and may entail subsequent limitations on that individual’s residential, vocational, and other social options. A meta-analysis [91] evaluated behavioral interventions used to manage agitation in older adults with dementia. The authors identified 23 articles published

613


between 1970 and 2004 examining participants 60 years and older with diagnoses of dementia in which a form of behavioral measurement and intervention was used to address agitation (broadly defined). Among the 23 articles, 15 described a single-subject or case study intervention. The results of this meta-analysis, organized by type of agitated behavior, are discussed in the following subsections of this chapter.

Wandering/hazardous ambulation Wandering is often associated with greater cognitive impairment in language, memory, orientation, and concentration [92]. Its occurrence predicts the use of physical restraints during the first year of nursing home residence [93]. Wandering is considered intrinsically reinforcing because it provides stimulation and exercise [94, 95]. Simple environmental interventions, such as providing individuals with a secure place to wander, reduce the negative sequelae of this behavior [96, 97]. However, this intervention is not always feasible for individuals living in the community. Other behavioral interventions that may be useful for wandering include the use of stimulus cues (i.e., labeling rooms appropriately and clearly, with visual as well as verbal cues), with contingent individual attention for non-wandering [98, 99]. The most commonly used technique for wandering is stimulus control intervention. This type of intervention manipulates environmental stimuli associated with a target behavior to change the likelihood of its occurrence. Techniques can include such strategies as multiple component cued recall interventions. Components of these interventions can include a fading cues procedure, where a series of increasingly direct prompts are given until an appropriate response is emitted. The directness of these prompts can then be gradually reduced, requiring the individual to respond appropriately with decreasing levels of environmental support. Another component involves spaced retrieval procedures, in which individuals perform the behavior over increasingly long intervals. These interventions are particularly useful in the management of older adults with dementia [100–104]. Other techniques used successfully to reduce wandering involve manipulating consequences to reduce wandering; for example, a behavioral strategy that rewards behaviors other than the wandering behavior (i.e., differential reinforcement of other behavior, or DRO, schedule). This approach identifies the consequence of the behavior by direct observation, and then

614

uses the most frequent consequence resulting from wandering as that which is given in the absence of wandering (e.g., attention, sensory stimulation, access to preferred activity or item, etc.). A backward process where a desired task is broken down into steps, and the steps are taught in reverse order and strung together with success of each step, appears to show particular promise as a means of decreasing wandering due to disorientation [105].

Disruptive vocalizations Disruptive vocalizations include loud requests for attention, chronic screaming, self-talk, negative remarks, and use of obscenities [106]. Several interventions may decrease the frequency of such behaviors, thereby improving the living and working conditions of the home for staff and other residents [107]. In the aforementioned meta-analysis by Spira and colleagues [91], eight studies were identified as examining interventions to reduce disruptive vocalizations in the elderly with dementia; only two of these studies included a sample size of more than five participants [108, 109] (N = 7; N = 12, respectively). In these two studies, less than half of the participants demonstrated improvement in their vocalizations. The reported effectiveness of DRO procedures was mixed, with some studies reporting clear benefits [110, 111] and others reporting mixed or no benefits [100, 108, 109]. Other studies, which did not meet criteria for the meta-analysis, offer some support for DRO [112], reinforcement coupled with planned ignoring [113, 114], and reinforcement coupled with redirection [115] for the management of disruptive vocalizations among persons with dementia. A study by Burgio and colleagues [116] reported that the use of “gentle ocean” and “mountain stream” audiotapes played through headphones produced a 23% decrease in disruptive vocalizations among nine nursing home residents with dementia. Another technique for this problem is referred to as “simulated presence therapy” (SPT). The idea is to simulate the presence of significant others using audiotapes of the significant individual recounting salient memories [117]. Audiotapes are made to reflect one half of a normal spontaneous conversation, then played on an auto-reverse tape player and delivered to the patient via headphones. In two studies involving 36 nursing home residents [117], the SPT procedure


was administered at times when behavior problems had been noted to be most likely to occur. There was a reported 91% reduction in problem behaviors; decreased staff burden was also reported. Other studies have tried variations on this procedure (e.g., [118, 119]) with variable results; of note, none of these studies included a no-treatment comparison group.

Physical aggression Physically aggressive behaviors may include pushing, spitting, grabbing, kicking, hitting, and other assaultive behavior. Verbally aggressive behaviors may include character attacks, competence attacks, background attacks, physical appearance attacks, teasing, ridicule, threats, and profanity, which inflict psychological pain on the recipient. Antecedents to aggressive behavior may include anticipation of pain, frustration with one’s inability to perform tasks independently, or limitations in ability to communicate. Behavioral interventions may reduce physical aggression among individuals with neuropsychiatric disorders. Successful interventions include antecedent control interventions, environmental adaptation, and DRO, often in combination with other cognitive– behavioral techniques. Antecedent control interventions focus first on the identification of antecedents to aggressive behaviors. Those antecedents are then modified so that they become incompatible with, or at least decrease the likelihood of, aggression. For example, an individual with TBI is noted to become aggressive when asked to go directly from lunch to a particular activity; an antecedent modification for that individual might include a brief return to his or her room after lunch, breaking the cycle of aggression followed by the request and, perhaps, allowing for rest prior to beginning the afternoon’s activities (which, secondarily, might also help reduce aggressive behaviors). Environmental adaptation is most successful when there are specific deficits that contribute to the aggressive behavior. For example, Rapp and colleagues [120] describe a 67-year-old individual with dementia who was unable to see out of his left eye after a stroke. His room was set up such that staff often approached him from the left, which repeatedly startled him and resulted in aggression against staff. His room was rearranged in a manner that reduced the likelihood of startling him in this manner; additionally, family and staff were informed of the relationship between this deficit and his aggressive behaviors and were taught to provide him with verbal cues while entering his room.

This led to a marked decrease in agitated and aggressive behaviors. Finally, various DRO strategies, such as earning preferred activities, can be used in conjunction with other behavioral interventions [106, 121]. Differential reinforcement of non-aggressive behavior combined with time-out from positive reinforcement and social skills training has been demonstrated to show an average of a 70% reduction in physically aggressive behavior and an average 80% decrease in verbally aggressive behavior [106, 117, 121]. The positive effects of these interventions also appear to generalize outside the setting in which they are learned. Agitated aggression also may be reduced by implementing various exercise strategies [50], or by environmental interventions such as white noise, decreased light intensity, and music [122].

Multiple behaviors Psychoeducational groups [123] as well as identification of antecedents of problem behavior and antecedents of cooperative behavior [124] may be useful elements of the management of multiple behavioral disturbances. Additionally, DRO schedules are useful in this circumstance. Combinations of antecedent control and DRO procedures are frequently effective in reducing physical and verbal aggression and refusal of typical activities of daily living (ADLs) (e.g., showering, changing clothes). Finally, the literature offers support for staff and/or family training in behavioral management for the purpose of reducing patient and caregiver distress [50, 125–127]. Two randomized control trials suggest that positive behavioral support (PBS) interventions for challenging behaviors after TBI may be useful; these PBS interventions include antecedent support-oriented techniques to train parents [128] and an anger management program involving education and self-awareness training [129].

Impulsive or risky behavior Many times, impulsive or risky behavior is difficult to manage because the individual is rewarded (or reinforced) by the consequences that result from this behavior. For example, Haley [111] described an elderly woman with dementia who repeatedly telephoned a relative. Functional assessment indicated that the relative was reinforcing the telephone calls by engaging in conversation with her during the calls (e.g., trying to convince her not to call so frequently). As an intervention, the relative would not speak to this

615


woman if she called more than three times in a given day. Thus, a differential reinforcement of low rates of behavior (DRL, where a reduced frequency of behavior is reinforced) was introduced. This DRL procedure resulted in a reduction in calls from ten per day to three or less.

Behavioral deficits Management challenges also may arise from behavioral deficits, especially those affecting functional and social abilities. Functional abilities are divided into two general categories, fundamental ADLs and instrumental activities of daily living (IADLs). The ADL category includes self-care tasks, such as personal hygiene and grooming, dressing and undressing, feeding, transfers between surfaces (i.e., bed to chair, chair to toilet, etc.), control over bowel and bladder functions, elimination, and ambulation. The IADL category includes activities that are not necessary for fundamental (i.e., self-care) purposes but that are needed to function independently in other respects; for example, preparing meals, managing money, performing housework, managing medications, using the telephone and other technologies, shopping for food and clothing, and securing shelter, among others.

Excess dependency This problem is defined here as over-reliance on other people, particularly for assistance or care in the physical, economic, social, or psychological domains. That is, individuals may exhibit less functional competence than they possess because so doing results in increased contact with others (including staff); for persons demonstrating this behavior, such contacts may be more salient rewards (or more important outcomes) than preserved independent functioning. The majority of environmental and behavioral interventions designed to improve performance of independent ADLs and IADLs are staff-focused, with the target being patterns of social interactions between the individuals and staff/caregivers working with these individuals. In one such study, Van Ort and Phillips [130] implemented antecedent nursing interventions to increase independent feeding in a nursing home setting. The environmental intervention included training staff to minimize extraneous noise, position residents at the dining table, place food directly in front of the residents, seat functionally impaired individuals next to self-feeders, and minimize interruptions

616

for staff engaged in feeding the residents. The behavioral intervention included training staff to use verbal and tactile prompts, to repeat instructions, to model desired behaviors, and to reinforce self-feeding attempts. The behavioral intervention entailed longer duration resident–staff interventions, with the assistance provided by staff matched well to the functional abilities of the resident. As a result, successful implementation of this intervention was relatively stafftime intensive. Both the environmental and behavioral interventions increased self-feeding and produced no adverse effects on residents’ nutritional status. In contrast, Baltes and colleagues [131] provided ten didactic group in-service sessions, designed to help increase independence-supporting behaviors and to facilitate implementation of a behavioral program. While independence-supporting behaviors did increase, dependent behaviors were not significantly reduced. These results suggest that approaches involving both environmental and behavioral components may be important in the development of interventions designed to reduce excess dependency.

Cognitive sequelae of neuropsychiatric disorders Cognitive problems are common features of many neuropsychiatric disorders. These problems, including difficulties with attention and concentration, memory disturbances, and executive dysfunction, may alter the effectiveness of behavioral interventions. Accordingly, developing behavioral interventions requires consideration of the cognitive capacities of the individual for whom those interventions are developed. If cognitive deficits underlie or otherwise contribute to the behavioral disturbances manifested by the individual, behavioral strategies, the time over which they are implemented, and expectations for their success need to be adapted in accordance with the individual’s cognitive deficits [132]. A variety of non-pharmacologic interventions have been explored for the treatment of cognitive complaints and deficits in individuals with brain disorders. A full discussion is beyond the scope of this chapter but the reader is referred to two excellent reviews of this literature [133, 134]. We highlight interventions that have been studied in the treatment of challenging behaviors including deficits in executive function, self-management/self-regulation, and social skills.


Executive dysfunction Executive functions include integrative, higher-level cognitive processes by which individuals monitor, manage, and regulate the orderly execution of goaldirected behavior. In the evidence-based reviews of Cicerone and colleagues examining strategies for remediating executive impairment after stroke and TBI [133, 134], the development of evidencebased recommendations for the treatment of these impairments was constrained by the small number of well-designed studies. However, there was evidence to suggest that interventions for problem-solving deficits were effective [135], and were recommended as a practice guideline. This training deconstructed complex problems into manageable steps, and was based on a social problem-solving model that emphasized problem orientation, problem definition and formulation, generation of alternatives, decision-making, and solution verification. Internal memory strategies were also used.

Self-management and self-regulation Individuals with neuropsychiatric disorders may demonstrate impulsive, unprovoked outbursts, or what is frequently referred to as “episodic dyscontrol.” They may demonstrate what appear to be overreactions to situations due to poor emotional control. Self-management is an effective treatment shown to produce rapid behavior change while increasing independence and decreasing reliance on supervision [136]. Self-management requires individuals to monitor and reinforce their own behavior. These techniques have been used to teach a variety of capacities, including social and daily living skills, and to reduce disruptive behavior. When these behaviors occur in a group setting, “proactive” interventions that provide concrete, clear, and consistent expectations to those at risk for problems with regulation may be useful. Publicly posted rules, in a house, classroom, or work setting, also may be used to identify accepted rules and consequences for rule breaking. Regardless of the method by which rules and behavioral expectations are communicated, it is best to ensure that those communications are clear and brief.

Social-interactive competence Impaired social perception negatively affects contingency management by interfering with accurate

perception and interpretation of social cues and social situations [137]. In such circumstances, behavioral and environmental interventions that address social competence may be required. A review by Struchen [138] identified 19 studies evaluating the effectiveness of social communication interventions for individuals with TBI; 13 of these were case studies or case series, and six were group studies. Interventions used in these studies included modeling, role-playing, feedback, self-monitoring, rehearsal, and social reinforcement. Only one study was classified as providing Class I evidence [139]; this study evaluated interpersonal process recall in a small group of inpatients, including individualized videotaped interactions, structured review of the interactions with feedback, development of alternative skills, modeling, and guided rehearsal. These interventions produced improvements in behavior in the treatment group at the end of the treatment and at 1 month follow-up. Other work has suggested that training of communication partners, as well as those with TBI or other disability, has a positive effect on communication effectiveness and acquisition of communication skills [140, 141].

Approach to the evaluation and management of challenging behaviors Developing a behavioral and/or environmental intervention is not a “one size fits all” process. There is an infinite array of behaviors that can be categorized as challenging, and behaviors that are acceptable in some contexts (e.g., loud yelling at an outdoor athletic contest) may be “challenging” in another context (e.g., loud yelling in a restaurant). The approach to the evaluation and management of challenging behaviors therefore is a complex undertaking. Nonetheless, there are general steps in this process with which clinicians working with persons with these behaviors need to be familiar.

Define the behavior The challenging behavior(s) require clear definition before any intervention can be developed or implemented. This task frequently is more of a challenge than it might appear to be at first pass. Commonly used terms to described challenging behaviors – for example, “inappropriate,” “bad,” “provocative,” or “challenging” – generally convey more about the feelings of the person using them than they do about the behaviors to which those feelings are related.

617


Characterizations or judgments about how the observer feels about the behavior as well as presumptions about the etiology of the behavior are best avoided. Instead, physical descriptions of the behaviors of concern (“making sexual comments to strangers” or “striking himself in the face”) are the best starting point when defining challenging behaviors. The ideal description of such behaviors offers details sufficient to allow someone who has not previously observed the behavior to recognize it when it happens. Toward that end, using a common language and arriving at a common label for specific target symptoms is needed to allow providers, family/caregivers, and others to be sure that they are communicating effectively about the behaviors of concern. Although we use the term “challenging” extensively in this chapter, it is important to be clear about for whom the behavior is a challenge. For example, masturbation may be upsetting to certain caregivers/family members. However, it is not a challenging behavior per se to the individual with the neuropsychiatric disorder unless it is of sufficient frequency and/or intensity to cause physical harm, or if it occurs in a public setting, which would make it more difficult to take the person out in public or put them at risk for encounters with local law enforcement or employers. Thus, the definition of the target behavior would not be “masturbation,” but “masturbation in public” or “vigorous masturbation resulting in excoriations or bleeding.”

Applied behavioral analysis Once the target behaviors are identified and an operational description agreed upon by all key observers, it is possible to proceed with an applied behavioral analysis. This refers to the process whereby the context in which the target behavior occurs is identified. Typically, the context is broken down into the antecedents of the behavior (what was going on immediately before the behavior), the behavior itself (using the agreedupon language – see above), and the consequences (what happened as a result of engaging in the target behavior). The last should probably be subdivided into both the consequences for the individual and also those present during the behavior (including their actions), as these often are distinct and equally important to the development of interventions directed at the target behavior. Although the observations should be as accurate as possible, the actual process can be

618

as simple as drawing an ABC (antecedents, behavior, and consequences) chart for family/caregivers and asking that they fill it in for a determined period of time based on the typical frequency of the target behaviors.

Quantify the behavior Once a target behavior is defined, it is critical to quantify the frequency of that behavior. Distressed caregivers offer descriptions of the frequency of challenging behaviors using phrases such as “all the time” or “a lot more than before.” These qualitative descriptions, while affectively informative, are not specific enough to allow for evaluation of the effectiveness of any intervention. Quantification allows those involved with the patient to accurately identify the true frequency of the behavior.

Develop a hypothesis of the etiology of the target behavior When combined with knowledge of the underlying neuropsychiatric disorder, the individual-specific burden of brain illness or injury, and knowledge of related brain–behavior relationships and circuitry, it should be possible to place the target behaviors somewhere on the continuum of volitional and reflexive behaviors. With this information, it is possible to develop a hypothesis about the etiology of the behavior or, in some cases, the cause of a change in the frequency and/or intensity of long-standing target behaviors. In fact, this determination is a prerequisite to treatment planning: it is not appropriate to develop or implement a behavioral or environmental intervention in a hypothesis-free environment. A hypothesis regarding the behavior (or change in behavior) informs the intervention, and the response to the intervention is used to further refine the hypothesis and subsequent interventions. An integral part of the hypothesis development must include careful consideration and appropriate neurodiagnostic data gathering to determine if a variety of other conditions are playing a critical role in the genesis or maintenance of the behaviors. These potential factors are summarized in Table 37.1. Only when these conditions have been vigorously sought out and actively excluded should such hypotheses as “need for more attention” be considered.


Table 37.1. Possible causes of target behaviors. PTSD – post-traumatic stress disorder.

Table 37.2. Common behavioral and environmental intervention paradigms.

Condition

Examples

Paradigms

Key Features

Medical conditions

Pain, sleep, medications, infection, other systemic disorders

Token economies

Neurological conditions

Seizures, progression of underlying disorder, development of another neuropsychiatric disorder

Psychiatric disorders

Depression, anxiety, PTSD, psychotic disorders

A system of behavior modification based on the principles of operant conditioning. It is one approach to a contingency management program. Specifically, these systems emphasize reinforcing positive behavior by awarding “tokens” for meeting positive behavioral goals

Change in environment

Residential, vocational, day program, fear of others in environment, other

Natural consequences

Change in family/caregivers

Case managers, therapists, who is at home, other staff

Change in burden of psychosocial stressor level

Finances, illness of loved one, developmental transitions

Consequences are outcomes that result from a person’s action, which can be either negative or positive. Consequences influence our behavior because we typically strive for positive outcomes or rewards. Natural consequences occur naturally; that is, they are not controlled or manipulated by anyone. For example, when you cook something and follow the recipe correctly, you end up with a delicious meal (positive consequence); when you put your finger in an electric socket, you get a shock (negative consequence)

Positive behavioral supports (PBS)

An empirically validated, function-based approach to eliminate challenging behaviors and replace them with pro-social skills. Its use can decrease or eliminate the need for more aversive interventions (i.e., punishment). PBS uses data-based decision-making using functional behavioral assessment and ongoing monitoring of intervention impact.

Shaping

A process in which a complex behavior is broken down into a series of gradual steps, starting with a simple, easily performed task and gradually progressing to more complex and difficult ones. Shaping identifies the behaviors that an individual is capable of performing and gradually requiring a more skillful level of performance before positive reinforcement is given. The complex skill is acquired gradually in small achievable steps so that the individual can master it

Differential reinforcement of other behaviors (DRO)

DRO is used to reduce a frequent behavior by reinforcing any behavior other than the undesired one. An example would be reinforcing a period of time in which no hitting or throwing occurs

Differential reinforcement of incompatible behavior (DRI)

DRI is used to reduce a frequent behavior without punishing it by reinforcing an incompatible response. An example would be reinforcing clapping to reduce yelling outbursts

Hypothesis-driven intervention Based on the hypothesis developed, an intervention that flows logically from the formulation of the prime generators of the target behaviors can be developed. If medical, neurological, or psychiatric illnesses are factors, then these conditions need to be treated first. If some of the target behaviors can be reasonably attributed to current medication use, efforts to eliminate or reduce the dose of the most likely medication suspects must be undertaken. If a behavioral approach is chosen, then it is important that it is well suited to the cognitive strengths and weaknesses of the individual (see Table 37.2). An inventory of potential positive reinforcers for the individual must be developed, with consideration given to the feasibility of using any reinforcer selected across all of the contexts in which the persons with the target behavior are encountered. After deciding on an approach and specific intervention (or set of interventions), clear communication of the nature and details of that intervention to individuals in all of the settings in which it will be implemented is essential. It is incumbent on the team leader (whether that leader is a physician, psychologist, or another qualified clinician) to ensure that staff and other caregivers in all settings are engaged in formulating the intervention and in its implementation. Simple but effective methods for quantifying the frequency and intensity of the target behaviors must be developed and disseminated across the different providers and family/caregivers. An appropriate schedule should be established for assessing how the

619


intervention is working and to provide opportunities to fine-tune or adjust it. Each time it is adjusted, there must be aggressive efforts made to ensure communication about those adjustments across all care sites. This care coordination activity is best accomplished by a single person responsible for oversight of the plan and its implementation and accountable to the treatment team for its functioning.

Recurrent evaluations of the plan (plan, do, check, act) As critical to the success of the intervention as the original applied behavioral analysis and the hypothesisdriven formulation of the plan is its ongoing reassessment. This reassessment, which is best scheduled, focuses on the implementation of the plan, the trajectory of change (if any) in the frequency and intensity of the target behaviors over time, and consideration of alternative hypotheses in light of either new information or failure to achieve desired behavioral goals.

Summary of this approach Several points are worth highlighting with respect to this description of the general approach to developing a behavioral or environmental intervention. The first is that the concepts used in this approach are not particularly complex. Many of these principles have been familiar for half a century or more, and the science underlying them is both straightforward and sound. Like other aspects of the evaluation and care of persons with neuropsychiatric disorders, the principles sometimes need creative re-interpretation in order to be applied effectively. Attention needs to be paid to the profile of the patient’s brain disease and the manner in which it is likely to affect the target behaviors of concern. Other causes of challenging behavior should have been excluded and/or treated effectively. The patient’s cognitive strengths and weaknesses also need to be understood and used to shape the nature and the details of the intervention developed. Persons with neuropsychiatric disorders often receive care and services from multiple providers, many of whose work takes place in distinct, and often entirely separate, areas within the healthcare system and who do not always share languages and cultures

620

of care. This reality of the world in which persons with neuropsychiatric disorders receive care necessitates that a team leader takes responsibility to ensure effective communication during the entire process of defining challenging behaviors, developing interventions for those behaviors, implementing those interventions, and evaluating their effectiveness. In short, the greatest challenge to the effective implementation of behavioral and environmental interventions is the work involved and the need for ongoing input, energy, and creative thinking. It is easier to prescribe a medication and hope for the best, but usually the outcome from pharmacotherapy alone falls short of the results produced by the combination of intensive behavioral evaluation, judicious pharmacotherapy targeted at specific conditions, and a wellinformed, carefully conceived, and hypothesis-driven behavioral or environmental plan.

Conclusion Neuropsychiatric disorders often produce disturbances of physical, emotional, behavioral, and cognitive functioning. These disturbances present serious challenges to affected individuals and their personal and professional caregivers, interfere with effective communication, and decrease quality of life. Although medications may be useful treatments for some challenging behaviors, these are best complemented by concurrently applied behavioral interventions. The latter are of particular interest in these populations since they do not entail the serious risks and/or treatmentlimited side effects associated with many pharmacotherapies. Behavioral interventions incorporate basic behavior management principles, and often include skillbuilding components. Many techniques include principles of behavior modification, by either increasing appropriate behaviors or decreasing inappropriate behaviors. As reviewed in this chapter, behavior therapy is not a single technique. There are many types of intervention strategies that are based on a common set of principles. The appropriate strategy depends on the target behavior, the goal of the intervention, the cognitive limitations of the individual, and the person responsible for maintaining implementation of the strategy. Informed by these principles, these interventions can be useful components of the treatment of a wide range of challenging behaviors among persons with neuropsychiatric disorders.


References 1. Schulz R, O’Brien AT, Bookwala J, Fleissner K. Psychiatric and physical morbidity effects of dementia caregiving: prevalence, correlates, and causes. Gerontologist 1995;35(6):771–91. 2. Burgio LD, Jones LT, Butler F, Engel BT. Behavior problems in an urban nursing home. J Gerontol Nurs. 1988;14(1):31–4. 3. Bayles KA, Kim ES. Improving the functioning of individuals with Alzheimer’s disease: emergence of behavioral interventions. J Commun Disord. 2003;36(5):327–43. 4. Lyketsos CG, Kozauer N, Rabins PV. Psychiatric manifestations of neurologic disease: where are we headed? Dialogues Clin Neurosci. 2007;9(2):111–24. 5. Farmer RF, Chapman AL. Behavioral Interventions in Cognitive Behavior Therapy: Practical Guidance for Putting Theory into Action. 1st edition. Washington, DC: American Psychological Association; 2008. 6. Cyert RM, March JG. A Behavioral Theory of the Firm. Cambridge, MA: Blackwell Publishers; 1992. 7. O’Neill RE. Functional Assessment and Program Development for Problem Behavior: A Practical Handbook. 2nd edition. Pacific Grove, CA: Brooks/Cole Publishing; 1997. 8. Wielkiewicz RM. Behavior Management in the Schools: Principles And Procedures. 2nd edition. Boston, MA: Allyn and Bacon; 1995. 9. Chau DT, Roth RM, Green AI. The neural circuitry of reward and its relevance to psychiatric disorders. Curr Psychiatry Rep. 2004;6(5):391–9. 10. Roth RM, Flashman LA, McAllister TW. Apathy and its treatment. Curr Treat Options Neurol. 2007;9(5): 363–70. 11. Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain 1992;49(2):221–30. 12. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 1999;80(1–2):1–13. 13. NIH Technology Assessment Panel on Integration of Behavioral and Relaxation Approaches into the Treatment of Chronic Pain and Insomnia. Integration of behavioral and relaxation approaches into the treatment of chronic pain and insomnia. J Am Med Assoc. 1996;276(4):313–18. 14. Donaldson S, Romney D, Donaldson M, Skubick D. Randomized study of the application of single motor unit biofeedback training to chronic low back pain. J Occup Rehabil. 1994;4(1):23–37.

15. Flor H, Birbaumer N. Comparison of the efficacy of electromyographic biofeedback, cognitive-behavioral therapy, and conservative medical interventions in the treatment of chronic musculoskeletal pain. J Consult Clin Psychol. 1993;61(4):653–8. 16. Flor H, Turk DC. Psychophysiology of chronic pain: do chronic pain patients exhibit symptom-specific psychophysiological responses? Psychol Bull. 1989; 105(2):215–59. 17. Rains JC, Penzien DB, McCrory DC, Gray RN. Behavioral headache treatment: history, review of the empirical literature, and methodological critique. Headache 2005;45(Suppl. 2):S92–109. 18. Goslin RE, Gray RN, McCrory DC et al. Behavioral and Physical Treatments for Migraine Headaches. Durham, NC: Agency for Health Care Policy and Research (contract no. 290–94–2025);1999. 19. Penzien DB, Rains JC, Lipchik GL, Creer TL. Behavioral interventions for tension-type headache: overview of current therapies and recommendation for a self-management model for chronic headache. Curr Pain Headache Rep. 2004;8(6):489–99. 20. Galvao DA, Newton RU. Review of exercise intervention studies in cancer patients. J Clin Oncol. 2005;23(4):899–909. 21. Knols R, Aaronson NK, Uebelhart D, Fransen J, Aufdemkampe G. Physical exercise in cancer patients during and after medical treatment: a systematic review of randomized and controlled clinical trials. J Clin Oncol. 2005;23(16):3830–42. 22. McNeely ML, Campbell KL, Rowe BH et al. Effects of exercise on breast cancer patients and survivors: a systematic review and meta-analysis. Can Med Assoc J. 2006;175(1):34–41. 23. Schmitz KH, Holtzman J, Courneya KS et al. Controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2005;14(7):1588–95. 24. Stevinson C, Lawlor DA, Fox KR. Exercise interventions for cancer patients: systematic review of controlled trials. Cancer Causes Control. 2004; 15(10):1035–56. 25. Adamsen L, Midtgaard J, Andersen C et al. Transforming the nature of fatigue through exercise: qualitative findings from a multidimensional exercise programme in cancer patients undergoing chemotherapy. Eur J Cancer Care 2004;13(4):362–70. 26. Crevenna R, Schmidinger M, Keilani M et al. Aerobic exercise for a patient suffering from metastatic bone disease. Support Care Cancer 2003;11(2):120–2. 27. Dimeo FC, Thomas F, Raabe-Menssen C, Propper F, Mathias M. Effect of aerobic exercise and relaxation training on fatigue and physical performance of cancer

621


patients after surgery. A randomised controlled trial. Support Care Cancer 2004;12(11):774–9. 28. Headley JA, Ownby KK, John LD. The effect of seated exercise on fatigue and quality of life in women with advanced breast cancer. Oncol Nurs Forum. 2004; 31(5):977–83. 29. Mustian KM, Katula JA, Zhao H. A pilot study to assess the influence of tai chi chuan on functional capacity among breast cancer survivors. J Support Oncol. 2006;4(3):139–45.

41. Lichstein KL, Morin CM. Treatment overview. In Lichstein KL, Morin CM, editors. Treatment of Late-life Insomnia. Thousand Oaks, CA: Sage; 2000, pp. 111–24. 42. Rybarczyk B, Lopez M, Benson R, Alsten C, Stepanski E. Efficacy of two behavioral treatment programs for comorbid geriatric insomnia. Psychol Aging 2002; 17(2):288–98.

30. Thorsen L, Skovlund E, Stromme SB et al. Effectiveness of physical activity on cardiorespiratory fitness and health-related quality of life in young and middle-aged cancer patients shortly after chemotherapy. J Clin Oncol. 2005;23(10):2378–88.

43. Morin CM, Hauri PJ, Espie CA et al. Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 1999;22(8):1134–56.

31. Turner J, Hayes S, Reul-Hirche H. Improving the physical status and quality of life of women treated for breast cancer: a pilot study of a structured exercise intervention. J Surg Oncol. 2004;86(3):141–6.

44. Ouellet MC, Morin CM. Efficacy of cognitivebehavioral therapy for insomnia associated with traumatic brain injury: a single-case experimental design. Arch Phys Med Rehabil. 2007;88(12):1581–92.

32. Fawzy FI, Cousins N, Fawzy NW et al. A structured psychiatric intervention for cancer patients. I. Changes over time in methods of coping and affective disturbance. Arch Gen Psychiatry 1990;47(8): 720–5.

45. Bright JI, Baker KD, Neimeyer RA. Professional and paraprofessional group treatments for depression: a comparison of cognitive-behavioral and mutual support interventions. J Consult Clin Psychol. 1999; 67(4):491–501.

33. Kabat-Zinn J. An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results. Gen Hosp Psychiatry 1982;4(1):33–47.

46. Dobson KS. A meta-analysis of the efficacy of cognitive therapy for depression. J Consult Clin Psychol. 1989;57(3):414–19.

34. Irwin MR, Cole JC, Nicassio PM. Comparative meta-analysis of behavioral interventions for insomnia and their efficacy in middle-aged adults and in older adults 55+ years of age. Health Psychol. 2006;25(1): 3–14.

47. Neimeyer RA, Robinson LA, Berman JS, Haykal RF. Clinical outcome of group therapies for depression. Group Analysis 1989;22(1):73–86. 48. Robinson LA, Berman JS, Neimeyer RA. Psychotherapy for the treatment of depression: a comprehensive review of controlled outcome research. Psychol Bull. 1990;108(1):30–49.

35. Montgomery P, Dennis J. Cognitive behavioural interventions for sleep problems in adults aged 60+. Cochrane Database Syst Rev. 2003;1:CD003161.

49. Lincoln NB, Flannaghan T. Cognitive behavioral psychotherapy for depression following stroke: a randomized controlled trial. Stroke 2003;34(1):111–15.

36. Morin CM, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry 1994;151(8):1172–80.

50. Teri L, Logsdon RG, Whall AL et al. Treatment for agitation in dementia patients: a behavior management approach. Psychotherapy 1998;35(4):436–43.

37. Morin CM, Bootzin RR, Buysse DJ et al. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998–2004). Sleep 2006;29(11): 1398–414. 38. Murtagh DR, Greenwood KM. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol. 1995;63(1): 79–89. 39. Smith MT, Perlis ML, Park A et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 2002;159(1):5–11.

622

40. Germain A, Moul DE, Franzen PL et al. Effects of a brief behavioral treatment for late-life insomnia: preliminary findings. J Clin Sleep Med. 2006;2(4): 403–6.

51. Deacon BJ, Abramowitz JS. Cognitive and behavioral treatments for anxiety disorders: a review of meta-analytic findings. J Clin Psychol. 2004;60(4): 429–41. 52. Gould RA, Otto MW, Pollack MH, Yap L. Cognitive behavioral and pharmacological treatment of generalized anxiety disorder: a preliminary meta-analysis. Behav Ther. 1997;28(2):285–305. 53. Mitte K. Meta-analysis of cognitive-behavioral treatments for generalized anxiety disorder: a comparison with pharmacotherapy. Psychol Bull. 2005;131(5):785–95.


54. Mitte K, Noack P, Steil R, Hautzinger M. A meta-analytic review of the efficacy of drug treatment in generalized anxiety disorder. J Clin Psychopharmacol. 2005;25(2):141–50.

67. Van Etten ML, Taylor S. Comparative efficacy of treatments for post-traumatic stress disorder: a meta-analysis. Clin Psychol Psychother. 1998;5(3): 126–44.

55. Pinquart M, Duberstein PR. Treatment of anxiety disorders in older adults: a meta-analytic comparison of behavioral and pharmacological interventions. Am J Geriatr Psychiatry 2007;15(8):639–51.

68. Sherman JJ. Effects of psychotherapeutic treatments for PTSD: a meta-analysis of controlled clinical trials. J Trauma Stress 1998;11(3):413–35.

56. Clum GA, Surls R. A meta-analysis of treatments for panic disorder. J Consult Clin Psychol. 1993;61(2): 317–26.

69. Mitte K. A meta-analysis of the efficacy of psychoand pharmacotherapy in panic disorder with and without agoraphobia. J Affect Disord. 2005;88(1): 27–45.

57. van Balkom AJ, Bakker A, Spinhoven P et al. A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral, and combination treatments. J Nerv Ment Dis. 1997; 185(8):510–16.

70. Chard K, Lewis J, Caldwell N et al., editors. Establishing the Effectiveness of Cognitive Processing Therapy (CPT). The Clinical Effectiveness of Empirically-supported Treatments for PTSD. Annual Meeting of the International Society for Traumatic Stress Studies; November 13, 2008, Chicago, IL.

58. Fedoroff IC, Taylor S. Psychological and pharmacological treatments of social phobia: a meta-analysis. J Clin Psychopharmacol. 2001;21(3): 311–24.

71. Monson CM, Schnurr PP, Resick PA et al. Cognitive processing therapy for veterans with military-related posttraumatic stress disorder. J Consult Clin Psychol. 2006;74(5):898–907.

59. Feske U, Chambless DL. Cognitive-behavioral versus exposure only treatment for social phobia – a meta-analysis. Behav Ther. 1995;26(4):695–720.

72. Bien TH, Miller WR, Tonigan JS. Brief interventions for alcohol problems: a review. Addiction 1993;88(3): 315–35.

60. Gould RA, Buckminster S, Pollack MH, Otto MW, Yap L. Cognitive-behavioral and pharmacological treatment for social phobia: a meta-analysis. Clin Psychol-Sci Pr. 1997;4(4):291–306.

73. Kahan M, Wilson L, Becker L. Effectiveness of physician-based interventions with problem drinkers: a review. Can Med Assoc J. 1995;152(6):851–9.

61. Taylor S. Meta-analysis of cognitive-behavioral treatments for social phobia. J Behav Ther Exp Psychiatry 1996;27(1):1–9. 62. Meyer V. Modification of expectations in cases with obsessional rituals. Behav Res Ther. 1966;4(4): 273–80. 63. Abramowitz JS. Effectiveness of psychological and pharmacological treatments for obsessive-compulsive disorder: a quantitative review. J Consult Clin Psychol. 1997;65(1):44–52. 64. van Balkom AJLM, van Oppen P, Vermeulen AWA et al. A meta-analysis on the treatment of obsessive compulsive disorder: a comparison of antidepressants, behavior, and cognitive therapy. Clin Psychology Rev. 1994;14(5):359–81. 65. Veronen L, Kilpatrick D. Stress management for rape victims. In Meichenbaum D, Jaremko ME, editors. Stress Reduction and Prevention. New York, NY: Plenum Press; 1983, pp. 341–74. 66. Calhoun K, Resick PA. Posttraumatic stress disorder. In Barlow DH, editor. Clinical Handbook of Psychological Disorders: A Step-By-Step Treatment Manual. 2nd edition. New York, NY: Guilford Press; 1993, pp. 48–98.

74. Noonan WC, Moyers TB. Motivational interviewing: a review. J Subst Mis. 1997;2:8–16. 75. Wilk AI, Jensen NM, Havighurst TC. Meta-analysis of randomized control trials addressing brief interventions in heavy alcohol drinkers. J Gen Intern Med. 1997;12(5):274–83. 76. Goldsmith RJ, Garlapati V. Behavioral interventions for dual-diagnosis patients. Psychiatr Clin North Am. 2004;27(4):709–25. 77. Handmaker N, Packard M, Conforti K. Motivation interviewing in the treatment of dual disorders. In Miller WR, Rollnick S, editors. Motivational Interviewing: Preparing People for Change. 2nd edition. New York, NY: Guilford Press; 2002, pp. 364–6. 78. Dunn C, Deroo L, Rivara FP. The use of brief interventions adapted from motivational interviewing across behavioral domains: a systematic review. Addiction 2001;96(12):1725–42. 79. Marlatt GA, Baer JS, Kivlahan DR et al. Screening and brief intervention for high-risk college student drinkers: results from a 2-year follow-up assessment. J Consult Clin Psychol. 1998;66(4):604–15. 80. Aubrey L. Motivational interviewing with adolescents presenting for outpatient substance abuse treatment. Dissertation Abstr Int. 1998; 1357.

623


81. Anton RF, O’Malley SS, Ciraulo DA et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. J Am Med Assoc. 2006;295(17):2003–17. 82. McQuaid JR, Granholm E, McClure FS et al. Development of an integrated cognitive-behavioral and social skills training intervention for older patients with schizophrenia. J Psychother Pract Res. 2000;9(3):149–56. 83. Koegel RI, Frea WD. Treatment of social behavior in autism through the modification of pivotal social skills. J Appl Behav Anal. 1993;26(3): 369–77. 84. Schreibman L, Whalen C, Stahmer AC. The use of video priming to reduce disruptive transition behavior in children with autism. J Positive Behav Interv. 2000; 2(1):3–11. 85. Granholm E, McQuaid JR, McClure FS et al. A randomized, controlled trial of cognitive behavioral social skills training for middle-aged and older outpatients with chronic schizophrenia. Am J Psychiatry 2005;162(3):520–9. 86. Granholm E, McQuaid JR, McClure FS et al. Randomized controlled trial of cognitive behavioral social skills training for older people with schizophrenia: 12-month follow-up. J Clin Psychiatry 2007;68(5):730–7.

95. Cohen-Mansfield J, Werner P, Marx MS. Screaming in nursing home residents. J Am Geriatr Soc. 1990;38(7): 785–92. 96. Burgio LD, Cotter EM, Stevens AB. Treatment in residential settings. In Hersen M, Van Hasselt VB, editors. Psychological Treatment of Older Adults: An Introductory Text. New York, NY: Plenum Press; 1996, pp. 127–45. 97. Ohta RJ, Ohta BM. Special units for Alzheimer’s disease patients: a critical look. Gerontologist 1988; 28(6):803–8. 98. Hussian RA. Geriatric Psychology: A Behavioral Perspective. New York, NY: Van Nostrand Reinhold; 1981. 99. Hussian RA, Davis RL. Responsive Care: Behavioral Interventions with Elderly Persons. Champaign, IL: Research Press; 1985. 100. Bird M, Alexopoulos P, Adamowicz J. Success and failure in 5 case-studies – use of cued-recall to ameliorate behavior problems in senile dementia. Int J Geriatr Psych. 1995;10(4):305–11. 101. Hussian RA. Stimulus control in the modification of problematic behavior in elderly institutionalized patients. Int J Behavl Geriatr. 1982;1:33–42.

87. Scattone D, Knight KR. Current trends in behavioral interventions for children with autism. Int Rev Neurobiol. 2006;72:181–93.

102. Hussian RA, Brown DC. Use of two-dimensional grid patterns to limit hazardous ambulation in demented patients. J Gerontol. 1987;42(5):558–60.

88. Hawley LA, Newman JK. Group interactive structured treatment (GIST): a social competence intervention for individuals with brain injury. Brain Inj. 2010; 24(11):1292–7.

103. Mayer R, Darby SJ. Does a mirror deter wandering in demented older-people? Int J Geriatr Psych. 1991; 6(8):607–9.

89. Braden C, Hawley L, Newman J et al. Social communication skills group treatment: a feasibility study for persons with traumatic brain injury and comorbid conditions. Brain Inj. 2010;24(11): 1298–310. 90. Cohen-Mansfield J, Billig N. Agitated behaviors in the elderly. I. A conceptual review. J Am Geriatr Soc. 1986;34(10):711–21. 91. Spira AP, Edelstein BA. Behavioral interventions for agitation in older adults with dementia: an evaluative review. Int Psychogeriatr. 2006;18(2):195–225. 92. Algase DL. Cognitive discriminants of wandering among nursing home residents. Nurs Res. 1992; 41(2):78–81. 93. Burton LC, German PS, Rovner BW, Brant LJ, Clark RD. Mental illness and the use of restraints in nursing homes. Gerontologist 1992;32(2):164–70.

624

94. Cohen-Mansfield J, Werner P. The effects of an enhanced environment on nursing home residents who pace. Gerontologist 1998;38(2):199–208.

104. Namazi KH, Rosner TT, Calkins MP. Visual barriers to prevent ambulatory Alzheimer’s patients from exiting through an emergency door. Gerontologist 1989; 29(5):699–702. 105. McGilton KS, Rivera TM, Dawson P. Can we help persons with dementia find their way in a new environment? Aging Ment Health 2003;7(5):363–71. 106. Vaccaro FJ. Application of social skills training in a group of institutionalized aggressive elderly subjects. Psychol Aging 1990;5(3):369–78. 107. Allen-Burge R, Stevens AB, Burgio LD. Effective behavioral interventions for decreasing dementia-related challenging behavior in nursing homes. Int J Geriatr Psychiatry 1999;14(3):213–28; discussion 28–32. 108. Bourgeois MS, Burgio LD, Schulz R, Beach S, Palmer B. Modifying repetitive verbalizations of community-dwelling patients with AD. Gerontologist 1997;37(1):30–9.


109. Doyle C, Zapparoni T, O’Connor D, Runci S. Efficacy of psychosocial treatments for noisemaking in severe dementia. Int Psychogeriatr. 1997;9(4):405–22. 110. Birchmore T, Clague S. A behavioural approach to reduce shouting. Nurs Times 1983;79(16):37–9. 111. Haley WE. A family-behavioral approach to the treatment of the cognitively impaired elderly. Gerontologist 1983;23(1):18–20. 112. Spayd CS, Smyer MA. Interventions with agitated, disoriented, or depressed residents. In Smyer MA, Cohn MD, Brannon D, editors. Mental Health Consultation in Nursing Homes. New York, NY: New York University Press; 1988, pp. 123–41. 113. Brink C. Urinary continence/incontinence. Assessing the problem. Geriatr Nurs. 1980;1(4):241–5, 75. 114. Carstensen LL, Fremouw WJ. The demonstration of a behavioral intervention for late life paranoia. Gerontologist 1981;21(3):329–33. 115. Whelihan WM. Psychotherapy With Elderly Clients: A Behavioral Approach. Paper presented at the Annual Convention of the American Psychological Association (Toronto, Ontario, Canada, August, 1978)

124. Boehm S, Whall AL, Cosgrove KL, Locke JD, Schlenk EA. Behavioral analysis and nursing interventions for reducing disruptive behaviors of patients with dementia. Appl Nurs Res. 1995;8(3):118–22. 125. Burgio LD, Stevens A, Burgio KL et al. Teaching and maintaining behavior management skills in the nursing home. Gerontologist 2002;42(4):487–96. 126. Farran CJ, Gilley DW, McCann JJ et al. Efficacy of behavioral interventions for dementia caregivers. West J Nurs Res. 2007;29(8):944–60. 127. Gonyea JG, O’Connor MK, Boyle PA. Project CARE: a randomized controlled trial of a behavioral intervention group for Alzheimer’s disease caregivers. Gerontologist 2006;46(6):827–32. 128. Wade SL, Michaud L, Brown TM. Putting the pieces together: preliminary efficacy of a family problem-solving intervention for children with traumatic brain injury. J Head Trauma Rehabil. 2006; 21(1):57–67. 129. Medd J, Tate RL. Evaluation of an anger management therapy programme following acquired brain injury: a preliminary study. Neuropsych Rehabil. 2000;10(2): 185–201.

116. Burgio L, Scilley K, Hardin JM, Hsu C, Yancey J. Environmental “white noise”: an intervention for verbally agitated nursing home residents. J Gerontol B Psychol Sci Soc Sci. 1996;51(6):P364–73.

130. Van Ort S, Phillips LR. Nursing intervention to promote functional feeding. J Gerontol Nurs. 1995; 21(10):6–14.

117. Woods P, Ashley J. Simulated presence therapy: using selected memories to manage problem behaviors in Alzheimer’s disease patients. Geriatr Nurs. 1995; 16(1):9–14.

131. Baltes MM, Neumann EM, Zank S. Maintenance and rehabilitation of independence in old age: an intervention program for staff. Psychol Aging 1994; 9(2):179–88.

118. Camberg L, Hurley A, Woods P et al. Selected Memories To Manage Problem Behaviors in Alzheimer’s Disease. Final Report: Executive Summary. West Roxbury: Department of Veteran Affairs.

132. Kehle TJ, Clark E, Jenson WR. Interventions for students with traumatic brain injury: managing behavioral disturbances. J Learn Disabil. 1996; 29(6):633–42.

119. Lund DA, Hill RD, Caserta MS, Wright SD. Video respite: an innovative resource for family, professional caregivers, and persons with dementia. Gerontologist 1995;35(5):683–7.

133. Cicerone KD, Dahlberg C, Kalmar K et al. Evidence-based cognitive rehabilitation: recommendations for clinical practice. Arch Phys Med Rehabil. 2000;81(12):1596–615.

120. Rapp MS, Flint AJ, Herrmann N, Proulx GB. Behavioural disturbances in the demented elderly: phenomenology, pharmacotherapy and behavioural management. Can J Psychiatry 1992;37(9):651–7.

134. Cicerone KD, Dahlberg C, Malec JF et al. Evidence-based cognitive rehabilitation: updated review of the literature from 1998 through 2002. Arch Phys Med Rehabil. 2005;86(8):1681–92.

121. Vaccaro FJ. Application of operant procedures in a group of institutionalized aggressive geriatric patients. Psychol Aging 1988;3(1):22–8.

135. von Cramon DY, Cramon GM-v, Mai N. Problem-solving deficits in brain-injured patients: A therapeutic approach. Neuropsych Rehabil Int J. 1991; 1(1):45–64.

122. Beck CK. Psychosocial and behavioral interventions for Alzheimer’s disease patients and their families. Am J Geriatr Psychiatry 1998;6(2 Suppl. 1):S41–8. 123. Haupt M, Karger A, Janner M. Improvement of agitation and anxiety in demented patients after psychoeducative group intervention with their caregivers. Int J Geriatr Psychiatry 2000;15(12):1125–9.

136. Pierce KL, Schreibman L. Teaching daily living skills to children with autism in unsupervised settings through pictorial self-management. J Appl Behav Anal. 1994; 27(3):471–81. 137. Ylvisaker M, Turkstra LS, Coelho C. Behavioral and social interventions for individuals with traumatic

625


brain injury: a summary of the research with clinical implications. Semin Speech Lang. 2005;26(4): 256–67.

newly brain-injured. Int J Clin Neuropsych. 1982; 4(3):139–43.

138. Struchen M. Social communication interventions. In High WM, Sander AM, Struchen MA, Hart KA, editors. Rehabilitation for Traumatic Brain Injury. Oxford: Oxford University Press; 2005, pp. 88–117.

140. Kagan A, Black SE, Duchan FJ, Simmons-Mackie N, Square P. Training volunteers as conversation partners using “Supported Conversation for Adults with Aphasia” (SCA): a controlled trial. J Speech Lang Hear Res. 2001;44(3):624–38.

139. Helffenstein DA, Wechsler FS. The use of interpersonal process recall (IPR) in the remediation of interpersonal and communication skill deficits in the

141. Ripich DN, Ziol E, Fritsch T, Durand EJ. Training Alzheimer’s disease caregivers for successful communication. Clin Gerontol. 2000;21(1):37–56.

626

Section III Chapter

38


Procedural interventions C. Alan Anderson and David B. Arciniegas

Despite the development of increasingly effective pharmacologic and psychotherapeutic treatments for neuropsychiatric conditions, there remains a subset of patients with refractory and disabling forms of obsessive-compulsive disorder (OCD), Gilles de la Tourette syndrome (GTS), major depressive disorder (MDD), schizophrenia, and anxiety, as well as intractable dangerous aggression and self-injurious behaviors. It especially is for this subset of patients that procedural interventions are sometimes considered and for whom such treatments may be life-saving. There are circumstances in which lesion-producing procedures such as cryothermy or radiofrequency ablation may be warranted. However, implantable neurostimulators as well as non-invasive electric and magnetic brain stimulation techniques expand the procedural treatment options for patients with medically and psychotherapeutically refractory neuropsychiatric conditions. Pre-treatment evaluations using structural and functional neuroimaging are improving the neuroanatomic targeting of these interventions and identifying the patients most likely to respond to neurostimulation. These technical advances, coupled with progress in the understanding of the biology of mental illness, generate interest in, and concern for the ethics of, procedural interventions for refractory neuropsychiatric conditions [1]. Understanding the potential applications of procedural interventions for the treatment of neuropsychiatric conditions is expected of subspecialists in Behavioral Neurology & Neuropsychiatry (BN&NP) [2]. Toward that end, this chapter reviews the history of invasive and non-invasive procedures for neuropsychiatric conditions, their putative neurobiological foundations, and their effects. The most frequently used procedural interventions are described briefly,

including lesional procedures, deep brain stimulation (DBS), vagal nerve stimulation (VNS), electroconvulsive therapy (ECT), and transcranial magnetic stimulation (TMS). Emerging therapies are identified, and their current and potential applications to the treatment of neuropsychiatric conditions also are considered briefly. As this review will highlight, the historical roots of procedural interventions in BN&NP are deep but this remains a rapidly evolving and growing area of neuropsychiatric therapeutics. Accordingly, the relatively modest goal of this chapter is to review the principles and general applications of procedural interventions for neuropsychiatric conditions. Readers interested in detailed reviews of the technical aspects of these procedures and their neuropsychiatric applications are referred to the references provided in this chapter and encouraged to update them with topicrelevant reviews of the literature published subsequent to this development. Provided with the information presented here and supplemented by additional reading and training, subspecialists in BN&NP will be well positioned to consider the potential relevance of procedural interventions to the management of the patients under their care.

Invasive procedural interventions Historical perspective Written records from 1500 BC describe skull trephination, a surgical intervention in which a hole is drilled or scraped into the skull, for the relief of melancholia. The practice of trephination developed much earlier than this, however: a human skull carbon dated to 5100 BC documents the existence of a survivor of


627


trephination (based on evidence of healing at the trephination site) [3]. This case represents the oldest known successful neurosurgical procedure, where success requires only post-procedure survival sufficient to permit partial healing of the patient’s skull [4]. Prior to the last century, trephination sometimes was performed to alleviate symptoms of psychosis, depression, headaches, and epilepsy. The presumed mechanism of action was to release pressure, or permit the escape of demons and other evil spirits. Historical details of trephination are provided by Roger Frugardi of Parma in The Practice of Surgery (c. 1180): “For mania or melancholy a cruciate incision is made in the top of the head and the cranium is penetrated, to permit the noxious material to exhale to the outside. The patient is held in chains and the wound is treated” [5]. Trephination also was used in the treatment of patients with depressed skull fractures and penetrating head wounds – an application, with modern modifications, that remains a part of neurosurgical practice [4, 5]. In the nineteenth century, Gottlieb Burckhardt surgically removed cortical tissue from frontal, temporal, and parietal regions including Broca’s and Wernicke’s areas in six patients described as demented with aggression [6, 7]. Burckhardt considered three of these “topectomies” to have had a good outcome, two to be partial successes, but one of his patients died as a consequence of the surgery. At least in part because of his colleagues’ disapproval, he never performed this procedure again. Similar tensions regarding the effectiveness and ethics of treating refractory psychiatric symptoms with destructive (i.e., cerebral lesional) interventions remain elements of the modern landscape for procedural treatments in neuropsychiatry. Lodovicus Puusepp, an Estonian neurosurgeon, operated on a series of patients with neuropsychiatric conditions between 1910 and 1937, including patients with diagnoses of epilepsy or mania [4]. Although the first three cases were deemed failures, the next 17 were considered successfully treated. The modern era of psychosurgery began in 1935 with the Portuguese neurologist Egas Moniz [4]. Moniz and a neurosurgeon, Almedea Lima, performed a prefrontal leukotomy on a 63-year-old woman described as having melancholia, anxiety, and delusions. Initially their approach was to trephinate the skull, allowing the free-hand injection of alcohol targeting the white matter of the frontal lobes. They postulated that destroying frontal connections would disrupt the fixed ideas that were the source of her

628

symptoms. Several months after the procedure they described her as cured, despite her requiring continued institutionalization. Lima and Moniz performed frontal white matter alcohol injections in a small number of patients before changing their technique. In order to have greater control over the lesions they created, a device called a leukotome was inserted into the substance of the brain through trephine holes in the skull. Once the leukotome was in place a wire loop at its tip was extended. Lima would then rotate the leukotome producing a one-centimeter intracerebral circular lesion. The procedure was performed bilaterally, always targeting frontal white matter; usually six lesions were made on each side. If the patient’s symptoms did not improve after the first series of lesions, the procedure would be repeated to create two or three additional lesions. Writing less than 4 months after the first of these surgeries, Moniz reported significant improvement in 14 of the first 20 patients treated with this procedure. Over a 2-year period Moniz and Lima published 13 articles, one surgical monograph, and a textbook on the procedure. Their reported success with refractory patients generated enormous interest in their approach. Acclaim for their efforts culminated in Moniz being awarded the 1949 Nobel Prize in Medicine and Physiology. At the time, the Nobel committee described his work as one of the most important discoveries ever made in psychiatric therapy [8]. In light of the notoriety and acclaim associated with this neurosurgical technique, it is not surprising that its use and evolution as a procedural intervention for psychiatric symptoms spread quickly throughout the world [9]. James Watts (a neurosurgeon) and Walter Freeman (a neurologist) at Georgetown University performed the first lobotomy in the USA in 1936 on a 63-year-old woman they described as anxious and depressed [10]. Watts and Freeman modified the procedure used by Moniz and Lima by introducing a leukotome through burr holes in the lateral aspect of the skull to make frontal white matter incisions using a vertical sweeping motion. Based on their experience with complications from their technique, including incontinence, seizures, and apathy, Watts and Freeman continued to adjust the extent and location of the white matter lesions they were creating. Of the first 200 patients treated with frontal leukotomy, they reported that 63% improved, 23% were unchanged, and 14% worsened or died [10].

Chapter 38: Procedural interventions

Despite the modifications in technique, common complications of this procedure included epilepsy, severe apathy, and socially inappropriate behavior. Performed in an operating room, these surgical procedures required general anesthesia as well as the services of a neurosurgeon. These restrictions limited the number of patients who could be treated with this technique. Based on his personal experience, Freeman argued that this procedure should be available to a wider population, and began searching for a new approach that would allow more flexibility in who could perform the procedure as well as medical settings where it could be done. Freeman subsequently began using an ice pick-like tool called an orbitoclast. Using this tool, he punched a hole in the superior aspect of the orbit with a hammer. Sweeping the orbitoclast back and forth produced the frontal white matter injury. The procedure was then repeated on the other side. Administration of electroconvulsive therapy just prior to the procedure provided anesthesia. Asserting that this approach obviated the need for an anesthetist and a neurosurgeon, Freeman began performing the procedure in his office. Over the next 20 years Freeman also performed it in offices and hospitals across the country [11]. Many other practitioners followed suit, and over that time more than 60,000 procedures were performed in the USA [4]. Freeman’s technique received broad, favorable coverage in both the medical and popular press in light of the fact that the patient populations of most psychiatric hospitals were very large and that there were few effective therapies to offer these patients. Eventually, however, this view began to change. With increasing awareness of the adverse effects of the procedure, and the introduction of the first effective antipsychotic medication chlorpromazine in the early 1950s, enthusiasm for the procedure declined and the number of patients receiving it reduced dramatically. By the 1970s, both medical opinion and public sentiment largely opposed the use of the procedure. In addition to questions about the effectiveness and hazards of the procedure, there was growing concern about abuses, as it was observed that lobotomies were often performed on minority patients, prisoners, and developmentally disabled individuals [4, 8, 11]. A federal commission convened in 1977 to review psychosurgery in the USA [8, 12]. To the surprise of many, the report issued by this commission described psychosurgery as beneficial in properly

selected patients, with (at the time of the commission’s work) no evidence of pervasive abuse of the procedure. The commission also called for further research to improve neurosurgical techniques applied to the treatment of psychiatric disturbances and advocated for improved methods of identifying patients for whom such procedures are beneficial. In the 35 years since that commission’s report, knowledge of structural and functional neuroanatomy as well as the neurobiology of mental illness have advanced substantially [13, 14]. Nonetheless, there remains a subset of patients with severe, refractory mental illness for whom conventional treatments are of limited benefit and/or intolerable and who might benefit from procedural interventions. New neurosurgical techniques, implantable neurostimulators, and methods of external neurostimulation (e.g., electronconvulsive therapy, transcranial magnetic stimulation) provide an expanded range of sophisticated procedural interventions for the treatment of the neuropsychiatric disturbances experienced by such patients. Advanced neuroimaging facilitates in vivo identification of the structures and networks underlying disturbances of cognition, emotional, and behavior and, hence, directs procedural interventions toward symptom-specific neural targets. Medical ethicists are engaged as consultants to clinicians and researchers working in this area, and serve as useful guides to the personal and societal implications of the often challenging clinical situations in which the use of procedural interventions for neuropsychiatric disturbances are considered [1, 15]. Collectively, these factors create a context in which it is both necessary and appropriate to consider procedural interventions as elements of the therapeutic repertoire of subspecialists in BN&NP.

Rationale for invasive procedural interventions Cognition, emotion, behavior, and sensorimotor function are subserved by discrete limbic-subcortical and frontal-subcortical circuits as well as large-scale selective distributed networks into which they are incorporated. Modern neurosurgical interventions target key structures in these circuits and networks for the purpose of modifying their function and, hence, improving neuropsychiatric function [16–20]. Although these circuits and networks are discrete, they share anatomic elements and they are reciprocally

629


and functionally interconnected. Modifying the structure or function in a single brain area (e.g., thalamus, subthalamic nucleus) therefore may alter several neuropsychiatric functions (e.g., motor control and executive function, emotional regulation and motivation). Additionally, a single neuropsychiatric function may be accomplished by modifying the structure or function of any one, or several, areas within a given circuit or network. A clear understanding of the structure and function of these systems is needed in order to predict the benefits of neurosurgical procedures disrupting connections as well as their potential adverse effects [18, 21–23]. In general, reports describing the neurosurgical treatments for these conditions are encouraging of their potential benefits and tolerability, regardless of the specific neurosurgical technique used. However, there appears to be a bias against publication of negative (including catastrophic) outcomes in this literature. Evaluating the efficacy of these neurosurgical treatments for psychiatric symptoms is made even more challenging by methodological variability in published reports (Table 38.1). Recent reports describe organized efforts to reduce these sources of variability by adopting, in procedural clinical trials, many of the methods used commonly in clinical trials of psychiatric medications [18]. Neurosurgical procedures may be used to treat a wide variety of severe and refractory neuropsychiatric conditions, including obsessive-compulsive disorder (Table 38.2) [15, 24–43], Gilles de la Tourette syndrome (Table 38.3) [44–55], and major depressive disorder (Table 38.4) [23, 56–70]. A more limited literature describes the use of neurosurgical interventions for other intractable neuropsychiatric conditions (Table 38.5), including treatment-refractory anxiety disorders [43, 71], aggression [72–81], self-injurious behavior [74, 76, 82, 83], substance dependence [84– 89], anorexia nervosa [90, 91], schizophrenia-related behavioral disturbances [8, 92–94], and the minimally conscious state [95–97]. Selecting a specific neurosurgical procedure for any of these neuropsychiatric disturbances requires knowledge of the relevant neural systems involved, the neurosurgical techniques available to beneficially modify the structure and/or function of those neural systems, and prior experience (i.e., both locally and as reported in the medical literature) using these techniques for similar purposes [18,98]. There are two appropriate roles of subspecialists in BN&NP in the care of persons undergoing invasive

630

Table 38.1. Sources of methodological variability in studies of neurosurgical interventions for neuropsychiatric disorders and symptoms.

Methods

Comments

Diagnostic assessment

In many reports, neuropsychiatric diagnoses are not predicated on widely accepted, standardized, structured clinical interviews anchored to state-of-the-art diagnostic criteria

Illness and symptom severity assessments

Symptom severity may reflect self-rating, clinician interview and observation, or informant-based assessment Include qualitative and/or quantitative assessments of condition severity

Outcome assessments

Outcomes are inconsistently anchored to standardized, valid, and reliable metrics of change in neuropsychiatric status Include subjective versus objective ratings of change, as well as qualitative or quantitative approaches

Use of comparison subjects

The inclusion of comparison subjects is inconsistent between studies of a given procedure for a specific symptom The adequacy (i.e., appropriate matching of subjects as well as the comparability of “sham” or other “control” interventions they receive) is highly variable

Blinding to treatment condition

Blinding patients and/or neurosurgeons to the intervention performed are undertaken inconsistently and difficult to accomplish Many studies do not use independent raters blind to diagnosis

Procedure standardization

The specific procedures and techniques used to effect neuropsychiatric change vary between institutions and may vary between patients within an institution

procedural interventions for neuropsychiatric conditions. The first is serving as a patient’s usual care provider who, based on his or her evaluation and/or ongoing care of a patient with one of these conditions, initiates referral to a neurosurgeon for evaluation and treatment. The second is acting as a consultant to either a referring physician or neurosurgeon during the pre- and post-surgical periods. Post-residency training and experience in the evaluation of patients


Table 38.2. Neurosurgical interventions for obsessive-compulsive disorder (OCD).

Table 38.3. Neurosurgical interventions for Gilles de la Tourette syndrome (GTS).

Procedure

Comments

Procedure

Comments

Ventromedial frontal leucotomy

No longer performed

Cingulotomy Anterior capsulotomy Subcaudate tractotomy Limbic leucotomy

Although used with success, ablative procedures of these types are performed less often since the advent of deep brain stimulation (DBS) Among these procedures, cingulotomy is the most commonly performed. If this procedure fails, limbic leucotomy may prove useful Neuropsychiatric and neurological procedure-related morbidities are common

Prefrontal leucotomy Medial frontal leucotomy Intralaminar and dorsomedial nuclei of the thalamus lesioning Ventrolateral and lamella medialis thalamus and zona incerta lesioning Cerebellar dentate nucleus lesioning Anterior cingulotomy Limbic leucotomy

Although lesional procedures sometimes are performed, none are clearly superior to the others Motor complications, including hemiparesis, dystonia, hemiballism, ataxia, dysarthria, and dystonia are reported Deep brain stimulation (DBS) appears to be replacing lesional neurosurgical interventions for refractory GTS

Deep brain stimulation

Received a humanitarian device exception from the US Food and Drug Administration in 2009 Targets of DBS for OCD include anterior limb of the internal capsule, subthalamic nucleus, dorsomedial nucleus of the thalamus, and nucleus accumbens May improve symptoms in approximately half of patients with otherwise refractory OCD Relatively benign side effect profile for most patients Positron emission tomography (PET) imaging may improve DBS targeting and predict treatment response

Vagal nerve stimulation

Early evidence suggests that this intervention may be of benefit to persons with treatment-resistant OCD; additional evidence is needed to evaluate this possibility

with neuropsychiatric conditions who are being considered for invasive procedural interventions is encouraged, and specific training to acquire competence in the post-procedure operation and adjustment of implanted neurostimulators is required. Although subspecialists in BN&NP are sometimes encouraged to participate in the intra-operative testing and setting of neurostimulators, the implantation of such devices as well as the performance of any lesional intervention is solely the province of a qualified neurosurgeon. The most common neurosurgical techniques used to address neuropsychiatric symptoms or conditions are lesional (or ablative) procedures, deep brain stimulation, and vagal nerve stimulation. Each of these techniques is described briefly in the following sections,


Targets of DBS for GTS include anterior limb of the internal capsule, thalamus (including midline and intralaminar nuclei), globus pallidus interna, and nucleus accumbens Neuropsychiatric (including cognitive) and other neurological side effects of lead placement and stimulation may occur Persistent symptomatic response after discontinuing stimulation raises the possibility that DBS placement-induced lesions may account in part for the benefits afforded by this procedure There is no clear “best target” of DBS for this condition

after which their applications to the treatment of neuropsychiatric conditions are reviewed.

Lesional interventions The most common lesional interventions include anterior capsulotomy, anterior cingulotomy, subcaudate tractotomy, and limbic leucotomy. Anterior capsulotomy disrupts tracts connecting the thalamus and orbitofrontal cortex. Anterior cingulotomy targets cortical tissue, and interrupts circuits linking the thalamus, frontal cortex, and the amygdala as well as ascending monoaminergic fibers originating in the brainstem [99]. Subcaudate tractotomy disrupts white matter tracts between orbitofrontal cortex, basal forebrain, the amygdala, and the hypothalamus [98, 100]. Limbic leucotomy combines the lesions produced with cingulotomy with those of subcaudate tractotomy. Less often, bilateral amygdalotomy, orbital gyrus

631


Table 38.4. Neurosurgical interventions for major depressive disorder (MDD).

Procedure

Comments

Subcaudate tractotomy Anterior capsulotomy Cingulotomy Limbic leucotomy

Although lesional procedures sometimes are performed, none are clearly superior to the others Approximately one-third to two-thirds of patients undergoing these procedures demonstrate a positive, usually partial, treatment response Deep brain stimulation (DBS) appears to be replacing lesional neurosurgical interventions for otherwise treatment-refractory depression


Targets of DBS for MDD include anterior limb of the internal capsule, white matter adjacent to the subgenual cingulate gyrus, lateral habenula, inferior thalamic peduncle, and nucleus accumbens Outcomes associated with this procedure are generally favorable Complications include hemorrhage, infection, seizures, and motor disturbances; treatment-induced hypomania, which abated with stimulation parameter modifications, is also reported


This procedure is generally tolerated well, but several months of post-procedure stimulation may be required to effect symptomatic improvements This procedure is an attractive alternative to ablative interventions and DBS because it avoids procedure-related injury to and/or disruption of the brain tissue

undercutting, thalamotomy, and hypothalamotomy have been used [98, 99]. Stereotactic targeting of frontal white matter or other cortical and subcortical structures using either computerized tomography (CT) or magnetic resonance imaging (MRI) permits the accurate and reproducible creation of lesions in the intended location [21]. Electrophysiological monitoring during the procedure supplements the information provided by structural imaging for destructive lesions or for the proper placement of stimulator leads [101]. Once the intended brain structure is targeted, multiple options exist for creating the lesion. The most common currently employed methods include gamma knife, radiofrequency thermal coagulation using an uninsulated probe that generates temperatures of 80 to 85 ◦ C,

632

or nitrogen-cooled cryotherapy probes that freeze the tissue [42]. Acute surgical complications associated with lesional interventions are not specific to the condition for which the procedure is performed, and instead reflect the nature of this intervention. Among the most serious of these complications are peri-operative death, hemorrhage, and wound infection [67]. More commonly, lesional interventions produce transient confusion, incontinence, headache, weight gain, and depression which typically improve over days to weeks following the surgical procedure [42, 67]. Persisting complications include cognitive impairment, seizures, dystonia, hemiparesis, incontinence, lethargy, and personality change [42, 46, 67, 102]. Given that these procedures produce permanent lesions in the brain, the persistence of procedure-induced adverse effects, when they occur, is to be expected. As noted in Tables 38.2 through 38.5, lesional (or ablative) therapies have been used to treat medically refractory movement, mood, and behavioral disturbances. At the present time, use of this type of neurosurgical intervention is relatively uncommon and generally limited to intractable OCD, GTS, aggression, and/or self-injurious behaviors. In light of the common complications noted above and the quickly expanding range of conditions for which DBS and VNS may be useful, lesional interventions are most appropriately regarded as treatments of last resort for any neuropsychiatric condition.

Deep brain stimulation Unlike lesional and/or ablative procedures, DBS modulates neuropsychiatrically salient circuits and networks with relatively minimal neurodestructive effects [103–105]. Using techniques originally developed for the treatment of Parkinson’s disease (PD) and other movement disorders, leads are inserted into the brain under stereotactic MRI guidance. Intra-operative electrophysiologic mapping performed during the introduction of the lead helps confirm proper placement in the target structure. A pulse generator inserted in the chest wall (analogous to a cardiac pacemaker) drives the electrical activity of the stimulator lead. Deep brain stimulation generates a complex threedimensional electrical field around the tip of the stimulator lead, the effect of which changes as a function of distance from the lead. An external magnetic controller allows adjustment of signal intensity, polarity,


Table 38.5. Neurosurgical interventions for neuropsychiatric conditions that are refractory to all other psychotherapeutic, behavioral, environmental, pharmacotherapeutic, and non-invasive procedural treatments.

Condition

Procedure

Comments

Intractable anxiety disorders

Capsulotomy

Two-thirds of patients experienced long-term symptomatic improvement More than half of patients experienced apathy and executive dysfunction, and approximately 15% developed seizures Early evidence suggests that this intervention may be of benefit to persons with treatment-resistant panic disorder or post-traumatic stress disorder; additional evidence is needed to evaluate this possibility


Intractable aggression

Amygdalotomy

Ablation of the posterior medial hypothalamus

May be accomplished by radiofrequency ablation, mechanical destruction, cryothermy, or the injection of wax, alcohol, or oil More than 80 reports describe use of this procedure for this condition; when effective, reduced aggressive and hyperactivity are the most common symptomatic benefits Alone or in combination with amygdalatomy, this procedure also has been used for treatment refractory aggression (including sexual aggression) Uncontrolled case series report favorable behavioral outcomes from this procedure

Self-injurious behavior

Limbic leucotomy Amygdalotomy DBS of the posterior hypothalamus

Severe self-mutilating behaviors may be reduced by these procedures; however, the literature describing their use for this purpose is very limited and does not permit adequate assessment of either benefits or risks

Substance dependence

Cingulotomy Hypothalotomy Substantia innominata or nucleus accumbens resection

Favorable outcomes are reported, the most effective techniques, optimal target structures, and most appropriate neurosurgical candidates are not well established Deep brain stimulation (DBS) may emerge as an alternative to these ablative procedures

Anorexia nervosa

Limbic leucotomy Prefrontal leucotomy Thalamotomy

Two small case series report generally favorable long-term symptomatic and functional outcomes from these procedures when coupled with post-procedure psychotherapy

Schizophrenia

Anterior cingulotomy, with concurrent posterior hypothalotomy and/or fundus stria terminalis lesioning

Target symptoms are not psychosis per se, but concurrent intractable aggression, self-injury, or assaultive or homicidal behaviors Reported outcomes of these procedures are mixed; aggression is the most consistently improved target symptom

Minimally conscious state


Target of lead placement is the anterior intralaminar nucleus of the thalamus and adjacent paralaminar regions When effective, DBS improves level of arousal and is associated with improvements in communication as well as interactions with others and the environment

frequency and pulse width, and permits fine-tuning of the stimulator in order to optimize beneficial effects and minimize adverse effects. Explanations for the effect of DBS on neural function include suppression of neuronal activity, modulation of neural transmission and modulation of neuronal network activity, and induction of long-term synaptic changes [106, 107]. The effects of DBS appear to differ between neurons and glial cells, as a function of the variability of ion channels between cells, and

between healthy and diseased tissue [106]. Whereas there are fundamental differences between DBS and the older ablative procedures, the clinical questions and ethical concerns are similar [18, 108]. Complications, like those associated with lesional interventions, are not specific to the condition for which this procedure is performed. Among the most serious complications associated with lead implantation are hemorrhage, seizures, and infection [105, 109–111]. Delayed complications related to the device

633


implantation include pulse generator malfunction as well as lead fracture or displacement. Battery life varies between patients, in large part due to differences in the parameters for the delivered pulse, and all batteries eventually require replacement. Other adverse effects described in patients treated with DBS include cognitive effects, sensory symptoms, and visual disturbances [110, 111]. With the need for follow-up to monitor all of these factors related to DBS, the decision to place the device amounts to a lifetime commitment to maintaining the device on the part of both the patient and the treatment team [42]. Although DBS is familiar to many clinicians as a treatment for essential tremor, dystonia, and the motor manifestations of PD [112], the clinical applications relevant to BN&NP are expanding rapidly. As noted in Tables 38.2 through 38.5, DBS appears promising as a neurosurgical treatment of intractable OCD, GTS, MDD, self-injurious behaviors, and minimally conscious state. Additional evidence of the efficacy and safety of DBS for these conditions is needed in order for this procedure to attain the levels of acceptance and use that it enjoys in PD, essential tremor, and dystonia. In the interim, however, subspecialists in BN&NP are encouraged to keep abreast of this literature and, when clinical circumstances warrant it, to consider DBS as a possible treatment option for patients with otherwise intractable neuropsychiatric conditions.

Vagal nerve stimulation Vagal nerve stimulation was initially used for the treatment of epilepsy. The observation that patients treated for seizures with VNS frequently had significant improvement in concomitant depressive symptoms led to the use of VNS as a primary treatment of depression. While the exact mechanism by which VNS alleviates depressive symptoms is unknown, stimulation of the vagus nerve influences projections to the solitary tract nucleus and thus modulates activity in the amygdala, dorsal raphe nuclei, locus coeruleus, and ventromedial prefrontal cortex [67]. A bipolar electrode is placed around the cervical portion of the vagus nerve, and stimulation is provided by a pulse generator placed in the anterior chest wall [69]. Because VNS involves lead placement on the vagus nerve in the neck, it avoids an invasive procedure of the central nervous system. Complications associated with VNS include voice alteration, hoarseness, cough, paresthesias of the

634

throat and chin, and shortness of breath [69]. Less common adverse effects include nausea, abdominal pain, syncope, and chest pain [69, 113, 114]. Peri-operative complications include infection, severe bradycardia and asystole, Horner’s syndrome, and partial left-sided facial paralysis [114]. Electrode fracture and device failure may occur but are uncommon [113]. Vagal nerve stimulation is used most often for the treatment of refractory epilepsy and/or depression [113]. There is emerging evidence that VNS also may be useful for the treatment of intractable OCD [43], panic disorder [43], post-traumatic stress disorder [43], and primary headache disorders [115]. However, VNS is not yet used routinely for these purposes and additional evidence is needed to evaluate its safety and efficacy for these or other neuropsychiatric conditions.

Non-invasive procedural interventions Brain function can be modified by applying electrical or magnetic stimulation through the head and without any form of neurosurgical intervention – that is, non-invasively. Among the current complement of non-invasive procedural interventions, electroconvulsive therapy (ECT) is the oldest and most commonly used. Transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), and transcranial direct current stimulation (tDCS) are additional examples of this category of neuropsychiatric treatment. All of these procedures evolved from the convulsive therapies, the history of which is considered briefly here. In this chapter, the two most common of these treatment approaches – ECT and TMS – are reviewed; readers are referred elsewhere for additional discussions of MST, tDCS, and related non-invasive neurostimulation procedures [116–118].

Historical perspective The suggestion that convulsions may improve neuropsychiatric conditions such as depression has its origins in antiquity. Whitrow [119], describing the background for the development of 1927 Nobel laureate (for Physiology or Medicine) Julius Wagner von Juaregg’s use of malaria therapy for general paresis of the insane (a late complication of neurosyphilis), notes that both Hippocrates and Galen described improvements in mental illness after seizures associated with malaria-induced fevers. In the mid-1500s, Paracelsus


introduced oral camphor-induced seizures as a treatment for psychiatric conditions [120], a practice which continued through the early 1930s. In 1934, Von Meduna (reportedly unaware of the previous history), introduced intramuscular camphor (in oil) injections as a treatment for catatonic schizophrenia; he replaced this approach shortly thereafter with intravenous infusion of pentylenetetrazol (also known as metrazol) [120]. Introduction of this treatment approach closely followed the development of insulin coma therapy in 1933 [121] and prefrontal leucotomy in 1935 [4, 121]. After the American Journal of Psychiatry published the proceedings of the international congress on convulsive therapy that was held in 1937, the use of metrazol-induced seizures for psychiatric disorders became common clinical practice [121]. Cerletti (a psychiatrist) and Bini (a neurophysiologist) pioneered ECT, the use of electricity to induce seizures for therapeutic purposes, in 1938 [120]. Their first patient had longstanding catatonia and mutism; following his first treatment with ECT, he spoke for the first time in years. Following on this and similar early successes, ECT was introduced to the USA in 1940. It became a relatively common treatment of psychiatric disorders (especially mood disorders) during the 1940s. During these years, curare was used as a muscle relaxant in order to mitigate treatmentrelated injuries associated with convulsions; as a result of fatalities associated with the use of this agent, it was replaced by succinylcholine and combined with general anesthesia in 1951 for the purpose of improving the safety of ECT [120]. By the late 1950s and early 1960s, the practice of ECT was relatively common and its use as a treatment of psychiatric disorders was supported by several controlled clinical trials [120–124]. These demonstrated response rates of depression to ECT that were comparable or superior to those of antidepressant medications [120]. Additionally, comparative efficacy studies of ECT for schizophrenia demonstrated that the long-term outcomes following treatment with this procedure were comparable to those afforded by neuroleptics (first-generation antipsychotic medications) and superior to psychotherapy or milieu treatment [125, 126]. Accordingly, ECT became a mainstay of treatment for severe psychiatric disorders by the early 1970s. Public opinion about ECT shifted dramatically following the portrayal of ECT as a tool for punishment

and behavioral control in the film One Flew Over the Cuckoo’s Nest (1975, based on the 1962 novel of the same name by Ken Kesey). In this movie, the protagonist (played by actor Jack Nicholson) is seen receiving ECT without muscle relaxants or general anesthesia and simulating a treatment-induced generalized tonicclonic seizure. This depiction of ECT more closely resembled the manner in which it was administered during the late 1930s (prior to the use of curare for muscle relaxation) than during the film’s production period. However, the combined effects of Nicholson’s powerful performance and the average person’s relative inexperience with ECT resulted in an immediate and long-lasting negative view of ECT amongst members of the general public. As a function of the depiction of ECT in this film, more than any other factor, the use of this procedure declined substantially over the following three decades. Despite these public image problems and waning use, the science of ECT evolved substantially during this same period. Constant voltage, sine wave stimulation devices were gradually replaced by constant current, brief pulse ECT devices, which minimized the adverse cognitive effects of treatment [120, 127]. Standards for the education and training of treatment providers and for the consent and delivery of ECT were promulgated by the American Psychiatric Association [128, 129], culminating in their 2001 report on ECT treatment, training and privileging [130]. As reviewed in Rudorfer et al. (2003) [120], the refinement of treatment techniques, the performance of controlled trials for acute mania, depression, and combined use with pharmacotherapies, and the publication of favorable editorials in the New England Journal of Medicine [131] and Journal of the American Medical Association [132] established an important and continued role of ECT in the management of neuropsychiatric disorders. Concurrent to advances in ECT, TMS developed as an alternative means of non-invasively modifying brain function [133]. Unlike ECT, which involves the direct application of electrical current, TMS capitalizes on Faraday’s law of induction. This law holds that the electromotive force in a closed circuit is equal to the rate of change of magnetic flux through the area enclosed by that circuit. The neurobiological application of this law dictates that extracranial application of pulsed magnetic fields induces changes in the electrical currents in the cortex underlying the site of their application. Neurons in the area of cortex to which TMS is applied depolarize and generate action

635


potentials. These, in turn, induce activity in the neural circuits and networks in which those neurons participate and, when the stimulation is sufficiently strong, produce observable changes in cognition, emotion, behavior, and/or sensorimotor function. This approach to neurostimulation presented several possible advantages over ECT. The application of TMS does not require general anesthesia and can be provided at levels that do not induce seizures. Additionally, the focal nature of TMS permits stimulation of discrete, neurobehaviorally salient circuits in an awake individual – thereby affording real-time objective assessment of the effects of TMS by its administrator and subjective report by its recipient. Additionally, early descriptions of this brain stimulation method did not engender the same type or force of negative public opinion as ECT. Collectively, these conditions established a context in which TMS developed both as a tool for the study of brain function in healthy individuals and also as a treatment for neuropsychiatric disorders. The clinical applications of TMS have been the subjects of increasing attention over the last three decades [134]. In 2008, the US Food and Drug Administration (FDA) approved TMS as a treatment for depression, leading to the rapid promulgation of TMS clinics in this country. Unapproved, or “off-label,” uses for the treatment of other neuropsychiatric conditions remain investigational; however, if history serves as a guide to the future, it seems likely that this technology will be used increasingly for such purposes as its providers gain experience and grow confident in their abilities. With this historical background, non-invasive procedural interventions remain important components of the therapeutic repertoire of subspecialists in BN&NP. As the literatures on ECT and TMS are extensive, a brief overview and summary is provided here in order to introduce readers to the general principles of these neuropsychiatric treatments and their most common and emerging applications. Readers interested in learning more about these subjects are referred elsewhere for detailed reviews of ECT [130, 135–138] and TMS [117, 134, 137–139].

Electroconvulsive therapy Electroconvulsive therapy uses electricity to induce seizures for therapeutic purposes. The most common use of ECT is for the treatment of depression, which is used to anchor this review of pre-treatment consideration and treatment parameters and to frame

636

the discussion of other clinical applications of this procedure.

Pre-treatment considerations As noted in the preceding discussion of the history of ECT, this procedure remains a subject of considerable public controversy. Obtaining informed consent for treatment is imperative; given the nature of the conditions for which ECT is used, this may entail obtaining consent from a legally authorized representative of the patient and/or permission to provide treatment under court order. Essential elements of the consent process are described in the report of the American Psychiatric Association’s Task Force on ECT [130]. Additionally, the current regulatory environment (especially in the USA) necessitates that physicians attend to additional local requirements for pre-treatment evaluations, other physician (including anesthesia) consultations, or procedures (including other treatments). Since ECT requires the administration of general anesthesia, including muscle relaxants, and also risks increasing intracranial pressure, performing a comprehensive pre-treatment general physical and neurological assessment is necessary [130]. This assessment should clarify the clinical indication for ECT as well as the types and responses to prior treatments for that condition. Treatment-related medical, neurological, dental, and anesthetic histories and risks also are evaluated. Although there are no absolute contraindications to ECT, there are situations that increase the risk for treatment-related adverse medical outcomes. The presence of a space-occupying intracranial lesion is potentially concerning in light of treatment-induced increases in intracranial pressure. However, the presence of slow-growing meningiomas (and other similar masses) that produce no mass effect does not present an unacceptably high, or pharmacologically unmanageable, treatment risk [140, 141]. Unstable angina, poorly compensated congestive heart failure, severe cardiac valve disease, unstable vascular aneurysms or malformations, recent myocardial infarction or stroke, and severe pulmonary disease, among other causes of increased anesthesia risk, present challenges to the safe administration of ECT. However, in most cases, the ECT-related risks associated with these conditions are manageable by an experienced anesthesiologist and therefore do not constitute treatment contraindications. Additionally, prior intracranial surgeries and


the presence of implantable devices (including DBS, VNS, and cardiac devices) do not present irremediable treatment risks for most patients; among patients with implantable devices, however, coordinating care with the clinicians responsible for their management is essential. Among medically and neurologically uncomplicated patients, routine pre-ECT laboratory evaluation is similar to that undertaken in most pre-anesthesia assessments: complete blood count, serum electrolyte levels (especially sodium and potassium), and electrocardiography (ECG) [130]. Among women with childbearing potential, performing a serum pregnancy test is prudent. The need for other tests, including additional blood chemistries, endocrinological assessments, liver or renal function tests, urinalysis, human immunodeficiency virus antibody titers, medication levels, and so forth, is determined by the specifics of each patient’s clinical presentation [142]. Chest roentgenogram (X-ray) is commonly performed as part of the pre-treatment work-up; lumbosacral spine imaging (a common element of the pre-treatment evaluation prior to the use of muscle relaxants during ECT), also remains appropriate for patients with a history of, or at risk for, osteoporosis, for older patients, or those with histories of back injuries. Cerebral neuroimaging may not be necessary in patients without histories of neurological conditions and in whom funduscopic and neurological examinations are entirely normal [120]. However, and as discussed in Chapter 26 (Structural neuroimaging), the conditions for which ECT might be used are ones for which the evaluation by subspecialists in BN&NP generally includes MRI. Accordingly, pre-treatment evaluation using MRI is encouraged for patients with known neurological comorbidities, treatmentrefractory primary psychiatric disorders, or atypical neuropsychiatric presentations.

Cognitive impairment and assessment Cognitive impairments are common among persons receiving ECT, including those arising as a result of the condition at which this treatment is directed, neurological comorbidities, or the effects of treatment itself [120, 130]. Treatment-related confusion (postictal confusion) is common and transient, with duration varying as a function of the specific parameters of treatment (longer with bilateral electrode placement and high electrical stimulus intensity – discussed further in the following section). Treatment-related

memory impairments are also common. These include impaired consolidation of information in the period preceding treatment (retrograde amnesia), impaired new learning and consolidation of information during the days or weeks during which treatment is administered and/or impaired new learning and consolidation following the treatment period (anterograde amnesia). In general, ECT-induced retrograde amnesia follows Ribot’s law, with memories for events proximate to treatment being affected more severely than more remote memories. Additionally, retrograde amnesia in this context also generally demonstrates the phenomenon of “shrinking,” whereby the period of time for which memory is impaired approaches the onset of treatment as time since treatment discontinuation elapses. Amnesia for events and information presented during the period of treatment also is common. Analogous to the effects of traumatic brain injury or other acute neurological insults on declarative memory, peri-event impairments in memory are not unexpected and are neurobiologically plausible. Similarly, problems with new learning, consolidation, and retrieval may continue in some patients following ECT discontinuation, but these impairments usually are transient and complete recovery is the norm [143]. For some patients, however, these may become persistent and distressing problems that lead to legal action against their treatment providers [144]. The process of pre-treatment informed consent therefore requires education of the patient and/or others providing consent to treatment about the likelihood of peri-ECT memory disturbances and the possibility of persistent post-ECT memory problems (retrograde, anterograde, or both). When explained fully, this information may mitigate patient distress about impaired recollection of events in the peri-ECT period. Additionally, performing pre-ECT neuropsychological testing in all patients capable of participating effectively in such assessments is prudent. As an element of this assessment, obtaining a detailed history about the patient’s cognitive abilities and functional status from a knowledgeable and reliable informant, including the effects of the patient’s neuropsychiatric condition on cognition and daily function, is essential. Information yielded by neuropsychological examination and informant interview may allow postECT cognitive impairments to be attributed more accurately to the condition for which this treatment was provided, neurodevelopmental, neurological,

637


and/or neuropsychiatric, ECT itself, or some combination of these factors.

Treatment parameters In the USA, ECT devices provide bidirectional brief pulses; these pulses vary by pulse width (e.g., 0.25–2.0 ms in standard ECT, or 0.25–0.5 ms in ultra-brief pulse ECT), pulse frequency (e.g., 40–90 Hz, or pulse pairs per second), duration of the train of pulses delivered (e.g., 0.5–8.0 s), and peak current (e.g., 0.5–1.0 amp). Charge is used as a single composite stimulus intensity parameter and is reported in millicoulombs (mC). Stimulus dosing is determined by a titrating to seizure threshold during the first treatment, after which subsequent treatments are administered with stimulus dosing at a specific level above seizure threshold. Seizure thresholds vary between patients by more than 40-fold [145, 146], and tend to increase over the course of ECT treatment. Accordingly, fixed-formula dosing schedules (as with most pharmacotherapies) are less useful than ones that are individualized to the patient receiving treatment [130, 147, 148]. The placement of stimulus electrodes requires balancing two considerations: treatment efficacy and cognitive toxicity. Bifrontotemporal stimulus electrode placement is the traditional method of ECT delivery. However, non-dominant (usually right hemisphere) unilateral (RUL) stimulus electrode placement is associated with less frequent, severe, and persistent memory impairment and a more rapid and robust antidepressant effect than bitemporal ECT. Many clinicians therefore begin treatment using a RUL stimulus electrode placement. Unfortunately, the use of RUL stimulus placement necessitates suprathreshold stimulus intensities that, in turn, increase the likelihood of treatment-related adverse cognitive effects [149–151]. Rudorfer and colleagues (2003) [120] suggest that a reasonable balance between efficacy and cognitive toxicity may be achieved using RUL ECT with stimulus intensity set 250% above seizure threshold. Response to treatment is monitored electroencephalographically and by visual monitoring of the convulsive response [130, 152]. Most ECT devices include two-channel electroencephalography (EEG) capability for scalp-electrode monitoring of ECTinduced seizures. Convulsive response is monitored in a distal extremity to which a blood pressure cuff is applied prior to muscle relaxant administration. Inflating this cuff to a level above systolic blood

638

pressure prevents the flow of muscle relaxants to the distal extremity while preserving the motor response to cerebral seizure. When RUL ECT is provided, applying the blood pressure cuff to the distal right lower extremity is recommended in order to permit assessment for the induction of bihemispheric seizure activity. Seizures generally begin by the time stimulus delivery is completed, and seizure activity on EEG generally lasts 10–15 seconds longer than observable convulsive responses (when they are observed at all). Although it is common practice for practitioners to use seizure duration of 25 or more seconds as a benchmark of seizure adequacy, the relationship between seizure duration and adequacy (i.e., effectiveness) is complex and a matter of controversy [149, 152–154]. In general, clinical response to treatment over the course of ECT is the most useful measure of the adequacy of induced seizures. In the USA, ECT is generally provided three times weekly for a total of 6–12 sessions; in the UK and Europe, treatment is more commonly provided twice weekly and for a fewer total number of sessions. The available evidence suggests that these approaches are equivalent in terms of therapeutic effect, but that thrice weekly treatment produces a more rapid response at the cost of increased cognitive toxicity [120, 155]. The stimulus intensity required to effect clinical improvement in target symptoms generally rises during treatment, and may be accompanied by increases in treatment-induced memory impairment and/or confusion. Additionally, the stimulus intensities used during the early portions of RUL ECT may become less effective and/or less well tolerated as treatment-induced seizure threshold rises. Continuous re-evaluation for clinical effectiveness is necessary and may sometimes prompt the use of either highdose RUL ECT or a switch to bilateral (bitemporal or bifrontal) ECT. In some clinical settings, multiple seizures are induced in a single treatment session. Also known as multiple ECT (or MECT), the purpose of this approach is to increase the rate of clinical response and decrease the total number of treatment sessions required to produce that response. Although this practice is discouraged as a treatment for psychiatric disorders [130], it may have a role in the treatment of intractable epilepsy or neuroleptic malignant syndrome [130]. Most patients receiving ECT require continued treatment with medications upon ECT discontinuation. In light of the severity of the conditions for which


ECT is prescribed, high rates of relapse following ECT discontinuation are common [120, 130]. When such relapses occur, maintenance ECT may be beneficial [120, 130, 156]. This generally involves treatment provided weekly after a successful index course of ECT and a gradual transition to less frequent treatments (e.g., once every 1–3 months).

Clinical applications The most common primary indications for ECT are: (1) an urgent need (either psychiatrically or medically) for a rapid response; (2) alternative treatments are associated with a higher risk than ECT; (3) the patient for whom treatment is considered is known to have a preferential response to ECT; and (4) patient preference for ECT [130]. In most circumstances, patients are referred for ECT on secondary bases, including: lack of adequate response and/or demonstrated intolerance to other treatments; or clinical deterioration to the point that the primary indications for ECT are met [130]. Depression is the most common clinical condition leading patients to meet one or more of these indications for ECT [157, 158]. This treatment is used most often for the treatment of persons with depression, especially those with psychotic or severely melancholic depressions as well as patients that are imminently suicidal or refusing life-sustaining sustenance as a result of their depression [159–161]. This procedure also may be useful and safe as a treatment for severe antepartum depression, especially among women for whom treatment with antidepressant medications is not possible. Bipolar depression, acute mania, and mixed mood states respond to ECT [162]; in these settings, ECT may be more effective and provide a more rapid treatment response than pharmacotherapies [120]. Despite its effectiveness, it is more commonly used as a secondor third-line treatment among patients whose bipolar disorders are refractory to pharmacotherapies or among patients developing a manic delirium [163]. Electroconvulsive therapy is rarely used as a treatment for schizophrenia, but may be useful for this condition when rapid global improvement and reduction of symptoms is required [164]. Additionally, ECT may be an effective treatment for comorbid depressive symptoms or recurrent major depression among persons with comorbid schizophrenia [165, 166].

The published literature does not support the use of ECT as a treatment for dysthymia, anxiety disorders, substance-use disorders, or personality disorders. When these conditions are comorbid with a mood disorder for which ECT is appropriate, however, they do not constitute contraindications to this treatment [120]. Patients with personality disorders and an ECT-appropriate mood disorder tend to respond less robustly and maintain treatment benefits less consistently than individuals without personality disorders [167, 168]. This does not imply that patients with comorbid depression and personality disorders are poor candidates for ECT, but it does suggest that this comorbidity may require modification of treatment response expectations among all parties to this treatment. Similarly, ECT may be of benefit for the treatment of severe mood disorders associated with neurological conditions, including stroke, traumatic brain injury, movement disorders, neurodegenerative dementias, and neurodevelopmental disorders. The use of ECT in these conditions may require adjustments for seizure threshold and increase susceptibility to cognitive toxicity. However, ECT appears to be a useful and clinically appropriate treatment for patients with severe mood disorders secondary to or comorbid with neurological disorders when those patients are unable to tolerate or are inadequately responsive to pharmacotherapies [120]. Catatonia, whether as a feature of a severe mood or psychotic disorder or as a manifestation of a primary neurological disorder, is often ECT-responsive [163, 169–171]. Although benzodiazepines are regarded widely as the most appropriate initial treatment for catatonia [172], ECT may be preferable to prolonged treatment with these agents and/or when patients continue deteriorating clinically despite their use. Neuroleptic malignant syndrome, which may be a form of malignant catatonia [173], also responds to ECT [174]. Finally, ECT may improve motor symptoms among patients with PD and reduce seizure frequency among patients with intractable epilepsy [120]. Since the introduction of invasive brain stimulation techniques and other neurosurgical interventions for these conditions, ECT is rarely used for these purposes in the USA and Europe [175]. In developing countries in which these procedures are unavailable or cost-prohibitive, however, ECT is used more often for these and related purposes [176].

639


Transcranial magnetic stimulation This neurostimulation technology developed in the 1980s as another method of non-invasively modifying brain function [133]. Pulsed magnetic fields are used to induce electrical current, neuronal depolarization, and altered activity in the neural circuits and networks in the area of cortex over which the magnetic fields are applied. The devices used to produce these magnetic fields generally depolarize local neurons up to a depth of approximately two centimeters. The application of single pulses during cortical activity reliably impairs cortical function by decreasing signal-to-noise ratio in information processing circuits, either as a result of introducing “noise” into those circuits or by enhancing cortical inhibition [177]. These effects are short-lived and do not persist beyond the period of stimulus application. By contrast, transcranial application of repetitive magnetic pulses (rTMS) produces persistent shifts in the efficiency of excitatory synaptic transmission and/or modulation of cortical inhibition; these shifts permit this method of neurostimulation to exert effects on neural function that persist beyond the period of stimulus delivery [177–179]. Collectively, these properties permit single-pulse and rTMS to be used for a variety of purposes, including mapping of brain function, measuring cortical excitability, and as a therapeutic intervention [134]. In most clinical contexts relevant to BN&NP, however, therapeutic uses of this technology employ rTMS [134, 180]. The intensity of TMS stimuli delivered for therapeutic purposes is based on the determination of motor threshold (MT), the smallest pulse that produces a motor evoked potential or a visible movement of the thumb, wrist, or fingers in at least half of ten stimulations. After establishing MT (which varies between patients and with the device used), the coil is placed at the intended site of stimulation and delivered at a pre-determined level relative to MT (e.g., 120% MT). This is a potential source of variance in treatment response and effectiveness: predicating nonmotor stimulation intensity on MT presumes that nonmotor neurons respond to such intensities in a manner similar to motor neurons. Additionally, maintaining stimulus intensity at a specific level relative to MT presumes that the distance between the coil and cortex does not differ substantially from that used to determine MT despite moving the device to a new location

640

over the scalp; since magnetic field strength decreases exponentially as a function of the distance from its source, violation of this presumption may result in large changes in stimulus intensity based simply on changing the location of stimulus delivery. The frequencies at which stimulation is delivered are divided into two general categories: low (≤1 Hz) and high (10–20 Hz). The neurobiological effects of stimulation at either low or high frequencies are complex; simplistically, low frequency stimulation tends to decrease neuronal excitability whereas high frequency stimulation tends to increase neuronal excitability [177, 179, 181]. Although very high frequency rTMS can induce seizures, following well-established and now longstanding safety guidelines minimizes this risk substantially [182]. Although optimal treatment parameters for the therapeutic use of rTMS remain subjects of active investigation, the available literature suggests that higher treatment intensities, number of pulses per session, and greater numbers of pulses per course tend to confer better outcomes [183]. Patients receiving rTMS do not require general anesthesia or muscle relaxants and remain awake and conversant during this procedure. Treatment using high-frequency rTMS within current safety guidelines does not induce seizures in most patients. However, its use should be undertaken with caution in patients with a personal or family history of epilepsy, another condition that substantially increases seizure risk, or taking medications that lower seizure threshold. The device used to deliver magnetic pulses to the brain produces a loud clicking sound (up to 120–130 dB at 10 cm from the coil) in the middle of the range of hearing frequencies (2–7 kHz); accordingly, the use of ear protection (to reduce sound pressure by 30 dB or more) during treatment with rTMS is appropriate. The delivery of magnetic pulses induces currents not only in brain tissues but also in electromagnetically sensitive superficial tissues, including scalp muscles. Headaches and scalp discomfort are common treatment-induced side effects, and are rarely severe enough to prompt treatment discontinuation. Because the magnetic field produced by rTMS may affect the function of implantable devices, provision of this treatment to patients with such devices (regardless of the location in the body in which they and their leads are implanted) requires consultation and collaboration with the clinician responsible for their management. Intracranial ferromagnetic objects (e.g., bullet fragments) and/or non-removable metal objects within


30 cm of the face of the treatment coil are contraindications to treatment with TMS.

Clinical applications Guided by knowledge of the neuroanatomy of cognition, emotion, behavior, and sensorimotor function, rTMS may be used to alter the function of neurobehaviorally salient circuits among patients with neurological conditions or psychiatric disorders. Although the cortical targets of treatment must be relatively superficial (i.e., within the approximately 2 cm depth to which this form of neurostimulation can be delivered), the range of neuropsychiatric disorders involving neural circuits whose function may be amenable to modification using rTMS is broad. At the time of this writing, rTMS is US FDAapproved as a treatment for adult patients with major depressive disorder who fail to achieve satisfactory improvement from one prior antidepressant medication used at or above the typical minimally necessary effective dose and duration. Meta-analyses of rTMS for depression report a mean weighted effect size of 0.55 (moderate) [134]. The target of rTMS is the dorsolateral prefrontal cortex (DLPFC); most studies targeting the left DLPFC employed high frequency (10, 15, or 20 Hz) rTMS whereas those targeting the right DLPFC generally used low (1 Hz) rTMS. The mean effect size associated with rTMS for depression targeting the left DLPFC was 0.53, right DLPFC was 0.82, and both (not simultaneously) was 0.47. This meta-analysis also concluded that the evidence marginally favored rTMS monotherapy over rTMS adjunctive to antidepressant medication, although this finding appears to reflect the contribution of rTMS monotherapy studies to this literature rather than studies formally comparing rTMS monotherapy versus combination therapy. Consistent with this indication and meta-analysis, rTMS is used most commonly in clinical practice as a treatment of major depressive disorders and often as an adjunct to ongoing antidepressant pharmacotherapies. Meta-analysis of clinical studies also suggests a possible role for the treatment of auditory verbal hallucinations (AVH) in schizophrenia using 1 Hz rTMS [134]. In most studies, rTMS targeted the left temporoparietal cortex; this was intended to induce persistent inhibition in posterior language-related cortex, and thereby to decrease aberrant (i.e., verbal hallucinatory) signal processing. The data available at the time of this analysis yielded a mean weighted effect size of

0.54, similar to that associated with its use as a treatment of depression. A subsequent randomized controlled study of 1 Hz rTMS for AVH in schizophrenia [184] failed to find a significant effect. The metaanalysis also failed to find an effect of rTMS on negative symptoms in schizophrenia. The use of rTMS as a treatment for the symptoms of schizophrenia remains investigational presently; however, it holds promise as a non-pharmacologic intervention for patients with schizophrenia predominated by AVH, for patients whose AVH are inadequately responsive to pharmacotherapies, or who are unable to tolerate pharmacotherapies for this problem. As reviewed in Slotema et al. (2010) [134], there are positive reports of rTMS as a treatment for catatonia, mania, post-traumatic stress disorder, OCD, GTS, panic disorder, bulimia nervosa, nicotine dependence, cocaine dependence, bulimia, and motor conversion disorder. Repetitive TMS also may improve dystonia [185], the motor symptoms of PD [185], including levodopa-induced dyskinesias [186], poststroke motor impairments [187] and aphasia [188, 189], and medically intractable epilepsy [190]. The literature describing the use of rTMS for these and other neuropsychiatric conditions is growing rapidly, and subspecialists in BN&NP will serve their patients well by remaining well informed of developments in this emerging area of neurotherapeutics.

Conclusion Procedural interventions comprise an expanding set of non-invasive and neurosurgical techniques. The psychosurgical treatments of the early twentieth century represented ambitious, albeit flawed, efforts to address human suffering, and their widespread misapplication engendered justified medical and public criticism. However, there are patients with extremely severe, disabling, and treatment-refractory neuropsychiatric conditions for whom medications, psychotherapies, and other environmental and behavioral interventions are ineffective. For these patients, modern procedural interventions, including an increasingly broad range of non-invasive neurostimulation therapies, offer safe and effective treatments for carefully selected patients with neuropsychiatric conditions that are not adequately responsive to conventional treatments. In the future, the repertoire of procedural interventions for neuropsychiatric conditions may further expand to include gene therapy, implantable drug

641


delivery systems, and neural transplantation [98]. Additional evidence is needed to evaluate the role of these and all other procedural interventions for neuropsychiatric conditions, as well as combinations of interventions for patients with the most behaviorally challenging and treatment-refractory disorders. As this evidence emerges, subspecialists in BN&NP are encouraged to consider its implications on the care of their patients. Carefully considered and skillfully performed, procedural interventions offer the potential to alleviate suffering and improve quality of life among persons whose neuropsychiatric conditions remain beyond the reach of conventional medical treatments.

References 1. Wind JJ, Anderson DE. From prefrontal leukotomy to deep brain stimulation: the historical transformation of psychosurgery and the emergence of neuroethics. Neurosurg Focus 2008;25(1):E10. 2. Arciniegas DB, Kaufer DI, Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association, Society for Behavioral and Cognitive Neurology. Core curriculum for training in Behavioral Neurology & Neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2006;18(1):6–13.

11. Heller AC, Amar AP, Liu CY, Apuzzo ML. Surgery of the mind and mood: a mosaic of issues in time and evolution. Neurosurgery 2006;59(4):720–33; discussion 33–9. 12. U.S. Department of Health, Education, and Welfare. Protection of human subjects. Use of psychosurgery in practice and research: report and recommendations of National Commission for the Protection of Human Subjects. Fed Regist. 1977;42(99):26,318–32. 13. Gray TS. Functional and anatomical relationships among the amygdala, basal forebrain, ventral striatum, and cortex. An integrative discussion. Ann N Y Acad Sci. 1999;877:439–44. 14. Heimer L. Anatomy of Neuropsychiatry: The New Anatomy of the Basal Forebrain and its Implications for Neuropsychiatric Illness. Amsterdam: Academic Press/Elsevier; 2008. 15. Kuhn J, Gaebel W, Klosterkoetter J, Woopen C. Deep brain stimulation as a new therapeutic approach in therapy-resistant mental disorders: ethical aspects of investigational treatment. Eur Arch Psychiatry Clin Neurosci. 2009;259(Suppl. 2):S135–41. 16. Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9(3):471–81.

3. Alt KW, Jeunesse C, Buitrago-Tellez CH et al. Evidence for stone age cranial surgery. Nature 1997; 387(6631):360.

17. Seminowicz DA, Mayberg HS, McIntosh AR et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 2004;22(1):409–18.

4. Feldman RP, Goodrich JT. Psychosurgery: a historical overview. Neurosurgery 2001;48(3):647–57; discussion 57–9.

18. Rabins P, Appleby BS, Brandt J et al. Scientific and ethical issues related to deep brain stimulation for disorders of mood, behavior, and thought. Arch Gen Psychiatry 2009;66(9):931–7.

5. Gross CG. ‘Psychosurgery’ in renaissance art. Trends Neurosci. 1999;22(10):429–31. 6. Burckhardt G. Uber Rindenexcisionen, als Beitrag zur operativen Therapie der Psychosen. Allgemeine Z Psychiatrie psychisch-gerichtliche Medizin 1891;47: 463–548. 7. Manjila S, Rengachary S, Xavier AR, Parker B, Guthikonda M. Modern psychosurgery before Egas Moniz: a tribute to Gottlieb Burckhardt. Neurosurg Focus 2008;25(1):E9. 8. Valenstein ES. Great and Desperate Cures: the Rise and Decline of Psychosurgery and other Radical Treatments for Mental Illness. New York, NY: Basic Books; 1986. 9. Swayze VW, 2nd. Frontal leukotomy and related psychosurgical procedures in the era before antipsychotics (1935–1954): a historical overview. Am J Psychiatry 1995;152(4):505–15. 10. Freeman WJ, Watts JW, Hunt T. Psychosurgery; Intelligence, Emotion and Social Behavior Following

642

Prefrontal Lobotomy for Mental Disorders. Springfield, IL: C. C. Thomas; 1942.

19. Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008;213(1–2):93–118. 20. Huey ED, Zahn R, Krueger F et al. A psychological and neuroanatomical model of obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 2008;20(4):390–408. 21. Hurley RA, Black DN, Stip E, Taber KH. Surgical treatment of mental illness: impact of imaging. J Neuropsychiatry Clin Neurosci. 2000;12(4):421–4. 22. DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol. 2007;64(1):20–4. 23. Hauptman JS, DeSalles AA, Espinoza R, Sedrak M, Ishida W. Potential surgical targets for deep brain stimulation in treatment-resistant depression. Neurosurg Focus 2008;25(1):E3.


24. Shah DB, Pesiridou A, Baltuch GH, Malone DA, O’Reardon JP. Functional neurosurgery in the treatment of severe obsessive compulsive disorder and major depression: overview of disease circuits and therapeutic targeting for the clinician. Psychiatry (Edgmont) 2008;5(9):24–33. 25. Irle E, Exner C, Thielen K, Weniger G, Ruther E. Obsessive-compulsive disorder and ventromedial frontal lesions: clinical and neuropsychological findings. Am J Psychiatry 1998;155(2):255–63. 26. Dougherty DD, Baer L, Cosgrove GR et al. Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am J Psychiatry 2002;159(2):269–75. 27. Kim CH, Chang JW, Koo MS et al. Anterior cingulotomy for refractory obsessive-compulsive disorder. Acta Psychiatr Scand. 2003;107(4): 283–90. 28. Oliver B, Gascon J, Aparicio A et al. Bilateral anterior capsulotomy for refractory obsessive-compulsive disorders. Stereotact Funct Neurosurg. 2003;81(1–4): 90–5. 29. Liu K, Zhang H, Liu C et al. Stereotactic treatment of refractory obsessive compulsive disorder by bilateral capsulotomy with 3 years follow-up. J Clin Neurosci. 2008;15(6):622–9. 30. Montoya A, Weiss AP, Price BH et al. Magnetic resonance imaging-guided stereotactic limbic leukotomy for treatment of intractable psychiatric disease. Neurosurgery 2002;50(5):1043–9; discussion 9–52. 31. Yaryura-Tobias JA, Stevens KP, Perez-Rivera R, Boullosa OE, Neziroglu F. Negative outcome after neurosurgery for refractory obsessive-compulsive spectrum disorder. World J Biol Psychiatry 2000;1(4):197–203. 32. Lipsman N, Neimat JS, Lozano AM. Deep brain stimulation for treatment-refractory obsessive-compulsive disorder: the search for a valid target. Neurosurgery 2007;61(1):1–11; discussion –13. 33. Mallet L, Polosan M, Jaafari N et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med. 2008;359(20):2121–34. 34. Nuttin BJ, Gabriels L, van Kuyck K, Cosyns P. Electrical stimulation of the anterior limbs of the internal capsules in patients with severe obsessive-compulsive disorder: anecdotal reports. Neurosurg Clin N Am. 2003;14(2):267–74. 35. Nuttin BJ, Gabriels LA, Cosyns PR et al. Long-term electrical capsular stimulation in patients with obsessive-compulsive disorder. Neurosurgery 2003;52(6):1263–72; discussion 72–4.

36. Rauch SL, Dougherty DD, Malone D et al. A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. J Neurosurg. 2006;104(4):558–65. 37. Swedo SE, Pietrini P, Leonard HL et al. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Revisualization during pharmacotherapy. Arch Gen Psychiatry 1992;49(9): 690–4. 38. Sachdev P, Trollor J, Walker A et al. Bilateral orbitomedial leucotomy for obsessive-compulsive disorder: a single-case study using positron emission tomography. Aust N Z J Psychiatry 2001;35(5):684–90. 39. Lakhan SE, Callaway E. Deep brain stimulation for obsessive-compulsive disorder and treatment-resistant depression: systematic review. BMC Res Notes. 2010; 3:60. 40. Sturm V, Lenartz D, Koulousakis A et al. The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders. J Chem Neuroanat. 2003;26(4):293–9. 41. Rauch SL, Dougherty DD, Cosgrove GR et al. Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive compulsive disorder. Biol Psychiatry 2001;50(9):659–67. 42. Read CN, Greenberg BD. Psychiatric neurosurgery 2009: review and perspective. Semin Neurol. 2009;29(3):256–65. 43. George MS, Ward HE, Jr., Ninan PT et al. A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders. Brain Stimul. 2008;1(2):112–21. 44. Martinez-Torres I, Hariz MI, Zrinzo L, Foltynie T, Limousin P. Improvement of tics after subthalamic nucleus deep brain stimulation. Neurology 2009;72(20):1787–9. 45. Rauch SL, Baer L, Cosgrove GR, Jenike MA. Neurosurgical treatment of Tourette’s syndrome: a critical review. Compr Psychiatry 1995;36(2): 141–56. 46. Temel Y, Visser-Vandewalle V. Surgery in Tourette syndrome. Mov Disord. 2004;19(1):3–14. 47. Cappabianca P, Spaziante R, Carrabs G, de Divitiis E. Surgical stereotactic treatment for Gilles de la Tourette’s syndrome. Acta Neurol (Napoli) 1987;9(4): 273–80. 48. Babel TB, Warnke PC, Ostertag CB. Immediate and long term outcome after infrathalamic and thalamic lesioning for intractable Tourette’s syndrome. J Neurol Neurosurg Psychiatry 2001;70(5):666–71. 49. Neuner I, Podoll K, Janouschek H et al. From psychosurgery to neuromodulation: deep brain

643


stimulation for intractable Tourette syndrome. World J Biol Psychiatry 2009;10(4 Pt 2):366–76. 50. Neuner I, Podoll K, Lenartz D, Sturm V, Schneider F. Deep brain stimulation in the nucleus accumbens for intractable Tourette’s syndrome: follow-up report of 36 months. Biol Psychiatry 2009;65(4):e5–6.

65. Greenberg BD, Nuttin B, Rezai AR. Education and neuromodulation for psychiatric disorders: a perspective for practitioners. Neurosurgery 2006;59(4):717–19.

51. Visser-Vandewalle V, Ackermans L, van der Linden C et al. Deep brain stimulation in Gilles de la Tourette’s syndrome. Neurosurgery 2006;58(3):E590.

66. Schlaepfer TE, Cohen MX, Frick C et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008;33(2):368–77.

52. Visser-Vandewalle V, Temel Y, Boon P et al. Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. Report of three cases. J Neurosurg. 2003;99(6):1094–100. 53. Houeto JL, Karachi C, Mallet L et al. Tourette’s syndrome and deep brain stimulation. J Neurol Neurosurg Psychiatry 2005;76(7):992–5. 54. Ackermans L, Temel Y, Cath D et al. Deep brain stimulation in Tourette’s syndrome: two targets? Mov Disord. 2006;21(5):709–13. 55. Mink JW, Walkup J, Frey KA et al. Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome. Mov Disord. 2006;21(11):1831–8. 56. Abosch A, Cosgrove GR. Biological basis for the surgical treatment of depression. Neurosurg Focus 2008;25(1):E2. 57. Kelly D. Therapeutic outcome in limbic leucotomy in psychiatric patients. Psychiatr Neurol Neurochir. 1973;76(5):353–63. 58. Kelly D, Mitchell-Heggs N. Stereotactic limbic leucotomy – a follow-up study of thirty patients. Postgrad Med J. 1973;49(578):865–82. 59. Kelly D, Richardson A, Mitchell-Heggs N. Stereotactic limbic leucotomy: neurophysiological aspects and operative technique. Br J Psychiatry 1973;123(573): 133–40. 60. Kelly D, Richardson A, Mitchell-Heggs N et al. Stereotactic limbic leucotomy: a preliminary report on forty patients. Br J Psychiatry 1973;123(573):141–8. 61. Ballantine HT, Jr., Bouckoms AJ, Thomas EK, Giriunas IE. Treatment of psychiatric illness by stereotactic cingulotomy. Biol Psychiatry 1987;22(7):807–19. 62. Spangler WJ, Cosgrove GR, Ballantine HT, Jr. et al. Magnetic resonance image-guided stereotactic cingulotomy for intractable psychiatric disease. Neurosurgery 1996;38(6):1071–6; discussion 6–8. 63. Mayberg HS, Lozano AM, Voon V et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45(5):651–60. 64. Jimenez F, Velasco F, Salin-Pascual R et al. A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic

644

peduncle. Neurosurgery 2005;57(3):585–93; discussion –93.

67. Andrade P, Noblesse LH, Temel Y et al. Neurostimulatory and ablative treatment options in major depressive disorder: a systematic review. Acta Neurochir (Wien) 2010;152(4):565–77. 68. Sachdev PS, Chen X. Neurosurgical treatment of mood disorders: traditional psychosurgery and the advent of deep brain stimulation. Curr Opin Psychiatry 2009; 22(1):25–31. 69. Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol. 2010;27(2):130–8. 70. Dougherty DD, Weiss AP, Cosgrove GR et al. Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for treatment of major depression. J Neurosurg. 2003;99(6):1010–17. 71. Ruck C, Andreewitch S, Flyckt K et al. Capsulotomy for refractory anxiety disorders: long-term follow-up of 26 patients. Am J Psychiatry 2003;160(3):513–21. 72. Lee GP, Bechara A, Adolphs R et al. Clinical and physiological effects of stereotaxic bilateral amygdalotomy for intractable aggression. J Neuropsychiatry Clin Neurosci. 1998;10(4):413–20. 73. Fountas KN, Smith JR. Historical evolution of stereotactic amygdalotomy for the management of severe aggression. J Neurosurg. 2007;106(4):710–13. 74. Fountas KN, Smith JR, Lee GP. Bilateral stereotactic amygdalotomy for self-mutilation disorder. Case report and review of the literature. Stereotact Funct Neurosurg. 2007;85(2–3):121–8. 75. Mpakopoulou M, Gatos H, Brotis A, Paterakis KN, Fountas KN. Stereotactic amygdalotomy in the management of severe aggressive behavioral disorders. Neurosurg Focus. 2008;25(1):E6. 76. Kiloh LG, Gye RS, Rushworth RG, Bell DS, White RT. Stereotactic amygdaloidotomy for aggressive behaviour. J Neurol Neurosurg Psychiatry 1974; 37(4):437–44. 77. Ramamurthi B. Stereotactic operation in behaviour disorders. Amygdalotomy and hypothalamotomy. Acta Neurochir Suppl (Wien) 1988;44:152–7. 78. Heimburger RF, Small IF, Small JG, Milstein V, Moore D. Stereotactic amygdalotomy for convulsive and


behavioral disorders. Long-term follow-up study. Appl Neurophysiol. 1978;41(1–4):43–51. 79. Kim MC, Lee TK, Choi CR. Review of long-term results of stereotactic psychosurgery. Neurol Med Chir (Tokyo) 2002;42(9):365–71. 80. Sano K, Mayanagi Y. Posteromedial hypothalamotomy in the treatment of violent, aggressive behaviour. Acta Neurochir Suppl (Wien) 1988;44:145–51. 81. Dieckmann G, Schneider-Jonietz B, Schneider H. Psychiatric and neuropsychological findings after stereotactic hypothalamotomy, in cases of extreme sexual aggressivity. Acta Neurochir Suppl (Wien) 1988;44:163–6. 82. Price BH, Baral I, Cosgrove GR et al. Improvement in severe self-mutilation following limbic leucotomy: a series of 5 consecutive cases. J Clin Psychiatry 2001; 62(12):925–32. 83. Kuhn J, Lenartz D, Mai JK et al. Disappearance of self-aggressive behavior in a brain-injured patient after deep brain stimulation of the hypothalamus: technical case report. Neurosurgery 2008;62(5):E1182; discussion E. 84. Balasubramaniam V, Kanaka TS, Ramanujam PB. Stereotaxic cingulumotomy for drug addiction. Neurol India 1973;21(2):63–6. 85. Dieckmann G, Schneider H. Influence of stereotactic hypothalamotomy on alcohol and drug addiction. Appl Neurophysiol. 1978;41(1–4):93–8. 86. Meyer JE. [Psychosurgical treatment of addiction?] Nervenarzt. 1974;45(4):223–4. 87. Gao G, Wang X, He S et al. Clinical study for alleviating opiate drug psychological dependence by a method of ablating the nucleus accumbens with stereotactic surgery. Stereotact Funct Neurosurg. 2003;81(1–4):96–104. 88. Lenhard T, Brassen S, Tost H, Braus DF. Long-term behavioural changes after unilateral stereotactic cingulotomy in a case of therapy-resistant alcohol dependence. World J Biol Psychiatry 2005;6(4):264–6. 89. Stelten BM, Noblesse LH, Ackermans L, Temel Y, Visser-Vandewalle V. The neurosurgical treatment of addiction. Neurosurg Focus 2008;25(1):E5. 90. Morgan JF, Crisp AH. Use of leucotomy for intractable anorexia nervosa: a long-term follow-up study. Int J Eat Disord. 2000;27(3):249–58. 91. Zamboni R, Larach V, Poblete M et al. Dorsomedial thalamotomy as a treatment for terminal anorexia: a report of two cases. Acta Neurochir Suppl (Wien) 1993;58:34–5. 92. da Costa DA. The role of psychosurgery in the treatment of selected cases of refractory schizophrenia: a reappraisal. Schizophr Res. 1997;28(2–3):223–30.

93. Black DN, Stip E, Bedard M et al. Leukotomy revisited: late cognitive and behavioral effects in chronic institutionalized schizophrenics. Schizophr Res. 2000; 43(1):57–64. 94. Stip E, Bigras MJ, Mancini-Marie A et al. Long-term effect of prefrontal lobotomy on verbal fluency in patients with schizophrenia. Brain Cogn. 2004;55(3): 466–9. 95. Schiff ND. Central thalamic deep-brain stimulation in the severely injured brain: rationale and proposed mechanisms of action. Ann N Y Acad Sci. 2009; 1157:101–16. 96. Schiff ND, Giacino JT, Fins JJ. Deep brain stimulation, neuroethics, and the minimally conscious state: moving beyond proof of principle. Arch Neurol. 2009; 66(6):697–702. 97. Schiff ND, Giacino JT, Kalmar K et al. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 2007;448(7153): 600–3. 98. Binder DK, Iskandar BJ. Modern neurosurgery for psychiatric disorders. Neurosurgery 2000;47(1):9–21; discussion 21–3. 99. Feldman RP, Alterman RL, Goodrich JT. Contemporary psychosurgery and a look to the future. J Neurosurg. 2001;95(6):944–56. 100. Malhi GS, Bartlett JR. A new lesion for the psychosurgical operation of stereotactic subcaudate tractotomy (SST). Br J Neurosurg. 1998;12(4):335–9. 101. Richter EO, Davis KD, Hamani C et al. Cingulotomy for psychiatric disease: microelectrode guidance, a callosal reference system for documenting lesion location, and clinical results. Neurosurgery 2004;54(3):622–28; discussion 28–30. 102. Mashour GA, Walker EE, Martuza RL. Psychosurgery: past, present, and future. Brain Res Brain Res Rev. 2005;48(3):409–19. 103. Wichmann T, Delong MR. Deep brain stimulation for neurologic and neuropsychiatric disorders. Neuron 2006;52(1):197–204. 104. Uc EY, Follett KA. Deep brain stimulation in movement disorders. Semin Neurol. 2007;27(2): 170–82. 105. Kern DS, Kumar R. Deep brain stimulation. Neurologist 2007;13(5):237–52. 106. Kringelbach ML, Jenkinson N, Owen SL, Aziz TZ. Translational principles of deep brain stimulation. Nat Rev Neurosci. 2007;8(8):623–35. 107. Tye SJ, Frye MA, Lee KH. Disrupting disordered neurocircuitry: treating refractory psychiatric illness with neuromodulation. Mayo Clin Proc. 2009; 84(6):522–32.

645


108. Kringelbach ML, Aziz TZ. Deep brain stimulation: avoiding the errors of psychosurgery. J Am Med Assoc. 2009;301(16):1705–7. 109. Gabriels L, Cosyns P, Nuttin B, Demeulemeester H, Gybels J. Deep brain stimulation for treatment-refractory obsessive-compulsive disorder: psychopathological and neuropsychological outcome in three cases. Acta Psychiatr Scand. 2003;107(4): 275–82. 110. Greenberg BD, Price LH, Rauch SL et al. Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues. Neurosurg Clin N Am. 2003;14(2):199–212. 111. Greenberg BD, Rezai AR. Mechanisms and the current state of deep brain stimulation in neuropsychiatry. CNS Spectr. 2003;8(7):522–6. 112. Lyons MK. Deep brain stimulation: current and future clinical applications. Mayo Clin Proc. 2011;86(7): 662–72. 113. George MS, Aston-Jones G. Noninvasive techniques for probing neurocircuitry and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Neuropsychopharmacology 2010;35(1):301–16. 114. Milby AH, Halpern CH, Baltuch GH. Vagus nerve stimulation in the treatment of refractory epilepsy. Neurotherapeutics 2009;6(2):228–37. 115. Jenkins B, Tepper SJ. Neurostimulation for primary headache disorders: Part 2, review of central neurostimulators for primary headache, overall therapeutic efficacy, safety, cost, patient selection, and future research in headache neuromodulation. Headache 2011;51(9):1408–18.

121. Fink M. Meduna and the origins of convulsive therapy. Am J Psychiatry 1984;141(9):1034–41. 122. Lancaster NP, Steinert RR, Frost I. Unilateral electro-convulsive therapy. J Ment Sci. 1958; 104(434):221–7. 123. Ottosson JO. Experimental studies of the mode of action of electroconvulsive therapy: Introduction. Acta Psychiatr Scand Suppl. 1960;35(145):5–6. 124. Greenblatt M, Grosser GH, Wechsler H. A comparative study of selected antidepressant medications and EST. Am J Psychiatry 1962;119:144–53. 125. May PR, Tuma AH, Dixon WJ et al. Schizophrenia. A follow-up study of the results of five forms of treatment. Arch Gen Psychiatry 1981;38(7):776–84. 126. May PR, Tuma AH, Yale C, Potepan P, Dixon WJ. Schizophrenia – a follow-up study of results of treatment. Arch Gen Psychiatry 1976;33(4):481–6. 127. Carney MW, Rogan PA, Sebastian J, Sheffield B. A controlled comparative trial of unilateral and bilateral sinusoidal and pulse E.C.T. in endogenous depression. Physicians Drug Man. 1976;7(9–12)8(1–8):77–9. 128. American Psychiatric Association Task Force on ECT. Electroconvulsive Therapy. Washington, DC: American Psychiatric Association; 1978. 129. American Psychiatric Association Task Force an ECT. The practice of ECT: recommendations for treatment, training and privileging. Convuls Ther. 1990;6(2): 85–120. 130. American Psychiatric Association. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training and Privileging – A Task Force Report. Washington, DC: American Psychiatric Association; 2001.

116. Wagner T, Valero-Cabre A, Pascual-Leone A. Noninvasive human brain stimulation. Annu Rev Biomed Eng. 2007;9:527–65.

131. Potter WZ, Rudorfer MV. Electroconvulsive therapy – a modern medical procedure. N Engl J Med. 1993;328(12):882–3.

117. George MS, Belmaker RH. Transcranial Magnetic Stimulation in Clinical Psychiatry. 1st edition. Washington, DC: American Psychiatric Publishing; 2007.

132. Glass RM. Electroconvulsive therapy: time to bring it out of the shadows. J Am Med Assoc. 2001;285(10): 1346–8.

118. Zyss T, Zieba A, Hese RT et al. Magnetic seizure therapy (MST) – a safer method for evoking seizure activity than current therapy with a confirmed antidepressant efficacy. Neuro Endocrinol Lett. 2010;31(4):425–37. 119. Whitrow M. Wagner-Jauregg and fever therapy. Med Hist. 1990;34(3):294–310. 120. Rudorfer MV, Henry ME, Sackeim HA. Electroconvulsive therapy. In Tasman A, Kay J, Liberman JA, editors. Psychiatry. 2nd edition. Chichester: John Wiley and Sons; 2003, pp. 1865–901.

646

133. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet 1985;1(8437):1106–7. 134. Slotema CW, Blom JD, Hoek HW, Sommer IE. Should we expand the toolbox of psychiatric treatment methods to include Repetitive Transcranial Magnetic Stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry 2010;71(7):873–84. 135. Fink M. Electroconvulsive Therapy: A Guide for Professionals and their Patients. Oxford: Oxford University Press; 2009.


136. Greenberg RM, Kellner CH. Electroconvulsive therapy: a selected review. Am J Geriatr Psychiatry 2005;13(4):268–81.

152. Weiner RD, Coffey CE, Krystal AD. The monitoring and management of electrically induced seizures. Psychiatr Clin North Am. 1991;14(4):845–69.

137. Swartz C. Electroconvulsive and Neuromodulation Therapies. Cambridge: Cambridge University Press; 2009.

153. Krystal AD, Coffey CE, Weiner RD, Holsinger T. Changes in seizure threshold over the course of electroconvulsive therapy affect therapeutic response and are detected by ictal EEG ratings. J Neuropsychiatry Clin Neurosci. 1998;10(2): 178–86.

138. Higgins ES, George MS. Brain Stimulation Therapies for Clinicians. 1 st edition. Washington, DC: American Psychiatric Publishing; 2009. 139. Pascual-Leone A. Handbook of Transcranial Magnetic Stimulation. London: Arnold; New York, NY: Oxford University Press [distributor]; 2002. 140. Krystal AD, Coffey CE. Neuropsychiatric considerations in the use of electroconvulsive therapy. J Neuropsychiatry Clin Neurosci. 1997;9(2):283–92. 141. Patkar AA, Hill KP, Weinstein SP, Schwartz SL. ECT in the presence of brain tumor and increased intracranial pressure: evaluation and reduction of risk. J ECT 2000;16(2):189–97. 142. Lafferty JE, North CS, Spitznagel E, Isenberg K. Laboratory screening prior to ECT. J ECT 2001;17(3):158–65. 143. Semkovska M, McLoughlin DM. Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol Psychiatry 2010;68(6):568–77. 144. Salters v. Palmetto Health Alliance Inc. et al. State of South Carolina Court of Appeals; 2007. 145. Sackeim H, Decina P, Prohovnik I, Malitz S. Seizure threshold in electroconvulsive therapy. Effects of sex, age, electrode placement, and number of treatments. Arch Gen Psychiatry 1987;44(4):355–60. 146. Sackeim HA, Devanand DP, Prudic J. Stimulus intensity, seizure threshold, and seizure duration: impact on the efficacy and safety of electroconvulsive therapy. Psychiatr Clin North Am. 1991;14(4):803–43. 147. Coffey CE, Lucke J, Weiner RD, Krystal AD, Aque M. Seizure threshold in electroconvulsive therapy (ECT) II. The anticonvulsant effect of ECT. Biol Psychiatry 1995;37(11):777–88. 148. Coffey CE, Lucke J, Weiner RD, Krystal AD, Aque M. Seizure threshold in electroconvulsive therapy: I. Initial seizure threshold. Biol Psychiatry 1995;37(10):713–20. 149. Sackeim HA, Prudic J, Devanand DP et al. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. N Engl J Med. 1993;328(12):839–46. 150. Abrams R. Stimulus titration and ECT dosing. J ECT 2002;18(1):3–9; discussion 14–15. 151. Abrams R. Electroconvulsive Therapy. 4th edition. Oxford: Oxford University Press; 2002.

154. Delva NJ, Brunet D, Hawken ER et al. Electrical dose and seizure threshold: relations to clinical outcome and cognitive effects in bifrontal, bitemporal, and right unilateral ECT. J ECT. 2000;16(4):361–9. 155. Charlson F, Siskind D, Doi SA et al. ECT efficacy and treatment course: a systematic review and meta-analysis of twice vs thrice weekly schedules. J Affect Disord. 2012;138(1–2):1–8. 156. Petrides G, Tobias KG, Kellner CH, Rudorfer MV. Continuation and maintenance electroconvulsive therapy for mood disorders: review of the literature. Neuropsychobiology 2011;64(3):129–40. 157. Bailine S, Fink M, Knapp R et al. Electroconvulsive therapy is equally effective in unipolar and bipolar depression. Acta Psychiatr Scand. 2010;121(6):431–6. 158. McClintock SM, Brandon AR, Husain MM, Jarrett RB. A systematic review of the combined use of electroconvulsive therapy and psychotherapy for depression. J ECT 2011;27(3):236–43. 159. Pagnin D, de Queiroz V, Pini S, Cassano GB. Efficacy of ECT in depression: a meta-analytic review. J ECT 2004;20(1):13–20. 160. Kho KH, van Vreeswijk MF, Simpson S, Zwinderman AH. A meta-analysis of electroconvulsive therapy efficacy in depression. J ECT 2003;19(3):139–47. 161. UK ECT Review Group Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 2003;361(9360):799–808. 162. Loo C, Katalinic N, Mitchell PB, Greenberg B. Physical treatments for bipolar disorder: a review of electroconvulsive therapy, stereotactic surgery and other brain stimulation techniques. J Affect Disord. 2011;132(1–2):1–13. 163. Fink M. Catatonia and ECT: Meduna’s biological antagonism hypothesis reconsidered. World J Biol Psychiatry 2002;3(2):105–8. 164. Tharyan P, Adams CE. Electroconvulsive therapy for schizophrenia. Cochrane Database Syst Rev. 2005;2:CD000076. 165. Thompson JW, Weiner RD, Myers CP. Use of ECT in the United States in 1975, 1980, and 1986. Am J Psychiatry 1994;151(11):1657–61.

647


166. Olfson M, Marcus S, Sackeim HA, Thompson J, Pincus HA. Use of ECT for the inpatient treatment of recurrent major depression. Am J Psychiatry 1998;155(1):22–9.

180. George MS, Nahas Z, Borckardt JJ et al. Brain stimulation for the treatment of psychiatric disorders. Curr Opin Psychiatry 2007;20(3):250–4; discussion 47–9.

167. Newton-Howes G, Tyrer P, Johnson T. Personality disorder and the outcome of depression: meta-analysis of published studies. Br J Psychiatry 2006;188:13–20.

181. Speer AM, Kimbrell TA, Wassermann EM et al. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry 2000;48(12):1133–41.

168. DeBattista C, Mueller K. Is electroconvulsive therapy effective for the depressed patient with comorbid borderline personality disorder? J ECT 2001;17(2): 91–8. 169. Fricchione GL, Kaufman LD, Gruber BL, Fink M. Electroconvulsive therapy and cyclophosphamide in combination for severe neuropsychiatric lupus with catatonia. Am J Med. 1990;88(4):442–3. 170. Fink M, Sackeim HA. Convulsive therapy in schizophrenia? Schizophr Bull. 1996;22(1):27–39. 171. Hermann RC, Ettner SL, Dorwart RA, Langman-Dorwart N, Kleinman S. Diagnoses of patients treated with ECT: a comparison of evidence-based standards with reported use. Psychiatr Serv. 1999;50(8):1059–65. 172. Rosebush PI, Hildebrand AM, Mazurek MF. The treatment of catatonia: benzodiazepines of ECT? Am J Psychiatry 1992;149(9):1279–80. 173. Philbrick KL, Rummans TA. Malignant catatonia. J Neuropsychiatry Clin Neurosci. 1994;6(1):1–13. 174. Davis JM, Janicak PG, Sakkas P, Gilmore C, Wang Z. Electroconvulsive therapy in the treatment of the neuroleptic malignant syndrome. Convuls Ther. 1991;7(2):111–20. 175. Theodore WH, Fisher R. Brain stimulation for epilepsy. Acta Neurochir Suppl. 2007;97(Pt 2):261–72. 176. Krishnamoorthy ES. Treatment of depression in patients with epilepsy: problems, pitfalls, and some solutions. Epilepsy Behav. 2003;4(Suppl. 3): S46–54. 177. Funke K, Benali A. Cortical cellular actions of transcranial magnetic stimulation. Restor Neurol Neurosci. 2010;28(4):399–417. 178. Siebner HR, Rothwell J. Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res. 2003;148(1):1–16. 179. Funke K, Benali A. Modulation of cortical inhibition by rTMS – findings obtained from animal models. J Physiol. 2011;589(Pt 18):4423–35.

648

182. Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalogr Clin Neurophysiol. 1998;108(1):1–16. 183. Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry 2003;160(5):835–45. 184. Slotema CW, Blom JD, de Weijer AD et al. Can low-frequency repetitive transcranial magnetic stimulation really relieve medication-resistant auditory verbal hallucinations? Negative results from a large randomized controlled trial. Biol Psychiatry 2011;69(5):450–6. 185. Wu AD, Fregni F, Simon DK, Deblieck C, Pascual-Leone A. Noninvasive brain stimulation for Parkinson’s disease and dystonia. Neurotherapeutics 2008;5(2):345–61. 186. Koch G. rTMS effects on levodopa induced dyskinesias in Parkinson’s disease patients: searching for effective cortical targets. Restor Neurol Neurosci. 2010; 28(4):561–8. 187. Khedr EM, Fetoh NA. Short- and long-term effect of rTMS on motor function recovery after ischemic stroke. Restor Neurol Neurosci. 2010;28(4):545–59. 188. Kakuda W, Abo M, Momosaki R, Morooka A. Therapeutic application of 6-Hz-primed low-frequency rTMS combined with intensive speech therapy for post-stroke aphasia. Brain Inj. 2011; 25(12):1242–8. 189. Schlaug G, Marchina S, Wan CY. The use of non-invasive brain stimulation techniques to facilitate recovery from post-stroke aphasia. Neuropsychol Rev. 2011;21(3):288–301. 190. Hsu WY, Cheng CH, Lin MW et al. Antiepileptic effects of low frequency repetitive transcranial magnetic stimulation: a meta-analysis. Epilepsy Res. 2011;96(3):231–40.

Index

Note: page numbers in italics refer to figures and tables, those in bold refer to boxes. abducens nerve (CN VI) 17, 322–3 abstraction, executive function 379, 380 abulia 67 academic performance 312 acalculia 376 accessory nerve (CN XI) 17 acetylcholine (ACh) 65, 238, 285, 520 acetylcholinesterase inhibitors (AChE) 504 attention impairment 520 declarative memory impairment 524 executive dysfunction 531 language impairment 527 visuospatial memory impairment 529 working memory impairment 522 achromatopsia 149 acoustic nerve see vestibulocochlear nerve (CN VIII) acquired immune deficiency syndrome dementia complex 51 action tendencies 269, 269–70 Activation Likelihood Estimation (ALE) activation maps 35 activities of daily living (ADL) 616 adaptive behaviors, basic emotion 268 addictive disorders, neurosurgical treatment 75 adenosine, sleep-promoting neuronal systems 99 adolescence, sleep 103 advanced sleep phase syndrome (ASPS) 104–5 affect 270–1, 275 assessment 354, 355, 356 emotion 271, 270–1, 274 emotional feelings relationship 271 mental status examination 354–6, 355 mood relationship 274 neurological basis 290–1 neurological distinction from mood 290 affect disorders 271, 273, 273, 546–7 classification 271 co-occurrence with mood disorders 273

medication-induced 548, 548 mood disorder distinction 273–4 see also prosody, affective affective placidity 273 affective processing, prefrontal cortex 138 ageusia 155 aggression 7, 41–2, 572–5, 579 acute 573–4 chronic 574–5 neurobiology 572 neurochemistry 573 physical 615 treatment 572–3, 574–5 aging 50 affective prosody 190 attitudinal prosody 190 sleep changes 103 deprivation recovery 103 neuronal systems 99 Process C 103 agitation 572–5, 613–14 acute 573–4 chronic 574–5 treatment 573, 574–5 agnosias 146, 368–9 apperceptive 146, 149 associative 146 auditory 151 cognitive impairment 521 finger 369 gustatory 155 integrative 146 interventions 521 olfactory 369 visual 369 agraphesthesia 153, 369 agraphia 177 akinesia 199 akinetic mutism 67, 73–4 akinetopsia 149, 218 alcohol abuse 477 alexias 177, 369 allostasis 290–1 allostatic overload 290 Alzheimer’s disease 50, 54, 438, 456 conceptual apraxia 201

genetic testing 7 implicit memory 167–8 insomnia 104 pharmacotherapy 104 posterior cortical atrophy 150, 219 sundowning syndrome 104 supportive psychotherapy 597 treatment 7 visuospatial dysfunction 219 amantadine, arousal disorders 94 American Board of Psychiatry and Neurology (ABPN) 3, 396 American Medical Association (AMA) 3 American Neurological Association (ANA) 3 American Neuropsychiatric Association 5 American Psychiatric Association (APA) 3 amnesia anterograde 164 electroconvulsive therapy 637 global 164–5, 168 implicit memory 167 perceptual skills learning 169 post-traumatic 315 retrograde 164–5 amnestic syndromes 69, 162 amputees, phantom limb sensations 153 amygdala 21–2, 138, 218 comportment dysfunction 256 extended 280–1 goal-directed behavior 138 motivation 138 anamnesis 349 ankle jerk reflex 329 anomia 357, 370 anopsias 149 anosmia 155 anosognosia 385 anterior brainstem injury 456 anterior capsulotomy 75, 631–2 anterior cerebral arteries (ACAs) 26 anterior cingulate (AC) circuit 60, 62–3 motivation 137–8

649

Index

anterior cingulate (AC) cortex divisions 233 dorsal cognitive division 233 lesions causing akinetic mutism 67 reward circuit 282 rostral-ventral affective division 233 anterior cingulate (AC) syndrome 67, 73–4 anterior cingulate–subcortical circuit 235, 579 anterior cingulotomy 631–2 anterior communicating artery (ACoA) 26 anterior inferior cerebellar arteries (AICAs) 34 anterior temporal cortex 167 anticonvulsants 551 antidepressants 548–51 brain level monitoring 423 classes 548–9 drug–drug interactions 552 interactions 550–1 seizure threshold lowering 550 side effects 550–1 antipsychotic drugs 554–7, 578 drug–drug interactions 551, 554–7 emotional outburst treatment 558 mania treatment 551 motor side effects 336 seizure threshold lowering 554 side effects 554–7 Anton’s syndrome 149 anxiety disorders 547–8 antipsychotic drugs 554 cognitive-behavioral therapy 592, 612 comorbid conditions 548 development 547–8 environmental interventions 612 paroxysmal episodes 547 treatment 548 apathy 134, 139, 578–9 depression differential diagnosis 579 diagnosis 140, 140 pharmacologic treatment 74 scales 579 treatment 579 aphasia 174–7, 369, 369–70, 526 Broca’s 174, 176, 177, 180 classic 371, 371 conduction 175–6, 181, 208–9 disorders of pantomime 186 progressive 180–1, 527 semantic 181, 181 subcortical 176–7 syndromes 176 transcortical motor/sensory 176

650

treatment 526–7 Wernicke’s 176, 177, 180 applied behavioral analysis 605, 618 apraxia 199–201, 373–4, 527–9 clinical relevance 199–200 conceptual 200–202 dementia 201 pathophysiology 201–2 testing 201 dissociation 200, 208–9, 210 gesture imitation problems 209 visual perceptual system failure 209 evaluation 528 ideational 200, 202, 374 ideomotor 200, 202–4, 208, 210 allocentric orientation errors 203 callosal disconnection 204–5 cortical lesions 208 corticobasal degeneration 207–8 corticospinal neurons 206–7 egocentric movement errors 203 inferior parietal lobe 206 intrahemispheric disconnection 205–6 mental state examination 374 motor cortex 207 pathophysiology 204–8 postural 203 premotor cortex 206–8 subcortical lesions 208 superior longitudinal fasciculus 208 treatment 210 white matter pathways 208 limb 199–200 limb-kinetic 200, 210, 209–10, 211, 373–4 definition/description 209–10 testing 209 treatment 210–11 melokinetic 373–4 treatment 528–9 verbal dissociation 208, 209, 210 aprosodias 185–6, 187, 188, 191, 371 comorbid with primary mood disorders 545 crossed 188 global/motor 191 treatment 527 arcuate fasciculus 206, 236 arm abductor muscles strength testing 326 see also upper extremities arousal 88–95, 350–2, 363–5 ascending systems 89, 89–90

balance mechanisms 90 cholinergic projections 89–90 cognitive impairment 517–19 distributed neural circuits 88 dopaminergic projections 89–90 emotion 270 feedback mechanisms 90 glutamatergic projections 89–90 neuroanatomy 88 neurophysiology 88–90 nuclei 89, 89–90 olfactory input 88–9 pathological processes 90 reticular formation role 16 serotonergic projections 89–90 thalamic nuclei 90 visual system inputs 89 arousal circuit 281 arousal disorders 88, 90–4 brain death 90–1 pharmacologic treatment 94 severe impairment 91–4 treatment 94–5 arterial spin labeling (ASL) 436–7 ascending reticular activating system (ARAS) 16, 99, 443 down-regulation in insomnia therapy 106 encephalitis lethargica 98 ventrolateral pre-optic region inhibition 100 wake-promoting systems 98–9 ascending reticular inhibiting system (ARIS) 16 association tracts 26 astereognosis 153 asterognosia 369 astrocytoma, MRI 425 ataxia 328 ataxic disorders 40–1 athymormia 139 attachment, disorganized 313 attachment theory in psychotherapy 588 attention 115–31, 365–7 control 115–19, 129, 128–9, 131, 226 functional models 117–19 guided search model 118–19, 130 visual search model 117–18 cueing tasks 116–17 executive 128 impairment 519–21 orientation to locations 120 selective attention model 128–30 spatial 119–24 spatial cueing 116–17 speed of processing 365, 519–21 pharmacotherapy 519–21 sustaining 365

Index

targets 365 tests 365–7 types 119–28 visual 116–17 visual search task 117, 118 visual working memory 126–8 visually guided search model 118 see also object-based attention attention-deficit hyperactivity disorder (ADHD) 70 pharmacologic treatment 73 attention deficit/disorders 121–2, 456 attentional blink 126–7, 127, 128 auditory agnosia 151 auditory cortex 150–1 auditory hallucinations 152, 347, 641 musical 152 auditory pathways 150 auditory perception/recognition 150–2 auditory sound/object agnosia 151 auditory system, what/where 150–1 auditory verbal agnosia 151 autism 261–2 autism spectrum disorders 261–2 auto-activation deficit 139 awareness 88–90 see also self-awareness awareness disorders 90–4 brain death 90–1 clinical scales 94 pharmacologic treatment 94 severe impairment 91–4 treatment 94–5 axons 25 regrowth 55 Babinski reflex 329 balance testing 330 Balint’s syndrome 146, 150, 217, 219 basal ganglia 19–20, 139, 219 disorders 68 function 20, 139 motor skill learning 169 perceptual skills learning 169 basal ganglia–thalamocortical circuit 234 basilar artery 26 behavior(s) causes of target 619 inseparable nature of brain 5 medical aspects 7–8 multiple 615 purpose serving 606–7 behavioral analysis, applied 605 behavioral data collection 605 behavioral deficits 616 behavioral disturbance 52 assessment 567 behavioral metaphors 570–1, 571

co-occurring cognitive impairment 567–8 diagnosis 567–70 dimensions 566–7 disinhibited 571–2 DSM classification 569 frequency 567 impulsive 571–2 intensity 567 labeling 569 medication side-effects vulnerability 570 neural circuitry damage 569 neurotransmitter disease-specific alteration 569–70 pharmacotherapy 566–81 psychiatric disorder comorbidity 568–9 psychopharmacology 570–1 self-awareness deficit 579–80 self-injurious 572–5 treatment effect evaluation 570 types 566–7 see also aggression; agitation; apathy; motivation; psychosis behavioral excesses 613–16 behavioral interventions 604–20 adaptation to cognitive capacity 607–8 anxiety disorders 612 behavioral deficits 616 behavioral excesses 613–16 cognitive impairment 514 consistency 609 depression 611 executive dysfunction 617 integrated treatment plan 607 neuropsychiatric disorders behavioral sequelae 611–16 cognitive sequelae 616–17 emotional sequelae 611–16 physical sequelae 609–11 nomenclature 604–5 paradigms 619 positive reinforcement 608 post-traumatic stress disorder 612 principles 605–9 reward 608 substance abuse disorders 612–13 behavioral metaphors 570–1, 571 behavioral neuroanatomy 12–30 brainstem 12–19 cerebellum 14 cerebral cortex 22–5 diencephalon 17–19 limbic system 20–2 mesencephalon 14–15 metencephalon 13–14

reticular formation 15–16 vascular supply 26–7 ventricular system 27–9 white matter 25–6 behavioral neurology/neuropsychiatry historical background 3–5 philosophical antecedents 4–5 state of field 5–6 behavioral supports, positive 605 behavioral therapy 590, 590–1 beta-blockers 558–9 biceps reflex 325 Binswanger’s disease 50, 490 biofeedback techniques, pain control 609 bipolar disorder 544–5 anticonvulsants 551 antipsychotic drugs 554 diacylglycerol gene 72 electroconvulsive therapy 639 frontal-subcortical circuits 72 mania 544–5 mood stabilizers 551–3 birth history 312 blind spots 250 blindness, circadian rhythm disorders 105 blindsight 149 brachioradialis reflex 325–6 brain inseparable nature of behavior 5 median zone 278 oscillatory phenomena 466 paramedian-limbic zone 278 structure 12, 13, 336–7 supralimbic zone 278 vascular supply 27, 26–7, 28 brain damage depression diagnosis with focal lesions 191 prosody 185–6 congenital lesions 190 early childhood lesions 190 lateralization 189 right brain 187–8 see also traumatic brain injury (TBI) brain death 90–1, 93–4 diagnosis 90–1 termination of care 91 brain electrical activity mapping (BEAM) 462–3 brain injury acquired and comportment dysfunction 259 EEG findings 456 social history 313–14 surgical 259 see also traumatic brain injury (TBI)

651

Index

brain tissue volume, morphometric analysis 424–6 brain tumors clinical presentation 485–6 EEG findings 456 gliomatosis cerebri 486 hematopoietic 486–96 brain–behavior relationships 6, 23 brainstem 16, 12–16, 19 arousal disorders 88 cerebellum connections 14 injury 456 metencephalon 13–14 motivation 134–5 myelencephalon 12–13 REM sleep 100 reticular formation 15–16, 135–6 breach of duty, tort law 412 Broca, Paul 174 Broca’s aphasia 174, 176, 177, 180 Broca’s area 174, 175, 175–7, 177, 181 function 179–80 Brodmann’s areas 23, 24, 147, 175, 230 prefrontal cortex 229, 232 primary visual area 214 bruits, listening for 321 Burckhardt, Gottlieb 628 calculation, mental status examination 375–6 Cambridge Neurological Inventory (CNI) 335 capacity diminished 411 medical decision-making 408 testamentary 410 capillaries 26 carbamazepine 553–4 carbon monoxide poisoning 478, 481 carotid arteries 26 catecholamines see dopamine; norepinephrine categorization see abstraction caudate nucleus 19–20 central executive 226 central nervous system (CNS) 12 neurotoxin vulnerability 474–5 central pattern generators (CPG) 109 cerebellar arteries 27, 28, 34 cerebellar cognitive affective syndrome (CCAS) 37, 36–7, 37, 38, 41 behavioral aberrations 38–9 children 38–9 emotional deficits 38–9 opsoclonus–myoclonus–ataxia 39 posterior fossa syndrome 38 cerebellar lesions clinical manifestations 35–8 development effects 40

652

disconnection syndromes 32 neuropsychiatric impairments 39, 40 cerebellar motor syndrome 35–6 cerebellar stroke 37–8 cerebellum 14, 32–42 activation maps 35 activation patterns 36 anatomy 32–3, 33, 34 behavioral neuroanatomy 14 blood vessels 34 brainstem connections 14 cerebral cortex connections 236–7 cognition 32–5, 41 cortex 14, 32 distributed neural circuits 32 dyslexia 41 electrical stimulation for behavioral disorders 41–2 emotion mechanisms 41 fissures 14, 32, 33 folia 14 functional topography 34–5 limbic 35 lobules 32, 34–5 nuclei 34 peduncles 34 primary psychiatric disease 40–1 Purkinje cell layer 14 sensorimotor control 35 sensorimotor projections 34 subdivisions 14 vermis damage 40 cerebral akinetopsia 218 cerebral arteries 27, 28 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 52 cerebral cortex 22–5 agranular areas 231 association areas 23–5 Brodmann areas 23 cerebellum connections 236–7 connections between modules 145–6 divisions 145 frontal lobes 24–5 granular areas 231 information flow 25 lamination 22 limbic areas 21 lobes 22–3, 23 paralimbic areas 21 primary motor cortex 23 Rolandic fissure 23 secondary motor cortex 23 subcortical structures 20, 25 Sylvian fissure 23 ventricular system 27–9, 29

cerebral hemispheres affective-prosodic deficits 189 arousal disorders 88 cerebellum connection 34 interhemispheric interactions 188–9 intrahemispheric disconnection in ideomotor apraxia 205–6 language specializations 179 lateralization in affective prosody 188–9 left dominance for language 175, 175, 184, 188–9 left lesions causing limb-kinetic apraxia 209–10 right involvement communication 186–9, 191–2 language 186–9, 191–2 visuospatial function 214–15 cerebrocerebellar connections 34 cerebrospinal fluid, ventricular system 27–9 cerebrovascular events, risk with antipsychotics 557 cerebrum, midbrain connections 14 challenging behavior 566–7 applied behavioral analysis 618 behavioral metaphors 570–1 causes 568 co-occurring cognitive impairment 567–8 definition 617–18 diagnosis 567–70 DSM classification 569 evaluation 606, 607, 617–20 hypothesis-driven intervention 619–20 labeling 569 management 617–20 medication side-effects vulnerability 570 neuropsychiatric disorders 607 neurotransmitter disease-specific alteration 569–70 psychiatric disorder comorbidity 568–9 psychopharmacology 570–1 quantification 618 recurrent evaluation of plan 620 self-awareness deficit 579–80 target behavior etiology 618 treatment effect evaluation 570 see also behavioral disturbance change model 595, 597 character 301–2 brain region activation/deactivation patterns 305 cooperativeness 302 descriptors of high and low scorers 302

Index

heritability 306 maturation 306 neurobiology 305 reinforcement effects on emotional state 303 self-directedness 302, 305 self-transcendence 302, 305, 306–7 Charcot, Jean-Martin 2, 47 Charles Bonnet syndrome 150 chemosensation 154–5 children cerebellar cognitive affective syndrome 38–9 infant sleep 102 posterior fossa syndrome 38 prefrontal cortex lesions 259–60 cholinergic innervation 15, 66 cholinergic system 65, 238 cholinesterase inhibitors, insomnia 104 choroid plexus 27–8 chronic fatigue syndrome (CFS) 104 chronic pain 104 chronic progressive external ophthalmoplegia (CPEO) 221 circadian rhythm disorders 101 blindness 105 insomnia 101, 104–5 night eating syndrome 109 circadian system, sleep timing regulation 100–1 circle of Willis 26 cisterna magna 27 citicoline 525 clock drawing test 375, 377 clumsiness 312 CNS lymphoma, MRI 425 cochlea 150 cognition 363–4, 364, 380–4 arousal assessment 363–5 ataxic disorders 40–1 attention assessment 365–7 bedside examination 363 calculation assessment 375–6 cerebellum 32–5, 41 declarative memory assessment 371–3 examination coding as neurobehavioral status exam 384 examination documentation 384 executive function assessment 376–9 information processing speed 365–7 kinesics 371 language assessment 369–71 paralinguistic assessment 371 praxis assessment 373–4 prosody 371 recognition assessment 368–9

screening 363 social 385 test results interpretation 380–4 potential confounds 380–1 qualitative interpretation 381 quantitative interpretation 381–3 visuospatial function assessment 374–5 working memory assessment 367–8 Z-scores 381–3 cognitive behavioral therapy (CBT) 591, 591, 592, 592 anxiety disorders 612 depression treatment 592, 611 insomnia 105 pain control 609 cognitive capacity 607–8 cognitive impairment 316, 363, 511–12 agnosias 521 alcohol abuse 477 arousal 517–19 assessment for electroconvulsive therapy 637–8 attention impairment 519–21 behavioral disturbance co-occurrence 567–8 behavioral interventions 514 compensatory interventions 514 competency 409 decisional capacity 383 education 513 environmental interventions 514 executive function 530–2 functional status 383–4 gnosis 521 hypoarousal 517–18 language 526–7 medications 515–17 memory 522–6 mild 315–16 neuropsychiatric disorders 616–17 neuropsychological testing 399, 512 patient assessment 512 pharmacotherapy 515–17 praxis 527–9 pre-treatment evaluation 512, 512–13 procedural memory 525–6 processing speed 519–21 prosody 527 recognition 521 rehabilitation 514–15 subtle neurological sign association 336 supportive therapy 513 treatment 513–17 visuospatial function 529–30

cognitive rehabilitation 514–15 attention impairment 519 declarative memory impairment 523–4 evidence-based recommendations 515, 516 executive dysfunction 531 visuospatial memory 529 cognitive therapies 591–2 colliculi 14 coma 91–2 medication impact on EEG patterns 457 pharmacotherapy 518–19 rehabilitation 94 coma stimulation protocols 518 commissural fibers 25 communication 174 affective 187 components 184–6 eye contact 353 gesturing 190 history-taking 310–11 language 357 mental status examination 356–8 neurological examination 321 non-verbal 356 paralinguistics 357–8 right hemisphere function 186 right hemisphere role 186–9, 191–2 social 617 speech 357 vocal–acoustic 184 voice 356–7 word-finding difficulty 357 community practice 6 competency cognitive impairment 409 dementia 409 forensic practice 408–10 to stand trial 409–10 complex motor acts, voluntary/involuntary 353 comportment 250–63 acquired brain injury 258–60 amygdala role 256 assessment 256–7 autism spectrum disorders 261–2 case study 250–1 childhood prefrontal lesions 259–60 components 251–2 definition 251 disease processes affecting 257–62 empathy 252, 257 frontotemporal dementia 257–8 functional neuroanatomy 252–6 insight 251, 257 judgment 251 measurement 256–7

653

Index

comportment (cont.) medial frontal circuit 255–6 mental status examination 353 orbitofrontal circuit dysfunction 254–5 prefrontal circuit 256 schizophrenia 260–1 self-awareness 251 social adaptation 251–2 temporal circuit 256 traumatic brain injury 258–60 comprehension 370–1 computed tomography (CT) 415, 417–19 acute subdural hygroma 423 contrast agents 418–19 cyanide poisoning 426 factors in selection 421 frontal lobotomy 426 helical (spiral) 417–18 MRI comparison 421 normal brain 418 parasagittal meningioma 424 subarachnoid hemorrhage 424 tissue appearance 418 xenon-enhanced 431–2 conduction aphasia 175–6, 181 confusional arousals 108–9 consciousness 365 see also arousal; awareness; coma; minimally conscious state consent electroconvulsive therapy 636–8 medical decision-making 408 contingency management 590 continuous arterial spin labeling (CASL) 437 contrast agents, neuroimaging 417, 420 CT 418–19 MRI 420 conversion disorder 312–13, 315 Coombe, Andrew 2 cooperativeness 302 coordination lower extremities 329–30 upper extremities 328 corneal reflex, examination 323 corpus callosum disconnection 204–5, 209 interhemispheric communication 204 limb-kinetic apraxia 210 cortical auditory disorder 151 cortical deafness 151 cortical sensory deficit 153 cortical–limbic pathways 71 corticobasal degeneration 207–8

654

corticopontine pathway 34, 236–7 corticospinal neurons 206–7 counter-conditioning 590 cranial nerves 16–17, 322–4, 357 myelencephalon 12–13 nuclei 16 cranium, venous drainage 27 criminal behavior 7 criminal responsibility, forensic practice 410–12 crying, paroxysmal 277 complex partial seizures 273 cueing tasks 116–17 Cullen, William 1–2 cyanide poisoning, CT 426 cyclic alternating pattern (CAP), sleep 102 D1 and D2 receptors, frontal-subcortical circuits 64 dangerousness assessment 360–2 deaf-hearing 151 declarative memory 164–7, 371–3, 373 delayed recall 372 impairment 523–5 cognitive rehabilitation 523–4 pharmacotherapy 524–5 deep brain stimulation (DBS) 632–4 applications 634 arousal disorders 94–5 complications 633–4 depression 75 fMRI 430–1 obsessive-compulsive disorder treatment 75 Tourette syndrome 75 defendants competency to stand trial 409–10 not guilty by reason of insanity 411 Dejerine–Roussy syndrome 153 delayed sleep phase syndrome (DSPS) 104–5 delirium, EEG findings 456 delusions 575–8 of control 156 mental state examination 361 dementia alcoholic 477 apathy diagnosis 140 carbon monoxide-induced encephalopathy 481 competency 409 conceptual apraxia 201 EEG findings 456 neurodegenerative 567–8 neurotoxic 481 semantic 167, 181

see also Alzheimer’s disease; frontotemporal dementia; white matter dementia dementia with Lewy bodies (DLB) insomnia 104 visuospatial dysfunction 219–20 denial, psychological 385 dependency, excess 616 depression apathy differential diagnosis 579 attention–cognition compartment model 71 behavioral interventions 611 behaviors 545–60 cognitive behavioral therapy 592, 611 cortical–limbic pathways distributed network failure 71 diagnosis with focal brain lesions 191 dopamine fronto-limbic deficiency 70–1 electroconvulsive therapy 639 environmental interventions 611 frontal-subcortical dysfunction 70–1 interpersonal therapy 593 neurological disorders 545, 545–6 neurosurgical treatment 75 pharmacotherapy 549–50 subgenual cingulate role 71 transcranial magnetic stimulation 641 vegetative–circadian compartment model 71 see also bipolar disorder; major depressive disorder depth perception 218 Descartes, René 4 development sleep across lifespan 102–3 white matter role 50 developmental coordination disorder 312 developmental history 312–13 diacylglycerol (DAG) gene, bipolar disorder 72 Diagnostic and Statistical Manual of Mental Disorders 4–5 behavioral disturbance 569 symptom terminology 346 diencephalon 17–19, 456 differential reinforcement of other behavior (DRO) 614 aggression 615 multiple behaviors 615 diffuse axonal injury (DAI) 52 diffusion tensor imaging (DTI) 422, 422, 435–6 apparent diffusion 435–6

Index

case study 431 data interpretation 436 eigenvalues/eigenvectors 436 fiber tracking 431 fractional anisotropy 436 healthy adult 436 tractography 48 white matter 50–1, 51 diffusion-weighted imaging (DWI) 419–20 digit span task 368 digital vigilance test 366 directional hypokinesia 215 disconnection syndromes, cerebellar lesions 32 disengage deficit 121, 130, 131 spatial cueing 121, 122 disinhibited behavior 571–2 dissociative disorder 312–13, 315, 315 distributed neural circuits 32, 50 arousal 88 visuospatial function 529 distributed source analysis 469 dopamine executive function 237–8 frontal-subcortical circuits 64, 65 fronto-limbic deficiency in depression 70–1 greater limbic system modulation 284 information processing 237–8 motivation 135–7 novelty seeking 304 nucleus accumbens 137 dopamine agonist drugs 72–3 dopamine receptors 65 dopaminergic agents 73–4 dopaminergic innervation 14 dopaminergic system motivation 135–6 REM sleep 100 substance abuse disorders 72 Doppler ultrasound 426 dorsal limbic pathway 236 dorsal visual system 148 dorsolateral prefrontal (DLPF) circuit 61, 62, 234–5 executive function 530 schizophrenia 72 dorsolateral prefrontal (DLPF) cortex 59–60 lesions 68 akinetic mutism 67 neglect 122–3 transcranial magnetic stimulation target 641 dorsolateral prefrontal (DLPF) syndrome 68, 73

dorsolateral prefrontal-subcortical circuit 282 dreaming 100 driving, executive control 128 drowsiness, medication impact on theta/delta activity 455–7 drug reward circuit 72 drugs of abuse neurotoxins 476, 476, 477 see also substance abuse disorders dual agency, forensic practice 408 dualism 4–5 Dynamic Causal Modeling (DCM) 472 dyscalculia 376 dysexecutive syndromes 164, 240 see also executive dysfunction dyslexia 181 cerebellar–vestibular interactions 41 dysnomia 370 dyspraxia 527–9 dysprosody 185 dystonia 154 Economo, Constantin von 98–9 electroconvulsive therapy (ECT) 636–9 amnesia 637 clinical applications 639 cognitive impairment assessment 637–8 consent 636–8 historical aspects 635 medication requirement 638–9 pretreatment considerations 636–8 pulses 638 response to treatment 638 risk assessment 636–7 stimulus dosing 638 stimulus intensity 638 treatment parameters 638–9 electroencephalography (EEG) 442–57 abnormal findings 449–52 activity assessment 448–9 age determination 447 alertness state 447 beta range activity 448–9, 451, 457 bipolar montage 445, 445–6, 448, 449 coherence measurement 471–2 coma patterns 457 common conditions 456 connectivity 470–2 continuous 446–7 conventional 446 delta activity 455–7 distributed source analysis 469 epilepsy 456 epilepsy monitoring unit 447 epileptiform discharges 451–2, 454, 457

evoked responses 463, 468 fast Fourier transform 461, 461, 466 filters 445 frequencies 443, 443 frequency domain averaging 465 hyperventilation stimulation 452–4 independent components analysis 469–70, 470 induced responses 463, 465, 468 intermittent rhythmic delta activity 450–1, 453 International System of Electrode Placement 444 interpretation 447–54 lambda waves 449, 452 measures 462 medication impact 455–7 motor evoked field 464, 468 mu rhythms 449, 451 phase 463–5 phase-locking 464, 466–7, 468 phase-resetting 467 photic stimulation 454 photoparoxysmal response 455 physiologic basis 442–3 polymorphic slowing 449–50, 452, 453 posterior dominant rhythm 447–8, 450, 455, 463 quantitative 447, 462 reactivity to stimulation/provocative maneuvers 452–4 recording types 446–7 referential montage 445, 446 rhythmic activity 443 rhythmic slowing 450–1 signals 442–3 amplification 443–5 displays 445–6 processing 443–5 recording 443 sleep architecture assessment 454 sleep patterns 101–2 slowing waveforms 449–51 source analysis 467–9 spectral analysis 461–3 theta activity 455–7 time versus frequency domain 461, 466 time–frequency transformation 465–6, 466, 467, 467 tracings 460 triphasic waves 457 electrophysiology advanced 459–72 domains 460–1 spectral techniques 461–3

655

Index

emotion 266–9 action tendencies 269–70 advances in understanding 266 affect 270–1, 271, 274 affect disorders 273 allostasis 290–1 arousal 270 assessment 354–6 basic 267–8, 268, 268, 268 brain activation 289 categories 267–70 action tendencies 269, 269–70 cerebellum, mechanisms 41 classes 267 control 286, 285–9 definitions 267, 354 dimensions 270 expression mechanisms 277 expression pathways 277–8 expression/experience in greater limbic system 285–6, 286, 287 facial expressions 268 frequency 270 functional neuroimaging 288–9 generation in greater limbic system 285–6, 286, 287 intensity 270 lateralization 287–90 limbic system 275–82 mental status examination 354–6 modal 268–9 mood 270–1, 271, 274 mood disorders 271–2 neurobiology 275–91 neuropsychological assessment effects 403 potency 270 relative frequency 269 right-hemisphere hypothesis 287 sadness 270 stress response 302 unpredictability 270 valence 270 valence-specific hypothesis 287–8 without emotional feeling 354 see also limbic system, greater emotional disturbance 543–60 anxiety disorders 547–8 lateralized neurological processes 289–90 medication-induced 548 sustained/transient 290–1 see also affect disorders; mood disorders; pathological laughing and crying (PLC) emotional feelings 267, 354, 356 action tendencies 269–70 affect relationship 271

656

allostasis 290–1 assessment 354–6 associations 354 basic 268 basic set 268 categories 267–70 dimensions 270 lateralization 287–90 limbic system 275–82 modal 268–9 mood relationship 271 neurobiology 275–91 relative frequency 269 emotional incontinence see pathological laughing and crying (PLC) emotional outbursts, treatment 558–9 emotional states 270 limbic system 21–2 orbitofrontal syndrome 67–8 reinforcement effects on temperament/character dimensions 303 emotional traits 270 empathy 252, 255–7 encephalitis lethargica epidemic (1917–1918) 98–9 encephalopathy acute 481 carbon monoxide poisoning 481 metabolic 457 toxic 412 environmental autonomy, executive function 379 environmental interventions 604–20 anxiety disorders 612 behavioral deficits 616 behavioral excesses 613–16 cognitive impairment 514 consistency 609 depression 611 executive dysfunction 617 integrated treatment plan 607 neuropsychiatric disorders behavioral sequelae 611–16 cognitive sequelae 616–17 emotional sequelae 611–16 physical sequelae 609–11 nomenclature 604–5 paradigms 619 positive reinforcement 608 principles 605–9 reward 608 substance abuse disorders 612–13 environmental toxins 476, 477, 477–8 epilepsy 456 photic stimulation in EEG 454 vagal nerve stimulation 634 epilepsy monitoring unit for EEG 447

epileptiform discharges, EEG 451–2 episodic memory 164–6 deficits 164–5 frontal lobe 165 hippocampus 165 imagining the future 165–6 medial temporal lobes 165 remembering the past 165–6 remember/know paradigm 164 epithalamus 19 ethics, forensic practice 407–8 event-related desynchronization (ERD)/synchronization (ERS) 466, 468 phase-locking 466–7 evidence neuropsychiatric 406–7 rules in forensic practice 412–13 excessive daytime sleepiness (EDS) 106 excitatory post-synaptic potentials (EPSP) 442–3 executive attention 128 Executive Clock Drawing Test (CLOX) 377 executive control 128, 226 executive dysfunction 225, 511 assessment 530 behavioral interventions 617 cognitive impairment 530–2 environmental interventions 617 frontal networks 239–40 treatment 530–2 executive function 225–43 abilities 227 abstraction 379, 380 acetylcholine role 238 assessment bedside 241–2, 242 instruments 240–1, 241 neuropsychological 240–1 association pathways 235–6 central executive 226 cholinergic system 238 clusters 227 cognitive models 226 complex motor sequencing 378–9 deficit in dorsolateral prefrontal syndrome 68, 73 definitions 225–8 dopamine 237–8 environmental autonomy 379 frontal lobe 228–35 frontal networks 239–40 frontal-subcortical circuits 234–5 frontocerebellar interactions 237–9 GABA role 237 glutamate 237 historical studies 228–9 impairment 511, 530–2

Index

judgment 385 language 377 mental status examination 376–9 neurochemical modulation 237–9 norepinephrine 237–8 Parkinson’s disease 73 pattern recognition 377–8 prefrontal cortex 225, 229–34 processes 227 serotonin role 238–9 set shifting 376–7 visuospatial function control 377 volition 227 experimental control 605 expert opinion, forensic practice 408, 412–13 extinction, cognitive therapies 591–2 extrapyramidal syndrome, antipsychotic motor side effect 336 eye contact, mental status examination 353 facial expressions of emotion 268 facial nerve (CN VII) 17, 323 familiarity 164 family history 311–12 family therapy 593–4, 594, 595 fast Fourier transform 461, 461, 466 fatigue 610 feature integration theory 117–18 feelings see emotional feelings fibromyalgia, insomnia 104 finger abductor muscles, strength testing 328 finger agnosia 369 finger extensor muscles, strength testing 327 finger jerk reflex 325–6 finger tapping sequence learning (FTSL) 169 Fisher test for ataxia 328 fist-edge-palm series 378 Florida Apraxia Battery–Extended and Revised Sydney (FABERS) 374 19-fluorine magnetic resonance spectroscopy (MRS) 423 focal neurobehavioral syndromes 53 foot see lower extremities foot dorsiflexor muscles, strength testing 329 foramen of Magendie 27 foramen of Monro 27 foramina of Luschka 27 forearm flexor muscles, strength testing 326 forebrain 134–5, 278–9 forensic assessment 406–13 forensic practice 407–8

areas of importance 408–13 capacity diminished 411 medical decision-making 408 testamentary 410 competency 408–10 to stand trial 409–10 conceptual framework 407 criminal responsibility 410–12 diminished capacity 411 dual agency 408 ethics 407–8 evidence rules 412–13 expert opinion 408, 412–13 free will 411–12 medical decision-making 408 mitigating circumstances 411 not guilty by reason of insanity 411 testamentary capacity 410 tort law 412–13 traumatic brain injury 412 formications 153 fornix 26 free will 411–12 Freeman, Walter 628–9 Freud, Sigmund 2–3, 4, 6 frontal eye field (FEF) damage 122–3 frontal lobe autism spectrum disorders 261–2 episodic memory 165 executive function 228–35 historical studies 228–9 language impairment 177 language mapping 178–9 spatial attention 122–3 stereotactic targeting of white matter 632 frontal lobotomy, CT 426 frontal network syndrome 239 frontal release signs 326 frontal-subcortical circuits 20, 59–76, 234, 234–5 amnestic syndromes 69 anatomy 61, 59–61 anterior cingulate circuit 62–3 behavioral circuit interactions with motor circuits 66 bipolar disorder 72 cholinergic system 65 circuit-discrete neurochemical organization 65 D1 and D2 receptors 64 direct pathway 60, 64 dopamine system 64, 65 dorsolateral prefrontal circuit 61 GABA fibers 64 Huntington’s disease 68 impulse control disorders 72–3 indirect pathway 60, 64

lateral orbitofrontal circuit 61–2 medial orbitofrontal cortex 63–4 motivation 137, 139 motor circuit 61, 66 movement disorders 68 neuropsychiatric syndromes 69–73 neurotransmitter systems 65–6 norepinephrine system 65–6 oculomotor circuit 61 open-loop elements 60–1 organization 61–4 prototypical syndromes 66–8 rostromedial limbic circuit 62 schizophrenia 72 serotonergic system 66 structure 59–60, 60 subcortical dementia 69 subgenual cingulate circuit 63 substance abuse disorders 72 frontal-subcortical dysfunction attention-deficit hyperactivity disorder 70 depression 70–1 mania 71 neurosurgical treatment 75 obsessive-compulsive disorder 69 pharmacological interventions 73–5 Tourette syndrome 69–70 treatment 73–5 frontocerebellar interactions 236–7 frontoparietal operculum lesion 186–7 frontoparietal system, saliency detection 118, 130 frontostriatal systems 59 frontotemporal dementia 104 comportment dysfunction 257–8 EEG findings 456 neuroimaging 258 presenting symptoms 258 toxic 481 functional behavioral assessment 605 functional magnetic resonance imaging (fMRI) 6, 423–4, 433–4 advantages 433–4 deep brain stimulation 430–1 light pain stimulation paradigm 431 limitations 434 signal fluctuation 433 spatial attention 123 spatial resolution 434 visual task 433 funduscopic examination 322 GABA (gamma-aminobutyric acid) 99, 237 GABA fibers, frontal-subcortical circuits 64 Gage, Phineas 250–1, 253 gait testing 330

657

Index

galanin, sleep-promoting neuronal systems 99 Gall, Franz Joseph 47 genetics 7 geniculostriate pathway 147–8 Gerstmann’s syndrome 150, 369, 376 Geschwind, Norman 6, 47, 175, 344 gestural kinesics 186 gestures 190 imitation problems 208, 209 Gilles de la Tourette syndrome see Tourette syndrome glial cells 12 gliomas 52 gliomatosis cerebri 486 Global Assessment of Relational Functioning (GARF) Scale 594, 595 globus pallidus 19, 20, 60 glossopharyngeal nerve (CN IX) 17, 324 glutamate, executive function 237 gnosis impairment 521 see also recognition goal-directed behavior 138 diminished 140 goal-oriented behavior 134 Granger causality 472 gray matter 15 development 50 volume reduction 260–2 Griesinger, Wilhelm 2 group therapy 598–9, 599 guided search model 118–19, 130 gustation, perception/recognition 154–5 gustatory agnosia 155 habenula 19, 66 hallucinations 146–7, 575–8 complex 150 gustatory 155 haptic 153 self-perception/-recognition 156 sleep alterations 147 tactile 153 visual 149–50 see also auditory hallucinations hallucinosis, peduncular 147 handedness 312 harm avoidance 300, 303, 304, 306 tort law 412 hazardous ambulation 614 headache 609–10 hearing, examination 323–4 heavy metal poisoning 478

658

heel-to-shin test 329–30 Heidelberger Scale for subtle neurological signs 334–5 hematopoietic tumors 486–96 hemianopia 149 hemispatial inattention 367, 375, 375 hemispatial neglect 530 hepatic impairment, neurotoxin activity 475 hereditary spinocerebellar ataxias (SCAs) 40–1 herpes simplex encephalitis, EEG findings 456 hip flexor muscles, strength testing 329 hippocampus 22 episodic memory 165 greater limbic system 282 memory function 22 semantic memory 166 visuospatial information 217–18 visuospatial memory 218 histamine deficiency in narcolepsy 107 greater limbic system modulation 285 history-taking 310–11, 314 collateral information 311 communication 310–11 contradictory account 311 developmental history 312–13 family history 311–12 general medical history 314 medical records 311 non-informative account 311 social history 313–14 Hughlings Jackson, John 186, 188 Huntington’s disease autosomal dominant transmission 7 EEG findings 456 frontal-subcortical circuits 68 personality alterations 68 somatosensory symptoms 154 visuospatial dysfunction 219 hydrocephalus 29, 52 5-hydroxytryptamine 1A (5-HT1A) agonists 74 5-hydroxytryptamine receptors (5-HT-R) 66 hyperprosody 185 hypersomnia 106–10 idiopathic 107 menstruation-associated 108 periodic 107–8 primary 107 psychiatric disorders 104 hyperventilation stimulation, EEG 452–4 hypoarousal 517–18 hypogeusia 155

hypoglossal nerve (CN XII) 17, 324 hypokinesia 199, 215 hypomania 544–60 hyposmia 155 hypothalamus 18–19, 19, 99, 100–1 hypoxic–ischemic injury 26, 90, 93 idiopathic hypersomnia (IH) 107 implicit memory 167–8 impulse control disorders 72–3 impulsive behavior 571–2, 579, 615–16 inattention, hemi-spatial 367, 375, 375 independent components analysis (ICA) 469–70, 470, 471 infants, sleep 102 inferior parietal lobe 206 information processing 365–7 dopamine/norepinephrine 237–8 serotonin 239 inhibitory post-synaptic potentials (IPSPs) 442–3 insanity, not guilty by reason of 411 insight comportment 251 deficit in schizophrenia 260–1 measurement scales 257 mental status examination 384–5 insomnia 103–6 Alzheimer’s disease 104 antipsychotic drugs 554 cholinesterase inhibitors 104 chronic fatigue syndrome 104 chronic pain 104 circadian rhythm disorders 101, 104–5 cognitive behavioral therapy 105 conditioned 105 fibromyalgia 104 GABAergic agents 105–6 medical disorders 104 movement disorders 105 paradoxical 105 pharmacological treatment 105–6 primary 105 psychiatric disorders 104 treatment 104, 105–6 ventrolateral pre-optic region lesions 98 instrumental activities of daily living (IADLs) 616 integrated treatment plan 607 intellectual performance 312 intermittent rhythmic delta activity (IRDA) 450–1 internal carotid artery (ICA) 26, 426 International Classification of Impairments, Disabilities and Handicaps (WHO) 409

Index

International System of Electrode Placement 444 interneurons 12 interpersonal and social rhythm therapy (IPSRT) 593 interpersonal psychotherapy 593, 593 intravascular lymphoma 493, 492–3, 494, 494–6 involuntary emotional expression disorder (IEED) see pathological laughing and crying (PLC) IQ, heritability 306 ischemic injury 26 judgment 385 comportment 251 mental status examination 385 K-complexes, sleep 101 Kearns–Sayre syndrome 221 kinesics 186, 357–8, 371 Kleine–Levin syndrome 107–8 Klüver–Bucy syndrome 138, 273 knee jerk reflex 329 knowledge mechanical 201–2 semantic 166 Korsakoff’s syndrome 73, 162 language 174–82 classical lesion model 174–7 problems with 177 communication 357 components 184–6 comprehension 370–1 disturbances 369 evaluation 526 executive control 377 fluency 357, 370, 377 functional imaging 184 hemispheric specialization 179 impairment 526–7 left cerebral hemisphere 175, 175, 184, 188–9 linguistic elements 184 mapping in frontal lobe 178–9 mental status examination 357, 369, 369–71 neurocomputational model 181–2 neuroimaging studies 177 paralinguistic elements 184–6 perisylvian area 175, 179, 181 processing 181 rehabilitation 526 repetition 370 right hemisphere role 186–9, 191–2 semantics 526 syntax 526 time intervals 181–2

lateral geniculate nucleus (LGN) 17, 147–8 lateral orbitofrontal circuit 61–2, 235 lateral ventricles 27 laughing paroxysmal 273, 277 see also pathological laughing and crying (PLC) The Law and Neuroscience Project 406 lead poisoning 478 learning disorders, EEG findings 456 leg extensor muscle strength testing 329 see also lower extremities legal defense, neuropsychiatric 406 lenticular nucleus 20 letter cancellation task 366 leucotomy 628, 631–2 lexical fluency tasks 377 Liepmann, Hugo 200 Lima, Almedea 628 limbic leucotomy 631–2 limbic pathways 236 limbic system 276 amygdaloid sphere of influence 279 behavioral neuroanatomy 20–2 caudal components 280 emotional states 21–2 emotion/emotional feelings 275–82 forebrain evolution 278–9 function 21–2 greater 279–82 arousal circuit 281 dorsal region 282, 287 emotion generation/expression/experience/ control 285–7 extended amygdala 280–1 humoral inputs 283 interoceptive inputs 283 motivational working memory circuit 281 neurotransmitter modulation 283–5 reward circuit 282 sensory inputs 283 ventral compartment 286–7 ventral striatopallidum 281 hippocampal sphere of influence 279 historical perspective 276–9 neurobiology 278 reciprocal cerebellohypothalamic projections 280 rostral components 280 shared behavioral specializations 279 limbic system–midbrain circuit 279 line bisection task 367, 367 lithium 551, 553

lobotomy 628–9 locked-in syndrome 92 locus coeruleus 13 long-term memory 162, 164 lower extremities balance testing 330 coordination testing 329–30 gait testing 330 neurological examination 328–31 postural reflexes 330 reflexes 329, 330 sensation testing 329 stance testing 330 strength testing 329 tone 328–9 walking assessment 330–1 Luria, Alexander R. 4 lymphoma, CNS 425 lymphomatosis cerebri 487–90 brain autopsy 488 CSF cytology 489–90 neuroimaging 489, 490 neuropathological assessment 490 pathological findings 487–8, 489 white matter hypermetabolism 490 M ganglion cells 148 magnetic resonance angiography (MRA) 432–3, 467 magnetic resonance imaging (MRI) 415, 419–21, 421 advanced imaging techniques 421–6, 432–7 arterial spin labeling 436–7 astrocytoma 425 CNS lymphoma 425 contraindications 421 contrast agents 420 CT comparison 421 diffusion-weighted imaging 419–20 gradient echo imaging 419 great vessels of the neck 433 hardware 416 metastatic melanoma 425 parasagittal meningioma 424 perfusion studies 422–3 radiofrequency pulses 419 safety 420–1 T1 and T2 432 tissue appearance 418 tissue sensitivity 419 toluene abuse 425 traumatic brain injury 424, 431 very ill hospitalized patients 421 voxel-based morphometry 424–6 white matter 50, 51 see also diffusion tensor imaging (DTI); functional magnetic resonance imaging (fMRI)

659

Index

magnetic resonance spectroscopy (MRS) 423, 434–5 chemical spectrum 435 types 434–5 uses 435 white matter 50 magnetization transfer (MT) imaging 421–2 magnetoencephalography (MEG) 459–72 advantages 460 coherence measurement 471–2 concept 459–60 connectivity 470–2 cost 460 distributed source analysis 469 evoked responses 463, 468 independent components analysis 470, 469–70, 471 induced responses 463, 465, 468 measures 462 motor evoked field 464, 468 phase 463–5 phase-locking 466–7, 468 quantitative 462 source analysis 467–9 spectral analysis 461–3 system 459 time and frequency representation 466 time–frequency transformations 465–6, 466, 467 tracings 460 major depressive disorder 543–4 neurosurgical interventions 632 malingering 482 mania antipsychotic drugs 551 behaviors 545–60 bipolar disorder 544–5 electroconvulsive therapy 639 emotional behavior lateralization 71 frontal-subcortical dysfunction 71 mood stabilizers 552–3 neurological disorders 545 right-sided temporal hypometabolism 71 secondary 546, 553 stroke association 546 symptoms 544 medial cingulate cortex 255–6 medial frontal circuit 255, 255–6 medial frontal cortex 233 connections 252 functions 255 lesions 255 neuroimaging 255–6 theory of mind 255

660

medial orbitofrontal cortex 63–4, 137–8 medial temporal lobes 165–6 median forebrain bundle 26 medical decision-making, forensic practice 408 medical history, general 314 medical malpractice, tort law 412 medical records, history-taking 311 medications acute encephalopathy 481 affect disturbance induction 548 affective symptoms 548 alternatives 504, 505–6 behavioral disturbance vulnerability to side effects 570 changes 502 cognitive impairment 515–17 consultations 507 continuous reassessment of treatment need 502–3 dose adjustments 502 dose escalation 501–2 drug–drug interaction vigilance 503 ease of use 500–1 EEG impact 455–7 evidence-based selection 500 expert opinion 501 generic 503–4 hypothesis-driven selection 500 improving life without disease 507 media reports 506–7 mood disturbance induction 548 neurotoxins 476, 476–7 newly approved 504–5 non-approved indications 504 off-label use 505 partial response augmentation 503 pharmaceutical company samples 505 prior clinical experience 501 psychiatric symptoms 499 recovery concerns 506 reluctance to take 506–7 second opinions 507 selection 500–1 side effect profiles 500 therapeutic alliance 498–9 therapeutic trials 502 unexpected benefits 506 use 501–3 medulla oblongata 12–13 melanoma, metastatic 425 melatonin 101, 105 memory 161–70 anatomical substrates 162 central executive system 163–4 clinical overview 162 dysexecutive syndromes 164

episodic buffer 163 familiarity 164 hippocampus function 22 episodic memory 165 impairment 162, 522–6 implicit 167–8 long-term 162, 164 multiple systems 162–70 non-declarative 167–70 orientation to place/time/situation 372–3 phonological loop 163 phonological storage/rehearsal 163 recollection 164 remote 373 short-term 162 slave systems 163–4 spatial 372 subtypes 161 system classification 161 verbal 372 visual 372 visuospatial sketch pad 163 see also declarative memory; episodic memory; procedural memory; semantic memory; visuospatial memory; working memory Mendez’ Clock Drawing Interpretation Scale 377 mental status examination 375 affect assessment 354, 355, 355–6 anamnesis 349 appearance 350–2 apraxia 373–4 arousal 350–2 attention 365–7 atypical clinical presentation 348 behavior 352–4 calculation 375–6 clinical interview 348–50 cognition 363–4, 364, 380–4 cognitive processes 349–50 communication 356–8 comportment 353 dangerousness assessment 360–2 declarative memory 371–3, 373 delusions 361 elements 345 emotional background 355–6 emotion/emotional feeling 354–6 engagement with examiner 354 examination-induced emotional/behavioral disturbances 349 executive function 376–9 eye contact 353 informant interviewing 349 information processing speed 365–7

Index

insight 384–5 instrument use 349 judgment 385 kinesics 357–8, 371 language 357, 369, 369–71 limitations 345 mood assessment 355, 354–6 motivation 354 motor behavior 352–3 neuropsychiatric phenomenology 345–50 neuropsychological assessment 396–7 non-cognitive processes 349–50 normal distribution 382 observation 348 obsessions 362 paralinguistics 357–8, 371 praxis 373–4 prosody 357–8 recognition 368–9 self-awareness 384–5 serial examination 345 speech disturbance 357 symptoms/signs 345–7, 347 atypical 348 clinician-administered instruments 350, 351 concurrent 346 distinction between 346 distinction from syndromes 347–8 negative 346–7 neurobiological excesses/deficits 347 positive 346–7 self-report instruments 350, 351 terminology 346 syndromes 347–8 thought content 358–62 thought process 358, 358 T-scores 382 visuospatial function 374–5 word-finding difficulty 357 working memory 367–8 Z-scores 381–2, 382, 383 mesencephalic dopaminergic reward system 588 mesencephalon 14–15 metabolic encephalopathy 457 metachromatic leukodystrophy (MLD) 51 metencephalon 13–14 methylphenidate 520, 524 midbrain 14–15 middle cerebral artery (MCA) stroke 216 transcranial Doppler ultrasound 426 mind–brain debate 4

mindfulness-based stress reduction 610 minimally conscious state 91, 93–4 diagnosis 93 prognosis 93 vegetative state differential diagnosis 93 Mini-Mental State Examination (MMSE) 364, 365–6, 371, 382 mitigating circumstances, criminal responsibility 411 mitochondrial myopathies 221 Modified Quantified Neurological Scale 335 modulatory neurotransmitter nuclei 15 Moniz, Egas 628 monoamine oxidase inhibitors (MAOIs) 549, 551 monoaminergic systems, motivation 135–6 Montreal Cognitive Assessment (MoCA) 364, 383 mood affect relationship 274 assessment 354–6 definition 270–1 emotion 270–1, 271, 274 emotional feelings 271 mental status examination 355, 354–6 neurological basis 290–1 neurological distinction from affect 290 types 275 mood disorders 271 affect disorder distinction 273–4 clinical implications 271–2 co-occurrence with affect disorders 273 EEG findings 456 electroconvulsive therapy 639 emotion 271–2 features 272 medication-induced 548 neurological disorders 545–6 primary 543–5 sleep 104 mood stabilizers 551–4 bipolar disorder 551–3 drug–drug interactions 554–6 mania treatment 552, 553 side effects 554, 555 morphometric analysis of brain tissue volume 424–6 motion perception 148 motivation 134–40 amygdala 138 anterior cingulate circuit 137–8 auto-activation deficit 139

basal ganglia 139 brain structures 134 brainstem 134–5 brainstem reticular formation 135–6 definition 134 dopaminergic system 135–6 forebrain 134–5 frontal-subcortical circuits 137, 139 loss 139–40 medial orbitofrontal cortex 137–8 mental status examination 354 monoaminergic systems 135–6 neurobiological basis 134–8, 139 nucleus accumbens 136–7 physiology 138–9 prefrontal cortex 137–8 striato-pallidal circuit 139 triggers 139 ventral tegmental area 135–6 motivation disorders 134, 273, 578–9 motivation enhancement therapy (MET) 612–13 motivational interviewing 595–6, 596, 612–13 motivational working memory circuit 281 motor acts, complex, voluntary/involuntary 353 motor circuit 61 motor cortex, ideomotor apraxia 207 motor disturbance, involuntary/voluntary 353 motor evoked field (MEF) 464, 468 motor sequencing, complex 378–9 motor skills 169–70 global amnesia 168 movement disorders, frontal-subcortical circuits 68 multiple behaviors 615 multiple sclerosis 51, 53, 592 multiple system atrophy (MSA) 39 muscle strength grading 327 see also lower extremities, strength testing; upper extremities, strength testing musical hallucinations 152 myasthenia gravis, depression 545–6 mycosis fungoides brain involvement 492 neuropathological assessment 490–2 pathological findings 491, 491–2 myelencephalon 12–13 myelin, white matter 48–9 myelinated fibers 48 myelination, white matter 49 activity-dependent 55

661

Index

narcolepsy 106–7 hallucinations 147 histamine deficiency 107 idiopathic hypersomnia differential diagnosis 107 National Hospital for the Relief of Paralysis, Epilepsy and Allied Diseases 2 neglect 120–1, 215–16 attentional blink 127 disengage deficit 121, 130–1 dorsal attention system 130–1 dorsolateral prefrontal lobe 122–3 extrapersonal 216 hemispatial 530 motor 215 motor-intentional 215 neural network model 121 object-based attention 125 parietal lobe 120–1 personal 216 sensory 215 sensory-intentional 215 temporoparietal junction 120, 130–1 temporoparietal junction damage 120 ventral attention system 130–1 ventral frontal cortex 130–1 visual 215–6 neocortex 22–3 nephrogenic systemic fibrosis 420 neural networks damage in behavioral disturbance 569 distributed 7 neuroanatomy 6, 228–40 Neurobehavioral Status Examination 384 neurobehavioral toxicology 480–2 acute encephalopathy 481 dementia 481 malingering 482 pseudoneurotoxicity 482 neurochemistry 6 neurocognitive tests 394 impairment detection 397 selection 397 neuroimaging advanced 430–40 case studies 430–1 clinical indications 415–16, 416 contrast agents 417 functional 6 historical background 4 patient preparation 416–17 post-imaging considerations 417 pre-imaging considerations 416–17 selection of technique 421

662

structural 6–7, 415–27 see also named modalities neuroleptic malignant syndrome 480, 554–6 Neurological Evaluation Scale (NES) 335–6 neurological examination 319–31 bruits 321 communication 321 cranial nerves 322–4 elements 320 lower extremities 328–31 paratonia 325 speaking to the patient 321 standardized 319–20, 321 subtle neurological signs 321, 333–9 upper extremities 324–8 neurology historical background 1–4 organic problems 2 post-graduate training 5–6 neurons 12 neuropathological assessment 485–96 brain tumor clinical presentation 485–6 gliomatosis cerebri 486 hematopoietic tumors 486–96 intravascular lymphoma 492–6 lymphomatosis cerebri 490 mycosis fungoides 490–2 neuropsychiatric disorders behavioral sequelae 611–16 cerebellar lesions 39, 40 challenging behavior 607 cognitive sequelae 616–17 emotional sequelae 611–16 frontal-subcortical circuits 69–73 legal defense 406 neurosurgical interventions for refractory conditions 632–3 pain 609 physical sequelae 609–11 psychotherapy 600 social skills training 613 white matter disorders 54, 54–5 neuropsychiatric evaluation 310–15 developmental history 312–13 family history 311–12 general medical history 314 history-taking 310–14 personal experience in exploration 314 social history 313–14 symptoms/signs 347 neuropsychiatric function 511, 511 Neuropsychiatric Inventory (NPI) 349, 352 neuropsychiatric phenomenology 314–16

dissociative symptoms 315 mental status examination 345–50 mild cognitive impairment 315–16 personality change 316 sleep-related 315 traumatic brain injury 315 neuropsychological assessment 394–404 applications 395 clinical interview 396 cognitive impairment testing 399, 512 collateral information 396 emotion effects 403 functioning levels 402 historical background 394–5 impairment detection 397 levels 401–2 measures 398 mental status examination 396–7 neurocognitive domains 398 neurocognitive tests 394, 397 norm-referenced data 394, 397, 400–1 patient cooperation 400 patients’ individual situations 401 patterns of scores 402 percentiles conversion table 401 personality effects 403 practice effects 402 premorbid cognitive functioning 401 procedures 396–403 psychometrists 400 record review 396 referrals 395 reliable change index 402 reports 403 test administration 400, 402 test batteries 399 brief 399 computerized 400 fixed/flexible 397–9 intermediate 399 specialty 399, 399 test interpretation 400–2 test scoring 400–3 neuropsychology, qualifications to practice 395–6 neurorehabilitation, traumatic brain injury 7 neurosis, origin of term 1–2 neurotoxicity alcohol abuse 477 antidote use 480 clinical history 478–9 diagnosis 478–80 laboratory testing 479

Index

neurobehavioral toxicology 480–2 neuroimaging 479–80 neurologic examination 479 prognosis 480 pseudoneurotoxicity 482 treatment 480 neurotoxicology 474–6 neurotoxins 476–8 categories 476 dose–response relationship 475–6 drugs of abuse 476, 476–7 environmental toxins 476, 477, 477–8 hepatic impairment impact 475 medications 476, 476–7 nervous system region 475 nervous system vulnerability 474–5 organic solvents 477–8 pesticides 478 renal impairment impact 475 solvents 477–8 white matter 481 neurotransmission 6 neurotransmitters 519, 569–70 nicotinic ␣4␤2/␣7 receptor antagonists 522, 524 night eating syndrome 109 night terrors 108–9 nightmares 109 NMDA receptor antagonists 549 attention impairment 520–1 declarative memory impairment 524 executive dysfunction 531 visuospatial memory impairment 529 nociception 152 non-rapid eye movement (non-REM) sleep 98, 101 alpha-2 noradrenergic agonists, orbitofrontal syndrome 74 norepinephrine executive function 237–8 greater limbic system modulation 284–5 information processing 237–8 norepinephrine system, frontal-subcortical circuits 65–6 not guilty by reason of insanity 411 novelty seeking 300–1, 303, 304–6 striatum involvement 304 nuclear magnetic resonance (NMR) see magnetic resonance spectroscopy (MRS) nucleus accumbens 60, 136–7 motivation 136–7 number cancellation task 366 object attribute task 124 object cueing paradigm 125

object-based attention 124, 124, 126 functional imaging 125–6 neglect 125 parietal lobe damage 125 superior parietal lobule 126 obsessions, mental status examination 362 obsessive-compulsive disorder 69 neurosurgical treatment 75, 630–1 pharmacologic treatment 74–5 obstructive sleep apnea 106, 315 oculomotor circuit 61 oculomotor nerve (CN III) 17, 322–3 olfaction 154–5 olfactory agnosia 369 olfactory nerve (CN I) 16, 322 olfactory system 154 opsoclonus–myoclonus–ataxia 39 optic chiasm 214 optic nerve (CN II) 17, 214, 322 lesions 149 optic radiations 147–8 optic tract 147–8, 214 orbitofrontal (OF) circuit 253–4, 254, 255 components 253 disruption 254–5 functions 254 orbitofrontal (OF) cortex 59–60, 233–4 activation 233–4 connections 252 direct pathway anatomy 62 lesions 67–8, 254–5 olfactory system 154 reward circuit 282 traumatic brain injury 259 orbitofrontal (OF) syndrome 67–8, 74 organic solvents, neurotoxins 477–8 organic–functional dichotomy 4–5 organophosphate pesticide neurotoxicity 478, 480 Ozeretskii test 378 P cells 148 pain chronic 104 neuropsychiatric disorders 609 palinacusis 151–2 pallidus see globus pallidus panic attacks 547 panic disorder 612 pantomime, disorders of 186 pantomime of transitive acts dissociation apraxia 208 ideomotor apraxia 203, 206 Papez circuit 20, 26, 278, 287 paralimbic system 276 paralinguistic cues 356 paralinguistics 357–8, 371

parasagittal meningioma 424 parasomnias 108–10, 315 central pattern generators 109 disorders of arousal 108–9 non-REM sleep 108–9 REM sleep 109 secondary 109–10 treatment 109 paratonia, neurological examination 325 paresthesias 153 parietal lobe attention deficit 121–2 disengage deficit 121 inferior 206 neglect 120–1 object-based attention 125 posterior 120, 215 sequencing disorder 202 simultanagnosia 217 spatial attention 120 visual search task 121 Parkinson’s disease cognitive behavioral therapy 592 with dementia, visuospatial dysfunction 219–20 depression 545 executive function 73 limb-kinetic apraxia 210–11 medial substantia nigra involvement 68 pharmacological intervention 73 putamen involvement 68 somatosensory symptoms 154 visual abnormalities 150 pathological laughing and crying (PLC) 39, 547, 546–7, 560 frequency 546–7 neuroanatomy/neurochemistry 546 treatment 557–9 patient, role in medical decision-making 408 pattern recognition, executive function 377–8 pedunculopontine tegmental cholinergic nuclei 15 perception 144–56 auditory 150–2 crossmodal integration 155–6 definition 144 disorders 146–7 agnosias 146 somatosensory 153–4 visual 149–50 disturbances 360 gustation 154–5 motion 148 olfaction 154–5 self-perception 156

663

Index

perception (cont.) sensory input 145 somatosensory 152–4 visual 147–50 disorders 149–50 visual system functional specialization 148 perceptual priming 145 perceptual skills learning 169 stages 169 perceptual system, organization 145–6 periaqueductal gray (PAG) 15 periodic limb movements of sleep (PLMS) 105 peripheral nervous system (PNS) 12, 474–5 perisylvian area 188 language 175, 179, 181 persistence 301, 303, 304–5 persistent vegetative state (PVS) 92–3 personality 299–307 complexity 305–6 definition 299 gene–environment interactions 305–7 heritability 300, 306, 306–7 humoral theory 299 inheritance 300, 306–7 neuropsychological assessment effects 403 temperament and character comprehensive model 299 see also character; temperament personality change 316 orbitofrontal syndrome 67–8, 74 pesticides, neurotoxins 478 phantom limb sensations 153 pharmacotherapy 498–508 attention impairment 519–21 behavioral disturbance 566–81 cognitive impairment 515–17 coma 518–19 consultations 507 continuous reassessment of treatment need 502–3 drug–drug interaction vigilance 503 evaluation 499–500 expert opinion 501 generic medications 503–4 initiation 498 insurance issues 504 pharmaceutical industry interactions 505 rating scale use 499 second opinions 507 therapeutic alliance 498–9 therapeutic trials 502 treatment priority 499–500 see also medications

664

phase-contrast angiography (PCA) 433 phobias, types 362 phonagnosia 151, 186 phonemes, articulation impairment 357 photic stimulation, EEG 454 Pick, Arnold 257–8 Pick’s disease see frontotemporal dementia pin prick perception 328 pineal body 19 planum temporale 179 pons 13 positive behavioral supports 605, 615 positive reinforcement 608 positron emission tomography (PET) 6, 437–8, 438, 439 posterior cerebral arteries (PCA) 26 stroke 216 posterior cingulate 282 posterior cortical atrophy (PCA) Alzheimer’s disease 219 Balint’s syndrome 219 visual deficits 150 visuospatial dysfunction 219 posterior dominant rhythm (PDR), EEG 447–8, 450, 455 posterior fossa syndrome 38 posterior inferior cerebellar arteries (PICAs) 34 posterior parietal lobe 120, 215 post-traumatic amnesia (PTA) 315 post-traumatic stress disorder (PTSD) 109, 190–1, 612 postural reflexes 330 praxis 199–211, 373–4, 527–9 neuroanatomy 528 see also apraxia prefrontal circuit 253, 256 prefrontal cortex affective processing 138 association pathways 235–6 childhood lesions 259–60 executive function 225, 229–34 functions 229 goal-directed behavior 138 heteromodal sector 231–2 medial 233 motivation 137–8 motor association areas 229–30 motor-premotor sector 229–31 paralimbic sector 232–4 subdivisions 229–32, 232, 234, 252–6 premotor cortex 206–9 supplementary motor area 207 primary central nervous system lymphoma (PCNSL) 486–7 primary sensory cortex 145

primary visual area 214 procedural interventions 627–42 complications 632 historical aspects 627–9 invasive 627–31 lesional interventions 631–2 vagal nerve stimulation 634 methodological variability 630 non-invasive 634–6 rationale 629–31 see also deep brain stimulation (DBS); electroconvulsive therapy (ECT); transcranial magnetic stimulation (TMS) procedural memory 168–70 assessment 525 impairment 525–6 treatment 525–6 Process C, sleep 102–4 Process S, sleep 101–2, 104 processing speed 365, 519–21 cognitive impairment 519–21 proprioception 152 prosody 185–6, 527 affective 186–8 aging 190 alcohol abuse 190 clinical settings 190–1 comprehension 190 disruption with left hemisphere damage 188–9 hemispheric lateralization 188–9 post-traumatic stress disorder 190–1 repetition 189 schizophrenia 190 spontaneous 189 attitudinal 190 brain damage 185–90 clinical disorders 185–6 elements 185 emotional 185 functional imaging 188 inarticulate 185 intellectual (attitudinal) 185 interhemispheric integration loss 189 intrinsic (linguistic) 185 mental status examination 357–8, 371 paralinguistic cue 356 prosopagnosia 149 pseudobulbar affect see pathological laughing and crying (PLC) pseudohallucinations 146–7 pseudoneurotoxicity 482 pseudoseizures, case studies 313 psychiatric disorders, challenging behavior comorbidity 568–9

Index

psychiatry functional problems 2 historical background 1–4 postgraduate training 5–6 psychic auto-activation loss 139 psychoanalysis 2, 4, 6 psychodynamic psychotherapy 597–8, 598 psychological trauma 312–13 psychometrists 400 psychopharmacology 4 psychosis 575–8 cerebellar electrical stimulation 41–2 neurological syndrome association 575, 576 treatment 578 psychosurgery 7, 628–9 US Federal Commission report 629 psychotherapy 7, 587–90 attachment theory 588 behavioral therapy 590, 590–1 cognitive behavioral therapy 591, 591, 592, 592 cognitive therapies 591–2 ECBIS domain 588, 589, 590, 599 family therapy 593–4, 594, 595 group therapy 598–9, 599 interpersonal therapy 593, 593 learning process 587–8 mesencephalic dopaminergic reward system 588 motivational interviewing 595–6, 596 neuropsychiatric disorders 600 psychodynamic 597–8, 598 psychological mechanisms of effects 587–8 supportive 596–7, 597 systems therapy 593–4, 594, 595 therapeutic alliance 587 types 588–99 public policy 7 pull test 330 pulsed arterial spin labeling (PASL) 437 pure anomia 180 pure word deafness 151, 180, 369 Purkinje cells 14, 32 putamen 19–20, 68 pyramidal neurons, EEG activity 442 Quantified Neurological Scale, Modified 335 rapid eye movement (REM) sleep 98, 100 dopaminergic system 100 dreaming 100 flip-flop switch 100

physiology 102 REM behavior disorder 109 receptive amusia 151 recognition 144–56 auditory 150–2 crossmodal integration 155–6 definition 144–5 disorders 146–7, 149–54 gustation 154–5 impairment 369, 521 mental status examination 368–9 olfaction 154–5 self-recognition 156 sensory domain-specific 368–9 somatosensory disorders 153–4 vision 147–50 visual system functional specialization 148 recollection 164 reflexes hammer 325 lower extremities 329, 330 primitive 326, 327 response grades 325 upper extremities 325–6 relaxation training 590, 609 reliable change index 402 REM behavior disorder (RBD) 109 renal impairment, neurotoxin activity 475 Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 399 restless leg syndrome (RLS) 105 reticular formation 16, 25 behavioral neuroanatomy 15–16 retinal ganglion cells 147 reward 608 reward circuit, greater limbic system 282 reward dependence 301, 303, 304 Ribot’s law 164–5 right hemisphere, medial surface 64 right-hemisphere hypothesis, emotion 287 risky behavior 615–16 Rolandic fissure 23 Romberg test 330 Rossi Scale for subtle neurological signs 334 rostromedial limbic circuit 62, 63 sadness 270 salience 134 saliency map 118, 130 schizophrenia affective prosody 190 auditory hallucinations 152 case study 313

cognitive behavioral therapy 592 comportment dysfunction 260–1 dorsolateral prefrontal circuit 72 EEG findings 456 electroconvulsive therapy 639 frontal-subcortical circuits 72 gray matter volume reduction 260 insight deficit 260–1 pharmacologic treatment 73 sleep disorders 104 subtle neurological signs 337–9 theory of mind 261 transcranial magnetic stimulation 641 seizures, complex partial 273 selective attention model 128–30 selective serotonin reuptake inhibitors (SSRIs) 74–5, 531–2, 549, 557–8 side effects 550–1 self-awareness comportment 251 deficit 579–80 mental status examination 384–5 self-directedness 302, 305 self-injurious behavior 572–5 acute 573–4 chronic 574–5 self-management 617 self-perception 156 self-recognition 156 self-regulation 617 self-transcendence 302, 305–7 semantic(s) 526 semantic aphasia 181, 181 semantic dementia 167, 181 semantic knowledge 166 semantic memory 166–7 degradation 201 sensation, upper extremities 328 sensory input 145 sensory system 145–6 sequencing disorder 202 serotonergic innervation 14–15 serotonergic system, frontal-subcortical circuits 66 serotonin 238–9, 283–4 set shifting 376–7 short-term memory 162 simulated presence therapy 614–15 simultanagnosia 146, 149, 216–17, 369 binding deficit 217 degenerative brain disorders 217 subtypes 217 single-photon emission tomography (SPECT) 6, 438–9

665

Index

sleep 98–110 across lifespan 102–3 adolescence 103 aging 99, 103 architecture 101–2, 449, 454 ascending reticular activating system 16, 443 cyclic alternating pattern 102 deprivation 103, 147 disturbance 98 EEG patterns 101–2 hallucinations 147 homeostatic systems 98 infants 102 K-complexes 101 local 102 mood disorders 104 morphology 101–2 motor skills acquisition 169 neuropsychiatric phenomenology 315 physiology 102 Process C 102–4 Process S 101–2, 104 spindles 101, 104, 443 stages 101 timing regulation 100–1 see also wake–sleep organization sleep disorders 103–10 behavioral interventions 610–11 circadian system 101 excessive daytime sleepiness 106–7 hypersomnias 106–10 narcolepsy 106–7, 147 obstructive sleep apnea 106 parasomnias 108–10 schizophrenia 104 see also insomnia sleep state misperception syndrome (SSMS) 105 sleep-promoting systems 99 sleep-related eating disorder 109 sleep–wake organization 98–100, 102 slow-wave sleep (SWS) system 98, 101, 102 social adaptation, comportment 251–2 social cognition, judgment 385 social communication 617 social skills training (SST) 613 social-interactive competence 617 Society for Behavioral and Cognitive Neurology 5 solvents, neurotoxins 477–8 somatosensory cortex pathways 152–3 somatosensory pathways, central 152 somatosensory perception 152–4 somatosensory processing streams 152–3

666

somatosensory recognition disorders 153–4 somatostatin/neuropeptide Y-containing interneurons 66 somesthesis 152 somnambulism 108–9 source analysis 467–9 spatial attention 119–24 frontal eye field damage 122–3 frontal lobe 122–3 functional imaging 123–4 neglect 120–1 parietal lobe 120 posterior parietal lobe 120 temporoparietal junction 120 spatial cueing 116–17 disengage deficit 121, 122 object-based 124 order of events 116 peripheral/central cue comparisons 123–4 spatial memory 372 speech communication 357 disturbance 357 examination 324 production 181–2 spinal accessory nerve (CN XI) 324 Stages of Change model 595, 597 stance testing 330 stem cell replacement 55 stereopsis 218 stimulus control 605 wandering 614 strength testing, upper extremities 326–8 stress, emotional response 302 striate cortex 214 striatopallidal circuit 139 striatopallidum, ventral 281 striatum 19–20, 304 cholinergic/dopaminergic system interactions 65 limbic/motor system interactions 66 sensorimotor systems 66 striosomes 66 stroke auditory hallucinations 152 basilar artery 216 cerebellar 37–8 depression 545 EEG findings 456 ischemic 26 mania association 546 middle cerebral artery 216 posterior cerebral arteries 216 simultanagnosia 216 subarachnoid hemorrhage 424 subcaudate tractotomy 631–2

subcortical dementia 69 ischemic vascular 50 subdural hygroma, acute 423 subgenual cingulate 71 circuit 63 substance abuse disorders behavioral interventions 612–13 behavioral therapy 590–1 dopaminergic system 72 environmental interventions 612–13 frontal-subcortical circuits 72 substantia nigra 14, 60 subtle neurological signs (SNS) 321, 333–9 antipsychotic motor side effects 336 assessment 333–6 behavioral problems 336 biological marker function 338 brain structure abnormality associations 336–7 Cambridge Neurological Inventory 335 clinical significance 336–8 cognitive impairment domains 336 disease associations 336 endophenotype function 338–9 functional outcome 337–8 genetic relationship with conditions 338–9 Heidelberger Scale 334–5 localization in brain 334, 337 Modified Quantified Neurological Scale 335 Neurological Evaluation Scale 335–6 research 338–9 Rossi Scale 334 schizophrenia 337–9 social function 337–8 sociodemographic variables 336 Woods Scale 334 sudden cardiac death 556–7 sundowning syndrome, Alzheimer’s disease 104 superior cerebellar arteries 34 superior colliculus ablation 214 superior longitudinal fasciculus 208, 214, 235 superior parietal lobule (SPL) 126 supplementary motor area (SMA) 207 support groups 594 supportive psychotherapy 596–7, 597 suprachiasmatic nucleus (SCN) 100–1 Sylvian fissure 23 symbol cancellation task 366–7, 367 synesthesia 155–6 syntax 526 systemic lupus erythematosus (SLE) 51, 545

Index

systemic motivational counseling (SMC) 595 systems therapy 593–4, 594, 595 tactile sensation 152 tardive akathisia 556 tardive dyskinesia 336, 556 tardive dystonia 556 task selection, executive attention 128 taste cells 154 taste sensation 154–5 tastes, primary 154 tectum 14 temperament 299–300, 300, 301–3, 303, 305 harm avoidance 300, 303, 304, 306 heritability 300, 306 novelty seeking 300–1, 303, 304–6 persistence 301, 303, 304–5 reinforcement effects on emotional state 303 reward dependence 301, 303, 304 stability 300 traits 300–1 temporal circuit 256 temporal lobe 179, 261–2 temporoparietal junction 120, 129, 130–1 neglect 120, 130–1 terminology for specialty 8 thalamic nuclei 18, 18 thalamus 18, 88 theory of mind 255, 261 therapeutic alliance 498–9, 587 thermoreception 152 thought content 358–62 inferences from non-engagement 362 lethal 360–2 thought process 358, 358, 359 time–frequency transformations 465–7 tinnitus 151–2 toluene abuse 425 tone testing lower extremities 328–9 upper extremities 324 tongue examination 324 tool use, conceptual apraxia 200–1 topectomy 628 tort law 412–13 touch testing 328 Tourette syndrome cortical–subcortical interaction alteration 70 frontal-subcortical dysfunction 69–70 neurosurgical treatment 75, 631 pharmacologic treatment 73

striatal neuron overactivity 69–70 tic pathophysiology 69 tic severity 69 toxic encephalopathy 412 toxic leukoencephalopathy (TL) 51–2, 53, 481 tractography, diffusion tensor imaging 48 transcranial Doppler ultrasound 426 transcranial magnetic stimulation (TMS) 41–2, 527, 640–1 clinical applications 641 frequency 640 historical aspects 635–6 stimulus intensity 640 transmodal cortex 145 traumatic brain injury (TBI) 8 arousal pathology 90 behavioral change 258–9 cognitive behavioral therapy 592 comportment dysfunction 258–60 MRI 424, 431 neuropsychiatric phenomenology 315 neurorehabilitation 7 orbitofrontal cortex 259 psychiatric comorbidity 568–9 tort law 412 vegetative state 93 white matter lesions 52 trephination 627–8 triceps muscle, strength testing 326 triceps reflex 325–6 tricyclic antidepressants 549–51, 557–8 trigeminal nerve (CN V) 17, 323 trochlear nerve (CN IV) 17, 322–3 T-scores 382 unawareness of deficit 385 Universal Cerebellar Impairment 41 Universal Cerebellar Transform (UCT) 41 upper extremities coordination testing 328 neurological examination 324–8 reflexes 325–6 sensation testing 328 strength testing 326–8 tone 324 vagal nerve stimulation 634 vagus nerve (CN X) 17, 324 valence 134, 270 valence-specific hypothesis 287–8 vascular dementia 456 vascular system 26–7, 27, 28 arteries 26 veins 27

vegetative state 91–4 diagnosis 92 diagnostic criteria 92 locked-in syndrome 92 minimally conscious state differential diagnosis 93 pathology 92 prognosis 92–3 progression from coma 92 ventral frontal cortex (VFC) 129, 130–1 ventral limbic pathway 236 ventral striatopallidum 281 ventral tegmental area (VTA) 14, 135–6 ventral visual stream lesions 149 ventral visual system 148 ventricular system 29, 27–9 ventrolateral pre-optic (VLPO) region ascending reticular activating system inhibition 100 insomnia 98 sleep-promoting neuronal systems 99 verapamil 552–4 verbal fluency tasks 377 verbal letter test 366 verbal trail making test (vTMT) 366 vertebral arteries 26 Vesalius, Andreas 47 vestibulocochlear nerve (CN VIII) 17, 323–4 violence/violent behavior 7, 256 see also aggression vision 147–50 visual acuity testing 322 visual agnosia 369 visual association areas 147 visual cortex 147, 214 visual field cuts 149 visual field testing 322 visual loss, cortically mediated 149 visual memory 372 visual neglect 215–16 visual object agnosia 150 visual pathway, primary 147–8 visual perception/recognition disorders 149–50 visual scanning 145 visual search task 117, 117, 118 bottom-up information 117–18 parietal lobe damage 121 top-down information 118–19 visual system 148 visual working memory 120, 126–8 visually guided search model 118 visuomotor adaptation 169 visuospatial clinical syndromes 215–18

667

Index

visuospatial function 214–21, 529–30 distributed neural circuits 529 dysfunction with neurological conditions 218–21 evaluation 529 executive control 377 mental status examination 374–5 visuospatial processing 214–15 visuospatial memory 217–18, 529–30 allocentric/egocentric 218 visuospatial information 217–18 working memory 217 vitamin B12 deficiency 52 vocalization, disruptive 614–15 voice 356–7 voxel-based morphometry (VBM) 424–6 wakefulness 16, 443, 455–7 wake-promoting systems 98–9 wake–sleep organization 98–100, 102 sleep-promoting systems 99 wake-promoting systems 98–9 walking 330–1 wandering 614 war 7 Watts, James 628–9 Wechsler Adult Intelligence Scale 401 Wernicke, Karl 174–5

668

Wernicke–Geschwind model of language 175, 176, 176 Wernicke–Korsakoff syndrome 477 Wernicke’s aphasia 176, 177, 180 Wernicke’s area 175, 175–6, 177, 181 function 180 planum temporale 179 white matter 47–56 aging role 50 Alzheimer’s disease 50, 54 anatomy 47–8 behavioral neuroanatomy 25–6 development role 50 distributed neural circuits 50 focal syndromes 52–3 historical background 47 myelin 48 myelination 49, 55 neuroimaging studies 7, 50–1, 51 pathways 49 physiology 48–50 plasticity 55 toxins 481 tractography 236 tracts 48 white matter dementia 53, 53–4, 486 neurobehavioral features 53–4 neuropsychological profile 54 white matter disorders 51–2, 52 axon regrowth 55

gray matter pathology 54 hematopoietic tumors 486–96 neurobehavioral syndromes 52–3, 53, 54 neuropsychiatric syndromes 54, 54–5 prognosis 55 stem cell replacement 55 treatment 55 Williams syndrome 220–1 Willis, Thomas 47 Woods Scale for subtle neurological signs 334 word-finding difficulty 357 word-selection anomia 180 working memory 162–4, 367–8 impairment 368, 522–3 World Health Organization (WHO), International Classification of Impairments, Disabilities and Handicaps 409 wrist extensor muscles, strength testing 327 written alternating sequence tasks 376 xenon enhanced computed tomography (Xe-CT) 431–2 Z-scores, mental status examination 381–2, 382, 383

Dr David B. Arciniegas, C. Alan Anderson, Christopher M. Filley-Behavioral Neurology & Neuropsychiatry-Cambridge University Press (2013)

Recommend Documents