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Κύρια Fatigue as a Window to the Brain (Issues in Clinical and Cognitive Neuropsychology)
Fatigue as a Window to the Brain (Issues in Clinical and Cognitive Neuropsychology)John DeLuca, Simon Wessely
Although fatigue has been actively investigated for more than 100 years, we have progressed little in either its theoretical or practical understanding. Fatigue has been considered to be both a symptom and an illness. Fatigue is a primary reason for patient visits to the physician's office, but it is difficult to measure and offers doctors little important information for diagnosis. Fatigue as a Window to the Brain gathers experts on a wide variety of disorders to consider what the presence of fatigue tells us about how the brain works—more specifically, to identify the neural mechanisms potentially responsible for fatigue. The book looks at many of the major conditions in which fatigue is observed, with the hope that patterns may emerge that will suggest paths for future research. It will be of interest to neuroscientists, clinical researchers, and physicians and other clinicians. After discussing the nature of fatigue—its history and epidemiology and its assessment, measurement, and interpretation—the book turns to specific conditions associated with fatigue. It considers neurological conditions, including multiple sclerosis and stroke; psychiatric conditions as well as the overall treatment of fatigue in psychiatry; and general medical conditions, including HIV, heart disease, lupus, cancer, and others. The book then offers an overview of treatment approaches. It concludes with a definition of fatigue—both "primary" and "secondary"—and suggestions for future study.
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f a t i g u e as a Window to the Brain edited by John DeLuca foreword by Simon Wessely Fatigue as a Window to the Brain Issues in Clinical and Cognitive Neuropsychology Jordan Grafman, series editor Patient-Based Approaches to Cognitive Neuroscience Martha J. Farah and Todd E. Feinberg, editors Gateway to Memory: An Introduction to Neural Network Modeling of the Hippocampus and Learning Mark A. Gluck and Catherine E. Myers Neurological Foundations of Cognitive Neuroscience Mark D'Esposito, editor The Parallel Brain: The Cognitive Neuroscience of the Corpus Callosum Eran Zaidel and Marco Iacoboni, editors Fatigue as a Window to the Brain John DeLuca, editor Fatigue as a Window to the Brain edited by John DeLuca A Bradford Book The MIT Press Cambridge, Massachusetts London, England © 2005 Massachusetts Institute of Technology All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without permission in writing from the publisher. MIT Press books may be purchased at special quantity discounts for business or sales promotional use. For information, please email firstname.lastname@example.com or write to Special Sales Department, The MIT Press, 5 Cambridge Center, Cambridge, MA 02142. This book was set in Stone serif and Stone sans by SNP Best-set Typesetter Ltd., Hong Kong. Printed and bound in the United States of America. Library of Congress Cataloging-in-Publication Data Fatigue as a window to the brain / edited by John DeLuca ; foreword by Simon Wessely. p. ; cm.—(Issues in clinical and cognitive neuropsychology) "A Bradford book." Includes bibliographical references and index. ISBN 0-262-04227-4 (hc : alk. paper) 1. Fatigue. 2. Neurophysiology. I. DeLuca, John, 1956– II. Series. [DNLM: 1. Fatigue—physiopathology. 2. Fatigue—etiology. 3. Fatigue—psychology. WB 146 F253 2005] QP421.F38 2005 612.8¢23—dc22 2004062102 Printed on recycled paper. 10 9 8 7 6 5 4 3 2 1 To my children, Jessica, Danielle, and Robbie, who inspire me to achieve and be the best I can be Contents Foreword by Simon Wessely Preface xix I The Nature of Fatigue ix 1 1 What Is Fatigue? History and Epidemiology Susan Torres-Harding and Leonard A. Jason 3 2 The Assessment and Measurement of Fatigue Christopher Christodoulou 3 Fatigue, Cognition, and Mental Effort John DeLuca II Fatigue in Neurological Conditions 19 37 59 4 Multiple Sclerosis and Fatigue 61 Lauren B. Krupp, Christopher Christodoulou, and Harold Schombert 5 Fatigue after Stroke 73 Maja Stulemeijer, Luciano Fasotti, and Gijs Bleijenberg 6 Fatigue after Traumatic Brain Injury 89 Elie P. Elovic, Nino M. Dobrovic, and Jonathan L. Fellus 7 Fatigue in Other Neurological Conditions Jonathan L. Fellus and Wahid Rashidzada 107 viii Contents III Fatigue in Psychiatric Conditions 125 8 The Diagnosis and Treatment of Fatigue in Psychiatry: A Historical Overview 127 Edward Shorter 9 Chronic Fatigue Syndrome and the Brain Susan K. Johnson and John DeLuca 10 Depression and Fatigue Susan K. Johnson 137 157 11 Fatigue and Somatization 173 Lesley A. Allen and Javier I. Escobar IV Fatigue in General Medical and Other Conditions 185 12 HIV-Related Fatigue 187 Natasha Dufour, Benoit Dubé, and William Breitbart 13 Fatigue and Sleep Stephen P. Duntley 209 14 Heart Disease, Cardiovascular Functioning, and Fatigue Scott Siegel and Neil Schneiderman 229 15 Fatigue in Systemic Lupus Erythematosus and Related Autoimmune Disorders 243 Elizabeth Kozora 16 Cancer and Fatigue: Insights from Studies of Women Treated for Breast Cancer 265 Paul B. Jacobsen and Kristine A. Donovan 17 Psychoneuroimmunology and Fatigue 281 Nancy G. Klimas, Mary Ann Fletcher, Kevin Maher, and Rasha Lawrence V Treatment of Fatigue 299 18 Rehabilitation and Treatment of Fatigue 301 Gudrun Lange, Dane B. Cook, and Benjamin H. Natelson Contents ix VI Conclusions 317 19 Fatigue: Its Definition, Its Study, and Its Future John DeLuca Contributors Index 331 327 319 Foreword Fatigue has always been an elusive creature. Poets write about it, newspapers argue about it, patients suffer from it, and scientists occasionally study it. This book represents a substantial, and coherent, attempt to at least partly overcome the neglect, but it is worth spending a moment considering why the subject has never received the serious professional attention it deserves. There are probably two main reasons for this. First, as several contributors to this book acknowledge, fatigue is difficult to define and measure. While the electrophysiologic fatigue of the myasthenic synapse revealed its secrets to neurophysiologists over a century ago, no such progress was made in measuring the far more common problem of subjective fatigue, although this was not for want of trying (Muscio, 1921). Fatigue, like pain, remains a private experience, which can be measured only at second hand. There will never be an objective fatigue test, in the sense that thyroid function has objective measures, independent of patient experience. There will never be a substitute for the ancient art of talking to patients, either directly as part of the clinical encounter, or indirectly through increasingly impersonal but more reliable questionnaires (Dittner, Brown, & Wessely, 2004). As medicine becomes ever more technological and distanced from the bedside, fatigue has not been a fertile topic for those aiming for the glittering research prizes. Neither I nor the authors of this book share this perspective, but regrettably fatigue studies have so far not figured high on any research funding agenda. The second reason is that fatigue is unfortunately not a very discriminative symptom for the busy clinician. Doctors afford more attention and respect to symptoms that provide useful diagnostic information, which is arguably their first and most important function—determining what is wrong with the patient. Hence, medical students are taught to pay close attention to symptoms such as hemoptysis, the presence of which indicates a short and usually serious differential diagnosis. Alternatively, the belief that your limbs are controlled by special rays broadcast from your television is equally important for a psychiatric differential diagnosis. xii Simon Wessely All of this is in marked contrast to the complaint of fatigue. The patient complaining of fatigue could be suffering from nearly any condition listed in a joint edition of the Oxford Textbooks of Medicine and Psychiatry. Establishing a complaint of fatigue, thus, barely advances the diagnostic process. More questioning, investigations, and of course, time are needed. This problem is evident even in this book, which includes contributions of a wide range of physical and psychological disorders, though many more could have been included, all strongly associated with fatigue. Human immunodeficiency virus (HIV), cancer, brain injury, lupus, and depression are all appropriately included, but perhaps only limited space prohibited the editor from requesting contributions on pulmonary disease (Breslin, van der Schans, Breukink, et al., 1998), hepatitis C (Wessely & Pariante, 2002) or other hepatic conditions (Kumar, 2002), renal disease (Brunier & Graydon, 1993), and many more. Fatigue is, therefore, the opposite of pathognomic, and hence unlikely to figure largely in medical curricula or multiple choice examinations. Yet for the patient, fatigue is a vitally important symptom. Not just a source of discomfort in its own right, it can also be associated with sometimes profound disruption of physical and mental function, with the corresponding impact on quality of life. Psychiatric epidemiologist Bruce Dohrenwend, in his classic midtown Manhattan study, asked professionals and laypeople alike to rate the importance they ascribed to symptoms. Easily the most discrepancy occurred with the complaint of fatigue. "Feeling weak all over for much of the time" was regarded as "very serious" by only 6 percent of psychiatrists and 9 percent of physicians, making it one of the least important of 43 listed symptoms (Dohrenwend & Crandell, 1970). In contrast, the same symptom was listed as one of the most important by nonprofessional samples (Dohrenwend & Crandell, 1970). Another surprising finding, which does little to increase doctors' interest in fatigue, is that the mechanisms underlying fatigue show considerable overlap between the discrete diagnostic entities. Poor sleep, integral to many disorders, is strongly associated with fatigue across the diagnostic spectrum. Depression, regardless of its cause, is always associated with reduced energy levels. Certain emotional reactions, such as catastrophizing, predict greater fatigue and disability in conditions as diverse as cancer, low back pain, and chronic fatigue syndrome, and probably in other diagnoses as well when someone bothers to look. Lack of exercise is likewise always associated with fatigue. For this reason, successful treatments are similarly broad based. If lack of exercise is correlated with fatigue in many disorders, it is not surprising that as Lange and colleagues (chapter 18) show, graded exercise effectively alleviates the fatigue found in numerous conditions. Likewise, cognitive behavioral therapy (CBT) is almost always effective. Foreword xiii This information should, and does in the hands of DeLuca and his colleagues, help counter some myths surrounding the treatment of fatigue and fatigue conditions. The book's numerous comparisons between conditions and across the medical/psychiatric divide help demystify interventions that are needlessly stigmatized as "psychiatric" (such as CBT) or considered dangerous or risky (such as graded exercise). Instead, we discuss them as what they are—useful adjunct treatments for disorders of impeccable physical origin (cancer, HIV, rheumatoid, multiple sclerosis) as well as for those whose origins remain obscure, such as chronic fatigue syndrome (CFS) or fibromyalgia (Sharpe, 1997). Treatment does not necessarily depend on an exact knowledge of the cause of chronic fatigue, only on understanding why it has not gone away. DeLuca, in his final contribution (chapter 19), makes a powerful case to label this chronic condition "secondary fatigue." To date, we have made more progress in treating this "secondary" fatigue than the primary causes. But at least we have made progress. But what do we now know about the mechanisms of fatigue and fatigability? The central message of this book is, pun intended, that fatigue is predominantly of central origin. Far and away the most promising biological approaches are neurobiological. And we can go further. For me, the most exciting recent developments in our conceptual understanding of fatigue come from the increasing emphasis on the sense of effort. As the editor's own elegant contributions confirm (chapters 3 and 9), patients who suffer from the quintessential fatigue condition, CFS, report greater cognitive effort and more cognitive impairment than is detectable on objective assessment. Put another way, CFS is a disorder of effort perception, both physical and mental. Patients require additional central resources to produce the same amount of mental work (as well as physical work) as neuroimaging is starting to demonstrate (chapter 9). Dedra Buchwald's influential and impressive research group have recently extended these observations to the question of sleep disturbance and CFS as well (Watson et al., 2003). We are at last moving away from fruitless attempts to show structural lesions in the central nervous system to studies of the actual impairment in CFS—the dynamics of physical and mental effort. Any book on chronic fatigue and its syndromes must sooner or later engage with psychiatry. Actually a few books pointedly do not, while in the United Kingdom an Internet and political campaign is currently underway to promote more research into CFS, a laudable aim, but under the banner of ABP—"anything but psychiatry." Something equally short-sighted is also taking place in one or two quasi-official circles in the United States, among people who ought to know better. Such intolerance will only hamper knowledge and increase the stigma, for psychiatry is like Banquo's ghost at Macbeth's dinner party—an unwelcome guest whose influence is most keenly felt by those who desire it the least. Thankfully, but not surprisingly, DeLuca and colleagues xiv Simon Wessely have no truck with such intolerance, preferring to engage with modern psychiatric research and the insights it provides. Yet, if only the blinkered continue to deny any role for psychiatry in our understanding of chronic fatigue, even the most farsighted have considerable difficulty determining exactly how psychiatry does interact with chronic fatigue. It is also true that those of us who specialize in psychiatry do not make things easier for our colleagues with our own systems of classification. For example, some commentators continue to see somatization as the new harbor for fatigue, but it is a harbor few wish to enter, not just those suffering from the complaint (Mayou, 2003). As Escobar (chapter 11) shows in his contribution, symptom counting alone is certainly simple and reproducible, but replete with difficulties and ambiguities. It is at least better than hysteria, although that is not saying much (Wessely, 2001). "Medically unexplained symptoms" seems a better description; it is intellectually less taxing and carries less baggage but is likely to be only a temporary staging post. It is left to one of the foremost historians of psychiatry, Edward Shorter (chapter 8), to make perhaps the most subversive contribution to the book. He draws attention to the strange disappearance of fatigue syndromes and synonyms from the psychiatric lexicon in the mid-twentieth century. From its central position in psychiatric thinking, it declined precipitously, and was finally booted out of the new bible of PC (psychiatric correctness), the DSM (Diagnostic and Statistical Manual of Mental Disorders). As Shorter perceptively points out, the ejection of fatigue syndromes from psychiatric classification paradoxically corresponds with its reintroduction into popular culture. Fatigue syndromes such as chronic brucellosis, hypoglycemia, effort syndrome, and most of all, neurasthenia disappeared from professional discourse in the mid-twentieth century. They were replaced by psychologization as fatigue was subsumed under depression and anxiety. Neurasthenia is not found in the new psychiatric bibles, but descriptions of the new depressive disorders emphasize the familiar fatigue and fatigability. This was never likely to find universal favor, however, especially with some sections of the public. Ejected from psychiatry, where were the new fatigue syndromes going to find a home? The sudden interest in chronic Epstein-Barr virus infection in the 1980s, with its high watermark being the 1988 CDC case definition (Holmes, Kaplan, Gantz, et al., 1988) represented an attempt to place fatigue syndromes under infectious diseases or immunology, but after two decades, the commentators, editorialists, and textbook contributors in those disciplines remain to be convinced. At the time of this writing, some vigorous efforts are being made to claim fatigue syndromes for neurology. This would be commendable if it took the broad approach embracing neuropsychiatry and neuropsychology epitomized by this volume. However, as those advancing this cause most often define neurology narrowly Foreword xv as the study of muscle and nerve, this approach is no more likely to be successful than it was in Victorian times (Wessely, Hotopf, & Sharpe, 1998). So have we progressed in our conceptualization and classification of the fatigue syndromes? Shorter clearly invites us to answer in the negative. And this situation is unlikely to change. The rapid rise of powerful lobby groups and the politics of PC means that fatigue is not likely to return to psychiatry, at least in its old form. The evidence for reintroducing at least one fatigue diagnosis or syndrome into Western psychiatry may be strong, but its chances of happening are remote. Neither the American Psychiatric Association, owners of the DSM, nor the World Health Organization (WHO), creators of the quixotic International Classification of Diseases, show any inclination to enter the bear pit, and who can blame them? So why then does fatigue continue to pose such problems, albeit fascinating problems, for medical science? To answer that question, we need to return to history. We are probably now in a transition period in conceptualizing fatigue in general and symptoms in particular. We are somewhere between the medicine of symptoms (description), which we have largely left behind, and the medicine of mechanisms (molecular pathology), which we aspire to but have not reached. Until the nineteenth century, chronic fatigue could not be a problem because symptom and disease were synonymous. The diagnosis of a patient with a fever was fever, and likewise for fatigue. Then along came the scientific revolution of the nineteenth century, the great German physiologists and pathologists, and the dawn of genuine understanding of pathological processes. From then on, the symptom was only a guide to the diagnosis. A patient would be fatigued, but the real problem was a dysfunction of the thyroid gland, or a lack of red blood cells. Once that problem was identified, the symptom of fatigue ceased to have much significance; scientific and therapeutic attention would now be focused on understanding and rectifying the pathology, be it endocrine, neoplastic, hematological, or whatever. This understanding of health and disease is fine for those whose symptoms correspond with a known pathological process. For them, medicine is indeed, as medical historian Roy Porter once put it, "the Greatest Benefit to Mankind," speaking for once without irony. If you are sick with medically explained illness, in the "double plus" box in table F.1, then your relationship with your doctor, and the roles each of your play are fine. The patient is sick and the doctors agree and validate that experience. They have a reasonable understanding of why the patient is sick, even when they cannot do much about it. At the other end of the spectrum, being in the "double negative" box (Health) is also unproblematic—the person feels well and the doctors, if asked, will agree that he or she is free from disease. Problems arise with those in the disease present but symptoms absent box. These people feel well, but are either about to get sick or carrying a disease of which they xvi Simon Wessely Symptom Disease as accepted by doctors in 2004 Present + Absent - Present + Absent - Medically explained illness Medically unexplained illness Prodromal, asymptomatic, latent, etc. Health are unaware. These are the targets of screening programs. In this genomic age, more and more people are likely to find themselves in this box, with often profound consequences, but that is another story. The most serious problems arise among those who have symptoms but contemporary medical opinion believes to be disease free—the current jargon term being "medically unexplained" illness. It is here that we find the fatigue syndromes. Patients in this box pose a real dilemma for doctors and patients alike. Doctors still, despite the increased understanding this book so ably demonstrates, still feel uneasy with this group, while sufferers definitely feel short-changed and stigmatized. There are many answers to this dilemma. For some, CFS already belongs in the double plus box, as a disease with a known pathology. Medical authorities have simply failed to recognize the evidence that already exists because they are ignorant, stupid, or corrupt. An Internet trawl will reveal examples of all these charges. However, as this book also demonstrates, many professionals are interested in fatigue who are neither stupid, ignorant, nor corrupt but have still to crack the conundrum. We are not there yet, but what this volume does show is the real progress that has been made in understanding fatigue, even if classification has yet to catch up. DeLuca and his colleagues have produced what is the best multiauthor book yet on the subject of fatigue in medicine and psychiatry. I congratulate all the contributors, and commend their efforts to the reader. —Simon Wessely References Breslin, E., van der Schans, C., Breukink, S., et al. (1998). Perception of fatigue and quality of life in patients with COPD. Chest, 114, 958–964. Brunier, G., & Graydon, J. (1993). The influence of physical activity on fatigue in patients with ESRD on hemodialysis. ANNAJ, 20, 457–461. Dittner, A., Brown, R., & Wessely, S. (2004). The assessment of fatigue: A practical guide to clinicians and researchers. Journal of Psychosomatic Research, 56, 157–170. Foreword xvii Dohrenwend, B., & Crandell, D. (1970). Psychiatric symptoms in community, clinic and mental hospital groups. American Journal of Psychiatry, 126, 1611–1621. Holmes, G., Kaplan, J., Gantz, N., et al. (1988). Chronic fatigue syndrome: A working case definition. Annals of Internal Medicine, 108, 387–389. Kumar, D. T. R. (2002). Fatigue in cholestatic liver disease—a perplexing symptom. Postgraduate Medical Journal, 78, 404–407. Mayou, R. (2003). Towards DSM-V: Replacing the somatoform section. Journal of Psychosomatic Research, 52, 363. Muscio, B. (1921). Is a fatigue test possible? British Journal of Psychology, 12, 31–46. Sharpe, M. (1997). Cognitive behavior therapy for functional somatic complaints: The example of chronic fatigue syndrome. Psychosomatics, 38, 356–362. Watson, N. F. J. C., Goldberg, J., Kapur, V., & Buchwald, D. (2003). Comparison of objective and subjective sleepiness in monozygotic twins discordant for chronic fatigue syndrome. Sleep, 26, A359. Wessely, S. (2001). What are the classifications of hysteria and why don't clinicians use them? In P. Halligan & C. Bass, eds. Conversion hysteria, pp. 63–72. Oxford: Oxford University Press. Wessely, S., Hotopf, M., & Sharpe, M. (1998). Chronic fatigue and its syndromes. Oxford: Oxford University Press. Wessely, S., & Pariante, C. (2002). Fatigue, depression and chronic hepatitis C infection. Psychological Medicine, 32, 1–16. Preface After many years of working with issues related to fatigue both clinically and in research, it has became clear how little we have progressed in our theoretical and applied understanding of fatigue and its impact on persons' lives. Even its definition was ubiquitous, unclear, and equivocal. How could we feel we could treat a symptom without a clear understanding of what it is? Some see the presence of fatigue as a major symptom of a psychiatric illness, while others see it as the result of damage to the brain. Still others view fatigue not as a symptom but as an illness. What do we really know about fatigue? Today, we face the same questions first asked after more than 100 years of scientific inquiry. This book can by no means address the varied and broad questions we need answered regarding the enigma of fatigue. Rather the purpose of this book is specific: to answer the question what does the presence of fatigue tell us about how the brain works? More specifically, what are the neural mechanisms associated with fatigue? Experts from a wide variety of conditions that result in fatigue have shared what they know about fatigue and the brain. We hope that bringing such experts together in a single volume will uncover some pattern(s) to form hypotheses that can drive future research in our quest to understand the underlying causes of fatigue. This book is divided into six parts. The first part discusses the nature of fatigue. It includes a chapter on the history of fatigue and its epidemiology. A second chapter presents information on assessing and measuring fatigue. The final chapter in this section discusses the issue of cognitive fatigue, its measurement and interpretation. Part II discusses specific neurological conditions that produce fatigue as a symptom. It includes chapters on multiple sclerosis, stroke, traumatic brain injury, and a more general chapter on other neurological conditions such as Parkinson's disease, dementia, and Lyme's disease. Part III covers psychiatric conditions in which fatigue is a major symptom. Beginning with a historical overview of fatigue in psychiatry, this section presents chapters on chronic fatigue syndrome, depression, and somatization. xx Preface Part IV includes chapters on general medical conditions in which fatigue is a major symptom. These include HIV, sleep disorders, heart disease and cardiovascular dysfunction, autoimmune disorders such as systemic lupus erythematosus, and cancer. A chapter on the emerging field of psychoneuroimmunology and fatigue is also provided. Part V consists of a single chapter on the treatment of fatigue. While individual chapters in sections III and IV also include information on treatment specific to particular disorders, this chapter provides a broad overview of treatment approaches to fatigue. Finally, part VI attempts to integrate what has been learned from the previous chapters. The goal of this final chapter is to provide an overall definition of fatigue, explore the brain mechanism that appears to be responsible for "primary" fatigue, and suggest future research and investigation. I have several people to thank for making this book a reality. I would like to thank George Prigatano, who first suggested that I write a book on the topic of fatigue. I would also like to thank Jordan Grafman, whose initial excitement about this project gave me the impetus to forge ahead. I thank Sara Meirowitz, my associate editor, for her patience and guidance throughout this process. Last, I thank all of the authors whos contributions turned an idea into a reality. I also wish to recognize and thank the following individuals who served as external reviewers for the manuscripts submitted for this book: Susan Johnson, Wilfred Van Gorp, Carol Armstrong, Nicholas Ponzio, Nancy Chiaravalloti, Gudrun Lange, Anthony Komaroff, and Benjamin Natelson. I am especially grateful to Simon Wessely, for his encouragement, suggestions, chapter reviews, time, and effort in helping me through this project. His attention and thoughtfulness provided the enthusiasm for me to persevere. Finally, I would like to thank Natasha Smith-Dargan and Violeta Gomez for secretarial support throughout the project. I The Nature of Fatigue 1 What Is Fatigue? History and Epidemiology Susan Torres-Harding and Leonard A. Jason Fatigue is a nonspecific symptom because it can be indicative of many causes or conditions including physiological states such as sleep deprivation or excessive muscular activity; medical conditions such as chronic inflammatory conditions, bacterial or viral infections, or autoimmune illnesses; and psychiatric disorders such as major depression, anxiety disorders, and somatoform disorders (Manu, Lane, & Matthews, 1992). Fatigue may be caused by prescription medications such as antihistamines, drugs prescribed for insomnia, or chemotherapy drugs. Fatigue may also result from unhealthy lifestyles, such as frequent disruptions in the wake-sleep cycle, excessive alcohol or caffeine intake, and psychosocial stressors, or from the delayed effects of traumatic events (Manu et al., 1992). Finally, fatigue may be "unexplained," when none of the above causes is present or the causes cannot be determined. Chronic fatigue syndrome has recently received considerable attention, and it is an illness characterized by unexplained severe, persistent, disabling fatigue (Fukuda et al., 1994). Some describe fatigue in terms of physiological data or "objective" observations of decreasing muscle performance or decrements in work or performance. For example, fatigue has been defined as a failure to maintain a required force or output of power during sustained or repeated muscle contraction (Stokes, Cooper, & Edwards, 1988) or as time-related deterioration in the ability to perform certain mental tasks (Broadbent, 1971). In contrast to physiological fatigue, some have defined fatigue as a subjective self-reported feeling of fatigue. This feeling of fatigue is what people generally report when they seek medical treatment (Berrios, 1990). Fatigue is sometimes defined as "tiredness," feeling tired, being fatigued, feeling weak in part of the body, tired or lacking in energy, or experiencing "everything [as] an effort" (Cope, 1992, p. 273). Physiological definitions are more easily measured, but the subjective feeling of fatigue is not directly observable (Berrios, 1990). Further, this feeling of fatigue does not always correspond directly with physiological manifestations (Berrios, 1990). In response to its complex nature, most measures of fatigue have moved away from single questions (i.e., "Do you feel tired?") to a more multidimensional approach. These measures assess the effect of fatigue on daily activities, mental and physical 4 Susan Torres-Harding and Leonard A. Jason aspects of fatigue, and other characteristics and related symptoms (Barofsky & West Legro, 1991; Chalder et al., 1993; Cope, 1992). Fatigue has also been described in terms of level of severity, level of impairment, physiological and psychological characteristics (physical vs. mental), and duration (Barofsky & West Legro, 1991; Cope, 1992). Whereas some researchers have proposed a categorical classification (i.e., absence or presence of fatigue), several research studies suggest that fatigue is best conceptualized on a continuum (Berrios, 1990; Loge et al., 1998; Pawlikowska et al., 1994; Wessely, 1998), with its variability reflecting degrees of severity (Pawlikowska et al., 1994). Despite these more recent attempts to compartmentalize fatigue, the major problem with such measures is their subjectivity. Historical Perspectives There has been considerable controversy over both what constitutes and what causes fatigue since the mid-nineteenth century (Wessely, 1991). By the mid-1800s, reports of upper-class women who were too weak to rise from bed were being reported frequently (Shorter, 1993). These women predominantly complained of fatigue and muscle weakness, but pain was often a prominent symptom as well. George Beard, an American neurologist, was one of the first to describe neurasthenia as a distinct clinical entity (Macmillan, 1976). The symptoms of neurasthenia included "general malaise, debility of all function, poor appetite, fugitive neuralgic pains, hysteria, insomnia, hypochondriases, disinclination for consecutive mental labor, severe and weakening attacks of headaches, and other symptoms" (Macmillan, 1976). By 1900, neurasthenia had become the single most common diagnosis in the domain of neuropathology and psychopathology. Before 1900, however, chronic unexplained fatigue was rarely distinguished from depression (Shorter, 1993). Neurasthenia appeared to be a "wastebasket" category, used alternately as a synonym for general nervousness and evolving psychosis, as the "male" equivalent of hysteria, as a synonym for minor depression, and as a diagnosis of fatigue states in patients who were not depressed (Shorter, 1993). Physicians before 1900 had difficulty distinguishing psychogenic from neurogenic weakness. When they described "exhausted" patients, it is unclear if the problems were due to subjective perceptions of fatigue or an objective dysfunction of the muscles (Shorter, 1993). Further, when persons were described as being too exhausted to rise from bed, it was unclear whether they were simply too tired or suffered from a neurological or medical disorder (Shorter, 1993). These complaints echo contemporary descriptions of unexplained fatigue illness. The diagnosis of neurasthenia began to fall out of use in the early 1900s, as the conceptualization of this illness shifted from physiological to psychogenic or psychological in origin (Wessely, 1991). Redefined as psychiatric, neurasthenia was less frequently diagnosed because of the stigma of psychiatric labels (Wessely, 1991). What Is Fatigue? 5 Further, the illness was diagnosed less frequently as more working class people began to suffer from it, and it began to fade from neurological textbooks (Wessely, 1991). Within the psychiatric domain, it was subdivided into various neuroses, including obsessive-compulsive disorders, anxiety neuroses, and hysteria (Wessely, 1991). However, the diagnosis of neurasthenia is still included in the latest revision of the International Classification of Diseases, Tenth Revision (World Health Organization, 1992), and continues to be diagnosed in parts of Europe, the former Soviet Union states, and parts of Asia, where it is considered a physical disorder (Wessely, 1991). In addition to neurasthenia, other illnesses with unexplained fatigue as a primary symptom were reported in the late nineteenth and early twentieth century. These illnesses were alternately termed effort syndrome, DaCosta's syndrome, irritable heart, disordered action of the heart, soldier's heart, and neurocirculatory asthenia. Irritable heart was noticed in the Crimean war, and later in the American Civil War (Hyams, Wignall, & Roswell, 1996). Its symptoms included diarrhea, rapid pulse, palpitation, shortness of breath, headaches, giddiness, disturbed sleep, itching skin, excessive perspiration, and indigestion. DaCosta attributed the syndrome to fevers, diarrhea, hard field service, wounds, rheumatism, scurvy, and other factors. This illness was seen as organic in origin. DaCosta believed the heart became irritable from overaction and was sustained in this state by disordered innervation (DaCosta, 1871). During the First World War, Lewis first described effort syndrome. Its symptoms included breathlessness, cyanosis, pain, palpitation, fainting, giddiness, headaches, especially after exertion, and complaints of fatigue. Infection was considered to be a dominant factor in the etiology, as Lewis noted that approximately 32 percent of the cases he studied began with an infectious disease (Bartley & Chute, 1947). In 1918, a group of military doctors termed similar cases "neurocirculatory asthenia" (Ivy & Roth, 1944). Initially, DaCosta's syndrome or irritable heart, Lewis's effort syndrome, and neurocirculatory asthenia were regarded as arising from anomalies of cardiac function. Over time, however, as efforts to find underlying physiological abnormalities were not successful, these illnesses began to be regarded as primarily psychosomatic or psychogenic. For example, some researchers held that these illness states were due primarily to the emotional reaction of the patient to misinterpretation of symptoms arising from effort (Ivy & Roth, 1944), fundamental nervous instability (Robey & Boas, 1918), or the effects of hyperventilation (Bartley & Chute, 1947). After World War II, a set of influential clinical studies by Paul Wood helped shift the conceptualization of effort syndromes from medical illness to psychoneuroses (Hyams, Wignall, & Roswell, 1996). Thus, the diagnoses of neurasthenia and such illnesses as neurocirculatory asthenia fell out of favor during the early twentieth century, as they were increasingly seen as psychogenic. However, it is notable that fatigue and chronic fatigue continued to be 6 Susan Torres-Harding and Leonard A. Jason described as symptoms in the research literature (Bartley & Chute, 1947). Some physicians felt that chronic fatigue was due primarily to psychogenic or psychological factors; for example, Kepler (1942) described chronic fatigue as an outcome of the Western way of life, best thought of as a "psychologic" disease of the "intelligentsia." Alvarez (1941) listed as the most common causes of chronic fatigue overwork neuroses, postinfective neurosis, neurosis associated with arthritis or fibrositis, nervous breakdown, constitutional inadequacy, cerebral thrombosis, equivalents of insanity, and actual insanity. Other physicians espoused a holistic approach, emphasizing the need to take into account both possible organic or physical factors, such as disease or overwork, and psychogenic or personality factors (Muncie, 1941; Wharton, 1938). For example, Wharton (1938) described patients with fatigue that was not relieved by average rest and whose symptoms appeared to be related to mental or physical depletion or both. He attributed this excessive fatigue primarily to overwork. Muncie (1941) noted that, though fatigue was among the complaints in nearly all important diseases, it was most prominent among endocrine-metabolic disorders, postinfectious states, and emotional and attitudinal states or personality maladjustment. Finally, Allen (1944) analyzed 300 cases in which the chief complaint was weakness or fatigue. Nervous conditions were considered responsible in 80 percent, and physical disorders accounted for 20 percent of the cases. These physical disorders included diabetes, heart disease, chronic infection, nephritis, anemia, and various neurological disorders. Industrial Fatigue Another area of research concerned the problem of industrial or occupational fatigue. In the early part of the twentieth century, attention focused on the experience and physiology of fatigue as it affected workers' productivity. To this end, Harvard University's Graduate School of Business set up a Fatigue Laboratory in 1927, where investigators continued research into various aspects of fatigue until 1947 (Chapman, 1990). Because worker fatigue impaired performance, a scientific and systematic study of fatigue was encouraged (Chapman, 1990). Henderson, one of the laboratory's founders, noted that "business leaders, engineers, physiologists, and the general public" all agreed fatigue was important, but found no agreement on its definition (Chapman, 1990). The purpose of the Fatigue Laboratory was therefore to describe the physiological experiences of fatigue in everyday life, and the scope of the studies extended beyond industrial fatigue to encompass exercise physiology and medical applications (Chapman, 1990). Industrial fatigue studies included investigations into muscular exercise and fatigue, resting conditions, and adaptations to physical stress. Some studies indicated that the rest cure, or enforced complete bedrest prescription, was actually contraindicated; physical exercise was considered an important therapeutic measure (Chapman, 1990). What Is Fatigue? 7 Ward (1941) noted in his study of 600 male and 1200 female workers that 4 percent were chronically fatigued. Many complained of feeling tired, and most also complained of back pain, loss of appetite, and insomnia, and were prone to irritability. Physical findings were increased pulse rate, low blood pressure, pallor, tremor, and weight loss. Ward concluded that anyone who works beyond 100 percent of his capacity is bound to develop fatigue-related symptoms, and overwork was a primary cause of chronic fatigue. Collier (1943) also recognized the hazards of chronic fatigue and noted that fatigue arising from overwork could lead to disease. Interestingly, although overwork was seen as a major contributor to chronic industrial fatigue, researchers such as Collier (1943) also emphasized the importance of psychological factors in industrial or occupational fatigue. Nearly all of the everyday problems of industrial fatigue, Collier noted, were psychological rather than physical (Collier, 1943). Outbreaks of Fatigue Illnesses During the twentieth century, several outbreaks of illnesses with fatigue of unknown etiology as a chief or principal symptom were also reported (Wessely, 1991; Levine, 1994). These unexplained fatigue illnesses were variously labeled epidemic neuromyasthenia, myalgic encephalomyelitis, Iceland disease, and atypical poliomyelitis. A major outbreak occurred in 1955 among the nursing and medical staff at the Royal Free Hospital in England (Wessely, 1991). Termed myalgic encephalomyelitis, the illness' symptoms included fatigue and muscle pain as well as other neurological signs (Shorter, 1993). Another outbreak of a severe fatigue illness, atypical poliomyelitis, occurred at the Los Angeles County Hospital in 1934 (Wessely, 1991). Levine (1994) describes several outbreaks of epidemic neuromyasthenia, another fatigue illness of unknown etiology with fatigue as a principal symptom that often encompassed neurological symptoms and signs. Outbreaks were reported in northern England (1955) among 233 males and females; in a private medical facility near Washington, D.C. (1953); and in Ridgefield, Connecticut (1955–1956), at a small medical research facility and neighboring community. Finally, in Lake Tahoe, Nevada, and the surrounding communities (1984–1986), an outbreak of 184 cases of a severe fatigue illness occurred. The symptoms of the Lake Tahoe outbreak included prolonged fatigue, abrupt onset of symptoms, severe pain, and prominent cognitive disorder (Levine, 1994). Contemporary Investigations into Fatigue Interest in fatigue was renewed in the late 1980s with the emergence of chronic Epstein-Barr virus syndrome. This syndrome explained chronic fatigue as a persistent viral illness caused by the same pathogen responsible for acute mononucleosis (Friedberg & Jason, 1998). Later renamed chronic fatigue syndrome, or CFS (Wessely, 8 Susan Torres-Harding and Leonard A. Jason 1998), the syndrome's criteria were developed in 1988 (Holmes et al., 1988), and later refined in 1994 (Fukuda et al., 1994). The 1994 criteria for CFS include severe, disabling fatigue lasting 6 months or more. The illness also requires four of eight additional symptoms: sore throat, headaches, lymph node tenderness or pain, joint pain, muscle pain, unrefreshing sleep, postexertional malaise, and memory or concentration difficulties. Finally, for a diagnosis of CFS, the fatigue must be "unexplained," that is, not better accounted for by another medical or psychiatric condition (Fukuda et al., 1994). Unexplained chronic fatigue has also been diagnosed as myalgic encephalomyelitis, ME (Wessely, 1991). The criteria for ME include fatigue after minimal exertion and delayed recovery of muscle power after exertion; symptoms of circulatory impairment; and central nervous system involvement (cerebral problems). These symptoms often have a chronic, fluctuating course (Ramsay, 1988). Fatigue has been a frequent reason for visits to physicians (Nelson et al., 1987), and the chief complaint in 4 to 9 percent of all visits to a family practitioner or internist (Manu, Lane, & Matthews, 1992). Studies of people presenting with fatigue in primary care settings show an estimated 7.6 to 32 percent of these patients have fatigue as either a symptom or chief complaint (Cathebras et al., 1992; Fuhrer & Wessely, 1995; Kroenke, Wood, Mangelsdorff, Meier, & Powell, 1988). Further, excessive fatigue affects a significant proportion of the general population. It has been noted to be a common symptom in both community-based studies (Cope, 1992; Pawlikowska et al., 1994) and primary care and hospital-based studies of fatigue prevalence (Fuhrer & Wessely, 1995; Cope, 1992). Fatigue can also have a powerful, adverse effect on quality of life (Nelson et al., 1987). The problem of chronic fatigue has also received considerable attention. Typically defined as excessive fatigue lasting more than 6 months (Fukuda et al., 1994), chronic fatigue is considered more severe and disabling then acute fatigue because of its persistent, chronic course (Fukuda et al., 1994). Chronic fatigue is estimated to occur in approximately 4 to 5 percent of the general population (Jason, Jordan et al., 1999). Gender and Fatigue Many studies have examined the role of gender in fatigue. Some studies have found gender differences in fatigue, with women more likely to report having both fatigue and chronic fatigue (Chen, 1986; Nelson et al., 1987; Loge et al., 1998; Nisenbaum et al., 1998; Jason, Jordan et al., 1988). Some researchers have also found that women tend to report more severe fatigue (Chen, 1986; Kroenke et al., 1988; Loge et al., 1998; Jason, Jordan et al., 1998; Nisenbaum et al., 1998; Pawlikowska et al., 1994). Further, women are also more than twice as likely to seek medical help for their fatigue (Cope, 1992). For example, two-thirds of the people in one study who presented with fatigue in a primary care practice were women (Nelson et al., 1987). However, some primary What Is Fatigue? 9 care and hospital studies have found no statistically significant gender differences in fatigue (Cathebras et al., 1995; Kirk, Douglas, Nelson, Jaffee, & Lopez, 1990). Ethnicity and Fatigue Relatively few studies have examined fatigue levels among different ethnic groups (Richman, Flaherty, & Rospenda, 1994). Cathebras and associates (1995), in examining English-speaking and French-speaking Canadians, found an ethnic difference in reported rates of fatigue, with French-speaking Canadians reporting more fatigue. Buchwald and others (1996), however, found no ethnic differences in their study of white and "nonwhite" (African American, Asian American, American Indian, and Latino) people attending a university health center. Similarly, Nisenbaum and coworkers (1998), in a representative sample of people living within the San Francisco urban area, failed to find any ethnic differences in reported levels of fatigue. However, Steele and associates (1998) reported higher levels of fatigue among Native Americans. Finally, Song, Jason, and Taylor (1999) found that the mean fatigue severity scores were significantly higher for African Americans and Latinos than for Caucasians. Although these community-based studies seem to point to some ethnic group differences, the problem of fatigue in multiethnic populations continues to be understudied. Selection bias may play a part in the lack of ethnic minority studies, as many primary care or hospital-based studies report few ethnic minority group members among their sample. People of color may have poorer access to quality health care, because of their disproportionate representation in lower socioeconomic populations (Richman, Flaherty, & Rospenda, 1994). This relative absence of people of color in research is especially disconcerting since some studies suggest they may be at higher risk for severe fatigue (Song, Jason, & Taylor, 1999), and inappropriate conclusions about the etiology of this illness may be drawn from a highly select, ethnically homogenous population. Community-based studies hold more promise of representing persons of color, and sampling from ethnically diverse populations may help to elucidate the prevalence and experience of fatigue in these traditionally understudied groups. Physical versus Psychological Causes of Fatigue The debate as to whether fatigue has primarily a physical or psychological etiology continues in contemporary investigations. Some researchers have distinguished between central and peripheral fatigue. Peripheral fatigue is defined as failure to sustain force or power output because of "failure in neuromuscular transmission, sarcolemmal excitation, or excitation-contraction coupling," implying neuromuscular dysfunction outside of the central nervous system, or CNS (Edwards, Newham, & Peters, 1991; Swain, 2000). In contrast, central fatigue is defined as resulting from failure to achieve and maintain the recruitment of high-threshold motor 10 Susan Torres-Harding and Leonard A. Jason units (Edwards, Newham, & Peters, 1991), implicating dysfunction in CNS neurotransmitter pathways (Swain, 2000). However, the contributions of neither peripheral fatigue nor central fatigue to overall subjective reports of fatigue is well understood. Clinical studies tend to focus on self-reported feeling of fatigue (Swain, 2000). Such studies often find a mixed presentation of both physical and psychological factors in unexplained chronic fatigue (Hall et al., 1994). Elevated rates of psychiatric comorbidity or indicators of psychological disorder have been found among chronic fatigue patients in primary care settings (Cathebras et al., 1995; Manu et al., 1989; McDonald, David, Pelosi, & Mann, 1993). Community-based studies have also found that persons suffering from chronic fatigue were more likely to have psychiatric symptoms or be diagnosed with psychiatric disorders (Lawrie et al., 1997; Pawlikowska et al., 1994). Somatic symptoms often occur together with self-reported fatigue as well. Manu and associates (1989) found that the most frequent somatic symptoms in fatigue patients were pain in extremities, joints, chest, and other parts of the body; shortness of breath; blurred vision; muscle weakness; and sexual indifference (Manu et al., 1989). Hartz and coworkers (1998) noted that the number of symptoms was strongly associated with the severity of fatigue, the response of fatigue to mental and physical activity, and the following participant characteristics: a greater frequency of sinus and respiratory infections, a higher frequency of migraines, a greater number of somatoform symptoms not included as criteria for CFS, and abstinence from alcohol (Hartz et al., 1998). Nisenbaum and associates (1998) found the most common symptoms experienced by fatigued persons were sleep problems, general weakness, muscle aches and pain, difficulty thinking or concentrating, depression, and unusual fatigue after exertion. These findings suggest that other somatic symptoms are likely to arise as unexplained severe fatigue persists (Nisenbaum et al., 1998). Factor analytic studies tend to find multiple factors or clusters of fatigue-related symptoms. Ray, Weir, Cullen, and Phillips (1992) analyzed a list of symptoms in 208 patients with postviral fatigue and found four factors: emotional distress, fatigue, somatic symptoms, and cognitive difficulty. Hall, Sanders, and Replogle (1998), in a sample of 197 primary care patients, performed a factor analysis using 34 reported symptoms. In this investigation, four clusters of symptoms emerged: organic symptoms, anxiety, depression, and mixed-anxiety depression. Nisenbaum and associates (1998) also conducted a factor analysis of 30 symptoms experienced by people who were fatigued for 6 months or more, finding fatigue/mood/cognition, flu-type, and visual problem factors (Nisenbaum et al., 1998). Finally, Jason and coworkers (2002) factor analyzed fatigue-related symptoms reported by 780 persons with chronic fatigue and found four factors: lack of energy, physical exertion, cognitive problems, and fatigue and rest. As Berrios (1990) noted, it is unclear whether the feeling of fatigue represents a primary state or a composite of symptoms that may vary depending on the etiology of the medical condition. These studies suggest that subjective unexplained fatigue What Is Fatigue? 11 may not always represent strictly "psychological" or "physical" etiologies; there may be separate physiological and psychological contributions to the experience of fatigue. This echos Bartley and Chute's recommendation in 1947, that fatigue and chronic fatigue research should examine the relative importance of multiple physical and psychological contributions (Bartley & Chute, 1947) to the experience of overall fatigue. Unexplained Fatigue in Chronic Fatigue Syndrome Only a small minority of patients presenting with chronic or severe fatigue are actually diagnosed with chronic fatigue syndrome. The prevalence of this disorder has been estimated at 0.24 percent (Reeves, 1999) to 0.4 percent ( Jason et al., 1999) in community-based studies, and 2.6 percent of patients in primary care (Wessely, Chalder et al., 1997). As fatigue is the defining symptom of this illness, all persons diagnosed with chronic fatigue syndrome have experienced severe and disabling fatigue for 6 months or more (Fukuda et al., 1994). The effects of this chronic, unexplained fatigue appear to differ from individual to individual, with some persons experiencing only mild impairment, while others experience severe or very severe limitations (Carrico, Jason, Torres-Harding, & Witter, 2004; Cox & Findley, 2000). The fatigue in CFS can lead to a markedly higher degree of impairment than is found other chronically ill populations (Anderson & Ferrans, 1997). As an illness of unexplained fatigue, CFS is diagnosed only when other fatiguecausing conditions are ruled out as the primary source of the fatigue. Because the fatigue is designated as "unexplained," some have proposed psychiatric explanations for the illness, while others propose several physiological hypotheses to explain the illness process and its resulting symptomatology. Regarding physiological findings, Clauw and Chrousos (1997) suggest that individuals who develop CFS might be genetically predisposed to develop this condition. In support of this, Torres-Harding and Jason (2003) found that persons with CFS were significantly more likely to report a family history of metabolic disorders than a control group. Recent twin studies of complex genetic and environmental relationships between psychological distress, fatigue, and immune system functioning suggest the need to acknowledge the increasing importance of the individual's genotype (Hickie, Bennett, Lloyd, Heath, & Martin, 1999). Clauw and Chrousos further posit that susceptible individuals might evidence a number of organ-specific illnesses before progressing to CFS. Supportive data support this thesis, showing CFS patients have had significantly more upper respiratory tract infections, lethargy, and vertigo than controls (Hamilton et al., 2001). Clauw and Chrousos also suggest that once CFS develops, either abruptly or slowly through viral infections or emotional stressors, the human stress response is blunted, along with blunting of the hypothalamic-pituitary axis and autonomic nervous system instability. Symptom heterogeneity might be due to different axes of the stress 12 Susan Torres-Harding and Leonard A. Jason response, either independently or concurrently functioning in aberrantly. Patients with CFS experience blunted biological stress response, and a low corticotrophinreleasing hormone (CRH) state is exacerbated if exercise further reduces cortisol levels; this postexercise adrenal insufficiency could be responsible for the patients' severe postexertional fatigue. One strength of such a biopsychosocial understanding of CFS is that it may bridge the theoretical gap between mind versus body explanations of these illnesses. Fatigue in Chronic Disease In addition to unexplained fatigue, the occurrence of fatigue in specific medical diseases has also been investigated. Fatigue has come be recognized as a serious symptom of many illnesses that can significantly impair a person's functioning and have a negative impact on quality of life in many chronic illnesses, including after cancer treatment (Bartsch, Weis, & Moser, 2003; Irvine, Vincent, Graydon, Bubela, & Thompson, 1994; Smets et al., 1993), systemic lupus erythematosus (SLE) ( Jacobson, Gange, Rose, & Graham, 1997), multiple sclerosis (Schwid, Covington, Segal, & Goodman, 2002), human immunodeficiency virus (HIV) infection, viral and cholestatic liver diseases, and rheumatoid arthritis (Swain, 2000). However, understanding fatigue in chronic medical disease continues to prove difficult. Even when fatigue is considered a primary or a common symptom, such as in multiple sclerosis or SLE, fatigue often does not correlate with disease status or physiological findings (Schwid, Covington, Segal, & Goodman, 2002; Krupp et al., 1990; Wang et al., 1998; Omdal et al., 2003). Despite the recognition that fatigue is an integral component of chronic disease, its etiology in many chronic illnesses is not well understood, although some have proposed it is mainly of central origin (Swain, 2000). Swain (2000) proposes that corticotropin-releasing hormone and chronic stress, cytokines and immune activation, central neurotransmitter pathways, and mood disorders such as depression are possible factors contributing to fatigue in chronic diseases. Further, different chronic illnesses may vary in the relative contributions of peripheral and central fatigue to the overall experience of fatigue (Swain, 2000). Finally, other factors such as stress, sleep disturbance, distress of other somatic symptoms, and personality traits have been reported to contribute to the subjective experience of fatigue in chronic disease (Berger, 2003; Irvine et al., 1994; Schwid, Covington, Segal, & Goodman, 2002). Summary The problem of excessive or unexplained fatigue has been common from the middle of the nineteenth century to the present day. Today, both unexplained fatigue and What Is Fatigue? 13 fatigue occurring as a symptom of illness are recognized as serious symptoms that can severely limit physical functioning and have a negative impact on quality of life. Research supports the involvement of multiple dimensions, with physiological, psychological, and psychosocial factors contributing to the experience of fatigue. Fatigue often occurs in conjunction with other somatic and psychiatric symptoms. The relationship between physiological fatigue or disease states and the feeling of fatigue remains poorly understood, partly because fatigue is difficult to define and measure. Unfortunately, theories on the nature of fatigue from the last century are closely echoed by contemporary views, with little progress made in understanding this symptom. A recurring theme in research, however, is the need for a biopsychosocial approach, incorporating physiological, psychological, and psychosocial factors, in understanding the experience of fatigue. Continued research into the factors contributing to fatigue may help elucidate this complex symptom. Acknowledgment The authors appreciate the financial support of NIAID and grant number AI49720. References Anderson, J. S., & Ferrans, C. E. (1997). The quality of life of persons with chronic fatigue syndrome. Journal of Nervous and Mental Disease, 185, 359–367. Allen, F. N. (1944). The differential diagnosis of weakness and fatigue. 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The epidemiology of chronic fatigue syndrome. Epidemiologia e Psychiatria Sociale, 7(1), 10–24. Wessely, S., Chalder, T., Hirsch, S., Wallace, P., & Wright, D. (1997). The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. American Journal of Public Health, 87, 1449–1455. Wharton, G. K. (1938). The fatigue syndrome. Canadian Medical Association Journal, 38, 339–342. World Health Organization (1992). International Classification of Diseases and Related Health Problems, Tenth Revision. Albany, NY: WHO Publications Center USA. 2 The Assessment and Measurement of Fatigue Christopher Christodoulou The Multifaceted Nature of Fatigue The quest to clarify the meaning and measurement of fatigue has challenged researchers and clinicians for many years. Despite its broad use in casual conversation and scientific discourse, or perhaps partly because of it, the term "fatigue" has defied efforts to provide a single, broadly acceptable definition. Instead, its meaning and measurement tend to vary with the circumstances in which it is used. In their classic text, Bartley and Chute (Bartley & Chute, 1947) reviewed dozens of definitions and views of fatigue presented in psychological and physiological texts, as well as articles, monographs, periodicals, and conferences. Broadly speaking, fatigue can be conceptualized as either a subjective feeling or a performance decrement (Wessely, Hotopf, & Sharpe, 1998). Bartley and Chute (Bartley & Chute, 1947) advocated a primary focus on the individual's feelings of fatigue. For example, among patients suffering from excessive fatigue the most salient feature might be the uncharacteristic feelings of exhaustion accompanying their pathological condition. This emphasis on subjective experience is also evident in a consensus definition of fatigue in persons with multiple sclerosis (MS) as "a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual or desired activities" (Multiple Sclerosis Council for Clinical Practice Guidelines, 1998). In contrast, athletic trainers, muscle physiologists, business leaders, and other results-oriented individuals tend to use measures that directly assess performance-based decrements associated with fatigue, such as reduced muscle strength after a period of exertion or increased error rate over time on tasks requiring vigilance. Consistent with an interest in measuring changes in objective performance, muscle fatigue has been defined as "any exercise-induced reduction in the maximal capacity to generate force or power output." (Vollestad, 1997, p. 220). The two conceptualizations of fatigue (as a feeling state versus performance decrement) are partly reflected in the two basic approaches to measuring fatigue through 20 Christopher Christodoulou self-report questionnaires or direct observation of behavior. Self-report measures are uniquely able to assess the feelings associated with fatigue, but can only indirectly assess changes in performance from the respondent's perspective. Direct observation of behavior provides objective measurement of behavioral performance changes associated with fatigue, but lacks the ability to assess underlying feelings. The different focuses on subjective feelings or performance decrements would not be so consequential if empirical studies did not often fail to find an association between these two approaches (Krupp & Elkins, 2000; Sharma, Kent-Braun, Mynhier, Weiner, & Miller, 1995). This chapter reviews and compares the two approaches to the measurement of fatigue. Pathological versus Normal Fatigue Fatigue measures have been designed for a variety of purposes. Some were designed to study individuals with medical disorders and others for healthy persons. Fatigue is a pathological feature of a variety of medical conditions, but it is obvious that otherwise healthy individuals also experience periods of fatigue. Pathological fatigue can be distinguished from nonpathological fatigue by a combination of features including greater intensity, longer duration, and more disabling effects on functional activities. Fatigue in healthy persons is generally a time-limited phenomenon that follows a period of exertion or sleep deprivation and is reduced if not eliminated by rest or sleep. Pathological fatigue, in contrast, remains after rest as a severe chronic condition, disrupting an individual's ability to carry out important daily social and occupational activities and obligations. As detailed in later chapters, pathological fatigue is one of the most common features identified in a broad range of medical conditions, including chronic heart disease, cancer, MS, chronic insomnia, and depression. In addition, fatigue can manifest as chronic fatigue syndrome (CFS) following the onset of persistent debilitating fatigue lasting 6 months or more and the exclusion of other known causes of the condition (Fukuda et al., 1994). Wherever possible, it is important to identify other causes of fatigue and existing comorbid medical disorders, in part because their treatment might reduce fatigue as well. For example, a recent study found that successful treatment of depression in MS patients also reduced their fatigue (Mohr, Hart, & Goldberg, 2003), although a similar study in oncology patients found no improvement in fatigue (Morrow, Hickok, Roscoe, et al., 2003). The development of fatigue in any situation is clearly a complex process, and a more comprehensive understanding of this multifaceted phenomenon will require a broad approach integrating information gathered from physiological, affective, cognitive, behavioral, and psychosocial factors (Wessely, Hotopf, & Sharpe, 1998). The Assessment and Measurement of Fatigue 21 Questionnaires A remarkable number of fatigue questionnaires have been developed over the years. Scales have been developed for use in a variety of clinical populations, including cancer (Hann, Denniston, & Baker, 2000; Piper et al., 1998; Stein, Martin, Hann, & Jacobsen, 1998), MS (Iriarte, Katsamakis, & de Castro, 1999; Krupp, LaRocca, Muir-Nash, & Steinberg, 1989; Multiple Sclerosis Council for Clinical Practice Guidelines, 1998), rheumatoid arthritis (Belza, 1995), CFS (Vercoulen et al., 1994), and myasthenia gravis (Grohar-Murray, Sears, Hubsky, & Becker, 1994; Kittiwatanapaisan, Gauthier, Williams, & Oh, 2003), as well as for healthy individuals engaged in work and sports (Ahsberg, Gamberale, & Kjellberg, 1997; Borg, 1970; Borg, 1982a; Borg, 1982b; Haylock & Hart, 1979; Kogi, Saito, & Mitsuhashi, 1970). While item content does vary to some extent with the targeted audience (e.g., questions regarding the particular vulnerability of MS patients to heat-related fatigue) (Schwartz, Jandorf, & Krupp, 1993), there is also a good deal of item similarity across scales. The questionnaires range in length from single stem scales (Borg, 1970; Borg, 1982b; Krupp et al., 1989; Lee, Hicks, & Nino-Murcia, 1991) to longer, multidimensional assessments (Schwartz et al., 1993; Smets, Garssen, Bonke, & De Haes, 1995; Stein et al., 1998). The authors of some multidimensional scales argue that including many factors is necessary to assess the complex pattern of fatigue patients experience (Stein et al., 1998). Those favoring more focused scales, however, might argue that pure measures of fatigue should be more homogeneous, perhaps measuring only the core feelings of fatigue and excluding such aspects as affective feelings, which might be better assessed by separate instruments. Item Scaling Some of the earliest scales included items requiring a binary response to indicate the presence or absence of a fatigue symptom (Kogi et al., 1970). The most common approach, however, is a Likert scale format, which gauges a fatigue symptom's severity/intensity by asking subjects to report the degree to which they endorse a particular item (e.g., "feeling exhausted") on an ordered scale (e.g., ranging from 0 = not at all to 5 = completely) (table 2.1). Alternatively, subjects can be asked to bisect the line of a visual analogue scale (VAS) for the same purpose. Fatigue researchers comparing the two formats have generally found they provide relatively equivalent data, but Likert scales are preferred because they are easier for subjects to understand and for the researchers to score (Hartz, Bentler, & Watson, 2003; Piper et al., 1998). Borg (Borg, 1970; 1982a; 1982b) has developed an interesting approach to measuring fatigue intensity that has been quite influential in the work of physiologists and those interested in measuring physical work capacity (Noble, 1982). His first scale measures ratings of perceived exertion (RPE), based on a series of verbal descriptors Healthy (Borg, 1970) (Borg, 1982a; Borg, 1982b) (Piper et al., 1989), Revised in (Piper et al., 1998) Borg Rating of Perceived Exertion (RPE) scale Borg Category Ratio scale (CR-10) Piper Fatigue Scale (PFS) Energy, fatigue Fatigue severity, situation-specificity, consequences of fatigue, responds to rest/sleep Sleep disordered and healthy Lyme, CFS, lupus, MS, dysthymia, healthy (Lee et al., 1991) (Schwartz et al., 1993) None MS, lupus, healthy (Krupp et al., 1989) None Single Item Visual Analogue Scale (VAS) of Fatigue Visual Analogue Scale for Fatigue (VAS-F) Fatigue Assessment Instrument (FAI) MS, lupus, healthy (Krupp et al., 1989) Rating of perceived exertion Rating of perceived exertion Behavioral/severity, affective meaning, sensory, Cognitive/mood Drowsiness and dullness, projection of physical disintegration, difficulty in concentration, Specified Fatigue Subscales Fatigue Severity Scale (FSS) Cancer Healthy (Koji), cancer (Haylock & Hart) Healthy Japanese (Kogi et al., 1970) English (Haylock et al., 1979) Fatigue Symptom Checklist Initial Population Author, Year Name of Scale Table 2.1 Fatigue scales 29 18 1 22 items (+5 short answer) 9 Single item Single item 30 Item Length 1–7 Visual analogue scale Visual analogue scale 1–7 0–10 0–10** 6–20* Yes/no Item Scoring Past 2 weeks Not stated Not stated, past 2 weeks appropriate*** Not stated One item asks for duration Now Now Now Time Frame 22 Christopher Christodoulou (Paul et al., 1998)***** (Smets et al., 1995) Multicomponent Fatigue Scale (Belza, 1995) Multidimensional Assessment of Fatigue (MAF) Mulitidimensional Fatigue Inventory (MFI) (Ahsberg et al., 1997) Students, physicians, cancer, CFS, soldiers (Grohar-Murray et al., 1994; Kittiwatanapaisan et al., 2003) Myasthenia Gravis Fatigue Scale (MGFS) Swedish Occupational Fatigue Inventory (SOFI)**** Rheumatoid arthritis (Fisk et al., 1994), Modified by (Multiple Sclerosis Council for Clinical Practice Guidelines, 1998) Fatigue Impact Scale (FIS) MS, myasthenia gravis Healthy persons in 16 different occupations Myasthenia gravis MS CFS (Vercoulen et al., 1994) Checklist Individual Strength (CIS) Primary care patients (Chalder et al., 1993) Fatigue Scale (FS) Perception of fatigue, task avoidance, observable motor signs or symptoms Degree, severity, distress, impact on activities of daily living General fatigue, physical fatigue, mental fatigue, reduced motivation, reduced activity Lack of energy, physical exertion, physical discomfort, lack of motivation, sleepiness Mental, physical Physical, cognitive, psychosocial Subjective experience of fatigue, concentration, motivation, physical activity Physical, mental 15 25 20 15 26 21 (short form: 5 items) 24 14 0–5 0–10 1–7 1–10 1–5 0–4 7-point scale Yes/No At present, & compared to recent past At present Not stated One item asks for duration In general since illness onset Past 4 weeks Not stated Not stated The Assessment and Measurement of Fatigue 23 (Stein et al., 1998) (Iriarte et al., 1999) (Hann et al., 2000) (Schwid, Covington, Segal, & Goodman, 2002) (Hartz et al., 2003) (Hockenberry et al., 2003) Multidimensional Fatigue Symptom Inventory (MFSI) Fatigue Descriptive Scale (FDS) Fatigue Symptom Inventory (FSI) Rochester Fatigue Diary (RFD) IOWA Fatigue Scale (IFS) Child Fatigue Scale (CFS) Children with cancer (also versions for parents & staff) Primary care patients MS Cancer MS Cancer Initial Population 12 (1 item, 12¥ over 24 hrs) 13 5 83, (short form: 30 items) Item Length Lack of energy, not able to function, altered mood 14 Cognitive, fatigue, energy, 11 productivity Lassitude (reduced energy) Spontaneous mention of fatigue, antecedent conditions, frequency, impact on life Intensity, duration, impact on quality of life Global, somatic, affective, behavioral, cognitive symptoms of fatigue Specified Fatigue Subscales Past 2 hours Past week Not stated Last week Time Frame Frequency Past week (yes/no), Intensity (1–5) 5-point scale Visual analogue scale 0–10 0–3 0–4 Item Scoring * Designed to increase linearly with workload & heart rate. Some items anchored with verbal expressions (e.g., very light = 9, very hard = 17). ** Borg designed this category scale to display ratio properties. Some items are again anchored with verbal expression. *** Krupp, personal communication. **** In Swedish. English translations of each item provided, but not validated. ***** A variation on the Chalder Fatigue Scale. Author, Year Name of Scale Table 2.1 (continued) 24 Christopher Christodoulou The Assessment and Measurement of Fatigue 25 (e.g., "very, very light" to "very, very hard") tied to a scale from 6 to 20. The RPE scale was designed to increase linearly with heart rates ranging from 60 to 200 beats per minute while subjects pedal a cycle ergometer, and, indeed, it correlates strongly with heart rate (r = 0.80 - 0.90) as well as other physiological variables (Borg, 1982b). Borg also developed a newer scale to provide a ratio level of measurement of verbal descriptors, on a scale from 0 to 10 (Category Ratio Scale, or CR-10) (Borg, 1982a; 1982b). This new scale has also displayed strong correlations with physiological measures (Borg, 1982b). One of the few studies to compare Borg's approach to traditional Likert and VAS scales found that the VAS was most reproducible, but the CR-10 was most sensitive to pharmacologically induced changes in general fatigue in healthy subjects (Grant et al., 1999). Characteristics Commonly Assessed by Fatigue Questionnaires Most scales, particularly the multidimensional ones, include items to assess both the feelings of fatigue and the perceived impact of fatigue on the lives of respondents (see Table 2.1). The subjective feelings measured include not only the core feelings of fatigue (e.g., tiredness), but also motivational (e.g., reduced motivation) and affective (e.g., negative affective feelings) feelings accompanying fatigue. To assess the impact of fatigue, some scales ask about the degree of interference with daily activities (e.g., occupational activities). Scales commonly distinguish between the impact of fatigue on mental/cognitive (e.g., impaired concentration) and physical/muscular (e.g., reduction in sustained physical activity) activities. It is important to note that, though subjective feelings and fatigue impact are separate categories of items, both types of items are measured on the basis of the subject's self-report rather than direct performance assessment. As stated earlier, directly measuring performance decrement (e.g., a decline in cognitive performance over time) is a separate approach to fatigue measurement. Feelings of Fatigue To measure the core feelings of fatigue, questionnaires generally ask respondents to report on the degree to which they feel tired, fatigued, sluggish, pooped, or worn out. The questionnaires that most emphasize the measurement of such feelings include the Piper Fatigue Scale (PFS) (Piper et al., 1998) and the Multidimensional Fatigue Symptom Inventory (MFSI) (Stein et al., 1998), which both include many fatigue synonyms. The Profile of Mood States (POMS), a more general self-report measure, also includes a fatigue subscale with a number of items examining core feelings of fatigue (McNair, Lorr, & Droppleman, 1992). A few fatigue-specific questionnaires measure affective feelings that commonly accompany fatigue (e.g., PFS and MFSI) (Hartz et al., 2003; Piper et al., 1998). Although the feelings assessed are generally negative (e.g., depressed, tense, distressed), it is important to note that not all fatigue is associated with negative affect. 26 Christopher Christodoulou For example, people often report a pleasant sense of fatigue after exercise. Piper's PFS scale measures this less common positive affect (Piper et al., 1998). Some questionnaires include items of a motivational nature, asking if persons feel unmotivated, indifferent, or apathetic. Among the scales emphasizing motivational items are the Multidimensional Fatigue Inventory (MFI) (Smets et al., 1995), the Checklist of Individual Strength (CIS) (Vercoulen et al., 1994), and the Swedish Occupational Fatigue Inventory (SOFI) (Ahsberg et al., 1997). Impact of Fatigue The degree to which fatigue interferes with daily activities can indicate pathology. The more fatigue negatively affects occupational, social, and basic activities of daily living (e.g., bathing, dressing), the greater its pathology. Among the self-report measures including items emphasizing interference with daily activities are the Fatigue Severity Scale (FSS) (Krupp et al., 1989), the Modified Fatigue Impact Scale (MFIS) (Multiple Sclerosis Council for Clinical Practice Guidelines, 1998), and the Fatigue Symptom Inventory (FSI) (Hann et al., 2000). Mental versus Physical Fatigue Fatigue scales commonly distinguish between fatigue's impact on mental/cognitive (e.g., impaired concentration) versus physical/muscular (e.g., reduction in sustained physical activity) activities (Ahsberg et al., 1997; Chalder et al., 1993; Multiple Sclerosis Council for Clinical Practice Guidelines, 1998; Paul, Beatty, Schneider, Blanco, & Hames, 1998; Piper et al., 1998; Smets et al., 1995; Stein et al., 1998; Vercoulen et al., 1994)). Scales measuring fatigue that interferes with physical/muscular activities include items such as "physically I feel only able to do a little" (Smets et al., 1995), or items referring to reduced sustained physical functioning (Krupp et al., 1989), weakness (Chalder et al., 1993), or a heavy feeling (Stein et al., 1998). Mental/cognitive impairment is assessed through items focusing on difficulties with vigilance/concentration (Chalder et al., 1993; Multiple Sclerosis Council for Clinical Practice Guidelines, 1998; Smets et al., 1995), confused thinking (Chalder et al., 1993; Multiple Sclerosis Council for Clinical Practice Guidelines, 1998), and decision-making problems (Multiple Sclerosis Council for Clinical Practice Guidelines, 1998). Factor analyses of a number of scales support a general differentiation between physical and mental self-reported fatigue (Ahsberg et al., 1997; Smets et al., 1995; Stein et al., 1998). Work by Ahsberg and colleagues (Ahsberg & Gamberale, 1998; Ahsberg, Gamberale, & Gustafsson, 2000; Ahsberg et al., 1997) on fatigue in occupational settings (i.e., SOFI) further supports this distinction. They found that persons employed in jobs that are physically highly demanding (e.g., firefighters and factory workers) experience greater physical fatigue, while those with monotonous, mentally demanding occupations (e.g., nightshift operators at a nuclear power plant) experience more The Assessment and Measurement of Fatigue 27 mental fatigue (Ahsberg et al., 1997). They also found that strenuous physical activity increases the scores of physical fatigue subscales (Ahsberg & Gamberale 1998), and demanding mental activity increases scores on mental fatigue subscales (Ahsberg et al., 2000). It should be noted, however, that neurophysiological differences between fatigue subtypes, which would lend additional support to such distinctions, have not been well established. Duration of Fatigue Many questionnaires neglect the important issue of fatigue duration (see Table 2.1), failing to ask subjects how long they have experienced fatigue symptoms. This omission is unfortunate because longer-lasting fatigue can signal greater pathology (Piper, 1989; Wessely et al., 1998). Many scales fail to specify the time frame in which respondents should focus when answering items (e.g., right now, over the past week, in general), reducing the measure's reliability and limiting its utility in assessing changes in fatigue over time or in response to experimental manipulation (though researchers could add a time specification to the scale's instructions). The most appropriate time frame depends in part on the clinical or research objective at hand. In examining the effects of physically demanding work on otherwise healthy individuals, present fatigue might be the appropriate focus. However, in examining pathological fatigue associated with a medical disorder, a longer duration may be more appropriate. A specific time frame can be helpful in monitoring changes in fatigue associated with disease course or treatment approach. Another temporal aspect of fatigue is its diurnal pattern, involving assessment of whether symptoms are worse at particular times of the day (Schwartz et al., 1993). Measurement of Performance Decrement Aside from questionnaires, the other major approach to assessing fatigue is the direct measurement of performance decrement. Almost any behavioral or cognitive performance could conceivably be assessed, including muscular contractions, eye blinking, overall motoric activity, and various cognitive tasks. Behavioral Measures of Performance Decrement One of the most common and useful behavioral measure of fatigue involves assessing of muscle fatigue. For example, muscle fatigue has been found to be higher in MS patients who report fatigue than in healthy controls (Sheean, Murray, Rothwell, Miller, & Thompson, 1997). The process of measuring muscle fatigue is not quite as straightforward as one might expect. If muscle fatigue is defined as "any exercise-induced reduction in the maximal capacity to generate force or power output" (Vollestad, 1997, p. 220), a key problem is in determining "maximal capacity." If a volunteer produces 28 Christopher Christodoulou only submaximal muscle contractions, his or her performance may remain steady for a long time. Obtaining maximal contractions from volunteers, however, is not easy even with continuous encouragement and feedback. An individual's level of muscle contraction can be limited by a lack of motivation, among many other factors (Vollestad, 1997). In some instances, electrical stimulation of the motor neurons or the muscle itself can generate maximal force. This electrical stimulation is independent of central nervous system factors, and the difference between the force it generates and the maximum achievable force by voluntary contraction provides an estimate of "central fatigue" (Vollestad, 1997). Central fatigue in this usage is a broad term that includes factors at or above the level of the upper motor neuron. Measuring changes in eye blink rate has been posited as measure of fatigue (Stern, Boyer, & Schroeder, 1994). Blink rates appear to increase with the amount of time spent on a task that requires vigilance (Stern et al., 1994). Increases in blink rate, reduction in blink amplitude, and long eye closure rates have also been associated with increasing error rates while performing cognitive tasks (Morris & Miller, 1996). In addition, correlations have been found between eye blink measures and self-reported measures of fatigue in highly trained fighter pilots (Morris et al., 1996). Another method of assessing the impact of fatigue is to measure an individual's level of overall physical activity with a motion-sensing device (Vercoulen et al., 1997). Differences in overall activity have been documented between healthy individuals and those with the fatiguing disorders of MS (in patients with low-level physical disability) and CFS (Vercoulen et al., 1997). This study also found significant correlations between overall activity levels and self-reported fatigue in CFS patients but not in MS patients or healthy controls (Vercoulen et al., 1997). Cognitive Measures of Performance Decrement Healthy persons with induced fatigue (e.g., through performance of cognitively demanding task) have been shown to display cognitive declines in planning ability and increases in perseverative errors compared to nonfatigued individuals (van der Linden, Frese, & Meijman, 2003). Healthy persons have also displayed shifts toward lower-effort, higher-risk responses after being fatigued by a simulated workday of mentally demanding tasks (Schellekens, Sijtsma, Vegter, & Meijman, 2000). Others researchers who examined the real-world consequences of long work hours found an increase in operator errors among employees working a 12-hour shift in nuclear power plants (Baker, Olson, & Morisseau, 1994). Sleep deprivation also induces fatigue-related performance decrements. One study found no correlation between sleep deprivation (£4 hr per night) and objective performance on tests of short-term and long-term verbal recall in medical students and residents (Browne et al., 1994). However, another study found a decline in the cognitive performance of medical residents on a standardized national medical exami- The Assessment and Measurement of Fatigue 29 nation with decreased sleep before the examination (Jacques, Lynch, & Samkoff, 1990). Among clinical populations, much recent work has focused on MS. Patients with this fatiguing disorder have shown declines over time in cognitive performance during mentally challenging tasks (Bryant, Chiaravalloti, & Deluca, 2004; Schwid et al., 2003) or following such tasks (Krupp et al., 2000) compared to healthy controls. However, in direct comparisons between the groups change scores are not always significant (Schwid et al., 2003) or even reported (Bryant et al., 2004). Studies examining the relationship between declines in cognitive performance and the subjective experience of fatigue have produced inconsistent findings. Some studies of MS patients have found no relation (Bryant et al., 2004; Krupp & Elkins, 2000); in others a relation was found only for some fatigue scales (Schwid et al., 2003). One study correlated increases in subjective mental fatigue with objective cognitive performance in myasthenia gravis patients but not in healthy controls (Paul, Cohen, & Gilchrist, 2002). Still another study examining healthy persons did find correlations between changes in self-reported fatigue and changes in cognitive performance (Schellekens et al., 2000). Advantages and Disadvantages of Different Approaches to Measuring Fatigue Fatigue questionnaires have a number of practical advantages over direct measures of performance. They are inexpensive, readily available, and quickly administered. They require little staff training, and place few demands on seriously ill patients, such as those undergoing chemotherapy. In contrast, objective measures of performance decrement, whether based on muscular or cognitive performance, are designed to be demanding and may place an undue burden on some patients. Measures of performance decrement also tend to be more specialized and less widely available, and may require expensive equipment and extensive training to administer. The important advantage of performance-based measures is that they provide data that is objectively verifiable by outside observers (e.g., a measurable decrease in grip strength over time), whereas subjective reports are directly accessible only to the respondent. Self-report measures are subject to influence by a variety of factors, including mood and recall biases, which can reduce their accuracy. Some methods seek to minimize such bias, for example, reducing recall bias by using handheld organizers (e.g., Palm Pilot) that cue persons to record their momentary fatigue-related symptoms at various points during the day (Whalen, Jamner, Henker, & Delfino, 2001). Recall bias is thus reduced because subjects are required to record their responses soon after the alarm and cannot delay or clump their responses. The possible impact of mood bias can be quantified and at least partially controlled by administering separate mood (Watson, Clark, & Tellegen, 1988) or depression scales (Nyenhuis et al., 1998). 30 Christopher Christodoulou The lack of correlation between direct measurement of performance declines and subject reporting of fatigue is a concern, but it is important to note that it is not proof of the superiority of "objective" performance-based measures. Self-reported measures may reflect, in part, the greater effort required to maintain a given level of performance. For example, patients may require greater effort to maintain a given level of performance than do healthy individuals; the self-reported fatigue scores may be higher even though there is no appreciable difference in the direct measurement of fatigue through performance decrement. Neurophysiological Correlates Functional neuroimaging studies have begun to shed light on neural correlates of various fatigue measures. Recent functional magnetic resonance imaging (fMRI) studies demonstrate reliable changes in brain activity in response to maximal and submaximal muscle fatigue in healthy persons (Liu et al., 2003; Liu, Dai, Sahgal, Brown, & Yue, 2002). For example, during sustained voluntary submaximal handgrip contraction, contralateral sensorimotor cortical activity increased sharply and then plateaued (Liu et al., 2003); sustained maximal contractions also led to an initial increase, but this was followed by a decline (Liu et al., 2002). The authors suggest that the initial increased activation may reflect an effort to strengthen the descending command of motor activity to compensate for the force-loss, and the later decreased activity during maximal contraction reflects subsequent inhibition by sensory feedback as fatigue worsens. Fatigue in MS patients has probably received the most attention in neuroimaging studies among clinical populations. An fMRI study comparing healthy persons to MS patients on a simple motor task found that patients with elevated fatigue scores on the FSS showed lower activation of cortical and subcortical areas involved in motor planning and execution (Filippi et al., 2002). An earlier positron emission tomographic (PET), study of MS patients found hypometabolism in the frontal cortex and basal ganglia were correlated with higher FSS scores (Roelcke et al., 1997). Though much remains to be learned, functional neuroimaging appears to hold the potential of enriching our understanding and improving our measurement of fatigue. In addition, the positive results from functional imaging contrast with the common failure to identify structural neuroimaging correlates of fatigue, particularly in most MS studies to date (Bakshi et al., 1999; Codella et al., 2002b; Codella et al., 2002c; Codella et al., 2002a; but see Colombo et al., 2000). Acknowledgments I would like to thank Lauren Krupp, William MacAllister, and Patricia Melville for their helpful comments, and Dawn Canfora for her invaluable editorial assistance. The Assessment and Measurement of Fatigue 31 References Ahsberg, E., & Gamberale, F. (1998). Perceived fatigue during physical work: an experimental evaluation of a fatigue inventory. International Journal of Industrial Ergonomics, 21, 117–131. Ahsberg, E., Gamberale, F., & Gustafsson, K. (2000). Perceived fatigue after mental work: an experimental evaluation of a fatigue inventory. Ergonomics, 43, 252–268. Ahsberg, E., Gamberale, F., & Kjellberg, A. (1997). Perceived quality of fatigue during different occupational tasks: development of a questionnaire. International Journal of Industrial Ergonomics, 20, 121–135. Baker, K., Olson, J.,