Citation
Objective Cognitive Fatigue in Parkinson's Disease

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Title:
Objective Cognitive Fatigue in Parkinson's Disease
Creator:
Kluger, Benzi
Place of Publication:
[Gainesville, Fla.]
Florida
Publisher:
University of Florida
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Language:
english
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1 online resource (54 p.)

Thesis/Dissertation Information

Degree:
Master's ( M.S.)
Degree Grantor:
University of Florida
Degree Disciplines:
Medical Sciences
Clinical Investigation (IDP)
Committee Chair:
Garvan, Cynthia W.
Committee Members:
Heilman, Kenneth M.
Graduation Date:
8/9/2008

Subjects

Subjects / Keywords:
Business executives ( jstor )
Chronic fatigue syndrome ( jstor )
Complaining ( jstor )
Disabilities ( jstor )
Diseases ( jstor )
Fatigue ( jstor )
Neurology ( jstor )
Parkinson disease ( jstor )
Symptomatology ( jstor )
Working memory ( jstor )
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
attention, fatigue, neuropsychology, parkinson, stroop
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bibliography ( marcgt )
theses ( marcgt )
government publication (state, provincial, terriorial, dependent) ( marcgt )
born-digital ( sobekcm )
Electronic Thesis or Dissertation
Medical Sciences thesis, M.S.

Notes

Abstract:
Non-motor symptoms in Parkinson?s disease (PD) are increasingly recognized as a significant source of suffering and disability. Fatigue in particular affects 33-58% of PD patients and is reported by one third to be their most disabling symptom. Unfortunately, the pathogenesis of fatigue in PD remains unknown and we have no effective treatments. Progress in this area is hampered in part because studies of fatigue in PD rely almost exclusively on subjective questionnaires. While these questionnaires provide valuable epidemiologic information, they are limited in their ability to probe deeper questions regarding pathophysiology. Prior research has demonstrated objective motor fatigue in PD patients but did not find a correlation between this objective fatigue and subjective complaints. While PD patients have deficits in cognitive function, no study to date has used an objective test of mental fatigue to understand the basis of subjective fatigue complaints in PD. The objective of this study was to develop objective tests of cognitive fatigue and to utilize these tests to determine whether PD patients have objective cognitive fatigue. A secondary objective was to determine the relationship between subjective and objective measures of fatigue. We recruited seven healthy subjects and six PD patients. Subjects completed two three hour sessions on separate days of continuous performance tasks. One session involved a continuous Stroop performance task to test executive function and the other session involved a visual search attention task. Reaction times and accuracy were recorded on a trial by trial basis. Fatigue was quantified as the percent change in performance from the first to the last block of trials. There was no evidence of significant differences between PD subjects and control subjects in their performance at baseline. PD patients demonstrated significant slowing across all aspects of the Stroop task as well as a significant increase in total errors over the three hour period. PD subjects also demonstrated a significant increase in errors of omission on the attentional task. Healthy controls only demonstrated significant changes in their speed of performance on incongruous color trials of the Stroop and false positive errors on the working memory trials of the attentional task. Several objective performance measures correlated with subjective fatigue measures. PD subjects showed greater cognitive fatigue than healthy controls. While this may be a source of disability in this patient population, further studies are needed to determine how this fatigue correlates with quality of life and disability. ( en )
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis:
Thesis (M.S.)--University of Florida, 2008.
Local:
Adviser: Garvan, Cynthia W.
Statement of Responsibility:
by Benzi Kluger.

Record Information

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UFRGP
Rights Management:
Copyright Kluger, Benzi. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Classification:
LD1780 2008 ( lcc )

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OBJECTIVE COGNITIVE FATIGUE IN PARKINSONS DISEASE By BENZI MICHAEL KLUGER A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2008 1

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2008 Benzi Michael Kluger 2

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To my parents and all of the amazing mentor s who encouraged me to pursue my dreams. 3

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ACKNOWLEDGMENTS This research was funded thr ough a clinical research traini ng grant from the American Academy of Neurology Foundation. My educational course work was made possible through the University of Floridas Advanced Postgra duate Program in Clinical Investigation. I would like to specifi cally acknowledge the following collea gues for their assistance in the development of my research ideas and career at the University of Florida: Thomas Arnold M.D., Dawn Bowers Ph.D., Mingzhou Ding Ph.D., Hubert Fernandez M.D., C ynthia Garvan Ph.D., Kenneth Heilman M.D., Lauren Krupp M.D., David Loring Ph.D., Kimford Meador M.D., Michael Okun M.D., William Perlstei n Ph.D., and William Triggs M.D. I would also like to thank th e following students for their commitment and hard work on this project: Tasmeer Hassan, Jennifer Moscoso, Candace Palmer, Joshua Proemsey, and Carla Vidal. 4

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TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................4 LIST OF TABLES................................................................................................................. ..........7 LIST OF FIGURES.........................................................................................................................8 LIST OF ABBREVIATIONS.......................................................................................................... 9 ABSTRACT...................................................................................................................................10 CHAPTER 1 INTRODUCTION................................................................................................................. .12 Significance of Fatigue in Parkinsons Disease......................................................................12 Defining Fatigue.....................................................................................................................12 Components of Fatigue.......................................................................................................... .13 Homeostatic Subjective Fatigue......................................................................................13 Psychological Subjective Fatigue....................................................................................14 Peripheral Fatigue............................................................................................................1 5 Central Fatigue................................................................................................................15 Pathological Fatigue...............................................................................................................16 Limitations of Self-Report Me asures of Subjective Fatigue..................................................17 Objective Neuropsychological Testing...................................................................................19 Objectives of this Study..........................................................................................................21 2 METHODS...................................................................................................................... .......23 Participants.............................................................................................................................23 Subjective Fatigue Questionnaires.........................................................................................23 Objective Fatigue of Executive Function...............................................................................23 Objective Atten tional Fatigue.................................................................................................24 Statistical Analyses........................................................................................................... ......25 3 RESULTS...................................................................................................................... .........27 Executive and Attentional Function at Baseline.....................................................................27 Objective Fatigue of Executiv e and Attentional Function.....................................................27 Correlation of Objective and S ubjective Measures of Fatigue...............................................27 4 DISCUSSION................................................................................................................... ......38 Objective Cognitive Fatigue in Healthy Older Adults...........................................................38 Objective Cognitive Fatigue in Parkinsons Disease..............................................................39 5

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Subjective Fatigue Complaints...............................................................................................40 5 FUTURE DIRECTIONS........................................................................................................42 Measurement of Fatigue in Clinical Populations....................................................................42 Neurophysiology.....................................................................................................................42 Fatigue Treatment...................................................................................................................44 6 CONCLUSIONS.................................................................................................................. ..45 LIST OF REFERENCES...............................................................................................................46 BIOGRAPHICAL SKETCH.........................................................................................................52 6

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LIST OF TABLES Table page 3-1. Stroop Performance at Baseline............................................................................................ .29 3-2. Attentional Performance at Baseline......................................................................................3 0 3-3. Objective Executive Performance Fatigue.............................................................................31 3-4. Objective Change in Attentional Performance.......................................................................32 3-5. Correlations between Subjective Outco mes and Objective Attentional Fatigue...................33 7

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LIST OF FIGURES Figure page 1-1. Components of fatigue..................................................................................................... ......22 2-1. Sample visual displays of attention fatigue trials...................................................................26 3-1. Baseline performance on Stroop task....................................................................................34 3-2. Attentional performance at baseline....................................................................................... 35 3-3. Fatigue in overall performance on Stroop task......................................................................36 3-4. Change in accuracy on attentional task with fatigue..............................................................37 8

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LIST OF ABBREVIATIONS 5-HT Serotonin CFS Chronic Fatigue Syndrome CNS Central Nervous System DSM-IV Diagnostic and Sta tistical Manual of Mental Disorders, Fourth Edition EEG Electroencephalography fMRI Functional Magnetic Resonance Imaging FSS Fatigue Severity Scale MEG Magnetoencephalography MFI Multidimensional Fatigue Index MS Multiple Sclerosis PD Parkinsons Disease TMS Transcranial Magnetic Stimulation 9

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Abstract of Thesis Presen ted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science OBJECTIVE COGNITIVE FATIGUE IN PARK INSONS DISEASE By Benzi Michael Kluger August 2008 Chair: Cynthia Garvan Major: Medical Sciences Non-motor symptoms in Parkinsons diseas e (PD) are increasingl y recognized as a significant source of suffering and disability. Fatigue in particular affects 33-58% of PD patients and is reported by one third to be their most disabling symptom. Unfort unately, the pathogenesis of fatigue in PD remains unknown and we have no e ffective treatments. Progress in this area is hampered in part because studies of fatigue in PD rely almost exclusively on subjective questionnaires. While these questionnaires provide valuable epidemiologic information, they are limited in their ability to probe deeper questions regardi ng pathophysiology. Prior research has demonstrated objective motor fatigue in PD pati ents but did not find a correlation between this objective fatigue and subjective complaints. While PD patients have deficits in cognitive function, no study to date has used an objective test of mental fati gue to understand the basis of subjective fatigue complaints in PD. The objectiv e of this study was to develop objective tests of cognitive fatigue and to utili ze these tests to determine whether PD patients have objective cognitive fatigue. A secondary objective was to determine the relationship between subjective and objective measures of fatigue. We recruited seven healthy s ubjects and six PD patients. Subjects completed two three hour sessions on separate days of continuous performance tasks. One session involved a 10

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continuous Stroop performance task to test execu tive function and the other session involved a visual search attention task. Reaction times and accu racy were recorded on a trial by trial basis. Fatigue was quantified as the percent change in pe rformance from the first to the last block of trials. There was no evidence of significant differe nces between PD subjects and control subjects in their performance at baseline. PD patients demonstrat ed significant slowing across all aspects of the Stroop task as well as a significant increase in total errors over the three hour period. PD subjects also demonstrated a signi ficant increase in errors of omission on the attentional task. Healthy controls only demonstr ated significant change s in their speed of performance on incongruous color trials of the Stroop and false positive errors on the working memory trials of the attentional task. Several objective performance meas ures correlated with subjective fatigue measures. PD subjects showed greater cogn itive fatigue than healthy controls. While this may be a source of disability in this pa tient population, further studies ar e needed to determine how this fatigue correlates with qual ity of life and disability. 11

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CHAPTER 1 INTRODUCTION Significance of Fatigue in Parkinsons Disease PD is the second most common neurodegenerative disease, with over 4.1million affected individuals worldwide, and an expected doubling of this figur e in the next 20 years due to the aging of our population (Dorsey, 2007) Although PD is trad itionally thought of as an extra-pyramidal motor disorder, more recent research highlights the prevalence and impact of non-motor symptoms, including c ognitive dysfunction, depression and fatigue (Chaudhuri et al., 2006). Fatigue was noted by James Parkinson (1817) in his original description of the disorder but it was not until 1993 that studies began describing its prevalence, progression and impact (Freidman and Friedman, 1993). All studies reported to date demonstrate a higher prevalence of fatigue in PD patients versus age-matched controls with a prevalence of around 40% (range 33 to 58%) compared to the general population prevalence of 10 to 25% (Freidman et al., 2007). Studies assessing the im pact of fatigue in PD further report that over half of PD patients feel that fatigue is one of their most severe and disabling symptoms (van Hilten et al ., 1993, Friedman and Friedman, 1993). Despite the clear impact of fatigue in PD, we do not understand its pathophysiology and do not have any adequate treatments (F errari et al., 2006). Defining Fatigue Fatigue is a normal phenomenon that we have all experienced a nd includes both subjective sensations and an objective deterioration in performance. While many authors use their own definition of fatigue, these definitions frequen tly confound fatigue with other related phenomena (particularly sleepiness) or are too vague to allow practical measurement. Ryan (1947) defines two distinct components of fatigue: 12

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1. Feelings of tiredness, weariness, or exhaustion (subjective fatigue). 2. A reduction in the capacity to perform a task as a result of continuous performance on the same task (objective fatigue). Objective fatigue, by definition, always affects performance on the task used to induce fatigue and may affect performance on other tasks, particularly if both tasks stress shared physiological substrates. Alternatively, fatiguing performance on one task may have no impact, or even enhance performance, on a subsequent unrelated task (Davranche and Audiffren, 2004). Like many complex constructs, studies of the phenom enology and physiology of fatigue in healthy adults and animal models reveal the utility of focusing our research efforts on understanding the components of fatigue rather than treating fatigue as a single entity. Components of Fatigue Although many branches of science ha ve approached the problem of fatigue, few authors have attempted to bring these findings together in a single model. The model proposed in Figure 1-1 presents a general framework for organizing the fatigue literatu re and applying it to clinical populations. These components are not meant to be mutually exclusive. In fact, they may all be present at one time in an indivi dual and may interact with eac h other. However, under certain task conditions and/or patholog ical states a specific compone nt of fatigue can dominate a subjects perceptions and/or performance. Once identified, our understandi ng of this component can direct further investigations into the pathophysiology underl ying task failure and perceived fatigue in patient populations. Similarly, by isol ating specific components we may be able to develop better directed treatments. Homeostatic Subjective Fatigue Homeostatic subjective fatigue serves a regulative function in prot ecting the organism from the damaging effects of prolonged activity and ener getic catastrophe. Seve ral lines of research 13

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have suggested that structures within the CNS act as a central governor to prevent total energy depletion (Noakes et al., 2004). While the signaling mechanisms and CNS targets are incompletely known, several potential pathways have been identified including inflammatory (IL-6), metabolic (cerebral glyc ogen depletion) and neuronal (increases of serotonin and decreases of dopamine) (Davis and Bailey, 1997). Animal models have suggested that the hypothalamus is at least one of th e CNS structures responsible for homeostatic fatigue that is mediated by 5-HT (Soares, 2007). While fatig ue has been noted with lesions of the hypothalamus, it is difficult to attribute fatigue directly to these lesions as these patients frequently have additional CNS lesions and often have associated hypersomnolence, circadian rhythm disturbances and endoc rine disturbances (Chaudhuri a nd Behan, 2004). While PD may affect the hypothalamus (Braak and Braak, 2000), it is unknown if these lesions are associated with fatigue in this population. Psychological Subjective Fatigue Psychological subjective fatigue is not directly related to ho meostatic mechanisms but rather reflects psychological factors including performance expect ations, motivation, arousal and mood. The strong association of depression and fati gue in PD supports the role of mood as a contributor to subjective fatigue (Alves et al., 2004). Experiments in healthy subjects have also shown that performance and sensations of effo rt may be altered by giving false feedback regarding temporal duration or force output (Wells et al., 199 3). Since PD subjects have disturbances of temporal estimation (Pastor et al., 1993) and magnitude estimation, these misperceptions may create a heightened sense of effort, similar to normal subjects under false feedback. 14

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Peripheral Fatigue Peripheral fatigue refers to decrements of task performance on the basis of dysfunction at the level of muscle or peripheral nerves. Th is fatigue is typically brought on by physically demanding motor tasks involving fre quent or prolonged muscle cont ractions. Peripheral fatigue is the predominant form of fatigue in many diseas es of the peripheral nervous system and muscle including myasthenia gravis and glycogen storage disorders (Chaudhuri and Behan, 2004). Many physiological and cellular mechanisms of periphera l fatigue have been proposed on the basis of direct electrical stimulations of nerve and muscle (Westerblad and Allen, 2004). However, the task of distinguishing peripheral from central fatigue can be quite challenging in a living organism under physiologic conditions (Gandevia, 2001). Although decrements in cognitive tasks are almost always due to central causes, decrements in motor tasks are rarely due to isolated peripheral dysfunction. Fo r instance, Hunter et al. (2005) demonstrated that subjects maintaining a static arm contra ction had different rates of fa tigue depending on whether they were given feedback based on their force out put or arm position, despite having identical physical loads. Although PD patients demonstrat e objective motor fatigue, these deficits are presumed to arise from central causes (Lou et al., 2003a). Central Fatigue Central fatigue refers to objective decrements in either cognitive or motor task performance due to changes within the central nervous system The choice of task is a critical tool in understanding fatigue as subtle changes in task demands can have large effects on performance (Barry and Enoka, 2007). These effects must be me diated by differences in the demands placed on specific CNS networks necessary for maintain ing optimal performance. Neurological lesions within these networks may increas e the vulnerability of these syst ems to fatigue induced stress. For example, agings effects on cognitive functio n appear to lead to accelerated rates of 15

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performance decline in tasks demanding divi ded attention but not on tasks demanding only sustained attention (Kallus et al ., 2005). This may be due to the selective effects of aging on the central nervous system which affect the c ognitive systems that mediate executive control (Gazzaley and DEsposito, 2007). Studies of cognitive fatigue in MS have also suggested that central fatigue may be domain specific (Krupp a nd Elkins, 2000). No studies to date have examined central fatigue in PD using cognitive tasks. Unlike peripheral fatigue, the mechanisms underlying central fatigue are unknown but may ge nerally be divided in to neurophysiological and energetic explanations (Dal sgaard and Secher, 2007). These e xplanations are not mutually exclusive, and may in fact be complementary, as energetic deficits can affect neuronal function (Takata and Okada, 1995). Whether central fatigue in PD is caused by alterations of global energy expenditure (Levi et al., 1990) or m itochondrial dysfunction (Martin, 2006) is unknown but plausible given the high rate s of chronic fatigue in patients with mitochondrial disorders (Fattal et al., 2007). Pathological Fatigue In healthy adults, fatigue is a tr ansient phenomenon brought about by prolonged exertion which diminishes with rest and does not typically inte rfere with daily functioning. This is in contradistinction to pathologica l fatigue which is frequently chronic, brought on by minimal exertion, does not fully improve w ith rest and causes si gnificant disability (Fukuda et al., 1994). While pathological fatigue may arise in otherwis e healthy individuals, pa thological fatigue is frequently associated with disease states, particularly neurological disorders (Chaudhuri and Behan, 2004). Fatigue associated with diseases may arise from a secondary cause. For example, fatigue in cancer patients is frequently secondary to anemia and responds to anemia treatment (Harper and Littlewood, 2005). Alternatively, fati gue may be a primary manifestation of a disease, such as the classical motor decremen ts seen with prolonged exertion in myasthenia 16

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gravis (Keesey, 2004). This fatigue is due to pa thological changes at th e neuromuscular junction and responds to treatment of the primary disease process. Possible secondary causes of fatigue in indi viduals with PD include sleep disorders, medications and depression (Yoshii, 2006). However, population based studies in PD demonstrate that sleep disorders (Shulman et al., 2001) and daytime somnolence (van Hilten et al., 2006) do not account for fatigue in the majo rity of PD subjects. This highlights the importance of distinguishing betw een sleepiness and fatigue in s ubjective ratings (Shen et al., 2006). Similarly, studies of the mo st common medications used in PD show no effect or even slight improvements in fatigue (Abe et al., 2001), despite reports of excessive daytime somnolence associated with these same medicati ons (Razmy et al., 2004). While several studies demonstrate a correlation between measures of de pression and fatigue (Alves et al., 2004), this may in part be due to methodological issues in the overlap of symptoms on fatigue and depression inventories including the DSM-IV. Even in studies demonstrating this correlation, nearly half of PD patients wit hout depression still report fatigue (Alves et al. 2004). Similarly, up to a one half of patients with major depression s till experience fatigue after their depression is successfully treated (Fava et al., 1994). In addition, fatigue appears to be independent of motor symptoms (Shulman et al., 2001) and disease severity (Friedman and Friedman, 1993). Longitudinal studies also suggest that PD patient s with fatigue continue to have fatigue, while those without fatigue rarely develop fatigue (F riedman and Friedman, 2001). Taken as a whole, these studies show that the majority of PD patie nts must have either primary fatigue or fatigue secondary to an as yet unidentified factor. Limitations of Self-Report Mea sures of Subjective Fatigue Although many self-reported sympto ms, including depression, pain and fatigue, are undoubtedly real sources of sufferi ng and disability for patients they present a challenge to study 17

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through the scientific method. While some advances have been made possible through improvements of subjective scal es, there is a great scientific need for the development of objective correlates of these symp toms. This includes physiologica l markers, biological models, neuropsychological tests and pro cedures for reproducing patient s symptoms. This proposal will address this need in the domain of PD fatigue by determinin g the objective neuropsychological correlates of subjective fatigue, assessing the use of prolonged cognitive performance as an objective measure and procedure for inducing fatigue, and utilizing electrophysiological techniques to determine physiological marker s and possible mechanisms of PD fatigue. Our knowledge of PD fatigue comes almost ex clusively from studies based on subjective scales (Friedman et al., 2007). While the data generated by these scales raises interesting epidemiological questions, one must be cautious in interpreting the results of these studies. A related limitation is the effect that cognitive deficits, mood and personality may have on the manner in which subjects interp ret and score test items independently of the underlying constructs these scales are purporti ng to measure. Literature in several domains demonstrate that self-report data may be prone to bias, includi ng memories of specific incidences (Kuiken, 1991), symptom frequency (Burton and Blai r, 1991) and reports of actual deficits (Stone et al., 2000). For instance, self-reports of cognitive dysfunction in subjects taking antiepileptic drugs correlate more with indices of anxiety and depression th an they do with the obj ective neuropsychological test scores (Elixhauser et al., 1999). In MS patients, subjectiv e ratings of fatigue correlated with self-reports of neuropsychological impairments but did not correlate with objective decrements in cognitive performance (Beatty et al., 2003). A further issue is the lack of external va lidation of these scales. As discussed above, subjective fatigue may reflect objective fatigue, bu t it may also exist independently of objective 18

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findings due to psychological fact ors or changes in the generation or perception of homeostatic feedback. Determining the relation of subjective co mplaints to objective measures of fatigue is thus critical to understanding the origin of these complaints. A strong correlation with objective measures would imply that subjective fatigue comp laints are secondary to objective components. Conversely, a lack of correlation would imply that other factors are more important in determining subjective complaints. Lou et al. (2 003a) found that while PD patients had evidence of increased objective motor fatig ue this objective fatigue did not correlate with subjective ratings, including subjective rati ngs of physical fatigue. More over, while levodopa treatment improved this objective motor fatigue it had no effect on subjective ra tings. This study is consistent with data from studies in MS and fa tigue which have also failed to find a correlation between objective motor fatigue a nd subjective ratings (S cwid et al., 1999). Wh ile there is some evidence to suggest that cognitive fatigue may be related to subj ective fatigue in MS (Greim et al., 2007), no study to date has assessed objective cognitive fatigue in PD. Objective Neuropsychological Testing A well designed battery of neuropsychologi cal tests can provide a gr eat deal of information regarding the mechanisms, localization and imp act of both anatomical and functional brain lesions (Lezak et al., 2004). St udies of patients with chronic fatigue syndrome (CFS) and MS have revealed distinctive neuropsychological profiles which specifi cally demonstrate deficits of attention, concentration and ex ecutive function (Busichio et al., 2004, Krupp and Elkins, 2000). In CFS these cognitive deficits have been shown to significantly correlate with disability and are thus a critical factor to consid er in the management of this di sorder (Christodoulou et al., 1998). The impact of fatigue on cognition in PD is cu rrently unknown but potentially significant given the prevalence of both cognitive deficits a nd subjective fatigue in this population. Neuropsychological testing also has the potential to elucidat e some of the functional CNS 19

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mechanisms underlying subjective fatigue. For instance, Krupp et al. (1994) administered a neuropsychological battery to both MS and CFS patients and found correlations between depression and cognitive function only in the CFS group. This study highlights the ability of neuropsychological testing to separate the contributions of mood and brain pathology to subjective fatigue across patient groups. We hypot hesize that subjective fa tigue in PD will be strongly correlated with mood as well as specific domains of cognitive function. PD is known to affect cognitive functioning, particularly in the domains of executive function and attention (Zgaljardic et al., 2003). In fact, a dysexecu tive syndrome reflecting both cortical and subcortical pathol ogy is one of the hallmarks of both cognitive dysfunction and dementia in PD patients (Bosboom et al., 2004). Several studies suggest that cognitive deficits may be associated with fatigue. Abe et al. (2000) demonstrated a significant correlation between frontal hypometabolism and fatigue ratings as well as a tr end for correlation with a frontally mediated neuropsychological test (the Wisconsin Card Sort test). MMSE scores have also been shown to correlate with fatigue ra tings (Alves et al., 2004). Deluca ( unpublished data ) has also demonstrated both decreased frontal and caudate activation to be a ssociated with fatigue in an fMRI experiment. We hypothesize that obj ective fatigue on prolonged tasks demanding executive control will be associated with subj ective fatigue complaints in PD patients. A second hallmark of cognitive deficits in PD is disturbances of atte ntion (Grande et al., 2006). These attentional deficits are seen early and prominently in tasks requiring divided attention (Sharpe, 1996). This defi cit probably reflects an inability of PD subjects to efficiently allocate top-down attentional reso urces, although deficits in botto m-up attention have also been reported (Lieb et al., 1999). Althoug h the role of attention deficits has not been studied in PD fatigue, a recent study in traumatic brain injury de monstrated that attentional deficits may be 20

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predictive of fatigue in pathol ogical states (Ziino and Ponsford, 2006). Similarly, studies of objective cognitive fatigue in multiple sclerosi s have demonstrated a correlation between sustained attention tasks (Greim et al., 2007) but not working me mory tasks (Bailey et al., 2007). We hypothesize that objective fatigue on prolong ed tasks demanding top-down attention will be associated with subjective fatigue complaints in PD patients. Objectives of this Study We have four major objectives for this research project: 1) To develop objective tests of cognitive fati gue testing executive and attentional functions. 2) To determine the pattern of objective cognit ive performance changes seen in healthy older adults and PD patients. 3) To determine if there are si gnificant differences in objectiv e cognitive fatigue between PD patients and healthy older adults. 4) To determine whether there is a correlation between objective and subjective measures of fatigue in PD patients. 21

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Figure 1-1. Components of fatigue. Letters in boxes refer to: a) known neuroanatomic cites mediating this component of fatigue; b) Normal function of this component of fatigue; c) Pathological states involvi ng this component. CFS chronic fatigue syndrome; EC excitation/contraction; MG myasthenia gravis; GSD glycogen stor age diseases; GBS Guillain-Barre syndrome; TBI traumatic brain injury; CVA cerebrovascular accident. 22

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CHAPTER 2 METHODS Participants This investigational protocol was approved by the University of Florida Institutional Review Board. All participants gave written informed consent. Six patients with PD (mean age +/SD; 56 +/12 years, 4 men) and seven healthy dext ral volunteers (61 +/14 years, 5 men) were enrolled. All subjects were screened for illnesses other than PD associated with fatigue including depression. All PD patients were diagnosed by a fellowship trained Movement Disorders neurologist using UK Brain Bank criteria (Hughes et al., 1992). PD patients were non-demented and in a mild to moderate stage of the disease (Hoehn and Yahr Stage of 3 or less). PD patients were tested in their best on state while taking their usual medications. Handedness was determined by the Edinburgh Handedness Inventory (Oldfield, 1971). All participants were asked to abstain from caffeine on the day of testing. Subjective Fatigue Questionnaires To measure subjective fatigue we used two previously standardized scales. The Multidimensional Fatigue Inventory (Smets et al., 1995) measures five independent dimensions of fatigue; general fatigue, physical fatigue, re duced motivation, reduced activity and mental fatigue. While this scale covers a wide range of symptoms, it is not particularly sensitive to overall fatigue severity and it does not have clear cut points. The Fatigue Severity Scale (Krupps et al., 1989) is a seven item questionnaire which queries fatigue generally but is sensitive to severity and has clear scoring (a score of 4 or greater signifies moderate to severe fatigue). Objective Fatigue of Executive Function Participants performed a computerized si ngle-trial, cued version of the Stroop task (Cohen et al., 1999) displayed on a PC using the Experimental Run Time System (Berisoft Corporation, 23

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Frankfurt, Germany). In this task subjects are presented wi th an instructional cue on each trial (word or color). This is followed by a 1,3 or 5 second interstimulus interval (ISI) followed by an imperative color word stimulus (red, blu e or green) written in colored letters. For the word task subjects were in structed to read the word, while in the color task subjects are instructed to name the color of the letters. On 60 % of the trials the color of letters and the word were congruent (e.g. red written in red letters), but on the other 40% the letters and word were incongruent (e.g. red written in green letters). Reaction times were determined by a microphone and voice activation software and responses were manually recorded in real time by a research assistant. After receiving a brief practice session (30 trials), subj ects are fitted with EEG electrodes (data not presented here) and were asked to perfor m the task for a single th ree hour session. Breaks for any purpose were taken only if requested, and the times of breaks noted. If a subject was unable to complete the task for any reason, the time of discontinuation was recorded. Objective Attentional Fatigue Participants performed a computerized target detection task. All presentations and response recordings were displayed on a PC using th e Experimental Run Time System (Berisoft Corporation, Frankfurt, Germany). Participants were instructed to maintain fixation on a central cross throughout the experiment to minimize eye m ovements. After learning two targets, subjects performed a visual search task in which they responded with one of two buttons depending on whether the target is present or absent. Targets were presented in one of three conditions (Figure 2-1): a) a visual search condition in which targets sh are two visual features with distracters (top-down attention); b) a pop-out condition in which distracters differ in a single visual feature (bottom-up attention) and; c) a working memory condition in which only one stimuli was present on the screen. Trials may be further divided into those with 1, 7 or 15 distracting items. Stimuli were 24

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presented in a continuous fashion to subjects in ba lanced blocks of 60 trials (24 visual search, 24 pop-out and 12 working memory, in cluding 50% target absent tria ls and 8 of each distracter number in the visual search and pop-out conditio ns). After receiving a brief practice session (40 trials or until competency is de monstrated), subjects were fitted with EEG electrodes and asked to perform the task for a single three hour sessi on. Breaks for any purpose were taken only if requested, and the times of breaks noted. If a subjec t is unable to complete the task for any reason, the time of discontinuation was recorded. Statistical Analyses Summary statistics were computed, summ arized and graphed (e.g. b ox and whisker plots) to identify outliers and/or impossibl e or implausible values and to check for distributional forms. For each block of 390 trials, error rates were calculated as the mean error and speed was calculated as the median reaction time to minimi ze the effect of outliers. To determine objective fatigue of our outcome measures we calculated the percent change from the first 390 trials (following a training trial) to the last 390 trials completed by each subject. Group comparisons were made using the Wilcoxon rank sum test and correlations were made using Spearman correlation. A two-sided alpha=0.05 wa s the level of significance used for all tests. SAS version 9.1 (SAS Institute, Cary, NC) was used for all data management and statistical analyses. 25

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a) b) c) Figure 2-1. Sample visual displays of atte ntion fatigue trials with target present: a) visual search (white \ is target) b) pop-out (grey / is target) c) working memory (white \ is target) 26

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CHAPTER 3 RESULTS Executive and Attentiona l Function at Baseline There were no significant differences between the two groups in any of our performance measures at baseline (all p > 0.10). Table 3-1 and Tabl e 3-2 summarize these results. Figures 3-1 and 3-2 demonstrate these results graphically for the two grou ps over different task types. Objective Fatigue of Executive and Attentional Function For this study, we defined objective fatigue as a statistically signifi cant difference between a performance measure recorded at baseline and du ring the last two blocks of testing. For the Stroop task, PD subjects showed si gnificant changes in speed across all task types, and in total errors (see Table 3-3). Healthy controls showed significant decrements onl y in their reaction time for the incongruous color condition. By doubling th e reaction times on error trials we calculated a total performance metric. Figure 3-3 demonstr ates these results graphically. There were no significant group differences across any outcomes. On the attentional task, PD pa tients demonstrated a significant increase in their errors of omission for both the pop-out and visual search condition, as well as a trend for false positive errors on the pop-out condition. For control subjects, a significant increase in false positive errors was noted only for the working memory condition. There were no significan t changes in reaction times nor where there significant group differences across any outcome m easure. These results are summarized in Table 3-4 and Figure 3-4. Correlation of Objective and Subjective Measures of Fatigue We performed an explorative analysis using Spearmans correlation to determine if the FSS, the MFI or any subscale of th e MFI was correlated with our objective measures of executive function fatigue. The only signifi cant correlations were between the percent change in Stroop 27

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performance and the General Fatigue Score of the MFI (r2=0.27, p=0.001) and the Reduced Activity Score (r2=0.17, p=0.045). For our attentional outcomes, we found a significant negative correlation between the total FSS score and changes in errors on all task types. Within the MFI, positive correlations were found between the General Fa tigue factor and errors of omission on the pop-out task and between the Reduced Activity f actor and errors of omission on working memory and false positive errors on the pop-out task. These results are summarized in Table 3-5. 28

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Table 3-1. Stroop Performance at Baseline; Mean (SD) Congruous Word Congruous Color Incongruous Word Incongruous Color Combined PD RT (msec) Error (%) 1332 (340) 0.1 (0.4) 1336 (365) 0.1 (0.3) 1661 (510) 10.9 (10) 1753 (418) 15.6 (13) 1462 (374) 5.3 (4.2) Controls RT (msec) Error (%) 1236 (223) 0.1 (3) 1250 (220) 0.4 (0.4) 1456 (297) 3.2 (3) 1533 (288) 11 (14) 1343 (241) 3.1 (3) 29

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Table 3-2. Attentional Performance at Baseline (Mean (SD) divided by ta sk type and target present (+) or absent (-). Pop-out + Working Memory + Visual Search + PD RT (msec) Error (%) 2416 (1400) 11.9 (22) 2516 (1270) 8.8 (18) 3013 (2900) 14.7 (21) 2709 (1900) 10.9 (16) 3506 (831) 16.7 (15) 5687 (3580) 11.3 (23) Controls RT (msec) Error (%) 1614 (640) 9.4 (22) 1397 (550) 9.8 (22) 2397 (2030) 12.3 (22) 1599 (790) 5.2 (11) 2480 (890) 19.0 (14) 4265 (1970) 8.4 (19) 30

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Table 3-3. Objective Executive Performance Fatigue (Percent change (SD) Congruous Word Congruous Color Incongruous Word Incongruous Color Combined PD RT Error 16.6 (11)* 0.0 (0.5) 22.4 (27)* 0.0 (0.4) 13.5 (17)* 4.3 (10) 20.0 (20)* 4.3 (7) 18.0 (13)* 1.8 (2)* Controls RT Error 11.8 (23) 0.0 (0.5) 8.9 (20) 0.0 (0.5) 11.7 (20) 1.1 (3) 18.5 (12)* 1.1 (8) 10.8 (19) 0.2 (2) significant change from baseline (p < 0.05) 31

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Table 3-4. Objective Change in Attentional Performance Pop-out + Working Memory + Visual Search + PD RT Error 23.8 (48) 7.3 (10)* 51.8 (107) 7.1 (10) ** 3.5 (15) 5.1 (10) 7.1 (23) -1.0 (1.7) 15.1 (28) 7.0 (8) 8.7 (18) 0.3 (8) Controls RT Error 3.9 (17) -0.9 (5) 8.5 (16) 0.3 (1) 9.4 (19) 0.5 (4) 17.5 (24) 2.4 (3) 1.0 (12) 2.4 (6) 8.9 (23) -0.3 (1) significant change from baseline (p < 0.05) ** trend for change from baseline (p < 0.1) 32

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Table 3-5. Correlations between Subjective Outcomes and Objective Attentional Fatigue. FSS = Fatigue Severity Scale; GF = General Fatigue; MF= Mental Fatigue; PF= Physical Fatigue; PO = Pop-out; RA = Reduced Activity; RM = Reduced Motivation; VS=Visual Search; WM = Working Memory. PO (+) PO (-) WM (+) WM (-) VS (+) VS (-) FSS -0.44 -0.47 -0.37 -0.57 -0.34 -0.29 GF 0.18 0.11 0.11 0.03 0.14 0.07 RA 0.09 0.25 0.30 0.03 -0.24 0.16 MF 0.04 -0.08 -0.07 -0.06 .11 -0.07 PF 0.00 -0.03 0.00 -0.13 -0.07 -0.05 RM -0.12 -0.07 0.05 -0.22 -0.32 -0.14 significant p < 0.05 33

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0 500 1000 1500 2000 2500 3000 CC CW IC IW Figure 3-1. Baseline performance on Stroop task. White is controls, black is PD. Tasks are (from left to right): congruous color naming, colo r word reading, incongruous color naming and incongruous word reading. 34

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Baseline Accuracy for Task Types Condition: Target Absent0 0.1 0.2 0.3 Visual Search Working Memory Popout Task TypeAccuracy Control PD Baseline Accuracy for Task Types Condition: Target Present0 0.05 0.1 0.15 0.2 0.25 0.3 Visual Search Working Memory Popout Task TypesAccuracy Control PD Figure 3-2. Attentional pe rformance at baseline. 35

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Objective Fatigue as Measured by Percent Change in Task Performance0 10 20 30 40 50 60 70 CC CW IC IWPercentage Change Control PD Subjects Figure 3-3. Fatigue in overall pe rformance on Stroop task. White is controls, black is PD. Tasks are (from left to right): congruous color nami ng, color word reading, incongruous color naming and incongruous word reading. 36

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Attentional Fatigue Condition: Target Absent-2 -1 0 1 2 3 4 5 6 7 8 Visual Search Working Memory Popout Task TypePercent Change In Accuracy Control PD Attentional Fatigue Condition: Target Present-2 -1 0 1 2 3 4 5 6 7 8 Visual SearchWorking Memory Popout Task TypePercent Change In Accuracy Control PD Figure 3-4. Change in accuracy on attentional task with fatigue. 37

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CHAPTER 4 DISCUSSION Objective Cognitive Fatigue in Healthy Older Adults Our experimental tasks were designed to have internal control conditions to allow us to distinguish focal fatigue of cerebral networks from either general fa tigue or other general factors such as boredom, loss of motivation and sleepiness. The pr olonged Stroop task was chosen as its continued performance would be expected to place specific demands on frontal-executive networks. Consistent with our predictions, older adults demonstrated a disproportionate decrease in performance on the incongrous color naming task which demands the most executive control compared to other task types. Our visual search task was chosen to distinguish effortful topdown attention from pr e-attentive bottom-up attention. We predicted that older adults would demonstrate a disproportionate increase in errors with fatigue on top-down visual search items. The finding of increased errors on the working memory item may reflect a susceptibility to working memory deficits with fatigue, a finding reported in CFS (Dobbs et al., 2001). Alternatively, both the visual search and popout tasks can be correctly answered without re lying on internal resour ces by searching for a stimuli which differs from the others. The wo rking memory task, on the other hand, requires internal resources as there ar e no external cues and this dependence on internal resources may be more susceptible to fatigue. Studies demonstrating involvement of medial frontal structures with fatigue are consistent with this hypothesis as these structures are associated with internally generated actions (Boksem et al., 2006). Performance strategies are known to effect variables such as speed and accuracy (Pfefferbaum et al., 1983). It is not surprising that they would also effect changes in these variables with fatigue. On the Stroop task, it appears that subjects sa crifice time to maximize 38

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their accuracy. This may be expected in that subj ects are typically aware of the correct response. In fact when subjects make errors they will of ten spontaneously correct their response or change their response mid-word. In contrast, subjects had almost no change in speed over time while performing the attentional task but had a signific ant increase in errors of omission. It is likely that subjects were unaware of th ese errors, although a second source of data such as event related potentials or eye tracking would be needed to prove this postulate. Objective Cognitive Fatigue in Parkinsons Disease In contrast to healthy older adults, PD subjects demonstrated more global impairments in function with the onset of fatigue Contrary to our expectations on the prolonged Stroop task, PD subjects showed significant slow ing across all tasks, with the smallest relative difference found for the congruous color naming task. This may be due to several factors. First, PD subjects had impairments in the incongruous color task at ba seline and may not change as significantly with fatigue due to a floor effect. Secondly, PD subj ects have objective moto r fatigue (Lou et al., 2003a) and may be expected to develop oromotor sl owing as well. This would lead to a general slowing across tasks due to the time of speech generation. This slowing may in fact surpass cognitive control as a rate limiting step and even allow subjects additiona l time to compute their response prior to speaking. Finally, cues for difficult tasks are know n to induce greater preparatory activity and attention compared to easier tasks (P erlstein et al., 2006). As PD subjects are more dependent than control subjects on external versus internal cueing (Jenkins et al., 2000), they may have a relative advantage in the face of strong as opposed to weak cues. PD subjects showed similar broad deficits across tasks types with our attentional experiment. This seems to be unlikely due to a simple general effect such as sleepiness or boredom in that PD subjects made increasing erro rs of omission, but did no t have alterations of false positives or reaction time. The most parsimonious explana tion for these findings would be 39

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that PD subjects have impairments in early pr e-attentive processes that worsen over time. Alternatively, PD subjects may have deficits in both attentive and pre-attentive processes that independently impair function on the various tasks. As discusse d in the introduction there is evidence that PD affects both pre-attentive and attentive processes (Lieb et al., 1999). A particularly rich way of explori ng this question would be the use of event related potentials to determine the timing of differences in the processing of stimuli presented at baseline and after fatigue. Subjective Fatigue Complaints Although significant correlation was found between the scores of General Fatigue and Reduced Activity on the MFI and Stroop performance, it is possible that this is a spurious association. With only six subjects, it is equally difficult to conclude that there is truly no association between objective a nd subjective variables. A larg er study is needed to more definitively answer this question. It is similarl y difficult to draw conclusions on the handful of positive correlations between elements of the MFI and attentional outcomes. The consistent negative correlations between the FSS and all at tentional variables were an unexpected finding. This may also reflect a spurious association, as ther e were no significant correlations when this analysis was re-run using Pearson s r. Alternatively, this may reflect an anosognosia for fatigue in those with greater attentional deficits. While it is possible associations may be dem onstrated in larger samples, the lack of significant correlations between subjective and objective measures of fatigue is consistent with data from numerous other studies comparing objec tive tests to self-report data. As discussed in the introduction, numerous authors have found that subjective complaints of cognitive deficits correlate with mood and other subjective estim ates but are not corre lated with objective neuropsychological testing (Beaty et al., 2003; Elixhauser et al ., 1999). This may indicate that 40

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subjective fatigue in PD subjects is a perceptual or psychological disturbance that is unrelated to objective function. Alternatively, it may indicate that we have not yet utilized an appropriate test of objective fatigue. Further studie s are needed to determine if e ither motor fatigue (Lou et al., 2003a), cognitive or attentional fatigue are associ ated with either quality of life or objective disability. 41

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CHAPTER 5 FUTURE DIRECTIONS Measurement of Fatigue in Clinical Populations As discussed in the Introduction, fatigue is a multidimensional phenomenon that encompasses many distinct components. While s ubjective fatigue is cl early problematic for many patient populations, further research is need ed to determine whether this symptom is a reflection of an objective deficit, a disturbance of homeostatic energy regulation, a perceptual disturbance or related to mood disorders. Determining an under lying etiology of subjective is important as these distinct causes would be hypot hesized to respond to di fferent treatments and arise from different regions of the neuraxis. The development of a standardized fatigue battery which contains both subjective questions as well as objective assessments of peripheral and c ognitive fatigue would greatly improve our ability to measure fatigue in clin ical populations. Given the limitations of selfassessments, it should provide a more consiste nt and reliable meas ure to study fatigue epidemiology as well as assess po tential fatigue treatments. As fatigue treatments develop, it would also help direct specific tr eatments to appropriate individua ls or populations on the basis of their fatigue profile. Finally, although subjective fatigue is clearly related to self-reported quality of life measures, a batt ery would allow for a better as sessment of the true causes of disability. Neurophysiology While the physiological basis of fati gue in PD is unknown, several research hypotheses may be made from data obtained in other populations affected by fatigue, f unctional imaging studies in PD and basic science studies of neuronal function and networks First, studies using EEG in healthy controls have shown that Event Related Potentials (ERP s) generated by medial frontal 42

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areas decrease over time as fatigue develops (Bok sem et al., 2006). This re presents an attractive potential neuroanatomical correlate for PD fatigue as these areas are known to be affected in PD (Mattay et al., 2002) and are hypothesized to underli e difficulties in intern ally generated action. Second, a large body of literature ha s implicated the involvement of the basal ganglia in fatigue across many populations, including PD (Chaudhuri and Behan, 2000). Third, neurocomputational models have shown that the accumulation of noise in a cortical network over time could explain many of the behavioral effects seen as subjects fatigue (Li and Sikstrom, 2002). As dopamine and norepinephrine are related to neuronal signal to noise ratios and are affected by PD this may represent a pharmacologi cal marker for fatigue. Finally, studies using transcranial magnetic stimulation (TMS) have de monstrated that PD patients have abnormal cortical excitability, po ssibly mediated through basal gang lia dysfunction (Lefaucher, 2005). Recent research has demonstrated the importance of inhibitory activity in maintaining normal local oscillatory activity as well long range communication betw een brain areas in cortical networks, both of which may be disrupted with fatigue in normal subj ects (Gevins et al., 1987) and have been hypothesized to underlie many PD deficits (Schnitzler and Gross, 2005). Moreover, Lou et al. (2003b) found subjective fa tigue to be associated with resting motor threshold in PD subjects. To begin to address the neurophysiologic basi s of PD fatigue we propose to analyze EEG data recorded while our subjects were completi ng our objective fatigue testing. We will utilize the Variable Signal Plus Ongoing Activity (VSP OA) model (Truccolo et al., 2002). Traditional ERP research averages many EEG traces which are time locked to a stimulus of interest to eliminate background noise and accentuate time locked activity. There are many well characterized ERPs which have been used for decad es to assess for changes in specific cortical 43

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activity across conditions or pa tient groups and may be used to address neuroanatomical questions regarding the potential role of medial frontal structures in PD fatigue. However, this procedure loses or distorts activ ity which is not precisely time locked to stimulus onset. The VSPOA model maximizes the information obtai ned through EEG by separating activity into stimulus related signal (single trial ERPs) and ongoi ng oscillatory activity on a trial by trial basis. As detailed below, the VSPOA model enables EEG data to be analyzed for aspects of basal ganglia function (such as coherence among networ k components), internal noise (by quantifying variability in the amplitude and timing of signal related processes) and cortical excitability (by examining the phases of gamma oscillations). As these hypotheses are not mutually exclusive, we can maximally utilize this rich data set to simultaneously address multiple aspects of neurophysiological functions potenti ally relevant to the pathophys iology and eventual treatment of PD fatigue. Fatigue Treatment Our ultimate goal is of course to develop treatments for PD fatigue. As we begin to answer critical questions regarding the causes and ne urophysiology of fatigue, we can utilize our knowledge of normal physiology to develop interventions. This would include pharmacological interventions based on our understanding of neural networks and circuitr y. Other interventions may include the potential of deep -brain stimulation to novel ta rgets (or alterations of DBS parameters to known targets), cortic al stimulation (via transcranial magnetic stimulation) or nonpharmacological interventions, including cognitive training. 44

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CHAPTER 6 CONCLUSIONS Fatigue is an important contributor to di sability and quality of life in PD patients. In this study we have demonstrated that PD patients deve lop attentional fatigue a nd fatigue of executive control at an accelerated rate compared to health y control subjects. Although this fatigue may be expected to impact daily functi on it is not definitively correlat ed with patients subjective complaints. Further research is needed to determ ine the cause of subjective fatigue complaints in PD subjects and to determine the components of fatigue most predictive of disability. 45

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BIOGRAPHICAL SKETCH As a psychology undergraduate, I became deeply fascinated with clinical neuroscience and began my pursuit of a career in academic medicine My experience in clinical research began in 1996 when I was awarded a University of Colora do Cancer Center Summer Student Fellowship focusing on the association between chronic ob structive pulmonary disease and lung cancer. After only three years at the University of Colo rado, Boulder, I earned a B.A. in psychology and was one of the first recipients of the University of Colorados certificate in Neuroscience and Behavior for my exceptional performance in phys iological and experimental course work. Upon graduating in 1997, I was awarded a second Summer Fellowship to investigate pediatric zinc metabolism at the University of Colorado Center for Human Nutrition. My contributions to this laboratory were recognized by the American Soci ety for Clinical Nutritions C. Everett Koop Award (given to the top selected research inte rn) and by the Western Me dical Student Research Forum for Best Abstract in th e area of clinical nutrition. At the age of 19, I was the youngest person accepted into th e University of Colorados School of Medicine Class of 2001. During my first two years of medical sc hool, I continued to perform research with the Cent er for Human Nutrition. During th is time I contributed to a manuscript on zinc homeostasis (Krebbs et al., 2000) and helped to inititiate a study of calcium homeostasis. I was also the University of Colorados representative to the Western Medical Student Research Forum. In this role, I promot ed research opportunities for medical students and reviewed research as a judge fo r their annual meetings. During my fourth year of medical school, I dedicated the majority of my elective time to clinical neurology and research. I helped to initiate a pilot study investiga ting the role of mitochondrial dys function in Alzheimers Disease 52

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and played a key role in developing a nove l method to extract mitochondrial DNA from brain tissue. I chose to pursue neurology residency at the Un iversity of Colorado for their excellent clinical training program and their support of resi dent research. During my residency, I became further interested in behavioral neurology, particularly its inters ection with movement disorders. I was fascinated by the basic sc ience and clinical research which suggested that similar physiological mechanisms may be responsible for the generation of both movements and cognition. In my elective time, I pursued this interest further by designing and perfoming a research study under the mentorsh ip of Dr. Donald Rojas, Ph.D This study investigated the localization and timing of the neuroanatomic netw orks involved in gene rating volitional actions by using a novel go/nogo task and magnetoencephalography (MEG). I was the principal investigator for this study and thus responsible for all aspects of the investigation from inception through analysis. My work on this project was recognized with the American Neuropsychiatric Associations 2005 Young Investigator Award. This study also convinced me that further training in neuropsychology and neur ophysiology would improve my ab ility to answer clinically relevant questions regarding th e physiology of behavior. After completing residency in June 2005, I be gan a three year Behavioral Neurology Fellowship at the University of Florida under the mentorship of Dr. Kenneth Heilman, M.D. This program is internationally rec ognized for its research contribu tions to neuropsychology and its record for training successful clinical inves tigators in this field. During this fellowship, I successfully applied for an NIH Loan Repaymen t Program grant and an American Academy of Neurology Foundation Clinical Res earch Training Fellowship to ex tend my research training. These highly competitive grants gave me an extra y ear of research support to further develop and 53

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refine my own line of programmatic research into the objective measurement and pathophysiology of clinical fatigue. Through this fellowship and asso ciated collaborative projects I have received in depth training in clinical behavioral neurology, neuropscyhological testing, transcranial magnetic st imulation, and functional imaging with a particular emphasis on electroencephalography a nd event related potentials. Also during this time, I successfully applied to the University of Floridas Advanced Postgrad uate Program in Clinical Investigation (APPCI), an NIH K-30 program. As an APPCI fellow, I am completing a masters degree in clinical investigation. During the last six months of my Behavior al Neurology Fellowship, I chose to focus my research in patients with Parkinsons disease (P D) due to the high burden of fatigue in this population. To further my understanding of PD and other movement disorders, I began a Movement Disorders Research Fellowship at UF in July of 2007 under the mentorship of Drs. Michael Okun and Hubert Fernande z. In addition to my neurophysio logic research, I have been actively collaborating with members of the Moveme nt Disorders Center to utilize their database to understand the neuropsychological and clinical characteristics most associated with PD fatigue. I have recently secured a joint appointment as an Assistant Professor in the Departments of Neurology and Psychiatry at the Un iversity of Colorado at Denver an d Health Sciences Center to start August 1, 2008. In many ways, this appointment is the culmination of the past 14 years of my dedication to clinical neuroscience. The Departments of Neurology, Psychiatry and the Colorado Neuromagnetic Imaging Center are commited to helping me start my own TMS laboratory as well as utilize their MEG facilities to continue my line of programmatic research. 54