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The Pupil as a Measure of Emotion-Modulated Arousal in Parkinson's Disease

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Title: The Pupil as a Measure of Emotion-Modulated Arousal in Parkinson's Disease
Physical Description: 1 online resource (57 p.)
Language: english
Creator: Dietz, Jenna
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: arousal, autonomic, emotion, parkinsons, pupil
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Parkinson s disease (PD) is a neurodegenerative disease that primarily affects motor function, but also has cognitive and emotional consequences. Previous studies have demonstrated muted physiologic reactivity to emotional stimuli in Parkinson s patients. In particular, a recent study showed that Parkinson s patients demonstrated a reduced skin conductance response (SCR), a measure of autonomic arousal, in response to pleasant and unpleasant pictures, as compared to a healthy older adult group. The basis for the reduced SCR in PD is unclear, but may relate to peripheral autonomic dysfunction (e.g., reduced nerve endings at the sweat gland) or to a more central arousal deficit. In the present study, we used another index of autonomic arousal, the pupillary response, to test the hypothesis that PD patients would show muted reactivity to emotional pictures due to a hypoarousal deficit. Participants included 14 nondemented PD patients and 12 healthy controls. Pupil diameter was recorded while participants viewed unpleasant, neutral, and pleasant images (total N=42) from the International Affective Picture System (IAPS). Analyses revealed a significant effect of picture valence (F(1.6,38.5) = 21.3, p < .01, partial eta squared=.47) such that, for both groups, emotional images (pleasant and unpleasant) elicited significantly greater pupil dilation than neutral pictures. There was no significant Group difference nor was there a Group x Emotion interaction. Results also showed that Parkinson s patients demonstrated a smaller light reflex compared to controls, as is consistent with previous literature. Moreover, both groups evidenced smaller light reflexes while viewing emotional pictures than when viewing neutral pictures (F(2,48)=9.14, p < .001, partial eta squared=.28), suggesting that sympathetic input to the pupil in the context of emotional picture viewing occurs early and is concurrent with the light reflex. Overall, the results of the current study demonstrate that Parkinson s patients show a differential arousal response to emotional stimuli (similar to that in a healthy control group) and suggest that our previous finding of a muted skin conductance response in PD is likely related to peripheral autonomic dysfunction.
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.
Statement of Responsibility: by Jenna Dietz.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Bowers, Dawn.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2012-04-30

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Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041713:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041713/00001

Material Information

Title: The Pupil as a Measure of Emotion-Modulated Arousal in Parkinson's Disease
Physical Description: 1 online resource (57 p.)
Language: english
Creator: Dietz, Jenna
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: arousal, autonomic, emotion, parkinsons, pupil
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Parkinson s disease (PD) is a neurodegenerative disease that primarily affects motor function, but also has cognitive and emotional consequences. Previous studies have demonstrated muted physiologic reactivity to emotional stimuli in Parkinson s patients. In particular, a recent study showed that Parkinson s patients demonstrated a reduced skin conductance response (SCR), a measure of autonomic arousal, in response to pleasant and unpleasant pictures, as compared to a healthy older adult group. The basis for the reduced SCR in PD is unclear, but may relate to peripheral autonomic dysfunction (e.g., reduced nerve endings at the sweat gland) or to a more central arousal deficit. In the present study, we used another index of autonomic arousal, the pupillary response, to test the hypothesis that PD patients would show muted reactivity to emotional pictures due to a hypoarousal deficit. Participants included 14 nondemented PD patients and 12 healthy controls. Pupil diameter was recorded while participants viewed unpleasant, neutral, and pleasant images (total N=42) from the International Affective Picture System (IAPS). Analyses revealed a significant effect of picture valence (F(1.6,38.5) = 21.3, p < .01, partial eta squared=.47) such that, for both groups, emotional images (pleasant and unpleasant) elicited significantly greater pupil dilation than neutral pictures. There was no significant Group difference nor was there a Group x Emotion interaction. Results also showed that Parkinson s patients demonstrated a smaller light reflex compared to controls, as is consistent with previous literature. Moreover, both groups evidenced smaller light reflexes while viewing emotional pictures than when viewing neutral pictures (F(2,48)=9.14, p < .001, partial eta squared=.28), suggesting that sympathetic input to the pupil in the context of emotional picture viewing occurs early and is concurrent with the light reflex. Overall, the results of the current study demonstrate that Parkinson s patients show a differential arousal response to emotional stimuli (similar to that in a healthy control group) and suggest that our previous finding of a muted skin conductance response in PD is likely related to peripheral autonomic dysfunction.
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.
Statement of Responsibility: by Jenna Dietz.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Bowers, Dawn.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2012-04-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041713:00001


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1 THE PUPIL AS A MEASURE OF EMOTION MODULATED AROUSAL IN By JENNA BRITTANY DIETZ A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2010

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2 2010 Jenna Brittany Dietz

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3 ACKNOWLEDGMENTS First and foremost, I would like to thank my outstanding mentors. I would like to thank Dawn Bowers for her constant support, outstanding leaders hip, and contagious enthusiasm. I would like to thank Margaret Bradley for allowing me to learn by her incredible example and helping to develop my skills as an experimental researcher in ways that I never thought possible. Thanks to the many members of the Cognitive Neuroscience Lab and t he CSEA for the support and friendship Thanks to the UF Movement Disorders Clinic for allowing us to work with their wonderful patients. Finally, I would like to extend heartfelt gratitude to my family for their unwav ering love and support.

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4 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 3 LIST OF TABLES ................................ ................................ ................................ ............ 6 LIST O F FIGURES ................................ ................................ ................................ .......... 7 ABSTRACT ................................ ................................ ................................ ..................... 8 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 10 Emotional Sympt ................................ ......................... 10 ............................ 12 The Bio informational Theory of Em otion ................................ ................................ 14 Application of the Bio Informational Approach to Emotional Dysfunction in ................................ ................................ ............................ 15 2 STATEMENT OF THE PRO BLEM ................................ ................................ ......... 20 Specific Aims and Hypotheses ................................ ................................ ............... 23 Primary Aim and Hypothesis ................................ ................................ ............ 23 Secondary Aims ................................ ................................ ............................... 23 3 METHODS ................................ ................................ ................................ .............. 25 Participants ................................ ................................ ................................ ............. 25 Materials a nd Design ................................ ................................ .............................. 26 Apparatus ................................ ................................ ................................ ............... 28 Procedure ................................ ................................ ................................ ............... 29 Data Reduction ................................ ................................ ................................ ....... 30 Data Analytic Plan ................................ ................................ ................................ .. 32 Preliminary Analyses ................................ ................................ ........................ 32 Primary Analysis ................................ ................................ ............................... 33 4 RESULTS ................................ ................................ ................................ ............... 35 Preliminary Analyses ................................ ................................ .............................. 35 Baseline Measurements of Pupil M otility ................................ .......................... 35 Analysis of Primary Aim ................................ ................................ .......................... 38 Effect of Picture Emotionality on Pupil Dilation ................................ ................. 38 Exploratory Analysis ................................ ................................ ............................... 39 Light Reflex and Emotion ................................ ................................ ................. 39 Analysis of Secondary Aims ................................ ................................ ................... 41

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5 Influence of Mood and Disease Severity Indices on the Pupillary Response ... 41 Subjective Picture Ratings of Valence and Arousal ................................ .......... 4 1 5 DISCUSSION ................................ ................................ ................................ ......... 44 Emotion Modulated Pupil Response in PD ................................ ............................. 44 Neural Mechanisms of the Emotion Modulated Pupillary Response and Implications for Pathology of Emotion Dysfunction in PD ................................ .... 46 Modulation of the Light Reflex ................................ ................................ ................ 48 Limitations ................................ ................................ ................................ ............... 49 Conclusion ................................ ................................ ................................ .............. 51 LIST OF REFERENCES ................................ ................................ ............................... 52 BIOGRAP HICAL SKETCH ................................ ................................ ............................ 57

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6 LIST OF TABLES Table page 3 1 adults samples. ................................ ................................ ................................ ... 26 3 2 Total number of invalid trials per group, per picture type. ................................ ... 31 4 1 Average change in pupil diameter ( mm) from baseline (mm) and standard deviation while viewing unpleasant, neutral, and pleasant pictures. ................... 38 4 2 Results of mixed ANOVA for the effect of picture emotionality on pupil dilation. ................................ ................................ ................................ ............... 39 4 3 Means and standard deviations for the magnitude of the light reflex for each ................................ .... 41 4 4 Results of mixed ANOVA for the effect of picture emotionality magnitude of the light reflex. ................................ ................................ ................................ .... 41 4 5 Means and standard deviations for subjective valence and arousal ratings by group. ................................ ................................ ................................ ................. 42

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7 LIST OF FIGURES Figure page 3 1 Pupil diameter plotted across the timecourse of one trial. The dependent variable used in primary an alysis is calculated as the average pupil diameter across a time window of 2.5 6 seconds post picture onset. The light reflex was scored as the maximum change in pupil diameter from 0 2 seconds. ......... 32 4 1 Pupil dilation to a black screen (top) and pupil constriction to a white screen ................................ 36 4 2 Pupil response following picture on set, averaged across all picture viewing reflex occurs in response to the picture onset and lasts from approximately 0 2 seconds, followed by increasing dilation of the pup il. ................................ ...... 37 4 3 Average pupil diameter while viewing affective pictures compared to neutral ................................ .. 39 4 4 unpleasant, neutral, or pleasant pictures. ................................ ........................... 40 4 5 Subjective arousal ratings for unpleasa nt, neutral, and pleasant pictures in ................................ .......... 43 4 6 Subjective valence ratings for unpleasant, neutral, and pleasant pictures in oup and healthy older adult group. ................................ ......... 43

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8 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science THE P UPIL AS A MEASURE OF EMOTION MODULATED AROUSAL IN By Jenna Dietz May 2010 Chair: Dawn Bowers Major: Psychology motor function, but also has cognitive and emotional consequences. Previous studies have demonstrated muted physiologic reactivity to emotional stimuli patients. In particular, a recent study showed that demonstrate d a reduced skin conductance response (SCR) a measure of autonomic arousal, in response to pleasant and unpleasant pictures as compared to a healthy older adult group. The basis for the reduced SCR in PD is unclear, but may relate to peripheral autonomic dysfunction (e.g., reduced nerve endings at the sweat gland) or to a more central arousal deficit. In the present study, we used another index of autonomic arousal, the pupillary response, to test the hypothesis that PD patients would show muted reactivity to emotional pictures due to a hypoarousa l deficit Participants included 14 nondemented PD patients and 12 healthy controls. Pupil diameter was recorded while participants viewed unpleasant neutral, and pleasant images (total N=42) from the International Affective Picture System (IAPS). Ana lyses revealed a significant effect of picture valence (F (1.6 38.5 ) = 21.3 p<.01, p 2 =. 47 ) such that, f or

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9 both groups, emotional image s ( pleasant and unpleasant ) elicited significantly greater pupil d ilation than neutral pictures. There was no significant Group difference nor was there a Group x Emotion interaction demonstrated a smaller l ight reflex compared to controls, as is cons istent with previous literature Moreover, both groups evidenced smaller light reflexes while viewing emotional pictures than when viewing neutral pictures ( F(2,48)=9.14, p<.001, p 2 =. 28) suggesting that sympathetic input to the pupil in the context of emotional picture viewing occurs early and is concurrent with the light reflex. Overall, t he results of the current study demonstrate show a differential arousal response to emotional stimuli (similar to that in a healthy control group) and suggest that our previous finding of a muted skin conductance response in PD is likely related to peripheral autonomic dysfunction.

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10 CHAPTER 1 INTRODUCTION Emotional Sym p (PD) is a degen erative disease of the central nervous system. It is the second most common neurodegenerative di and is typically recognized by its cardinal motor symptoms of tremor, rigidity, postural instability, and bradykinesia. Less recognized are the emotional symptoms experienced by PD patients which can impact the ir menta l health, quality of life, and social relationships. For example, many patients have difficulties with the behavioral expression of emotion, such as the masked face or the inability to register emotional facial expression, and a lack of expressive pros ody, which can cause particular difficulties in the context of social relationships due to misleading or ambiguous social cues. Moreover, experience high rates of apathy, depression and anxiety. Prevalence of depression in PD is est imated to be approximately 30 40% (Slaughter, Slaughter, & Nichols, 2001). On the one hand, mood dysfunction such as depression is common in many serious, chronic illnesses due to the psychological burden of living with a debilitating condition H oweve r, it has been debated to what extent mood difficulties in PD are depend on some extent on the nature of a given individual s predisposition and coping skills, versus to what extent emotional symptoms are byproducts of the disease itself (c.f. Frisina, Borod, Foldi, & Tenenbaum, 2008). In all likelihood, depression in PD is likely linked to multiple underlying etiologies; however, at least some evidence points to mood dys function as being intrinsic to the neuropathology of PD itself.

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11 For instance, studies have shown that PD patients endorsed significantly higher levels of depression than paraplegics, amputees, and people with other medical conditions that are also chronic and physically debilitating (Wartburton, 1967; Horn, 1974; Robins, 1976). However, these studies have been criticized for not adequately controlling for disease severity or duration, variables that are important contributors in the development of depressi on. A more recent study that controlled for symptom duration group and other movement disorders such as Dystonia and an Essential Tremor group (Miller et al., 2006) However r ecent evidence has suggested that apathy, rather than depression, may be A pathy is a syndrome marked primarily by a loss of motivation and has cognitive, affective and behavioral components (Marin, 1991). The cognit ive component includes loss of interest and lack of concern. The behavioral component includes a lack of effort and reduced behavioral activation or productivity. The affective component is one of emotional indifference which is Greek fo a lack of responsivity to both pleasant and unpleasant stimuli. While apathy can certainly be a feature of depression, apathy as a unique syndrome is dissociable from depression in that it lacks the key symptom of sad or dysphoric mood that is inherent to depression. A recent study compared rates of depression, apathy, and both apathy and depression in PD and a comparative movement disorder population, dystonia ( Kirsch Darrow, Fern andez, Marsiske, Okun, & Bowers, 2006 ) The groups were matched in terms of disease severity and duration.

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12 Apathy, specifically, was found to be more severe and more frequent in the PD g roup than in the dystonia group, with 29% of en dorsing clinically significant apathy in the absence of depression whereas no dystonic patients endorsed significant apathy in the absence of depression. This finding lends support that apathy may actually be a core feature of P D pathology (Kirsch Darrow et al. 2006). The exact neuropathological mechanism underlying emotional dysfunction in PD is unclear. The most well studied related pathology is the depletion of dopaminergic neuro ns in the substantia nigra This pathology is also the most overtly recognized in terms of the symptoms it produces since it d isrupts a major source of input to the striatum of the basal ganglia which has severe motor consequences Moreover, t his dopam inergic input ordinarily serves to fine tune a vast array of motor, cognitive, and affective functions mediated by the basal ganglia. These functions are thought to be linked to six distinct and parallel cortico subcortical loops that were outlined by Ale xander, Delong, and Strick (1986). Two of these loops, one of which projects to the anterior cingulate cortex and another that projects to the lateral orbitofrontal cortex, are considered to be limbic based loops that sub serve a variety of functions relat ed to emotional processing, including reward based learning and motivated behavior Of note, one of the primary consequences of dysfunction of the anterior cingulate cortex is an amotivational apathetic state (Cummings & Miller, 2007). Disruption of thes e limbic loops due to dopamine depletion in the substantia nigra represent s one potential mechanism underlying emotional dysfunction in PD. Another possibility is that emotional symptoms result from dysfunction of another primary dopaminergic circuit in th e brain, the mesolimbic pathway, which projects from

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13 the ventral tegmental area to the ventral striatum. This pathway is implicated in emotion, motivation, and reward based behavior. A third possibility is that emotional symptoms are linked to Lewy body p athology in PD only manifest after the loss of approximately eighty percent of dopaminergic neurons in the substantia ni gra ( see Roth, 1986 ), evidence based on post mortum studies now shows that extensive Le wy body pathology is acquired prior to the onset of clinical motor symptoms. A Lewy body is an aggregation of alpha synuclein fibrils that develop inside neurons and can lead to cell death (see Engelender, 2008) Braak et al. (200 3 ) have outlined six stag es of the development of Lewy body pathology in PD the earliest of which originate in cranial nerves V and IX (vagus and glossopharyngeal), brain stem autonomic centers, and the amygdala prior to any clinical manifestation of PD (see Braak et al 2003 ; Hawkes, Tridici, & Braak, in press). In fact, clear and consistent Lewy body pathology of the amygdala, particularly in the central nucleus, has been documented (Harding, Stimson, Henderson, & Halliday, 2002). Thus, damage to the amygdala is particularly relevant in considering potential mechanisms of emotional dysfunction in PD, due to its ubiquitous role in emotional information processing. Beyond that, the central nucleus of the amygdala is directly connected to brainstem autonomic centers and the hy pothalamus, thus contributing to increased autonomic activation in the context of emotional arousal Because of t he fact that the central nucleus and other brain stem autonomic centers (e.g., intermediate reticular zone, locus coeruleus, and caudal raphe nuclei) have been found to have consistent and early Lewy body pathology in PD, it is possible that disrup tion of autonomic

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14 activation or a hypoarousal phenomenon is linked to emotion dysfunction in PD. This idea is particularly relevant in considering ap athy, which is characterized by blunted affect, or a lack of responsivity to both pleasant and unpleasant stimuli that may be driven by hypoarousal to emotional stimuli The Bio informational Theory of Emotion To understand the nature and origin of emoti onal blunting in apathy it is instructive to investigate its function within an underlying framework of a bioinformational theory of emotion (Lang, 1995) are characterized primarily by th e activation of primitive and evolutionarily evolved appetitive and aversive motivational systems in the brain. These systems mediate basic approach and avoidance behavior that, from an evolutionary perspective, serve to sustain life and defend against th reat. The activation of these motivational systems is constituted by the parameters of valence and arousal. While valence determines which of the opponent motivational systems is selected, arousal is though t to reflect the intensity of motivational activation, irrespective of valence (Lang, 199 5 ). Extensive research has shown that emotionally evocative pictures can evoke an array of reliable psychophysiological responses that are uniquely affected by the he donic nature (valence) and intensity (arousal) of the picture (see Lang, Greenwald, Bradley, & Hamm, 1993) These responses can be thought to reflect the extent of central activation and preparation for action. During a passive picture viewing context, a ctivation of the motivational system is rarely strong enough to actually elicit motivated behavior; thus, we conceptualize changes in central and peripheral physiology during picture viewing to primarily represent a state of affective vigilance and active orienting to a motivationally salient stimulus.

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15 Application of the Bio Informational Approach to Emotional Dysfunction in Exploration of the pattern of psychophysiological responses to affective stimuli in PD patients can help to inform our conceptualization of a disease related breakdown in the typical bio informational model of emotion processing that occurs in patients with PD Comparison of psychophysiological responsivity in to well established psychophysiolog ical correlates of emotion also aims to determine at what node, within an information processing model, emotion processing becomes aberrant in PD. Additionally, our expanding knowledge of the neuropathology of PD can, in turn, help to inform us of the rel evant underlying neurophsyiological and neuroanatomical correlates of the bio informational model. Due to these many relevant and informative applications, psychophysiological correlates of emotion in PD have served as the focus for a number of recent stu dies. Two of these studies have been investigations of the startle response to affective stimuli response to a brief burst of white noise. The magnitude of the blink is m odulated by emotional valence, such that it is potentiated (larger) when participants are viewing unpleasant, aversive pictures. This phenomenon can be conceptualized as the augmentation of a defensive reflex ( the startle eyeblink) in the context of an on going aversive state, during which the defensive system is already primed. In contrast, the startle eyeblink is actually attenuated (smaller) when participants are viewing pleasant, appetitive pictures, conceivably because the ongoing affective motivation al state is incongruent with the defensive reflex elicited by a noxious stimulus (for a review, see Lang, Bradley, & Cuthbert 1990).

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16 d blunted startle potentiation to aversive pictures compa also rated the unpleasant pictures as less arousing than the control group. Bowers et al. (2006) interpreted this result as a deficit in translating an aversive motivational state into an appropriate phys iological response. Because the amygdala plays an important role in potentiation of the startle reflex and given what is known about amygdala based translational gdala is under tonic inhibitory control from the prefrontal cortex and is disinhibited via dopaminergic input, particularly du ring emotional states ( Marowsky, Yanagawa, Obata, & Vogt 2005; Inglis and Moghaddam, 1999 ). Bowers et al. (2006) hypothesized th at disinhibition of the amygdala is disrupted due to dopamine dysfunction in PD, leading muted startle potentiation in response to aversive pictures. Following this interpretation, it was predicted that startle attenuation would be most pronounced in resp onse to fear eliciting pictures, given that the amygdala has a pronounced role in fear conditioning (Davis, 1992.) Therefore, a second study was conducted that investigated the startle response to fear versus disgust (conta minations, mutilations) picture categories (Miller, Okun, Marsiske, Fennell, & Bowers, 2009). t le magnitude to fear eliciting stimuli between the PD and control group. A subsequent analysis comparing high arousing aversive pictures to low arousing aversive pictures revealed a trend such that startle potentiation was greater when participants in the control group viewed high arousing unpleasant picture s compared to low arousing unpleasant pictures consistent with previous r esearch showing that startle potentiation is modulated by arousal

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17 (Cuthbert, Bradley, & Lang, 1996) There was no difference, however, in the magnitude group. Thus, it was hypothesized that aberrant startle reactivity in PD is linked to a hypoarousal deficit. To elaborate Miller suggested that demonstrate a normal level of arousal in response to low to moderately arousing stimuli but they reach a theoretical ceiling whereby they demonstrate inadequate or a lesser level o f arousal to highly arousing affective stimuli than the healthy control group Thus, highly arousing aversive stimuli (such as mutilation pictures) are needed to detect differences in physiological reactivity between controls and PD patients With an arousal specific hypothesis in mind, it was befitting to investigate a measure of physiological reactivity that is more directly linked to arousal than the startle reflex The skin conductance response (SCR) is an index of sympathetic mediated autonomic arousal, measured via electrodermal activity at the surface of the palm. Previous studies h ave consistently shown that SCR chang es are greater while participants view pleasant and unpleasant pictures, compared to neutral pictures and that this response is strongly correlated with emotional arousal (Lang, Greenwald, Bradley, & Hamm, 1993) Bowers et al. (2008) demonstrated that PD patients show ed a reduced SCR to emotional (both unpleasant and pleasant) pictures compared to healthy older adults, and SCRs were negatively correlated with apathy but not depression symptoms. These findings indicated that as apathy severity increased, t he s kin c onductance response decreased. These results seemed to suggest an arousal

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18 s pecific hypothesis with respect to aberrant physiological reactivity to affective stimuli and apathy in PD However, using the skin conductance as a measure of arousal in PD may be confounded by autonomic nervous system dysfunction that broadly affects cardiovascular, gastrointestinal and sudomotor systems in the early stages of PD ( Akaogi, Asahina, Yamanaka, Koyama, & Hattori, 2009; Micieli, Tosi, Marcgesekkum, & Cavallin i 2003) Dabby et al (2006) demonstrated significantly reduced innervation of the sweat glands at the palm that is present in early Therefore, another measure is needed to more fully investigate emotion modulated arousal i n PD A recent study conducted by Bradley et al. showed that pupil dilation compared to neutral pictures (Bradley, Miccoli, Escrig, & Lang, 2008) The study also demon strated that the pupillary response covaried with the skin conductance response, indicating that pupillary dilation to high arousing stimuli is an index of sympathetic activation w ithin a picture viewing context and is also tightly coupled with arousal. T hus, the pupil is a fitting alternative to the skin conductance measure, in order to investigate physiologic arousal in PD Therefore, it is relevant to discuss neural mechanisms that influence pupil motility and previous findings on pupil motility in PD Pupil constriction is predominantly contr olled via parasympathetic input to the sphincter muscle from the Edinger Westphal nucleus whereas pupil dilation is predominantly controlled via sympathetic input to the dilator muscle from the thoracic cell colum ns in the spinal cord However, pupil dilation can result from either direct sympathetic input which is modulated by noradrenergic

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19 brain stem nuclei, the hypothalamus, and the central nucleus of the amygdala, or from inhibition of parasympathetic input t o the sphincter muscle, primarily mediated by reticular and direct and indirect cortical pathways (Lowenstein, 1955). Previous investigations of pupil motility in PD have consistently found that s show a reduced amplitude of the initial light reflex ( Beaumont, Harris, Leendertz, & Phillipson 1987; Harris, 1991; Micieli et al ., 1991 ; Granholm et al ., 2003) but no differences in the maximum dilation during dark adaptation (Micieli et al., 1991) or in response to tropicamide an acetylchol ine antagonist which blocks the parasympathetic input to the sphincter muscle (Granholm et al., 2003). Thus the results of these previous st udies do not preclude utilizing the pupil as an index of arousal mediated pupil dilation in PD The primary aim of the current study was to utilize the pupil as a measure of autonomic arousal to investigate whether Parkinson patients would display emotion modulated arous al similar to that described in normal individuals by Bradley et al. (2008). Findings from this st udy could potentially help us determine whether previous skin conductance findings in our lab may be related to peripheral autonomic dysfunction or indicative of a centrally instantiated hypoarousal phenomenon in PD

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20 CHAPTER 2 S TATEMENT OF THE PROBLEM Ma dysfunction. Although there is some debate over the extent to which symptoms are secondary psychological reactions to a chronic and debilitating illness or whether they are the inh erent result of PD pathology, increasing evidence shows that at least some emotional symptoms and or mood dysfunction is inherent to the underlying progression However, the exact neural mechanisms underlying emoti it is not yet understood whether dysfunction is predominantly related to disruption of basal ganglia loops or more diffuse Lewy body pathology in mesolimbic and mesocortical systems. A long the same vein, it is unclear as to whether emotional dysfunction is a dopamine specific phenomenon, as is the case for motor symptoms, or if the emotional systems have to a unique dopamine independent neurophysiological basis. Understanding the spec ifics with respect to neurophysiology of non motor symptoms will have important implications for pharmacological treatment. Moreover, f rom a cognitive perspective, it remains unclear as to what node within an information processing model of emotional pro cessing is affected by PD pathology. Affective stimuli activate motivational systems that initiate a cascade of perceptual and motor processes. Disruption of these processes in PD might occur very early, affecting the initial orienting response to motiva tionally significant stimuli, or may be related to a lack of enhanced perceptual processing or preparation for action, slightly later component s of the orienting cascade (Bradley, 2009) Additionally, it is possible that emotional symptoms in are less related to a deficit in the orienting response

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21 to affective stimuli (as is most relevant in a picture viewing context ; see Bradley, 2009 ) and more a result of failure to engage appropriate downstream limbic motor interfaces. The development of a b io informational model of emotion dysfunction in PD is needed to understand the cognitive mechanisms at play and to be able to target cognitive behavioral interventions that are specific to emotional and behavioral difficulties atients. Various studies in our lab have sought to tease out the pattern of aberrant wed muted startle potentiation to aversive pictures compared to healthy older adults. It was hypothesized that the lack of start le potentiation was due to diminished amygdala activation in PD and that this effect would likely be strongest for threat rela ted stimuli, related startle potentiation (Lang, Davis, & Ohman, 2000). However, the Miller et al. (2009) study show ed that there was no difference between controls and in startle poten tiation to threat in response to high arousing stimuli. Miller sp eculated that the deficit in emotional ted to a hypoarou sal phenomenon. She proposed a threshold theory, such that differences in physiologic reactivity between controls and are driven by high arousing stimuli because reach a threshold at which a higher state of arou sal cannot be elicited.

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22 To test the hypothesis that PD patients experience an arousal specific deficit, skin conductance response s to emotional and neutral pi ctures were examined in the same PD patients who participated in the Bowers et a l. (2006) stud y This study showed that response to p leasant and unpleasant stimuli compared to healthy older adults. However, responses to neutral pictures were also diminished, raising the possibili ty of a global attenuation of this response system. While these results seemed to lend support towards an arousal specific deficit in an alternative interpretation relates to peripheral autonomic system dysfunction that is commonly o bserved in even during the early stages substantial denervation at the sweat glands in the palm (Dabby et al., 2006), which are the source for measuring electroderma l activity related to central autonomic activation during emotional picture viewing. Therefore, it is possible that abnormalities of the skin conductance response in PD are a reflection of peripheral nervous system dysfunction, as opposed to a centrally i nstantiated hypoarousal phenomenon. Thus, the current study sought to use an alternative measure of centrally modulated arousal. A recent study showed that the pupil dilates more to both pleasant and unpleasant pictures compared to neutral pictures, and t hat this response covaries with the skin conductance response (Bradley et al., 2008). To date, there is no significant evidence of related damage to the peripheral nerve fibers that ascend from the thoracic cell column of the spinal cord to co ntrol dilation of the pupil S tudies have shown no differences in magnitude of pupil

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23 compared to controls (Micieli et al. 1991; Granholm et al. 2003). Thus, the pupil seems to be a viable alternative to skin conductance a s a measure of arousal in PD. Specific Aims and Hypotheses Primary Aim and Hypothesis The primary aim of the current study is to test the hypothesis that PD patients have muted autonomic arousal to emotional pictures. To test this hypothesis, we used th e pupil response as an index of autonomic arousal W e recorded pupil diameter while es of pleasant, unpleasant, and neutral pictures. The predictions were as follow s: s patients are autonomically hypoaroused to emotional stimuli, then the P D group will show a smaller increase in pupil dilation to emotional pictures compared to a group of healthy older adults. This finding would correspond to the previous SCR results. Alternatively, if the PD group and controls show similar changes in pupil dilation to emotional vs neutral pictures, this would indicate that Parkinson patients do not have pervasive autonomic hypoarousal. Secondary Aim s A secondary aim of the curren t study is to compare subjective ratings of valence and arousal between the PD and healthy older adult group s Most p revious studies have shown minimal differences in subjective ratings of valence and arousal and subjective emotional experience (Miller et al., 2009 ; Mikos et al ., 2009 ; cf Bowers et al., 2006 ; Weiser Muhlberg, Alpers, Macht, Ellgring, & Pauli 2006 ). Thus, it is predicted that there will be no difference in subjective ratings of valence and arousal between the ups.

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24 Another secondary aim of the current study is to explore the relationship between disease severity and mood variables and the emotion modulated pupillary response. To do so, the emotion modulated pupillary response for each individual will be calcula ted as the average difference in dilation to neutral vs. emotional pictures. This variable will be correlated with disease variables such as disease duration, Hoehn Yahr scores (a measure that indicates the stage of disease progression) and the UPDRS mot or scores (an index of severity of motor symptoms) and mood variables including scores on the Beck Depression Inventory and the Apathy Scale. Bowers et al. (2008) found a moderate association between skin conductance responses and scores on the Apathy Sc ale. Thus, it is predicted that, if the pupil response parallels our previous findings of a muted skin conductance response in there may be a positive association between the emotion modulated pupillary response and apathy.

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25 CHAPTER 3 METHODS Participants Fourteen twelve healthy older adults niversity of Florida Movement Disorders Clinic and were test opamine replacing medications. The control group was recruited from the community and from spouses of PD patients. Participants were characterized as nondemented (M ini Mental State Exam >25), free of any self reported major psychiatric dis turbance (e.g., major depression or anxiety, psychotic symptoms, etc.) and had no history of surgery in the brain (e.g., deep brain stimulation for treatment of PD symptoms.) Two participants were candidates for deep brain stimulation surgery. Table 1 displays the demographic and clinical characteristics of the PD and control group. Overall, participants were well educated and predominantly male (17 men and 9 women.) They ranged in age from 57 to 81 years ; the PD group was slightly younger than the co ntrol group ( PD mean=69.4 years; control mean=74.4 years, p=.06 ) With respect to antidepressant usage, 7 out of the 14 PD patients compared to 2 out of the 12 controls were currently taking corrected X 2 were calculated (due to cell counts<5) to compare the gender and antidepressant usage ratio between the PD and control groups N either was statistically significant ( p=78 for gender, p=.17 for antidepressants ). The only significant difference between the grou ps was in Mini Mental State Examination (MMSE; Folstein et al., 1975) scores such that the PD group scored an average of 1.2 points lower than the control group ( t ( 24 ) =2.23 p<.05) On the Beck Depression Inventory II (BDI II, Beck et al.,

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26 1996), t here was a marginal effect such that the PD group scored higher than the Control group (t(24) = 2.11, p = 05). Even so, the BDI score of the PD group ( mean of 8.1 ) fell well below the cutoff for depression (14). The PD patients ranged from moderate to severe disease severity, according to standard staging and severity criteria including the Hoehn Yahr classification (Hoehn and Yahr, 1967) and the motor score of the Unified Parkinson Disease Rating Scale (UPDRS; Fahn et al., 1987). The UPDRS and Hoehn Yahr sta ging took place within 6 months of the experimental protocol. Table 3 1 and healthy older adults samples. Parkinson's Group (N=14) Control Group (N=12) P Value Gender (M / F) 10 / 4 7 / 5 0.78 Antidepressant (Y / N) 7 / 7 2 / 10 0.17 Age 69.4 (8.4) 74.4 (3.9) 0.06 Education 18.4 (3.6) 16.5 (3.8) 0.19 Mini Mental State Exam (MMSE) 28.2 (1.7) 29.4 (0.9) 0.04 Beck Depression Inventory (BDI) 8.1 (6.2) 3.8 (4.0) 0.05 Apathy Scale (AS) 8 .2 (4.9) 7.2 (3.4) 0.54 State Anxiety (STAI Y1) 29.1 (11.9) 29.0 (11.5) 0.98 Trait Anxiety (STAI Y2 30.8 (11.3) 32.9 (12.1) 0.65 Disease duration 7.4 (3.5) Levodopa Equivalent Dosage (LED) 737.1 (537.9) UPDRS "On" Meds 25.1 (6.9) Hoehn Yahr "On" Meds 2.3 (0.4) Note: Categorical variables are presented as ratios; quantitative variables are presented as Mean (Standard Deviation). Variables marked with an asterisk (*) denote significant group differences at alpha=.05. Materi als and Design Forty two pictures 1 were selected from the International Affective Picture System (IAPS; L ang, Bradley, & Cuthbert, 2008) consisting of 14 unpleasant ( mean 1 The library numbers for IAPS pictures used in this study are: pleasant: 2080, 4220, 4607, 4641, 4660, 4680, 5470, 7330, 8030, 8080, 8200, 8370, 2160, 8280 ; neutral: 2190, 2200, 5500, 7000, 7010, 7030,

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27 pleasure/arousal = 2.4, 6.4 ), 14 neutral ( mean pleasure/arousal = 5.0, 3.0 ), and 14 pleas a nt ( mean pleasure/arousal = 7.4, 5.9 ) pictures. Unpleasant and pleasant stimuli were significantly more arousing than the neutral stimuli, based on the IAPS normative arousal ratings (t=14.7, p<.001 for unpleasant and t=3.4, p<.001 for pleasant) N ormative arousal ratings did not significantly differ between pleasant and unpleasant picture categories (t=2.04, p=.143) The stimulus set was adapted from the set used in the Bow ers et al. (2006) startle study. Six additional pictures were included in analysis and 3 pictures were replaced to ensure that pleasant and unpleasant picture categories did not differ from one another in average arousal. Unpleasant pictures in cluded mutilations, vicious animals, physical violence, etc. whereas pleasant pictures consisted of babies, couples, food and sports activities The neutral picture category included pictures of buildings, office scenes, plants, furniture, etc. Pictures were landscape (1024 x 768) in orientation and were displayed in 16 bit grayscale. Using Adobe Photoshop ( version 5.0.2 ; Adobe Systems Inc., San Jose, CA ), the mean luminosity of the selected pictures was modified such that the mean and distribution of lu minosity values for each of the pictures sets (pleasan t, neutral, unpleasant) did not differ following the methods used in the Bradley et al. (2008) pupillometry study. Additionally, a blank white slide ( luminosity= 255 according to luminosity parameters indicated by Adobe Photoshop version 5.0.2 for a slide filled with default a blank black slide (luminosity =0 see Adobe Photoshop ) 7090, 7130, 7170, 7500, 7550, 7700, 6150, 7190 ; unpleasant: 1090, 1301, 2120, 3000, 3010, 3100, 3130, 3530, 6230, 6370, 9040, 9 050, 7380, 9810

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28 were included i maximum dila tion and maximum constriction to a null (non picture) stimulus. A grayscale slide and a centered black fixation cross were displayed for 3 seconds before picture presentation on each tr ial. The first four trials alternated between the white and black slides (white, black, white black), each presented for 6 seconds and each followed by an intertrial interval of 4.5 seconds. Following the initial four trials, each IAPS picture was prese nted for 6 seconds, followed by a variable inter trial interval ranging from 4.5 to 8.5 seconds S tartle probe s were also delivered at either 4200, 5000, or 5800 ms post picture onset; however, startle data are not reported. The IAPS p ictures were prese nted in blocks of s ix, with two pictures from each condition (pleasant, neutral, unpleasant) in each block. The order of pictures within each block was generated randomly and each participant saw the picture set in the same order. Apparatus Picture pres entation was controlled by an IBM compatible computer running Presentation software (Neurobehavioral Systems, San Francisco, CA). Pictures were displayed on a 19 in. monitor (Samsung SyncMaster 191T) located in the experimental room Pupil diameter was rec orded using an ASL EYE TRAC 6000 eyetracker system (Applied Science Laboratories, Bedford, MA), which allows free movement of the head and consists of a video right eye. A magnetic sensor, at tached to a headband, tracked and adjusted for head movement. The recording video camera was located in a wood box in front of the subject, and a red translucent screen obscured it from view. Pupil diameter was

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29 sampled at 60 Hz for 3 s econds prior to pictu re onset, for 6 s econds during picture onset, and 3 s econds following picture offset. Procedure Upon arrival at the laboratory, each participan t signed a consent form and was subsequently administered the MMSE. He or she was then seated in a chair in a sm all, sound attenuated, dimly lit room. Ambient light intensity was the same for every experimental session. The magnetic headband for tracking head movements was placed on start le response were also placed on the participant (data not reported. ) The participant was then told that he or she would be viewing a series of pictures T he participant was told not to look away or close his or her eyes, but rather to continue viewing th e picture the entire time it was on the screen. The session began with the participant view ing the alternating white and black slides (2 of each) This was followed by two neutral pictures that served as filler trials to orient the participant to the pic ture viewing task and followed by the series of 42 pictures used in analysis. When the participant was finished viewing the pictures, the headband and sensors were removed, and the participant completed a series of mood questionnaires. Finally, the parti cipant rated each picture he/she saw along the dimensions of valence and arousal using the Self Assessment Manikin (Bradley and Lang, 1994) a cartoon figure for making ratings on using a 1 to 9 ordinal scale For valence, ratings ranged from unpleasant ( 1) to neutral (5) to pleasant (9) For arousal, ratings ranged from calm (1) to neither calm nor excited (5) to very excited (9) At the completion of the study, the participant was debriefed, paid, a nd thanked for participating.

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30 Data Reduction A series of steps were taken to reduce the raw pupil data collected for use in analysis. It was necessary to account for time points where the technology did not reliably detect a signal in order to sample a valid measurement of pupil diameter and also to account for time points where pupil samples were not collected due to blinks. Trials that had 50% or more of pupil samples missing (due failure of the EyeTracker system to obtain automatic discrimination of the pupil ) were considered invalid trials and eliminated from the data. Because the number of dropped trials for each individual was positively skewed, nonparametric Mann Whitney U tests were conducted to investigate whether the number of invalid trials differed by group. Three separate Mann Whitney U tests w ere conducted, one for each condition (unpleasant, neutral, pleasant). There were no significant between group differences in the number of trials droppe d for the unpleasant condition ( Mann Whitney U = 60.5, p= .23), neutral condition (Mann Whitney U = 52 .5, p=.11) or the pleasant condition (Mann Whitney U = 70.5, p=.49 ). Figure 3 2 lists the total number of invalid trials by condition and group. Total n umber of invalid trials per participant never exceed ed 10 (<25% total trials.) If pupil discriminati on failed to be achieved for greater than 25% of trials, the data for that participant was deemed inval id was not included in analysis Four participants were thus excluded ( 1 PD and 3 controls). Anecdotally, these were typically individuals with very sm all pupils and clouded eye whites which made it very difficult to obtain automatic detection of the pupil with the ASL technology. For all valid trials, pupil samples where the pupil was obscured due to blinks were identified and linear interpolation was used to estimate pupil size (using an algorithm provided by the Applied Science Laboratories File Analysis Program, ASL Results, version 1.11.02 .) Momentary loss es of pupil

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31 discrimination (not due to blinking) where the technology failed to obtain a pup il measurement, were manually filtered out post linear interpolation. Table 3 2. Total number of invalid trials per group, per picture type. Unpleasant Neutral Pleasant Parkinsons 11 23 14 Controls 5 8 8 Figure 3 1 provides an illustration of the average pupil diameter (mm) across the time course of an individual trial and shows how each variable was calculated for analysis. Based on the average d waveform s, the initial light reflex during picture vie wing was scored as the maximum magnitude of pupil constriction in a window from 0 to 2 s econds after picture onset. Pupil diameter in response to each picture type (unpleasant, neutral, and pleasant) was calculated as the average pupil diameter in the time window following the initial light reflex, 2.5 to 6 seconds after picture onset In order to score the magnitude of the light reflex for each individual, a one second pre picture baseline, measured in millimeters, was calculated for each trial and this baseline was subtracted from subsequent pupi l samples throughout the trial in order to obtain the change from baseline. The average initial light reflex for each participant was then scored as the maximum pupil constriction in a window from 0 to 2 s econds after picture onset, averaged across all pi cture viewing trials.

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32 Figure 3 1 Pupil diameter plotted across the timecourse of one trial. The dependent variable used in primary analysis is calculated as the average pupil diameter across a time window of 2.5 6 second s post picture onset. The light reflex was scored as the maximum change in pupil diameter from 0 2 seconds. Data Analytic Plan Preliminary Analyses Baseline pupil diameter and average light reflex. Before proceeding to the primary analysis, a number of preliminary analyses were conducted to examine baseline features of pupil motility between the groups. An independent t test was conducted to investigate differences in baseline pupil diameter, measured as the average pupil diameter one second prior t o picture onset, between the groups. An independent t test was also conducted to examine whether the average light reflex 1 second Pre picture Baseline Time Window Averaged Across to calculate DV: 2.5 6 seconds post pic onset Light Reflex: Minimum Change from Baseline 0 2 seconds

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33 Pupil reactivity to black and white slides. Separate independent t tes ts were slide and maximum constriction to a whi t e slide. For the maximum dilation analysis, maximum dilation was calculated as the average change in pupil diameter from 2.5 6 seconds post slide onset. For the maximum constriction analysis, the light reflex was obtained by averaging across both (2) trials and scoring the minimum pupil diameter between 0 2 seconds Primary Analysis In order to test the predict ion that Pa would show a muted pupillary response to emotional pictures compared to a healthy control group, a mixed analysis of variance was conducted with magnitude of pupil diameter as the dependent variable Group (Parkinson vs. Control) w as t he between subjects factor and Emotionality (Unpleasant, Neutral, Pleasant) w as the within subject factor Potential differences in subjective ratings of valence and arousal were explored by conducting two separate mixed analyses of variance with Group (Pa Controls) as the between group factor and Emotionality (Unpleasant, Neutral, Pleasant) as the within subject factor. Lastly, all continuous variables, including the emotion modulated pupillary response variable, disease severity, and mood variables were screened for violations of normality by investigating skewness and kurtosis values for each distribution and conducting Shapiro Wilks tests of normality. The distribution for the emotion modulated pupillary response variable (average pupil diameter during emotional pictures minus average pupil diameter to neutral pictures) was rath er leptokurtic; thus nonparametric

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34 to explore associations between disease severity indices, mood variables, and the emotio n modulated pupillary response.

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35 CHAPTER 4 RESULTS Preliminary Analyses Baseline Measurements of Pupil Motility Sets of initial analyses were conducted in order to examine indices of pupil motility including baseline pupil diameter, pupil reactivity t o simple black and white screens, and the basic light reflex. Pupil d iameter To determine whether there were baseline difference s in pupil diameter between the PD and Control groups, pupil magnitude was examined during the one second period prior to pict ure onset. During this time subjects were viewing a black cross on a grey screen Mean pupil diameters (mm) and standard deviations were 4.8 (.83) for the PD group and 4.6 ( .67 ) for the Control group. These values were not significantly different base d on an inde pendent t test (t(24) = .74, p = .47) Since there was no significant difference in baseline pupil diameter between the groups, it was deemed appropriate to use the raw magnitude of pupil diameter for the primary analysis. Pupil r eactivity to simple b lack and white s lides Pupil response s to two, alternating plain black and plain white slides were examined in an attempt to gage maximum dilation and maximum constriction to a null (non picture) stimulus. It was of particular interest to ens ure that there were no significant differences in the maximum feasible dilation between the groups in order to rule out the possibility that a baseline difference in maximum pupil motility might confound between group comparisons of magnitude of pupil dila tion to emotional pictures. Figure 4 1 average pupil dilation in mm to a black screen presented for six seconds, averaged

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36 across two trials ( luminosity value =0 ). The maximum dilation in mm was calculated as the average change fro m baseline (one second pre picture) across 2.5 6 seconds post slide onset There was no significant difference in average magnitude of pupil dilation to a black screen between the groups (t(24)=.24, p=.82), indicating that maximum extent of dilation was c omparable between the groups =.50 mm (.32), Control group: Mean (SD) = .47 mm (.17)) Figure 4 1 also illustrates luminosity value =255 ). av erage magnitude of constriction (Mean (SD) = .61mm (.31) was smaller than cont rols (Mean (SD) = .76mm (.28); however, this difference was not statistically significant (t(20)=1.17, p=.26). Figure 4 1. Pupil dilation to a b lack screen (top) and pupil constriction to a white screen

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37 Light Reflex Figure 4 2 shows the average change in pupil diameter for the PD and Control groups throughout the duration of pictu re dis play, averaged across all emotional and neutral pictures (total N = 42.) As shown, b oth groups appeared to demonstrate an initial light reflex to the pi cture onset from 0 2 seconds. This was followed by pupil dilation during the remainder of the picture display (2.5 6 seconds post picture onset.) The light reflex for each individual was scored as the minimum change in pupil diameter from 0 2 seconds after picture onset. To determine whether there were group differences in the magnitude of the light ref lex, a n independent samples t test found that the light reflex was significantly smaller in the PD group compared to the control group (t(24) = 4.08, p < .001). Figure 4 2 Pupil response following picture onset, averaged across all picture viewing reflex occurs in response to the picture onset and lasts from approximately 0 2 seconds, followed by increasing dilation of the pupil.

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38 Anal ysis of Primary Aim Effect of Picture Emotionality on Pupil Dilation The primary aim was to assess whether or not demonstrate an emotion modulated pupillary response and examine how this response compares t o controls. Figure 4 3 show s the average pupil diameter from 2.5 to six seconds while viewing each picture type (pleasant, unpleasant, neutral) Table 4.1 shows the m ean pupil diameter associated with pleasant, unpleasant, and neutral pictures for each group. To test the prediction that would show a muted arousal response to affective pictures, a Grou p (2) x Emotion (3) mixed analysis of v ariance (ANOVA) was conducted using pupil dia meter as the dependent variable. sphe ricity assumption was violated ( p<.05 ); therefore Greenhouse Geisser F approximations are reported. Results of the AN OVA yielded a significant main effect of picture emotionality (F (1.6,38.5 ) = 21.3 p<.0 0 1, p 2 =. 47 ) Post hoc comparisons revealed that both unpleasant and pleasant pictures elicited significantly greater pupil dilati on compared to neutral pictures = 5.22 and 4 .85 respectively, p s<.0 01 .) There was no significant difference in the pupillary response to pleasant and unpleasant images (t(24)=.59 p=.56 ). No other main effects or interactions were significant (i.e., neither Group, nor Group X Emotion). Results of the ANOVA are presented in Table 4 2. Table 4 1. Average change in pupil diameter ( mm) from baseline (mm) and standard deviation while viewing unpleasant, neutral, and pleasant pictures Parkinson Controls Unpleasant 4.9 (0.86 ) 4.5 (0. 68 ) Neutral 4.7 (0. 79 ) 4.4 (0. 69 ) Pleasant 4.8 (0. 87 ) 4.5 (0. 7 0 )

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39 Figure 4 3. Average pupil diameter while viewing affective pictures compared to neutral and healthy older adults Table 4 2 Results of m ixed AN OVA for the effec t of picture emotionality on pupil dilation df F Sig. Partial Eta Squared Emotion 1.606 21.316 .000 .470 Emotion x Group 1.606 .678 .483 .027 Error (Emotion) 38.536 Group 1 .978 .332 .039 Error (Group) 24 Exploratory Analysis Light Ref lex and Emotion As an exploratory analysis, the magnitude of the light reflex was calculated for each condition: pleasant, unpleasant, and neutral. Figure 4 4 displays the magnitude of

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40 the pupillary light the Control gr oup As illustrated by Figure 4 4 the light reflex is smaller when participants viewed emotional compared to when they viewed neutral picture s. Results of a Group (PD, Control) X Emotion (Pleas ant, Neutral, Unpleasant) ANOVA revealed a sig nificant main effect for Emotion (F(2,48)=9.14, p<.001, p 2 =. 28). Post hoc comparisons indicated that the light reflex was significan tly smaller when subjects viewed emotional pictures (both pleasant and unpleasant ) compared to neutral pictures Means and standard deviations for each picture category are presented in Table 4 3. There was also a significant main effect of grou significantly smaller light reflex across all picture categories compared to the healthy older adults (F(1,24)= 20.83 p<.001, p 2 =. 4 5 ) Figure 4 4 unpleasant, neutral, or pleasant pictures.

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41 Table 4 3 Means and standard deviations for the magnitude of the ligh t reflex for each Unpleasant Neutral Pleasant Parkinsons .18 (.12) .26 (.14) .18 (.12) Controls .40 (.14) .44 (.12) .37 (.10) Table 4 4 Results of mixed ANOVA for the effect of picture emotion ality magnitude of the light reflex. df F Sig. Partial Eta Squared Emotion 2 9.144 .000 .276 Emotion x Group 2 .442 .646 .018 Error ( Emotion ) 48 Group 1 20.825 .000 .465 Error (Group) 24 Analysis of Secondary Aims Influence of Mood and Disea se Severity Indices on the Pupillary Response In order to investigate the effect of mood symptoms on the emotion modulated pupillary response, the difference between average pupil diameter during emotional pictures (positive and negative) and pupil diamet er during neutral pictures was calculated for each individual. There was no significant correlation between emotion specific changes in pupil dilation and BDI II or Apathy Scale scores N or was there a significant correlation between this variable and in dices of Parkinson disease severity (disease duration, Hoehn Yahr stage, LED, UPDRS). Additionally Parkinson disease severity variables did not significantly correlate with the magnitude of the light reflex ac ross all picture viewing trials or average d ilation during picture viewing trials. Subjective Picture Ratings of Valence and Arousal The mean valence and arousal ratings made by the PD and Controls are shown in Table 4 5. A Group (2) x Valence (3) mixed ANOVA was conducted to determine if the Parki s

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42 sphericity assumption was violated (p<.01); therefore Greenhouse Geisser F approximations are reported. The analysis revealed a main effect of emotionality on arousal ra tings, F(1.4,32.1)=35.63, p<.001, p 2 =.61. Planned contrasts demonstrated that emotional pictures (both pleasant and unpleasant) were rated as more arousing than neutral pictures, F s(1,23) = 38.28 and 48.24 for unpleasant and pleasant respectively, p s <.001. There were no significant differences in average subjective ratings of arousal between groups (p=.40) nor was there a signific ant Group x Valence interaction (p=.49.) The same mixed ANOVA model was conducted to examine subjective valence ratings between groups, using Greenhouse Geisser F approximations. The analysis yielded a main effect of valence, F(1.3,30.0) =155.35, p<.00 1, p 2 =.87. Planned contras ts demonstrated unpleasant images were rated as less pleasant than neutral images, F (1,23)=119.31, p< .001 and pleasant images were rated as more pleasant than neutral images, F(1,23)=119.78, p<.001. There was no significant difference in average subjective ratings of valence between groups (p=.73) N or was there a significant Group x Valence interaction ( p=.83) Table 4 5 Means and standard deviations for subjective valence and arousal ratings by group. Valence Arousal Parkinson Control Parkinson Control Unpleasant 2.57 (1.1) 2.63 (1.1) 6.17 (1.5) 5.48 (2.3) Neutral 5.22 (.57) 5.39 (.67) 3.19 (1.3) 3.11 (2.1) Pleasant 7.11 (.52) 7.06 (1.0) 5.78 (1.2) 5.01 (2.4)

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43 Figure 4 5 Subjective arousal ratings for unpleasant, neutral, and pleasant pictures in Figure 4 6 Subjective valence ratings f or unpleasant, neutral, and pleasant pictures in

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44 CHAPTER 5 DISCUSSION Emotion Modulated Pupil Response in PD older ad ults show an emotion modulated pupillary respo nse, such that the pupil dilated significantly more to emotional (both pleasant and unpleasant ) than neutral pictures. These results somewhat conflict with those of Bowers et al. (2008) who failed to find a n e motion modulated skin conductance response in PD patients. It is possible that the attenuated skin conductance findings may have been secondary to peripheral autonomic dysfunction that commonly occurs in PD Thus, the reduced skin conductance response in PD may represent an index of severity of disease progression and impairment of the peripheral autonomic nervous system rather than an index of Furthe r more, the results of the current study help to disentangle the potential mechanisms underlying emotional abno Bowers et al. (2006) speculated that may have a deficit in translating an aversive motivational state into a physiological response due to decrease d disinhibition o f the To elaborate, the amygdala is typically under tonic inhibitory control from the prefrontal cortex and is disinhibited via dopaminergic input particularly during emotional states (Marowsky et al., 2005; Inglis and Mo ghaddam, 1999 ). Bowers et al. (2006) hypothesized that disinhibition of the amygdala is disrupted due to dopamine depletion in PD. Miller et al. (2009) elaborated on this hypothesis, speculating that emotional deficit s in PD are arousal dependent, and th at differences in physiologic reactivity in are specifically driven by muted reactivity

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45 to high arousing stimuli, and that these stimuli may have driven the lack of startle modulation to aversive stimuli in the Bowers et al. (2006) st udy. Miller et al. (2009) specifically proposed that differences in the magnitude of the startle reflex to aversive stimuli in the Bowers (2006) study were likely driven by the large proportion of mutilation pictures in the unpleasant picture category, su the use of high arousing stimuli. However, given that the current study utilized the same stimulus set of the Bowers et al. (2006) stu dy and there was no difference between controls and in the pupil response to unpleasant and pleasant stimuli it is unlikely that the previously reported muted startle potentiation in PD is due to hypoarousal to high arousing stimuli. an arous al specific deficit, but may be indicative of abnormal activation of the defensive motivational system Potentiation of the startle reflex is thought to refl ect the priming of the motivational system t hat mediates defensive behavior (Lang, Bradley, & Cuthbert, 1997) thus in some way re flecting motor respon ses are functionally independent and temporally downstream components of the emotional response cascade that are preceded by initial orienting and attention processes that are also modulated by affective arousal. As Bradley (2009) explains, there are mult iple components of the passive orienting response, including heightened arousal, increased attention and enhanced perceptual processing, and preparation for action. The defense cascade model (Lang, Bradley, & Cuthbert,1997) suggests that as defensive dist ance

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46 diminishes (and threat becomes more imminent), emotional intensity (arousal) increases and the motivational system (and its physiological correlates) shift from increased orienting and enhanced perceptual processing to mobilization for action. Theref ore, it is possible that the emotion modulated pupillary response in PD is reflective of early arousal mediated increase in orienting an d enhancement of perceptual processes (see Bradley 2009) whereas aberrant startle reactivity in PD reflects inadequate or abnormal activation of the defensive response system at the somato motor level This interpretation suggests that different functional components of the disease. A lthough the arousal mediated increase in the orienting response to affective pictures (as measured by the pu pil) appears normal, there may be dysfunction in the concurrent activation of motivational systems that m odulate preparation for action. Support fo r this hypothesis is reflected by aberrant startle reactivity in disease and also ecological support, evidenced by the fact that often demonstrate diminished behavioral activation that is frequently recognized as apathy. N eural Mechanisms of the Emotion Modulated Pupillary Response and Implications for Pathology of Emotion Dysfunction in PD It is of note to discuss what the results of the current study imply about neural mechanisms underlying emotional processes in PD by ut ilizing what is known about underlying modulatory pathways to the pupil While significant attention has b e e n granted to neural mechanisms underlying cognitive effects on the pupil (e.g.: Steinhauer, Siegle, Condray, & Pless, 2004; Steinhauer, Condray, & Kasparak, 2000)

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47 less has been directed towards elucidating the exact mechanisms underlying the effect of emotional processes on the pupil. However, the emotion modulated pupillary response closely covaries with sympathetic activation (Bradley et al., 200 8) and is likely driven by enhanced sympathetic input to the pupil via modulatory input from the central nucleus of the amygdala and the hypothalamus (see Ranson and Clark, 1959 as cited in White and Depue, 1999) Since the pupil response to affective sti muli did not differ between it seems that these limbic/cortico limbic It has also been suggested that emotion effect s on the pupil are partially driven by central inhibition of the Edinger Westphal nucleus that is primarily influenced by cortical and reticular inputs linked to arousal (Lowenstein 1955; Bonvallet and Zbrozyna 1 963; Steinhauer et al. 2000; St e i nhauer et al., 2004). Thus, this mecha nism may also contribute to the emotion modulated pupillary response observed in the current study. integrity of parasympathetic pathway to the pupil in the PD group is in question. The fact that this pathway may be jeopardized in PD and yet we see a robust effect of emotion on the pupil in the PD group lends support to the conjecture that this effect is primarily sympathetically driven. Nonethless although the sma ller light reflex in was expected and is consistent with previous research (Beaumont et al., 1987; Harris, 1991; Micieli et al., 1 991; Granholm et al., 2003), it s neural basis is not clear. Dysfunction of the light reflex may be link ed to hyporeactivity of dopamine retinal cells, pathology in the Edinger Westphal nucleus itself, or pathology along the peripheral pathway to the pupil, possibly

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48 in the ciliary ganglion (Granholm et al., 2003). Thus, it remains unknown whether the underl ying pathology occurs along the afferent pathway to the Edinger Westphal nucleus or the efferent pathway to the pupil. If the pathology resides in the afferent pathway, central inhibition effects on the EW nucleus would be re latively spared and could st ill contribute to the emotionality effect on the pupil observed in the current study Modulation of the Light Reflex Central inhibition of the EW nucleus has also been linked to modulation of the light reflex. Interestingly, an unforeseen finding of the c urrent study was that the light reflex was smaller when participants viewed emotional pictures This finding was not reported in the previous study conducted by Bradley et al. (2008). However, p rior studies have shown that both increasing task demand and threat of shock can result in a smaller light reflex (Steinhauer et al., 2000; Bitsios, Szabadi & Bradshaw, 1996), suggesting that arousal can have an effect on the magnitude of the light reflect Previous authors have explained an arousal related modul ation of the reflex as direct inhibition of the EW nucleus ; however, could reflect the summative effect of light reflex related parasympathetic input to the pupil concurrent with increased sympath etic activity in the context of emotional picture viewing This would suggest that the effect of emotionality on pupil dilation begins early (<1 second post picture onset) and is sustained throughout the following 1 6 second window However, it cannot be ignored that these results dissent from those reported by Bradley et al. (2008). Therefore stimulus properties may somehow be involved, although there was a concerted effort to control for luminosity across picture types. Future studies should seek to p rovide a dditional knowledge about the precise nature and time course of emotion effects on the pupil which will help to inform the design and

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49 methods of data analysis in future studies. Furthermore, future studies should make a more concerted effort to e lucidate the precise relative influences of sympathetic and parasympathetic inputs to the pupil during emotion processing contexts, independent of cognitive load manipulations. Limitations There were some limitations in the current study. The sample siz e was small particularly for study with clinical patients. Although smaller sample sizes are typical in experimental psychop h ysiology in the current study may not be representative of a typical or comprehensive disease samp le. For instance, 3 on a scale of 1 5, which is relatively limited However, this included only patients whose symptoms were already bilateral, thus eliminating a source of variability that co uld be particularly relevant since pupil diameter was measured unilaterally. Furthermore, half of the antidepressants. Although the chi square test indicated that the difference in ratio of antidepressant usage was not statistically significant, it is unclear whether or not antidepressants may have affected the pupil motility or the emotio n modulated pupillary response. Prior studies have shown that norepinephrine reuptake inhibitor s, in particular can increase res ting pupil diameter and reduce the amplitude of the pupillary light reflex (Phillips, Bitsios, Szab adi, & Bradshaw, 2000; Siepmann, Ziemssen, Mueck Weymann, & Siepmann, 2007) However, it is unlikely the light reflex diff erences in our study are related to antidepressant usage, as previous studies have shown this effect, including one that examined ne wly diagnosed PD patients who were not yet taking any medications (Micieli et al., 1991).

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50 p was tested on their dopamine replacing medications, thus it is unclear whether or not the results of the current study would be the same had the patients been tested in a hypodopaminergic state. It was elected to te for a few reasons. For one, testing patients on their dopaminergic medications is better representative of their daily state of functioning. It is important to understand emotional processes in patients on dopaminergic medications because, although th ey gain improvements in motor function while on these medications, they continue to experience emotional symptoms. This is likely because dopamine differentially affects motor, limbic, and cognitive functions and, in theory, each function requires a uniqu e dopaminergic dosage in order to achieve optimal functioning ( Cools, 2006; Rowe et al., 2008). It is also relevant to note that the time of most recent dose of medication varied between subjects in the current study ; thus, the level of in vivo dopamine f or any given subject at the time of testing was variable Lastly this sample of II and apathy scores were not indicative of significant depression or apathy, nor were they significantly different from the control group. Therefore, although we did not observe a difference in the emotion modulated specifically apathet differences in their physiological responses to affective stimuli. A subgroup of apathetic particular p attern of disease progression that differentially affects underlying limbic

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51 and/or autonomic systems. On the other hand, potential differences evidenced by a subgroup of could also reflect a byproduct of the fact that these patients are, in fact, depressed or apathetic, which returns us to the age or the Conclusion Thus, the current study at least serves as a baseline, showing that a sample of relatively emotionally healthy on dopam ine replacing medication, show normal emotion modulated arousal responses to both unpleasant and pleasant stimuli as measured by pupillary response. This finding can serve as the baseline for comparison in future studies that investigate particular subgro ups of patients (i.e.: apathetic vs. non apathetic). It also serves to fill in a piece of the puzzle in developing a bio informational model of emotion dysfunction in PD. Specifically, the results of the current study demonstrate that Parkin show an initial, emotion modulated orienting response similar to that which we would expect in a healthy control group This raises the possibility that emotion dysfunction in PD may occur at a later component in the emotional response cas cade and relate more to inadequate activation of motivational systems that support motivated behavior.

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5 7 BIOGRAPHICAL SKETCH Jenna Dietz is from Lancaster, Pennsylvania. She attended the University of Delaware where she majored in neuroscience. Ms. Dietz graduated magna cum laud e in 2008 with an Honors Bachelor of Arts degree with Distinction While at the University of Delaware, she studied under the mentorship of Dr. Robert Simons and gained research experience in the psychophysiology of emotion and attention. She is currently pursuing her doctorate in Clinical and Health Psychology at the University of Florida, where she is specializing in Neuropsychology.