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Diminished Affective Modulation of Startle to Threatening Stimuli in Parkinson's Disease


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DIMINISHED AFFECTIVE MODULATION OF STARTLE TO THREATENING STIMULI IN PARKINSONS DISEASE By KIMBERLY M. MILLER 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 2004

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Copyright 2004 by Kimberly M. Miller

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ACKNOWLEDGMENTS I would like to acknowledge my research mentor, Dawn Bowers, for her constant availability and support. I would like to thank the graduate students and research assistants in the Cognitive Neuroscience Laboratory who helped in the collection of this data. I would like to thank Michael Okun and his colleagues at the Movement Disorders Center for providing access to patients, and the patients themselves who endured many long hours of testing. iii

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TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................iii LIST OF TABLES .............................................................................................................vi LIST OF FIGURES ..........................................................................................................vii ABSTRACT .....................................................................................................................viii CHAPTER 1 INTRODUCTION........................................................................................................1 Motor and Cognitive Symptoms in Parkinsons Disease.............................................2 Emotional Processing in Parkinsons Disease..............................................................4 Mood Disturbance in Parkinsons Disease............................................................4 Expression and Perception of Emotion in Parkinsons Disease............................5 Physiologic Reactivity...........................................................................................7 Pathophysiology of Emotional Changes in Parkinsons Disease.................................9 Neural Circuitry Involved in Emotional Behavior..............................................10 Amygdala Pathology...........................................................................................11 Rationale for the Present Study..................................................................................12 Hypotheses and Predictions........................................................................................14 Hypothesis 1........................................................................................................14 Hypothesis 2........................................................................................................14 Exploratory Questions.........................................................................................15 2 METHODS.................................................................................................................17 Participants.................................................................................................................17 Materials.....................................................................................................................19 International Affective Picture System Slides.....................................................19 Self Assessment Manikin (SAM)........................................................................21 Procedures...................................................................................................................21 Data Collection....................................................................................................21 Data Reduction of the Eyeblink Component of the Startle Response.................22 Statistical Analyses..............................................................................................23 iv

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3 RESULTS...................................................................................................................26 Startle Eyeblink..........................................................................................................26 Pleasant versus Unpleasant Pictures....................................................................26 Threatening versus Other Unpleasant Pictures....................................................27 Subjective Ratings: Valence and Arousal...................................................................29 Pleasant versus Unpleasant Pictures....................................................................29 Threatening versus Other Unpleasant Pictures....................................................30 Eyeblink Magnitude and BDI Correlations................................................................31 4 DISCUSSION.............................................................................................................35 Basic Acoustic Startle in PD Patients.........................................................................36 Possible Effects of Depression on the Present Findings.............................................38 The Role of the Amygdala in Response to Threatening/Fearful Stimuli...................39 Dissociation of Subjective Ratings and Physiological Response...............................40 Limitations of the Present Study.................................................................................42 Directions for Future Research...................................................................................44 LIST OF REFERENCES...................................................................................................47 BIOGRAPHICAL SKETCH.............................................................................................56 v

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LIST OF TABLES Table page 1-1 Patient and Control Characteristics..........................................................................20 3-1 Means and SDs of Pleasantness and Arousal Ratings for Unpleasant and Pleasant Pictures.......................................................................................................30 3-2 Means and SDs of Pleasantness and Arousal Ratings for Threatening and Other Unpleasant Pictures..................................................................................................31 3-3 Correlations Between Number of Years with Parkinsons Disease, BDI Score, Hoehn and Yahr Stage, and UPDRS Motor Subscale Score....................................33 vi

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LIST OF FIGURES Figure page 1-1 Simplified Direct Loop in the PD patients Dysfunctional Motor System................3 1-2 Two Hypothesized Striato-Thalamo-Cortical Loops Involved in Emotion.............11 3-1 Peak Eyeblink Amplitudes for Unpleasant versus Pleasant Pictures.......................28 3-2 Peak Eyeblink Amplitude for Threat versus Other Unpleasant Pictures.................29 vii

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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 DIMINISHED AFFECTIVE MODULATION OF STARTLE TO THREATENING STIMULI IN PARKINSONS DISEASE By Kimberly M. Miller May 2004 Chair: Dawn Bowers Major Department: Clinical and Health Psychology Rationale. Studies of patients with Parkinsons disease have suggested various deficits in emotional processing. These impairments may be linked to a decrease in dopamine levels regulating key limbic circuitry, and pathology of the amygdala in Parkinsons patients. In the present study, the issue as to whether patients with Parkinsons disease display normal emotional modulation of startle to unpleasant and pleasant pictures was examined. Furthermore, within the category of unpleasant pictures, reactivity to threat-eliciting versus other types of aversive pictures was investigated. It was hypothesized that Parkinsons patients would show diminished emotional reactivity in general to the emotional pictures, based on suggestions of amygdala and limbic circuitry dysfunction. Additionally, it was hypothesized that Parkinsons patients would exhibit reduced emotional reactivity, relative to controls, to threat-eliciting pictures specifically, due to the role of the amygdala in processing of threatening stimuli. viii

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Methods. To test this hypothesis, twenty Parkinsons patients and fifteen age-matched healthy Controls viewed standard sets of pleasant, unpleasant, and neutral pictures for six seconds each. During this time white noise bursts were binaurally presented to elicit startle eyeblinks. Subjective ratings of valence and arousal were also obtained. The Parkinsons patients were tested while on dopaminergic medication. Results. Data were analyzed using 2 X 2 repeated measures Analyses of Variance. Both the Parkinsons patients and Controls showed significantly larger startle amplitude during unpleasant versus pleasant pictures, which is the normal pattern of emotion modulation. This effect was significantly weaker and less robust in the Parkinsons patients than the Controls, as revealed by a Group X Affect interaction. Specifically, startles to negative pictures were significantly smaller in Parkinsons than Controls, with no group differences for pleasant pictures. Within the unpleasant pictures, Controls showed a significantly larger startle amplitude during threatening versus other types of unpleasant pictures, whereas the Parkinsons patients did not. The Parkinsons and controls rated the emotional pictures similarly. Conclusions. The current study found that Parkinsons patients were less emotionally reactive than controls to aversive pictures, specifically with regards to threat-eliciting pictures. The basis for this diminished reactivity is unknown, but may reflect pathological changes in the amygdala of PD patients, a structure consistently implicated in processing of fearful stimuli, as well as a reduction in dopamine levels within limbic neural circuitry. ix

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CHAPTER 1 INTRODUCTION Parkinsons disease (PD) is the second most common neurodegenerative disorder next to Alzheimers disease, affecting approximately half a million to a million people in the United States (McDonald, Richard, & DeLong, 2003). About 50,000 new cases are reported annually, and this figure is rising as the average age of the population increases (National Institute of Neurological Disorders and Stroke, 2001). Slightly more males than females suffer from Parkinsons disease. The average age of onset is approximately 60-65 years old, although a small proportion of PD patients (5-10%) display symptoms before age 40 (Fahn, 2003; Lang & Lozano, 1998). The likelihood of developing PD increases with age, with a lifetime risk of about 2% (Fahn, 2003). Although the motor and cognitive symptoms of Parkinsons disease have been well studied over the years, relatively few studies have specifically examined changes in emotional reactivity. This is surprising in light of the fact that aspects of the neural circuitry affected by dopaminergic depletion in PD involve limbic regions that are known to be important in emotional behavior (i.e., amygdala, nucleus accumbens, orbitofrontal region). Thus, the goal of the present study was to investigate emotional reactivity in Parkinsons disease by using experimental measures that assessed physiologic reactivity to emotional pictures. To do this, patients physiological responses to pictures of varying valence and arousal levels were measured and compared to the responses of control subjects. Before turning to a review of the literature on emotional processing in PD, the core symptoms of Parkinsons disease will be briefly discussed. 1

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2 Motor and Cognitive Symptoms in Parkinsons Disease Behaviorally, Parkinsons disease is characterized by motor symptoms including resting tremor, bradykinesia (slowed movement), rigidity (increased muscle tone), and akinesia (difficulty initiating or maintaining a body movement (Hughes, Ben-Shlomo, Daniel, & Lees, 1992; Hughes, Daniel, Kilford, & Lees, 1992)). Additionally, Parkinsons patients may experience diminished facial expressivity (masked facies), loss of postural reflexes, and/or motoric freezing when attempting to walk (Fahn, 2003). These motoric symptoms are thought to be caused primarily by a depletion of dopaminergic neurons in the substantia nigra. This dopaminergic depletion then affects a whole cascade of structures involved in the production of voluntary movement, particularly the basal ganglia. A diagram of the neural circuitry involved in Parkinsons disease is depicted in Figure 1-1. It has been estimated that patients with PD have an approximately 60-85% loss of dopaminergic neurons in the substantia nigra (Pogarell & Oertel, 1999). As such, dopamine replacement therapy (using levodopa, a dopamine precursor that is able to cross the blood-brain barrier) is the major medical approach to treating the motor symptoms of Parkinsons (Fahn, 2003). Initially, the motor symptoms of Parkinsons disease are dramatically improved by dopaminergic therapy. Over time, however, medications become less effective and are associated with dramatic on and off fluctuations in symptoms. This has led to recent surgical treatments for Parkinsons disease, including the implantation of small stimulating micro-electrodes into specific brain regions within the basal ganglia (i.e., globus pallidus internus, subthalamic nucleus). The basic idea behind deep brain stimulation and other surgical treatments for Parkinsons disease is to change the imbalance of activation and inhibition that results from dopaminergic depletion (Benabid, 2003).

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3 Figure 1-1. Simplified Direct Loop in the PD patients Dysfunctional Motor System. The striatum receives excitatory projections from the cortex, but input from the SNc is impaired due to a reduction of dopamine. This results in the striatum not receiving enough excitatory input to exert its inhibitory influence over the MGP and SNr. The MGP and SNr, free of inhibition from the striatum, provide inhibitory influence over the thalamus, thus preventing the thalamus from providing excitatory output to the cortex. The inhibition of the thalamus and lack of cortical activation results in poverty of movement. (SNc = substantia nigra pars compacta, MGP = medial globus pallidus, SNr = substantia nigra pars reticularis). Although the motor symptoms of Parkinsons disease are the primary focus of pharmacotherapy and surgical treatments, various nonmotor symptoms also occur and can be particularly disturbing and disabling. These include insomnia, autonomic dysfunction, mood disturbance, psychosis, and cognitive changes. Common cognitive sequalae are slowed thinking (bradyphrenia), impaired set-shifting, reduced working memory, and forgetfulness (Cools, Barker, Sahakian, & Robbins, 2001; Dimitrov, Grafman, Soares, & Clark, 1999; Fahn, 2003; Gauntlett-Gilbert, Roberts, & Brown, 1999; van Spaendonck, Berger, Horstink, Borm, & Cools, 1995). Moreover, about 20% of Parkinsons patients develop a frank dementia (Brown & Marsden, 1984), which is

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4 most common in PD patients with a later age of onset. When a patient suffers from both dementia and PD, they are referred to as having Parkinsons plus syndrome (Fahn, 2003). Myriad studies have investigated the pattern of motoric and cognitive deficits found in Parkinsons disease. Fewer have delved into the domain of emotional changes that accompany Parkinsons disease, the focus of the current study. In the following sections, a brief overview of some of the emotional changes that accompany Parkinsons disease will be presented. Emotional Processing in Parkinsons Disease Emotional processing can be broadly conceptualized as encompassing four domains: mood (subjective emotional experience), perception, expression, and physiology. Research to date suggests that Parkinsons patients may exhibit difficulties in at least three of these domains. Each of these will be briefly reviewed below. Mood Disturbance in Parkinsons Disease A variety of studies have consistently found mood disturbances among patients with Parkinsons disease, with an average of 40-50% of PD patients experiencing depressive symptoms (Cummings, 1992; McDonald et al., 2003; Zgaljardic et al., 2003). Accumulating evidence over the years suggests that depression in PD may be secondary to the underlying neuroanatomical degeneration, rather than simply a reaction to psychosocial stress and disability, although the latter may clearly play a role as well. The incidence of depression is correlated with changes in central serotonergic function and neurodegeneration of specific cortical and subcortical pathways (Burn, 2002; Mayberg et al., 1990). In addition to decreasing quality of life, depression and other psychiatric

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5 disturbance in Parkinsons patients appear to exacerbate motoric symptoms (Cummings, 1992). Other common psychiatric disturbances in Parkinsons disease are anxiety and apathy (Fahn, 2003). Apathy refers to diminished emotional reactivity to both positive and negative events, lack of motivation to engage in goal-directed behavior or cognition, and a subjective sense of indifference (Marin, 1991). Between 40 and 50% of Parkinsons patients have been described as meeting criteria for apathy, based on various apathy scales (Isella et al., 2002; Starkstein, Mayberg, Preziosi, Andrezejewski, Leiguarda, & Robinson, 1992), with higher levels of apathy in Parkinsons patients relative to equally disabled patients with severe osteoarthritis (Pluck & Brown, 2002). Those patients with high levels of apathy are not more likely to be depressed or anxious than those with the lowest levels of apathy (Pluck & Brown, 2002). Instead, apathy has been correlated with increasing cognitive impairments. Like depression, it has been argued that apathy is more likely a direct consequence of disease related physiological changes than a psychological reaction or adaptation to disability (Brown & Pluck, 2000; Pluck & Brown, 2002). Expression and Perception of Emotion in Parkinsons Disease In addition to mood disturbances, patients with Parkinsons disease also have difficulty communicating emotion using various nonverbal signals such as facial expression and emotional tone of voice (Blonder, Gur, & Gur, 1989; Borod et al., 1990; Buck & Duffy, 1980; Jacobs, Shuren, Bowers, & Heilman, 1995 Smith, Smith, & Ellgring, 1996). In fact, one of the common clinical features of Parkinsons disease is masked facies, a term that refers to the expressionless facial demeanor of PD patients. Diminished facial expressivity occurs relatively early in the disease course and is

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6 unrelated to depression (Katiskitis & Pilowsky, 1991; Smith, Smith, & Ellgring, 1996). Recent studies using sophisticated computer imaging techniques have found that the facial movements in Parkinsons disease are actually smaller in amplitude, slower to initiate, occur less frequently, and correlate with other motor symptoms of Parkinsons disease such as bradykinesia (Bowers et al., in press). Unfortunately, diminished use of nonverbal communication signals by Parkinson patients poses significant problems, ranging from misdiagnosis of depression to the misattribution of negative emotion states by family members and health care providers. The research literature regarding the perception of emotional information (faces, scenes, prosody) is inconsistent at best. Some investigators have found that Parkinsons disease patients are impaired when asked to identify emotional faces, emotional prosody, or emotional scenes (Blonder et al., 1989; Jacobs et al., 1995; Scott, Caird & Williams, 1984; Sprengelmeyer et al., 2003). Others, however, have not documented differences between Parkinsons disease patients and healthy controls (Adolphs, Schul and Tranel, 1998; Madeley, Ellis, & Mindham, 1995). Some possibilities that may account for these discrepancies are methodologic inconsistencies regarding the stage of severity of Parkinsons disease, whether patients are tested on versus off medications, and the extent of co-existing cognitive impairment or mood disturbance. Recently, a particular interest has emerged with respect to the possibility that Parkinsons patients may have difficulties with processing of specific emotions such as fear or disgust relative to other emotions. Some researchers have found that PD patients appear to be more impaired at recognizing aversive facial expressions (i.e., anger, disgust, fear) than other expressions. For example, Kan and colleagues (Kan,

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7 Kawamura, Hasegawa, Mochizuki, & Nakamura, 2002) found that PD patients were selectively impaired at recognizing fear and disgust facial expressions. However, not all researchers have found impairments in recognition of emotional facial expressions (Adolphs et al., 1998; Madeley et al., 1995). Physiologic Reactivity Another approach for examining emotional behavior involves monitoring patients physiological reactivity to emotional materials. To date, there are no published studies of psychophysiologic reactivity to emotional materials in patients with Parkinsons disease. This is surprising, since using physiology as an index of emotional reactivity in a Parkinsons sample has several advantages. First, it does not require a voluntary motor response (as measurements of facial expressivity or vocal prosody do), thereby eliminating the confounding problem that the movements being used as an index of expressivity may be affected by the motor symptoms of PD. Secondly, measurement of physiological reaction does not depend on self-report (as many paper-and-pencil measures of mood do), and thus the demand characteristics associated with it are minimal. Finally, because the response that is being measured is near impossible to voluntarily control, it does not rely on the subjects attention, motivation, or cooperation (Bradley, 2000). Skin conductance. One type of physiological reaction frequently measured in psychological research is skin conductance response (SCR) to emotional stimuli. This is accomplished by applying electrodes that essentially measure palm sweat to the inside of the hands. The larger the SCR, the larger the physiological arousal the subject has experienced in response to the emotional stimuli. Although measurement of SCR can be useful, it does have serious limitations. First, individuals vary considerably in how their

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8 SCR to emotional stimuli habituates over time. Some individuals habituate after a few trials, whereas others do not appear to habituate much at all. Secondly, 15-20% of healthy people are nonresponders; that is, they to do not exhibit a discernable difference in SCR to varying types of stimuli (Bradley, 2000; OGorman, 1990). Finally, excess motor activity (such as tremor in the hands) can dramatically interfere with skin conductance recordings (Bradley, 2000). For these reasons, SCR data do not always produce consistent results, may not detect subtle between-groups differences in physiological responding, and may not be the most appropriate physiologic measure for patients with a movement disorder. Startle eyeblink response. Another widely used index of emotional reactivity is the affective modulation of the startle eyeblink response (Lang, Bradley, & Cuthbert, 1990; Vrana, Spence, & Lang, 1988). It is this measure that was chosen to serve as the index of emotional reactivity in the present study. In order to understand the mechanism of this phenomenon, it is first necessary to describe the basic startle response and how it is neurally mediated. In mammals, an automatic startle response occurs at the abrupt onset of a stimulus, such as a jarring noise or flash of light. It is characterized by limb and trunk movements of the body, as well as a reflexive eyeblink (Bradley & Vrana, 1993). A variety of studies over the past decade have documented that size of the startle eyeblink is directly modulated by an individuals affective state (i.e., negative, positive). In humans, startle response magnitude (as indexed by reflexive eyeblink) is augmented during emotionally aversive tasks and attenuated during more pleasant tasks. This valence modulation of startle is observed across a variety of tasks involving slide viewing, imagining emotional situations, and anticipation of shock (Bradley, Cuthbert, &

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9 Lang, 1990, 1991; Grillon, Ameli, Woods, & Merikangas, 1991; Lang, Bradley, & Cuthbert, 1990). Lang et al. (1990) proposed that startle response magnitude reflects the valence of the individual's central motivational state (appetitive versus aversive), rather than being a tactical response in a specific affective context. The neural circuitry underlying the startle response has been exquisitely mapped out by Mike Davis and colleagues (Davis, 1992; Davis, Gendelman, Tischler, & Gendelman, 1982). Davis' group has shown that the basic startle circuitry is mediated entirely subcortically (at the level of the brainstem-spinal cord), and can be directly modulated by the amygdala (at least in rodents) via its projection to the brainstem. Electrical stimulation of the amygdala in rats facilitates startle (Rosen & Davis, 1988), while lesions of the amygdala diminish fear potentiated and shock sensitized startle responses while leaving the basic startle intact (Hitchcock & Davis, 1991; Hitchcock, Sananes, & Davis, 1989). Further, lesions at some cortical sites that relay information to the amygdala appear to attenuate fear potentiated startle in rodents (Rosen, Hitchcock, Miserendino, Falls, Campeau, & Davis, 1992). In humans, temporal lobe ablations involving the amygdala are associated with reduced startle potentiation during the viewing unpleasant pictures. Taken together, these findings suggest that increases in the startle response during negative emotional states may reflect the amygdalas role in both threat detection and in modulating subcortical startle circuitry. Pathophysiology of Emotional Changes in Parkinsons Disease Before turning to the rationale for the current study, the question arises as to the basis for changes in emotional behavior in Parkinsons disease. There appears to be at least two possible mechanisms that might potentially affect emotional processing in

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10 Parkinsons disease. First, the reduction in nigrostriatal dopamine found in PD influence neural circuits that have been implicated in emotion. Secondly, evidence has been found that the amygdala, a key limbic structure, exhibits significant pathological changes in Parkinsons disease. Each of these possible mechanisms will be discussed below. Neural Circuitry Involved in Emotional Behavior The deficits in emotional processing described previously may be linked to limbic circuitry subserved by the neurotransmitter dopamine. There are three main systems through which dopamine may affect emotional processing in PD: the striato-thalamo-cortico loops, the mesolimbic circuit, and the mesocortical circuit. Beginning with the first of these, Alexander, DeLong, & Strick (1986) proposed a network of five parallel striato-thalamo-cortical circuits that allow frontal cortical activity to be modulated by ascending input from the basal ganglia/thalamus through direct and indirect pathways. Two of these circuits involve key limbic areas such as the orbitofrontal cortex (OFC), the anterior cingulate cortex (ACC), and the nucleus accumbens. General schematas of these two circuits are depicted in Figure 1-2. Outside of these striato-thalamo-cortical circuits, the dopamine-mediated mesolimbic pathway is implicated in emotional processing as well. The ventral tegmental area has dopaminergic connections to the ventral striatum (which consists of the nucleus accumbens and olfactory tubercle) of the basal ganglia. Changes in dopaminergic input to the ventral striatum can then affect the associated striato-thalamo-cortical circuits, and thus depletion of dopamine may affect the ability of limbic structures to influence frontal cortical activity. Finally, the mesocortical circuit connects the ventral tegmental area to the cortex, and provides yet another way in which dopamine

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11 A) B) Anterior Cingulate Cortex Lateral Orbitofrontal Cortex Ventral Striatum (Nucleus Accumbens) G.P. rostrolateral/ SN r Thalamus MD & VA Caudate (ventromedial) G.P. mdm/ SN r Thalamus MD Figure 1-2. Two Hypothesized Striato-Thalamo-Cortical Loops Involved in Emotion. A) ACC loop, B) OFC loop. G.P.= globus pallidus, SNr = substantia nigra pars reticulata, mdm = medial dorsomedial. depletion may affect emotional functioning. Cortical dopamine release modulates the descending cortico-striatal fibers, potentially influencing the activity of the striato-thalamo-cortico circuits (Brown & Pluck, 2000). In summary, there are myriad hypothesized dopamine-mediated circuits that connect the limbic system to the frontal cortex and thus allow for emotional modulation of cognitive processes. The depletion of dopamine that characterizes Parkinsons disease may affect regulation of these circuits, potentially leading to dysfunction in emotional processing. Amygdala Pathology One of the key limbic structures involved in emotion is the amygdala, a small almond-shaped structure located within the anterior temporal lobe. The amygdala has consistently been implicated in the recognition of fearful stimuli and responding to

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12 threatening situations. Monkeys with lesions of the amygdala do not display normal fear reactions to threatening stimuli, such as snakes (Amaral, 2003; Klver & Bucy, 1939). In humans, lesions of the amygdala have been associated with behavioral placidity, diminished physiologic reactivity, and impairments in recognizing fearful faces (Aggleton, 1992; Calder, Young, Rowland, Perrett, Hodges, & Etcoff, 1996; Young, Aggleton, Hellawell, Johnson, Broks, & Hanley, 1995). Electrical stimulation of the amygdala elicits many of the behaviors used to define the state of fear, such as tachycardia, increased galvanic skin response, corticosteroid release, and increased startle (Davis, 1992). Recently, several investigators have found evidence of pathological changes in the amygdala of Parkinsons patients. In a post-mortem study, Harding and colleagues (Harding, Stimson, Henderson, & Halliday, 2002) found a 20% reduction in the amygdala volumes of PD patients compared to normal controls. Ouchi and colleagues (1999) found a 30-45% reduction of dopamine agonist binding in the amygdala of PD patients, which they speculated might be due to a loss of pre-synaptic dopamine terminals in this region. Additionally, post-mortem studies have found the presence of Lewy bodies in the amygdala of PD patients (Braak & Braak, 2000). The fact that the amygdala has been shown to exhibit neuropathology in PD brings up the issue as to whether Parkinsons patients might have a diminished emotional reactivity to threatening stimuli, or difficulty interpreting expressions of fear in others. The findings thus far with respect to these questions are reviewed below. Rationale for the Present Study To date, there are no published studies that have used psychophysiology as a marker of emotional responsiveness in Parkinsons disease. Because of the symptoms of

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13 PD include motor rigidity and slowing, using facial expressivity or vocal prosody as an index of emotional reactivity (as has been done in past studies) may potentially confound motoric deficits with emotional deficits. Thus, measurement of affective startle eyeblink magnitude may provide a clearer methodological approach to investigating emotional reactivity in this patient group. Seignorel and colleagues (Seignorel, Miller, Bowers, & Okun, 2003) found no significant differences in either latency or magnitude of startle eyeblink responses in a group of PD patients compared to controls, suggesting that despite motor impairments, basic eyeblink startle startle remain intact in Parkinsons patients. Similar findings with respect to the magnitude of basic startle responses have also been described by other researchers (Kofler et al., 2001; Vidailhet, Rothwell, Thompson, Lees, & Marsden, 1992). The primary purpose of the present study was twofold: 1) To determine if PD patients and controls differ in degree of startle modulation produced by positive and negative stimuli; and 2) To determine if PD patients exhibit less startle potentiation to threatening stimuli, relative to controls. To date, no studies have investigated PD patients reaction (as opposed to ability to recognize) to non-facial threat-evoking stimuli. For this reason, the issue of whether PD patients exhibit a normal response to threatening stimuli is unknown, although observations of amygdala pathology raise the possibility that threat responding may potentially be disrupted. The only existing studies that address threat processing in PD patients have focused on the ability to recognize fearful facial expressions. Findings from these studies have been mixed. In a task involving recognition of prototypical emotional facial expressions, Sprengelmeyer et al. (2003) found that medicated PD patients were specifically impaired at recognizing anger

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14 and fear, compared to controls. However, when these same patients were tested on a different emotion recognition task (involving morphed images of emotional expressions), they demonstrated no deficit. Kan et al. (2003) found that PD patients were impaired in the recognition of fear and disgust when moving facial stimuli were used. Thus, these studies raise the possibility that recognition of fearful faces may be impaired in PD patients, but do not address the issue of whether an abnormal reaction to a threat-eliciting stimulus exists at the physiologic or subjective level in Parkinsons. Hypotheses and Predictions In healthy subjects, unpleasant stimuli are consistently associated with larger blinks compared to pleasant stimuli. Keeping this in mind, the following hypotheses were made: Hypothesis 1 Parkinsons disease patients will display diminished emotional reactivity relative to normal controls, as indexed by startle modulation during affective pictures. Thus, it was predicted that PD patients would exhibit a significantly smaller eyeblink magnitude than controls while viewing unpleasant slides, and a significantly larger eyeblink magnitude than controls while viewing pleasant slides. This prediction is based on the observations that PD patients show 1) reduced striatal dopamine, which may affect dopamine-mediated limbic circuits; and 2) amygdala neuropathology, which may affect the ability of the amygdala to modulate the basic startle response. Hypothesis 2 Parkinsons patients will show a more diminished emotional response to threatening pictures as compared to other categories of unpleasant pictures. Specifically, it was predicted that PD patients would display a significantly smaller eyeblink

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15 magnitude than controls in response to threatening slides, whereas their eyeblink magnitude during other unpleasant pictures would not significantly differ from that of controls. This prediction is based on the fact that the amygdala is known to play a key role in responding to threatening stimuli, is implicated in the fear-potentiated startle, and exhibits pathology in PD patients. Exploratory Questions In addition to the major hypotheses described above, several exploratory questions were addressed. For example, would Parkinson patients rate the affective pictures as intensely emotional as the controls in terms of valence? This is an important question for several reasons. First, if PD patients rated the emotional pictures as less intense, then this might be due to perceptual problems in appraising the stimuli, which could potentially influence emotional reactivity. Alternatively, reduced ratings might be due to some alteration in emotional appraisal. As mentioned previously, approximately 40% of PD patients experience apathy (Marin, 1996). One component of apathy is diminished emotional response to both positive and negative events. Whether this holds true for positive and negative pictures in an experimental setting, which is obviously much different from the natural environment, is unknown. If it does indeed hold true, then patients with PD should find unpleasant pictures less unpleasant than controls, and pleasant pictures should be rated as less pleasant than control ratings. On the other hand, Smith et al. (1996) found that PD patients rated emotional scenes from movies no differently from healthy controls. This raises the possibility that patients in the current study might rate pictures similarly to controls, yet nevertheless show differences in emotional reactivity as indexed by startle. This situation would suggest a decoupling between appraisal and the translation of the results of this appraisal into a motivational

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16 state. The amygdala is thought to play a pivotal role in this translational process based on lesion studies of patients who have undergone resection of the mesial temporal region including the amygdala (Bowers et al., 1998). Should a decoupling be found in Parkinsons patients, this finding would be consistent with some abnormality in the translational process, possibly related to alterations in amygdala functioning. An additional question was whether controls and PD patients would find the pictures similarly arousing. If PD patients are experiencing emotional blunting, one might expect them to find the emotional stimuli less arousing than controls. Finally, it was important to determine if any differences between patients and controls emotional startle modulation could be attributed to differences in level of depression. Therefore, an additional exploratory goal was to investigate any possible association between depressive symptoms and startle eyeblink magnitude.

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CHAPTER 2 METHODS Participants Participants included twenty patients with idiopathic Parkinsons disease and fifteen healthy age-matched controls. The Parkinsons patients were recruited through the Movement Disorders Center of the University of Florida and had been evaluated within the preceding three months by a movement disorders neurologist (Dr. Okun or Dr. Fernandez). As part of their routine workup in the Movement Disorders Clinic, the Parkinsons patients received standard measures for staging the severity of their motor symptoms and disease course. These included: the United Parkinson Disease Rating Scale-Third Edition 1 (motor subscale [Fahn & Elton, 1987]), a modified Hoehn-Yahr scale 2 (Hoehn & Yahr, 1967), and the Schwab and England Activities of Daily Living 3 (Schwab & England, 1969). Patients were evaluated on these scales off medication (12 hours after last levodopa dose) and again one hour after taking their medication (on state). During this clinical evaluation, PD patients were also screened for dementia (Mini-Mental State Exam [Folstein, Folstein, & McHugh, 2001]), depressed mood (Beck 1 This is a rating tool designed to assess the severity of various motor symptoms over the course of the disease. Higher scores indicate greater severity. Patients were assessed while on and off dopaminergic medication. 2 This scale is used to rate the stage of severity/disability in the PD patient. Stages range from 1-5, with five being the most severe (cannot walk without assistance, or is confined to wheelchair). Patients were assessed while on and off dopaminergic medication. 3 This rating scale is an index of the PD patients level of functioning in activities of daily life. Scores range from 0-100%, with 100% indicating complete independence, and 0% indicating that the patient is bedridden. 17

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18 Depression Inventory [Beck, 1978]), and decreased quality of life (Parkinson Disease Quality of Life Scale-39 [Peto, Jenkinson, & Fitzpatrick, 1998]). To be included in the PD group, patients had to meet stringent diagnostic criteria for Parkinsons disease, be free of other neurologic or medical illness that would compromise their participation (or interpretation of findings), and be free of dementia and significant psychological distress (i.e., a psychiatric disorder). The clinical diagnosis of idiopathic PD was based on: (a) the presence of at least two of four cardinal motor signals (i.e., akinesia, bradykinesia, resting tremor, rigidity [Hughes, Ben-Shlomo, et al., 1992; Hughes, Daniel, et al., 1992]); and (b) a demonstrated therapeutic response to dopamine replacement therapy, as defined by a marked improvement in Parkinsonian motor signs, based on the motor subscore of the United Parkinson Disease Rating Scale (UPDRS) following administration of levodopa during their screening neurologic examination. A demonstrated good response to levodopa therapy was required in order to exclude patients with Parkinsons plus syndromes (e.g., Shy-Drager, multiple system atrophy, Lewy body disease, corticobasal degeneration). Only Parkinson patients who scored in the nondemented range on the Mini-Mental State Exam (>26) were invited to participate in the present study. The PD patients included sixteen men and four women, who ranged in age from 43 to 85 (X = 61.9, SD = 10.0). As a group, they had been treated for Parkinsons disease for eleven years and were in the mid-stages of their disease, based on staging criteria from the Hoehn and Yahr scale. This information is depicted in Table 1-1. In order to assess depressive symptomatology, all patients received the Beck Depression Inventory (BDI) on the same day they received the experimental emotional tasks. The BDI scores

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19 for the PD patients included in the present study ranged from two to nineteen (means and standard deviations are shown in Table 1-1). Two patients met criteria for Mild Depression (BDIs = 14 and 19), as defined by Beck, Steer, & Brown (1996). Control participants included fifteen healthy individuals (ten men, five women) who had been recruited from the community. Any control participant with reported psychiatric disorder, head previous head injury, learning disability, or neurological disorder was excluded. Controls were also given the BDI. There were no instances in which Control participants produced BDI scores that exceeded thirteen (the recommended cutoff score for Mild Depression; Beck et al., 1996). A comparison of patient and control demographic variables is presented in Table 1-1. As shown, the PD and Control groups did not significantly differ with respect to age (t(33)= 1.90, p = .40), although the mean age of the PD patients was about ten years greater than that of the controls. The reason for this discrepancy related to the young age of two of the control subjects (these subjects were twenty-five and twenty-nine years old, respectively). Additionally, the PD patients were slightly more educated than the controls (t (28.7)= 2.04, p = .05). The PD patients had a mean of fifteen years of education, whereas controls had a mean of 13.5 years of education. Finally, PD patients and controls significantly differed with respect to their mean BDI scores (t(31) = 3.06, p<. 005), with BDI scores of the PD group (X = 8.5) being significantly higher than those of the Controls (X = 4.1). Materials International Affective Picture System Slides Participants viewed a subset of forty-four pictures (twelve pleasant, twelve unpleasant, twelve neutral, and eight filler) taken from the International Affective

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20 Table 1-1. Patient and Control Characteristics PD patients Controls (N= 20) (N= 15) Men: Women 16:4 10: 5 Age 62.9 (10) 53.8 (15.2) ns Yrs. Ed 15. (2.9) 13.5 (1.3) p = .05 Hoehn-Yahr* 2.7 (.52) -UPDRS motor* 27.2 (10.2) -Yrs. with PD 10.8 (6.0) -BDI 8.5 (4.0) 4.1 (4.0) p < .005 Assessed while on dopaminergic medication. Picture System (Lang, Bradley, & Cuthbert, 2001a). Efforts were made to equate the pleasant and unpleasant pictures on the basis of normative ratings of arousal (Lang, Bradley, & Cuthbert, 2001b); however, a t-test revealed that the normative sample of men and women found the unpleasant pictures to be more arousing on average than the pleasant pictures, t(11) = 2.73, p < .05 (mean of Unpleasant pictures = 6.6, SD = .664; mean of Pleasant pictures = 5.8, SD = 1.03 [ratings range from one to nine, with nine being the most arousing]). 4 The experiment began with two filler slides for practice, followed by six blocks of seven trials. Each block contained two unpleasant slides, two pleasant slides, two neutral slides, and one filler slide, presented in randomized order. In order to investigate the impact of threatening pictures on emotional reactivity, the negative pictures were further divided into two additional categories: Threat versus other unpleasant pictures. Threat slides were defined as any slide suggesting imminent attack, such as a snake preparing to bite, a gun pointed at the viewer, or a dog with saliva-dripping fangs spread open. All remaining unpleasant pictures were then 4 These normative ratings were obtained from a large sample of college students, and thus may not be applicable to older participants. Additionally, the male to female ratio of the normative sample differs from that of the current study.

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21 categorized as other unpleasant pictures. This post-hoc division resulted in seven threat pictures and five other unpleasant pictures. The IAPS numbers for the threat pictures are: 1090, 2120, 1300, 3000, 3530, 6230, 6370). The IAPS numbers for the other unpleasant pictures are: 3010, 3100, 3130, 9040, 9050). Threat pictures had a mean normative arousal rating of 6.40 (SD = 0.862) and other unpleasant pictures had a mean normative arousal rating of 6.56 (SD = 0.52 [Lang, Bradley, & Cuthbert, 2001b]). Self Assessment Manikin (SAM) Each participant rated the pictures for valence (pleasant, unpleasant) and arousal using the Self Assessment Manikin (SAM). SAM is a graphic display depicting a cartoon figure that varies along the dimensions of valence and arousal (Greenwald, Cook, & Lang, 1989; Lang, 1980). For valence, nine versions of the cartoon figure were shown, ranging from positive to neutral to negative. For arousal, nine versions of the cartoon figure were shown ranging, from sleepy to neutral to highly excited. During the experiment, participants were asked to rate their reactions to each IAPS picture immediately after viewing it by referring to the SAM figures. The SAM figures were vertically displayed on a computer screen in front of the participants. The participants verbally gave their valence and arousal ratings which were heard, via an intercom, by an investigator in an adjacent room. Procedures Data Collection Prior to beginning the study, informed consent was obtained from each participant according to University and Federal guidelines. All testing took place in the Cognitive Neuroscience Laboratory of the UF Brain Institute. The session began with completion of various questionnaires, including the BDI. This was followed by a detailed

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22 description of the study and attachment of electrodes over the face and hands. (For the purpose of the present study, only the startle component will be described). After cleaning the area under the eye, two 3 mm Ag/AgCl electrodes were filled with a conducting gel (Medical Associates, Inc., Stock # TD-40, Lot # 70204) and were positioned under the left and right eyes to record EMG activity from the orbicularis oculi muscle. Electrodes were affixed to the skin surface with adhesive collars. During the experiment, participants sat in a reclining chair that was located in a sound-attenuated and electrically shielded 12x12 room. Visual stimuli were displayed on a 21 computer monitor located directly in front of the participant. After the participant was taught how to use SAM and practiced with two sample slides, the experiment commenced. Each trial began by presentation of the picture for six seconds. During this time, startle eyeblinks were elicited by a 50 ms burst of white noise (95dB, instantaneous rise time) that was delivered binaurally via Telephonics (TD-591c) headphones. A Colbourn S81-02 module generated the white noise bursts that were gated through a Colbourn S82-24 amplifier. These white noise bursts (startle probes) were randomly presented at various points following picture onset (i.e., 4200, 5000, or 5800 ms) and counterbalanced across valence category. Following each picture, the SAM figure appeared on the computer screen and the participant verbally rated his/her subjective level of valence and arousal. Data Reduction of the Eyeblink Component of the Startle Response The eyeblink component of the startle response was measured by recording EMG activity from the orbicularis oculi muscle beneath each eye. The raw EMG signal was amplified and frequencies below 90 Hz and above 1000 Hz were filtered using a Colbourn bioamplifier. Amplification of acoustic startle was set at 30,000. The raw signal was then rectified and integrated using a Colbourn Contour Following Integrator

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23 with a time constant of 200 ms. This information was sent to a Scientific Solutions A/D board interconnected with a custom personal computer. Digital sampling at 1000 Hz began 50ms prior to startle probe onset and continued at this rate for 250 ms after the probe onset. The startle data were reduced off-line using custom software programs. These programs automatically eliminate trials with an unstable baseline and derive baseline, peak, and blink amplitude values in arbitrary A-D units for each trial. Each trial was scored for amplitude (i.e., peak baseline in microvolts) during the 25-130 ms interval following startle onset. Trials that failed to reach peak during this interval were rejected. Latency to peak blink magnitude (in ms) was also derived on a trial-by-trial basis. Statistical Analyses To test the first prediction (PD patients will exhibit a significantly smaller eyeblink magnitude than controls while viewing unpleasant slides, and a significantly larger eyeblink magnitude than controls while viewing pleasant slides), valence-modulation of startle was evaluated by conducting a 2 (PDs, controls) X 2 (pleasant, unpleasant) Repeated Measures Analysis of Variance with eyeblink magnitude T-scores as the dependent variable. The eyeblink magnitudes in response to neutral pictures were not included in the analysis for several reasons. First, although the neutral pictures have normative subjective valence ratings that fall midway between ratings of pleasant and unpleasant pictures, individuals physiologic responses to these pictures vary widely. One subject may respond to an ostensibly neutral picture as if it is somewhat negative in valence, while another may respond to the same picture as if it is positive in valence. Furthermore, research suggests that individual differences in current state anxiety levels can affect startle modulation while viewing emotionally valenced pictures (Grillon,

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24 Ameli, & Davis, 1993). Potentially, the same subject could respond differently to the same neutral picture on two separate occasions, depending on factors such as the individuals mood and the situation. Finally, the inclusion of only strongly valenced pictures in the analysis, as opposed to more ambivalent pictures, increased the chances of detecting any potential differences between the PD and Control groups. To test the second prediction (PD patients will display a significantly smaller eyeblink magnitude than controls in response to threatening slides), a 2 (PDs, controls) X 2 (threat, other unpleasant) Repeated Measures Analysis of Variance was conducted, with eyeblink magnitude as the dependent variable once again. Next, to investigate whether PD patients and controls rated pleasant and unpleasant slides similarly with respect to valence, a 2 (PDs, controls) X 2 (pleasant, unpleasant) Repeated Measures ANOVA was conducted, with subjective valence ratings as the dependent variable. This analysis was then repeated with threat and other unpleasant pictures as the independent variables. To investigate whether PD patients and controls differed in their arousal ratings of pleasant and unpleasant pictures, a 2 (PDs, controls) X 2 (pleasant pictures, unpleasant pictures) Repeated Measures ANOVA was conducted with subjective arousal ratings as the dependent variable. This analysis was then repeated with threat and other unpleasant pictures as the independent variables. A final set of analyses examined the relationship between emotional reactivity, as indexed by startle magnitude, and scores on the Beck Depression Inventory. Although only two of the PD patients scored below the clinical cutoff for depression on the Beck Depression Inventory, the PD patients did obtain significantly higher scores on the BDI

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25 (X = 8.5) than the Controls (X = 4.1). Thus, correlational analyses were performed in order to learn whether BDI scores varied in any systematic way with emotional reactivity, as indexed by startle. A startle reactivity index score was derived using the following formula: [Unpleasant T-score] [Pleasant T-score]. This index score is a measure of overall emotional reactivity; the larger the difference between the eyeblink peak magnitudes for pleasant and unpleasant pictures, the greater reactivity to the stimuli the participant is displaying. A second correlational analysis was performed using an index score derived from the Threat and Other Unpleasant pictures (i.e., [Threat T-score] [Other Unpleasant T-score]).

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CHAPTER 3 RESULTS Startle Eyeblink Startle eyeblink responses were converted to T-scores (X=50, SD=10) following the procedures of Bradley & Vrana (1993). This was done order to minimize between-subject variability in the absolute size of startle responses that might otherwise obfuscate the pattern of the relationship among pleasant, neutral, and unpleasant conditions. For each participant an overall mean startle magnitude (and standard deviation) was derived from the values of that subjects individual trials. T-scores for each subject were computed on a trial-by-trial basis, based on the unique array of values for a particular subject. From these data, average startle responses (T-scores) were derived for the unpleasant, neutral and pleasant pictures. Because startle values were similar for the left and right eyes, a composite score was created (by averaging the left and right eye T-scores) and used as the dependent value in the analyses described below. Since left and right eye startle values did not significantly differ, for instances in which one eye contained greater than 50% invalid trials, values from the other eye were used instead of a composite score. Valid trials were defined as blinks that reached peak amplitude during the 25-130 ms interval following startle onset. Pleasant versus Unpleasant Pictures The initial analysis examined whether Parkinson patients differed from Controls in their emotional reactivity during pleasant versus unpleasant pictures. A repeated measures Analysis of Variance (ANOVA) was conducted, with Group (PDs, Controls) as 26

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27 the between-subjects factor and Type Affect (pleasant, unpleasant) as the within-subjects factor. Results revealed a significant main effect for Type Affect (F(1, 33) = 31.39, p<.001). Consistent with previous findings (Bradley & Vrana, 1993), startle eyeblinks during unpleasant pictures (X = 51.4, SD = 2.41) were significantly larger than those during pleasant pictures (X = 48.1, SD = 2.10). Additionally, there was significant Type Affect X Group interaction (F(1,33)= 4.60, p<.05). This is depicted in Figure 3-1. Post hoc t-tests indicated that: (a) for the PD group, startle eyeblinks were significantly larger during unpleasant (X = 50.62, SD = 2.67) than pleasant pictures (X = 48.60, SD = 2.23; t(19) = 2.35, p < .05); (b) for the Control group, startle eyeblinks were significantly larger during unpleasant (X = 52.17, SD = 1.71) than pleasant pictures (X = 47.67, SD = 1.80; t(14) = 6.43, p < .001); (c) for unpleasant pictures, the Controls (X = 52.17, SD = 1.71) exhibited significantly larger eyeblinks than the Parkinsons patients (X = 50.62, SD = 2.67; t(33) = -2.11, p < .05; (d) for pleasant pictures, Controls (X = 47.67, SD = 1.80) and Parkinsons patients (X = 48.60, SD = 2.23) did not significantly differ with respect to peak eyeblink amplitude (t(33) = 1.33, p > .19). In summary, these findings indicate that both groups displayed greater emotional reactivity, as indexed by startle modulation, during unpleasant versus pleasant picture viewing. However, the Controls reactivity was significantly greater than the Parkinsons patients during presentation of unpleasant pictures. Threatening versus Other Unpleasant Pictures A second ANOVA was conducted in order to determine whether Parkinsons patients were less reactive to threat versus other types of unpleasant emotional pictures. One control and four PD patients were excluded from this analysis due to the fact that

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28 Parkinson's Controls45 50 55 Unpleasant Pictures Pleasant Pictures T-score of Peak Blink Amplitude Figure 3-1. Peak Eyeblink Amplitudes for Unpleasant versus Pleasant Pictures these participants had less than 50% valid trials for either the threatorother unpleasant category.A repeated measures ANOVA was conducted with Group (PD, Controls) as the between-subject factor and Type Affect (Threat, Other unpleasant) as the within-subject factor. Results of this ANOVA revealed a significant main effect for Type Affect (F(1, 28)= 15.4, p<.001), indicating that startle eyeblink responses were larger during threatening pictures (X = 53.36, SD = .612) as compared to other types of unpleasant pictures (X = 49.21, SD = .696). Again, the Condition X Group interaction was significant (F(1, 28)= 5.31, p<.05). Post hoc t-tests indicated that: (a) for the PD group, startle eyeblinks did not significantly differ with respect to peak eyeblink amplitude for threat (X = 51.91, SD = 4.10; t(15) = -1.05, p >.30) versus other unpleasant pictures (X = 50.20, SD = 3.84); (b) for the Control group, startle eyeblinks were significantly larger while viewing threat (X = 54.80, SD = 2.17) versus other unpleasant pictures (X = 48.22, SD = 3.76; t(13) = -5.13, p <.001); (c) for threat

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29 pictures, the Controls exhibited significantly larger eyeblinks (X = 54.80, SD = 2.17) than the Parkinsons patients (X = 51.91, SD = 4.10; t(30) = -2.74, p < .05); (d) for other unpleasant pictures, Controls (X = 48.22, SD = 3.76) and Parkinsons patients (X = 50.20, SD = 3.84) did not significantly differ with respect to peak eyeblink amplitude (t(30) = 1.20, p > .20). Parkinson's Controls45 50 55 60 T-score of Peak Blink Amplitude Threat Pictures Other Unpleasant Pictures Figure 3-2. Peak Eyeblink Amplitude for Threat versus Other Unpleasant Pictures In summary, Controls demonstrated greater emotional reactivity to threat pictures in comparison to the other unpleasant pictures, where as the Parkinsons patients did not. However, both groups responded similarly to the other unpleasant pictures. Subjective Ratings: Valence and Arousal Pleasant versus Unpleasant Pictures A third set of analyses was conducted to examine subjective ratings of the emotional pictures by the Parkinsons patients and Controls. The mean valence and

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30 arousal ratings for the pleasant and unpleasant pictures are depicted in Table 3-1. Two PD patients and two controls were excluded due to missing data. The valence ratings and the arousal ratings were independently analyzed in separate Group X Type Affect (Pleasant, Unpleasant) repeated measures ANOVAs. Results of the valence ANOVA indicated a main effect for Type Affect (F(1,29) = 54.2, p<.001). Namely, unpleasant pictures (X = 2.85, SD = 1.68) were rated as significantly more negative than the pleasant pictures (X = 6.80, SD = 1.48). The Group X Type Affect interaction was not significant, F(1,29) = 2.08, p = .16. Results of the ANOVA for the arousal ratings revealed no significant main effects or interactions. Taken together, these findings indicate that the pleasant and unpleasant pictures elicited ratings that differed in terms of Table 3-1. Means and SDs of Pleasantness and Arousal Ratings for Unpleasant and Pleasant Pictures. Unpleasant Pleasant Unpleasant Pleasant Valence* Valence* Arousal Arousal PD Patients 2.57 (1.70) 7.14 (1.16) 5.22 (2.01) 6.10 (1.36) Controls 3.24 (1.65) 6.32 (1.77) 5.78 (1.66) 5.47 (1.67) Valence ratings ranged from 1 (highly negative) to 9 (highly pleasant). Arousal ratings ranged from 1 (low arousal) to 9 (high arousal) valence. However, both the Controls and PD groups found the negative and positive pictures to be similar in terms of how arousing they found them. Threatening versus Other Unpleasant Pictures A fourth set of analyses was conducted to examine subjective ratings of the threat and other unpleasant pictures by the Parkinsons patients and Controls. The mean valence and arousal ratings for these categories are shown in Table 3-1. As with the analyses of subjective ratings for pleasant and unpleasant pictures, two PD patients and two controls were excluded from the analyses due to missing data. The valence ratings

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31 and the arousal ratings were independently analyzed in separate Group X Type Affect (Pleasant, Unpleasant) repeated measures ANOVAs. Results of the valence ANOVA indicated a main effect for Type Affect, F(1,29) = 10.3, p<.005. Suprisingly, participants subjectively found the other unpleasant pictures (X = 2.49, SD = 1.93) to be more unpleasant than the threatening pictures (X = 3.11, SD = 1.62), even though both groups showed greater startle eyeblink potentiation for the threatening pictures. The Group X Type Affect interaction was not significant, F(1,29) = 0.308, p= .58. Results of the ANOVA for the arousal ratings revealed no significant main effects or interactions. Taken together, these findings indicate that both groups found the other unpleasant pictures more unpleasant the threat pictures, although greater startle potentiation was Table 3-2. Means and SDs of Pleasantness and Arousal Ratings for Threatening and Other Unpleasant Pictures. Threatening Other Unpleasant Threatening Other Unpleasant Valence* Valence* Arousal Arousal PD Patients 2.86 (1.71) 2.16 (1.80) 5.42 (2.15) 4.94 (2.33) Controls 3.45 (1.47) 2.95 (2.01) 5.76 (1.74) 5.80 (1.89) Valence ratings ranged from 1 (highly negative) to 9 (highly pleasant). Arousal ratings ranged from 1 (low arousal) to 9 (high arousal) demonstrated for threat pictures. However, participants did not find the two categories of pictures to differ in terms of level of arousal they evoked. Eyeblink Magnitude and BDI Correlations A final set of analyses examined the relationship between emotional reactivity, as indexed by startle magnitude, and scores on the Beck Depression Inventory. Although all but two Parkinsons patients and none of the Controls scored below the cutoff for Mild Depression on the BDI, the PD patients did obtain significantly higher scores (X = 8.5) than the Controls (X = 4.1). Thus, correlational analyses were performed in order to

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32 learn whether BDI scores varied in any systematic way with emotional reactivity, as indexed by startle. A startle reactivity index score was computed ([Unpleasant T-score] [Pleasant T-score], see Chapter 2 for an explanation of this formula) to serve as a measure of overall emotional reactivity. The Pearsons product-moment correlation between this index score and the BDI score was nonsignificant (r = -0.167, p = .352). Two control subjects were excluded from the analysis due to missing BDI scores. A second correlational analysis was performed using an index score derived from the threat and other unpleasant pictures (i.e., [Threat T-score] [Other Unpleasant] T-score). The results of this analysis indicated that the Pearsons correlation between this difference score and BDI scores was again nonsignificant (r = -0.304, p = .102). In summary, these findings suggest that level of depressive symptomatology, as indexed by the BDI, does not vary in any systematic fashion with emotional modulation of startle. Next, correlational analyses were performed in the Parkinsons disease group to examine the relationships among the Hoehn and Yahr stage (assessed while on medication), UPDRS motor subscale score (assessed while on medication), duration of illness, and BDI score. These analyses were performed in order to determine if severity or duration of Parkinsons disease is associated with depression symptomatology. The correlations between these variables are displayed in Table 3-3. The correlation between Hoehn and Yahr stage and BDI score was nonsignificant (r = -.008, p > .97), as was the correlation between number of years with Parkinsons disease and BDI score (r = .089, p > .62). However, UPDRS score and BDI score were significantly positively correlated, r= .518, p < .05. Although the UPDRS and Hoehn and Yahr both measure level of motor impairment, the UPDRS assesses impairment at the level of highly specific motor

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33 symptoms and has a greater range of possible scores. This may be why a significant correlation was found between the UPDRS and the BDI, but not Hoehn and Yahr Stage and BDI. Finally, UPDRS score and Hoehn and Yahr stage were highly significantly correlated in the positive direction (as would be expected since they both assess level of motor impairment in the PD patient), r = 67, p < .005, and Hoehn and Yahr stage and years with PD were significantly positively correlated, r = .44, p = .05. In sum, these analyses demonstrate that a) degree of motor impairment (as assessed by Hoehn and Yahr stage) increases with duration of illness; and b) greater motor limitation is associated with greater depression severity. Correlational analyses were also performed between the general index of startle reactivity ([Unpleasant T-score] [Pleasant T-score]) and UPDRS motor subscale score, Hoehn and Yahr stage, and years with PD in order to determine if severity or duration of Parkinsons disease is associated with reduced startle reactivity. Hoehn and Yahr stage and startle reactivity index were significantly negatively correlated, r = -0.70, p < .005, as Table 3-3. Correlations Between Number of Years with Parkinsons Disease, BDI Score, Hoehn and Yahr Stage, and UPDRS Motor Subscale Score. Yrs. PD BDI Hoehn &Yahr UPDRS motor subcale Yrs. PD 1.00 0.089 0.444* 0.107 BDI -1.00 -.008 .518* Hoehn & Yahr --1.00 .665** UPDRS motor subcale ---1.00 *. Correlation is significant at the .05 level (two-tailed). **. Correlation is significant at the .01 level (two-tailed). were number of years with illness and startle reactivity index, r = -0.36, p < .05. Additionally, the correlation between UPDRS score and startle reactivity approached

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34 significance, r = -0.48, p = .053. Taken together, these findings suggest that greater motor impairment and longer disease duration in Parkinsons patients are associated with reduced emotional reactivity, as indexed by startle modulation.

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CHAPTER 4 DISCUSSION The present study sought to examine two hypotheses. The first hypothesis was that Parkinsons patients would show diminished emotional reactivity to affectively valenced pictures. This led to the specific prediction that PD patients would exhibit a significantly smaller eyeblink magnitude than controls while viewing unpleasant slides, and a significantly larger eyeblink magnitude than controls while viewing pleasant slides. This prediction was based on previous findings that PD patients show reduced striatal dopamine, which may affect dopamine-mediated limbic circuits; as well as amygdala neuropathology, which may affect the amygdalas modulation of the basic startle response. The second hypothesis was that Parkinsons patients would exhibit greater emotional blunting for threatening pictures, as opposed to other categories of negative pictures. Specifically, it was predicted that PD patients would display a significantly smaller eyeblink response than controls in response to threatening slides, whereas their eyeblink responses during other unpleasant pictures would not differ from that of controls. This prediction was based on the fact that the amygdala is known to play a key role in responding to threatening stimuli, is implicated in fear-potentiated startle, and exhibits pathology in PD patients. Hypothesis 1 was partially supported by the data. Parkinsons patients exhibited significantly smaller eyeblink responses than controls while viewing the unpleasant pictures; however, their eyeblink responses during pleasant pictures did not differ from 35

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36 those of controls. Thus, the PD patients demonstrated diminished emotional reactivity to negatively valenced pictures but not positively valenced pictures. Hypothesis 2 was also supported by the data. That is, PD patients exhibited significantly smaller eyeblink responses while viewing threatening pictures relative to controls. The patients and controls did not differ significantly with respect to eyeblink responses during other types of unpleasant pictures. In summary, PD patients demonstrated diminished emotional reactivity to unpleasant pictures compared to healthy controls (as indexed by startle eyeblink modulation), but did not differ from controls in terms of emotional reactivity to pleasant pictures. Furthermore, this effect seems to be driven by the PD patients diminished emotional reactivity towards threatening stimuli specifically. Basic Acoustic Startle in PD Patients Before discussing some possible explanations for the present findings, an obvious question concerns whether the Parkinsons patients might have a basic defect in startle eyeblink reactivity per se. Conceivably, Parkinsons patients could have motor abnormalities that might reduce or minimize the size of the eyeblink response itself. This, in turn, would result in reduced size of startle eyeblink responses during negative emotional pictures, giving rise to the impression of diminished emotional reactivity to unpleasant and threatening stimuli. To explore this, it is necessary to look at past research on the basic startle response in patients with Parkinsons disease. Vidailhet and colleagues (1992) examined startle eyeblink responses elicited by an abrupt noise in eleven patients with idiopathic PD and a group of controls. Both the magnitude of the startle eyeblink response and the pattern of muscles recruited were similar in the PD patients and controls. However, the latency of the eyeblink response was significantly

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37 delayed in the Parkinsons patients. Similar findings were described by Kofler and coworkers (2001). In contrast, Seignorel and colleagues (2003) found no significant differences in either latency or magnitude of startle eyeblink responses in PD patients and controls. In the present study, basic startle data were available from ten controls and ten Parkinsons patients. Basic startle eyeblink responses were obtained immediately prior to presentation of the emotional pictures. These data consisted of twelve startle eyeblink responses that had been elicited in response to a burst of white noise delivered through headphones. The results of a one-way ANOVA revealed no significant differences between the PD and Control groups in terms of latency to peak startle eyeblink, (F(1,18) = 1.62, p >.20 [Control mean = 73.3 ms, SD = 8.27; PD mean = 66.9 ms, SD = 13.5]). Similarly, there was no significant difference between the PD patients and Controls with regard to the magnitude of the startle eyeblink response (F(1,18) = 2.50, p>.10 [Control mean = .0170 mV, SD = .009; PD mean = .0113 mV, SD = .008]) Taken together, some inconsistency exists with respect to latency of basic startle eyeblink responses described in the literature. Some studies report slowed startle eyeblink responses in Parkinsons patients (Kofler et al., 2001; Vidailhet et al., 1992), whereas others have found no difference between PD patients and Controls (Bowers, Miller, Springer, Foote, & Okun, submitted; Seignorel et al., 2003). Importantly, however, all studies are consistent with respect to magnitude of startle responses in Parkinson patients and controls. Specifically, the PD patients appear normal with regards to the absolute size of the startle eyeblink peak. This, of course, is the variable of interest in the current study.

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38 Possible Effects of Depression on the Present Findings One possible explanation for the present findings is that the PD patients had diminished potentiation of startle eyeblink in response to unpleasant pictures due to depression and/or apathy. Every attempt was made to exclude PD patients that may be depressed from the study by only including patients that did not meet criteria for Major Depression. However, two of the twenty PD patients did meet criteria for mild depression as determined by BDI score, and PD patients and controls did significantly differ with respect to mean BDI scores. Another possibility is that some of the patients may have experienced depression in the past and abnormal emotional reactivity may have persisted (even though they were asymptomatic at the time of testing). Findings from a recent study with depressed patients suggest that this is an unlikely explanation. Using pictures from the International Affective Picture System, Allen and coworkers (Allen, Trinder, & Brennan, 1999) found that moderate to severely depressed subjects (BDI scores ranging from 19 to 29) showed normal emotional startle modulation. Patients who were extremely depressed (i.e., BDI scores greater than 30) showed a larger startle potentiation for pleasant versus unpleasant pictures (i.e., they responded to the pleasant pictures as if they were aversive). Although this study involved a small sample size, it suggests that abnormal startle modulation is not exhibited by depressed subjects unless they are severely depressed; furthermore, the pattern of startle potentiation found was opposite to that of the current study. Namely, the PD patients in the present study demonstrated normal startle modulation for pleasant pictures, but diminished startle modulation for unpleasant pictures. Similarly, the pattern of responding in the current study does not appear to be due to a generalized apathy. Since apathy is the diminished reaction to all stimuli, both

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39 positive and negative (Marin, 1996), one would expect a diminished reaction to emotional pictures of all valence categories if apathy were indeed the driving force behind the observed responses in PD patients. However, the present study did not formally test level of apathy by use of standard scales, and thus this possibility cannot be addressed by the current data. The Role of the Amygdala in Response to Threatening/Fearful Stimuli The finding of reduced emotional responsivity to unpleasant pictures, and more specifically, threatening pictures, is consistent with previous reports of pathological changes in the amygdala of patients with Parkinsons disease (Braak & Braak, 2000; Harding et al., 2002; Ouchi et al., 1999). Several studies of patients with lesions that include the amygdala have reported impaired identification of fear facial expressions (Adophs et al. 1994, 1995; Calder et al. 1996; Young et al. 1995;). Additionally, fMRI studies have found that the viewing of facial expressions of fear is associated with robust amygdala activation (Breiter et al., 1996; Davidson & Irwin, 1999; Davis & Whalen, 2001; Morris et al., 1996; Whalen et al., 1998). Importantly, however, amygdala activation is sometimes found for other negative facial expressions of emotion as well, including disgust (Schienle et al., 2002) and anger (Tessitore et al., 2002). In an experiment utilizing threatening pictures from the IAPS series (similar to the current study), Hariri et al. (2003) found a significant bilateral amygdala BOLD response when healthy subjects were asked to simply match a picture to a picture identical to it. In light of this evidence implicating the amygdala in the processing of threatening stimuli, it is possible that the PD patients in the present study suffer from significant amygdala pathology that is causing a diminished emotional reactivity to threat-evoking stimuli. The Parkinsons patients in the current study each received head MRI scans; however, at this

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40 time volumetric measurements of the amygdala have not been performed, and thus this prediction remains speculative. Additionally, Tessitore et al. (2001) have found evidence that dopamine may modulate the functioning of the amygdala. The implication of this finding with regards to the current study is that dopamine modulation of the amygdala may be disrupted in PD patients due to loss of striatal dopamine. An alternative or additional explanation for the current findings is that reduced dopaminerigic innervation (i.e., nigrostriatal, mesolimbic, and/or mesocortical) in PD patients may be disrupting the neural circuitry involved in emotion processing. Although the patients in the present study were tested while on dopaminergic medication, it is unlikely that this makes them similar to healthy people with respect to dopamine levels. For example, Ouchi and coworkers (1999) found a reduction of dopamine (DA) agonist binding in the amygdala, striatum, and orbitofrontal cortex of unmedicated PD patients. The authors suggested that this might be due to a loss of presynaptic DA terminals in these regions. To relate this back to the present study, a loss of dopaminergic terminals would decrease levadopa binding in the medicated patients, leaving them with abnormally low DA levels even when on medication. Additionally, the results from Ouchi and colleagues laboratory suggest an alteration in the mesocortical, mesolimbic, and striato-thalamo-cortico orbitofrontal dopaminergic systems functioning in PD patients. As mentioned previously, these are circuits thought to be involved in emotional processing. Dissociation of Subjective Ratings and Physiological Response Interestingly, although the PD patients showed diminished modulation of startle in response to negative stimuli (particularly threatening stimuli) compared to controls, the two groups did not differ with respect to their subjective ratings of valence and arousal

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41 levels in response to the pictures. Although the literature is sparse, there is evidence that decoupling of subjective emotional experience and physiological response can occur in patients following brain damage. For example, a dissociation between skin conductance responses (SCRs) and verbal report during anticipatory anxiety of electric shock was reported by Slomine et al. (1999). Patients with both right and left hemisphere brain damage exhibited smaller SCRs than healthy controls while anticipating the shock, yet all groups reported feeling less pleasant, less in control, and more aroused while awaiting shock as opposed to during a no-shock condition. In contrast, Meadows & Kaplan (1994) reported that patients with right hemisphere damage showed diminished SCRs to emotional and neutral slides relative to controls, while patients with left hemisphere brain damage exhibited increased SCRs to both emotional and neutral slides. The groups did not differ with respect to subjective ratings of the slides, or in orienting and habituation to loud tones. Decoupling of physiological and subjective emotional responses in Parkinsons disease patients has not been discussed in the literature, and is certainly an area towards which future research should be directed. Although the mechanism underlying this decoupling is unknown, one possibility is that subjective emotional experience typically incorporates feedback from the bodys physiological pattern of response. In Parkinsons disease as well as other neurological disorders, brain abnormalities can cause a functional disconnect between the two (Slomine et al., 1999). Alternatively, it may be that patients know the typical valence rating that is expected from them for each slide (i.e., mutilation pictures should be rated as very unpleasant, puppies as pleasant) and are conforming to experimenter demand characteristics.

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42 Limitations of the Present Study Several limitations of the current study must be acknowledged. First, the study suffers from a small sample size, and thus it is uncertain whether these findings would be replicated in a larger sample. Secondly, women and men were included together, although men and women are generally regarded as responding to emotional stimuli differently, and expressing emotional reactivity to different degrees. 5 The study also utilized a rather homogeneous sample of Parkinson patients who were highly educated and who had moderate motor impairments (mean Hoehn-Yahr stage of 2.7). Further research is needed to determine whether the same pattern of affective startle modulation exits in patients with milder or more severe PD. Turning to a methodological critique of the study, one limitation is the fact that the analysis of eyeblink magnitude to threatening versus other types of fearful stimuli was conducted post-hoc. Thus, the original set of forty-four pictures was designed to measure emotional reactivity to neutral, pleasant, and unpleasant stimuli; later, pictures depicting imminent attack were grouped together and labeled as threatening, and all other remaining unpleasant pictures were grouped together and labeled other unpleasant pictures. Ideally, a larger sample of pictures should be used, expressing a variety of threatening situations, and designed explicitly to assess startle modulation during viewing of threatening stimuli versus other specific types of aversive stimuli (for example, disgust-eliciting pictures). 1 However, separate t-tests conducted on PD and control data yielded no significant differences between men and women for unpleasant or pleasant blink magnitudes (controls unpleasant: t(13) = -0.038, p >.9; controls pleasant: t(13) = 0.31, p > .7; PD unpleasant: t(18) = -0.089, p > .9; PD pleasant: t(18) = 0.56, p > .5).

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43 Another limitation of the current study is that startle eyeblink modulation to unpleasant and pleasant stimuli was assumed to reflect emotional reactivity to the valence of the pictures. However, the arousal level of a picture also affects startle modulation by intensifying the magnitude of the eyeblink in the direction of the individuals motivational activation (i.e., appetitive/pleasant or defensive/unpleasant). Namely, the more arousing an unpleasant picture is to a participant, the greater the startle potentiation. Similarly, the more arousing a pleasant picture is to a participant, the more attenuated the startle eyeblink (Bradley, Codispoti, Cuthbert, & Lang, 2001). It may be that Parkinsons patients display an overall pattern of hypoarousal in response to emotional materials. If this is true, than Parkinsons patients might have shown a smaller difference between unpleasant and pleasant picture eyeblink magnitudes relative to controls because they did not exhibit a level of arousal that would serve to intensify the magnitude of their eyeblink in line with the direction of the picture valence. Although PD patients reported experiencing levels of arousal equivalent to those of Controls, they also rated picture valences similar to Controls, suggesting that their subjective experience and physiologic reactions are not necessarily congruent. Thus, the possibility that the findings of the current study were due to a general diminished psychophysiologic reactivity to emotional material in Parkinsons patients cannot be ruled out. A further limitation is that analyses in the present study used T-scores, as opposed to raw eyeblink magnitudes, as a way to measure emotional startle modulation. This was done to minimize individual differences in eyeblink magnitude modulation, such that all subjects could be compared on a common metric. However, it is possible that converting raw scores to T-scores could obscure differences between the PD group and Controls. In

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44 the future, raw startle data should be analyzed as well, to check that it exhibits the same pattern as the transformed data. Finally, the current study did not use a manipulation check to determine whether participants subjectively felt threatened during presentation of slides categorized as threatening. Although PD patients did exhibit diminished startle eyeblink potentiation for threatening pictures compared to controls, this assumes that threat was indeed the emotion subjectively experienced by participants, which may or may not have been the case. This issue is further confounded by the fact that both groups rated the other unpleasant stimuli as being more unpleasant than the threatening stimuli, yet they displayed larger eyeblink potentiation during viewing of the threatening pictures. Directions for Future Research Future directions for research include an exploration as to whether different subtypes of PD are associated with differential patterns of affective startle eyeblink modulation. For example, some researchers classify PD patients as either akinetic/rigid or tremor predominant, depending on the key symptoms of the individual patient (Ransmayr, Poewe, Ploerer, Birbamer, & Gerstenbrand, 1987; Ransmayr, Poewe, Plorer, Gerstenbrand, Leidlmair, & Mayr, 1986). It is thought that the akinetic/rigid type involves greater involvement of the mesolimbic and mesocortical pathways, and thus these patients may display more aberrant patterns of startle modulation. The emotional modulation of startle paradigm could also be used in different groups of patients with basal ganglia disorders, such as those with essential tremor, Progressive Supranuclear Palsy, and Huntingtons Disease, as a way to measure emotional reactivity in these patient groups without the confounding variable of motor output abnormalities. It may be that disorders that often appear clinically similar on the behavioral level (such as essential

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45 tremor and PD) may be distinguished from one another by their pattern of emotional startle modulation. Another important future line of research will be to determine if diminished reactivity to threatening pictures correlates with measures of amygdala pathology, such as decreased amygdala volume or decreased BOLD signal (relative to controls) during fMRI with concurrent presentation of threatening pictures. The results of the current study, supported by past literature, suggest that reduced emotional reactivity to threatening stimuli may be linked to amygdala abnormalities, but this hypothesis is purely speculative as of now. Additionally, PD patients should be tested off their dopaminergic medications using the emotional startle modulation paradigm, in order to determine how dopamine levels affect emotional reactions as assessed by the startle paradigm. An idea for a future study might include threatening pictures from the IAPS series intermixed with disgusting pictures. Previous investigators have used pictures such as body excrement, food contamination, and unsanitary conditions in an attempt to evoke disgust in participants (e.g., Schienle et al., 2002; Shapira et al., 2003;). Studies have implicated several structures that are part of the nigrostriatal loop affected in PD as being involved in the recognition of disgust. For example, in an fMRI study, Sprengelmeyer and coworkers (1998) found that viewing pictures of facial expressions of disgust caused activation of the left anterior insula, right anterior globus pallidus, and putamen in healthy subjects. Activation of the left anterior insula, bilateral putamen, and right globus pallidus and caudate nucleus was reported by Phillips et al. (1997), who presented images of faces depicting different degrees of disgust intensity to normal controls. As such, one might predict that PD patients presented with disgust-evoking pictures would exhibit

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46 diminished startle potentiation, much as they displayed a diminished startle potentiation in response to threat-evoking stimuli in the present study. To conclude, the finding of reduced emotional reactivity to negative stimuli in PD patients, and threatening stimuli specifically, does not appear to be an artifact of a motor output problem or depressive symptomatology. For these reasons, it offers a unique advantage compared to other measures of emotionality in PD (such as facial expressivity or vocal prosody), which are wrought with the confounding problem that these movements may be affected by the motor symptoms of PD. Furthermore, the acoustic startle is an involuntary physiological reaction that is very difficult, if not impossible, to inhibit or voluntarily control, and thus does not rely on the participants attention or motivation (Bradley, 2000). These characteristics make measurement of affective modulation of eyeblink amplitude a paradigm that may afford a purer, more objective method of exploring emotional reactivity in patients with basal ganglia disorders.

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LIST OF REFERENCES Adolphs, R., Schul, R., & Tranel, D. (1998). Intact recognition of facial emotion in Parkinsons disease. Neuropsychology, 12(2), 253-258. Adolphs, R., Tranel, D., Damasio, H., & Damasio, A. (1994). Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature, 372(6507), 669-772. Adolphs, R., Tranel, D., Damasio, H., & Damasio, A.R. (1995). Fear and the human amygdala. The Journal of Neuroscience, 15, 5879-5892. Alexander, G.E., DeLong, M.R., & Strick, P.L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357-381. Allen, N.B., Trinder, J., & Brennan, C. (1999). Affective startle modulation in clinical depression: Preliminary findings. Biological Psychiatry, 46, 542-550. Amaral, D.G. (2003). The amygdala, social behavior, and danger detection. Annals of the New York Academy of Sciences, 1000, 337-347. Beck, A.T. (1978). Beck depression inventory. San Antonio, TX: The Psychological Corporation. Beck, A.T., Steer, R.A., & Brown, G.K. (1996). Beck depression inventory-Second edition manual. San Antonio, TX: The Psychological Corporation. Benabid, A.L. (2003). Deep brain stimulation for Parkinson's disease. Current Opinion in Neurobiology, 13(6), 696-706. Blonder, L.X., Gur, R.E., & Gur, R.C. (1989). The effects of right and left hemiparkinsonism on prosody. Brain and Language, 36, 193-207. Borod, J.C., Welkowitz, J., Alpert, M., Brozgold, A.Z., Martin, C., Peselow, E., & Diller, L. (1990). Parameters of emotional processing in neuropsychiatric disorders: Conceptual issues and a battery of tests. Journal of Communication Disorders, 23, 247-271. 47

PAGE 57

48 Bowers, D., Bosch, W., Gokcay, D., Peden, C., Pedraza, O., Miller, K., Bongiolatti, S., Springer, U., Okun, M. (in press). Faces of emotion in Parkinson's disease: Micro-expressivity and bradykinesia during voluntary facial expressions. Journal of Cognitive Neuroscience. Bowers, D. Gilmore, R. Bauer, R., Rogish, M., Kortenkamp, S., Gokay, D., Bradley, M. & Roper, S. (1998, November) Affect modulation of startle is disrupted by right, but not left, temporal resections involving the amygdala. Poster session presented at the meeting of the Society for Neuroscience, Los Angeles, 1998. Bowers, D., Miller, K., Springer, U., Foote, K., Okun, M. (2003). Startling facts about emotion in Parkinsons disease. Manuscript submitted for publication. Braak, H., & Braak, E. (2000). Pathoanatomy of Parkinsons disease. Journal of Neurology, 247(Suppl. 2), II/3-II/10. Bradley, M. (2000). Emotion and motivation. In L. Tassinary, J. Cacioppo, & G. Berntson (Eds.), Handbook of psychophysiology. New York, NY: Cambridge University Press. Bradley, M.M., Codispoti, M., Cuthbert, B.N., & Lang, P.J. (2001). Emotion and motivation I: Defensive and appetitive reactions in picture processing. Emotion, 1(3), 276-298. Bradley, M.M., Cuthbert, B.N., & Lang, P.J. (1990). Startle reflex: Emotion or attention? Psychophysiology, 27, 513-522. Bradley, M.M., Cuthbert, B.N., & Lang, P.J. (1991). Startle and emotion: Lateral acoustic probes and the bilateral blink. Psychophysiology, 28, 285-295. Bradley, M.M., & Vrana, S.R. (1993). In N. Birbaumer, & A. Ohman (Eds.), The structure of emotion: Psychophysiological, cognitive, and clinical aspects (pp. 270-287). Seattle, WA: Hogrefe & Huber. Breiter, H.C., Etcoff, N.L., Whalen, P.J., Kennedy, W.A., Rauch, S.L., Buckner, R.L., Strauss, M.M., Hyman, S.E., & Rosen, B.R. (1996). Response and habituation of the human amygdala during visual processing of facial expression. Neuron, 17, 875-887. Brown, R.G., & Marsden, C.D. (1984). How common is dementia in Parkinsons disease? Lancet, 2, 1262-1265. Brown, R.G., & Pluck, G. (2000). Negative symptoms: The pathology of motivation and goal-directed behaviour. Trends in Neuroscience, 23, 412-417. Buck, R., & Duffy, R.J. (1980). Nonverbal communication of affect in brain-damaged patients. Cortex, 16, 351-362.

PAGE 58

49 Burn DJ. (2002). Beyond the iron mask: Towards better recognition and treatment of depression associated with Parkinson's disease. Movement Disorders, 17(3), 445-454. Calder, A.J., Young, A.W., Rowland, D., Perrett, D.I., Hodges, J.R., & Etcoff, N.L. (1996). Facial emotion recognition after bilateral amygdala damage: Differentially severe impairment of fear. Cognitive Neuropsychology, 13, 699-745. Cools, R., Barker, R.A., Sahakian, B.J., & Robbins, T.W. (2001). Mechanisms of cognitive set flexibility in Parkinsons disease. Brain, 124, 2503-2512. Cummings, J.L. (1992). Depression and Parkinson's disease: A review. American Journal of Psychiatry, 149, 443. Davidson, R.J., Irwin, W. (1999). The functional neuroanatomy of emotion and affective style. Trends in Cognitive Science, 3(1), 11-21. Davis, M. (1992). The role of the amygdala in conditioned fear. In J. Aggleton (Ed.), The amygdala: Neurobiological aspects of emotion, memory, and mental dysfunction (pp. 255-305). New York, NY: Wiley Publishers. Davis, M., Genderlman, D.S., Tischler, M.D., & Gendelman, P.M. (1982). A primary acoustic startle circuit: lesion and stimulation studies. Journal of Neuroscience, 2(6), 791-805. Davis, M., Whalen, P.J. (2001). The amygdala: Vigilance and emotion. Molecular Psychiatry, 6(1), 13-34. Dimitrov, M, Grafman, J., Soares, A.H., Clark, K. (1999). Concept formation and concept shifting in frontal lesion and Parkinsons disease patients assessed with the California card sorting task. Neuropsychology, 13, 135-143. Fahn, S. (2003). Description of Parkinsons disease as a clinical syndrome. Annual New York Academy of Sciences, 991, 1-14. Fahn, S., Elton, R.L. (1987). Unified Parkinsons disease rating scale. In S. Fahn, C.D. Marsden, M. Goldstein, D.B. Calne (Eds.), Recent developments in Parkinsons disease, Volume 2 (pp. 153-163). Florham Park, NJ: Macmillan Healthcare Information. Folstein, M.F., Folstein, S.E., & McHugh, P.R. (2001). Mini-Mental state examination. Odessa, FL: Psychological Assessment Resources. Gauntlett-Gilbert, J., Roberts, R.C., Brown, V.J. (1999). Mechanisms underlying attentional set-shifting in Parkinsons disease. Neuropsychologia, 37, 605-616.

PAGE 59

50 Greenwald, M., Cook, E., & Lang, P. (1989). Affective judgment and psychophysiological response dimensional covariation in the evaluation of pictorial stimuli. Journal of Psychophysiology, 3, 51-64. Grillon, C., Ameli, R., Foot, M., & Davis, M. (1993). Fear-potentiated startle: Relationship to the level of state/trait anxiety in healthy subjects. Biological Psychiatry, 33(8-9), 566-574. Grillon, C., Ameli, R., Woods, S.W., Merikangas, K., & Davis, M. (1991). Fear-potentiated startle in humans: Effects of anticipatory anxiety on the acoustic blink reflex. Psychophysiology, 28(5), 588-595. Harding, A.J., Stimson, E., Henderson, J.M., & Halliday, G.H. (2002). Clinical correlates of selective pathology in the amygdala of patients with Parkinsons disease. Brain, 125, 2431-2445. Hariri, A.R., Mattay, V.S., Tessitore, A., Fera, F., & Weinberger, D.R. (2003). Neocortical modulation of the amygdala response to fearful stimuli. Biological Psychiatry, 53, 494-501. Hitchcock, J.M., & Davis, M. (1991). Efferent pathway of the amygdala involved in conditioned fear as measured with the fear-potentiated startle paradigm. Behavioral Neuroscience, 105(6), 826-842. Hitchcock, J.M., Sananes, C.B., Davis, M. (1989). Sensitization of the startle reflex by footshock: Blockade by lesions of the central nucleus of the amygdala or its efferent pathway to the brainstem. Behavioral Neuroscience, 103(3), 509-518. Hoehn, M., & Yahr, M. (1967). Parkinsonism: Onset, progression, and mortality. Neurology, 17, 427-442. Hughes, A.J., Ben-Shlomo, Y., Daniel, S.E., & Lees, A.J. (1992). What features improve the accuracy of clinical diagnosis in Parkinsons disease: A clinicopathologic study. Neurology, 42, 1142-1146. Hughes, A.J., Daniel, S.E., Kilford, L., & Lees, A.J. (1992). Accuracy of clinical diagnosis of idiopathic Parkinsons disease: A clinicopathological study of 100 cases. Journal of Neurology, Neurosurgery, and Psychiatry, 55, 181-184. Isella, V., Melzi, P., Grimaldi, M., Iurlaro, S., Piolti, R., Ferrarese, C., Frattola, L., & Appollonio, I. (2002). Clinical, neuropsychological, and morphometric correlates of apathy in Parkinsons disease. Movement Disorders, 17(2), 366-371. Jacobs, D.H., Shuren, J., Bowers, D., & Heilman, K.M. (1995). Emotional facial imagery, perception, and expression in Parkinsons disease. Neurology, 45, 1696-1702.

PAGE 60

51 Kan, Y., Kawamura, M., Hasegawa, Y., Mochizuki, S., & Nakamura, K. (2002). Recognition of emotion from facial, prosodic, and written verbal stimuli in Parkinsons disease. Cortex, 38(4), 623-630. Katsikitis, B.A., & Pilowsky, M.D. (1988). A study of facial expression in Parkinsons disease using a novel microcomputer-based method. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 362-366. Katsikitis, B.A., & Pilowsky, M.D. (1991). A controlled quantitative study of facial expression in Parkinsons disease and depression. The Journal of Nervous and Mental Disease, 179(11), 683-688. Klver, H., & Bucy, P.C. (1939). Preliminary analysis of the temporal lobes in monkeys. Archives of Neurology and Psychiatry, 42, 979-1000. Kofler, M., Muller, J., Wenning, G.K. Reggiani, L., Hollosi, P., Bosch, S., Ransmayr, G., Valls-Sole, J., & Poewe, W. (2001). The auditory startle reaction in parkinsonian disorders. Movement Disorders, 16(1), 62-71. Lang, P.J. (1980). Behavioral treatment and biobehavioral assessment: Computer applications. In J.B. Sidowski, J.H. Johnson, & T.A. Williams (Eds.). Technology in mental health care delivery. Norwood, NJ: Albex Publishing Corp. Lang, P.J., Bradley, M.M., & Cuthbert, B.N. (1990). Emotion, attention, and the startle reflex. Psychological Review, 97(3), 377-395. Lang, P., Bradley, M., & Cuthbert, B. (2001a). The international affective picture system (photographic slides). Gainesville, FL: The Center for Research in Psychophysiology, University of Florida. Lang, P., Bradley, M., & Cuthbert, B. (2001b). International affective picture system (IAPS): Instruction manual and affective ratings: Technical Report A-5. Gainesville, FL: The Center for Research in Psychophysiology, University of Florida. Lang, A.E, & Lozano, A.M. (1998). Parkinsons disease: First of two parts. The New England Journal of Medicine, 339(15), 1044-1053. Madeley, P., Ellis, A.W., & Mindham, R.H.S. (1995). Facial expressions and Parkinsons disease. Behavioural Neurology, 8, 115-119. Marin, R.S. (1991). Apathy: A neuropsychiatric syndrome. Journal of Neuropsychiatry and Clinical Neuroscience, 3, 243-254. Marin, R.S., (1996). Apathy: Concept, syndrome, neural mechanisms, and treatment. Seminars in Clinical Neuropsychiatry, 1, 304-314.

PAGE 61

52 Mayberg, H.S., Starkstein, S.E., Sadzot, B., Preziosi, T., Andrezejewski, P.L., Dannals, R.F., Wagner, H.N. Jr., & Robinson R.G. (1990). Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson's disease. Annals of Neurology, 28(1), 57-64. McDonald, W.M., Richard, I.H., & DeLong, M.R. (2003). Prevalence, etiology, and treatment of depression in Parkinson's disease. Biological Psychiatry, 54(3), 363-75. Meadows, M.E., & Kaplan, R.F. (1994). Dissociation of autonomic and subjective responses to emotional slides in right hemisphere damaged patients. Neuropsychologia, 32(7), 847-56. Morris, J.S., Frith, C.D., Perrett, D.I., Rowland, D., Young, A.W., Calder, A.J., & Dolan, R.J. (1996). A differential neural response in the human amygdala to fearful and happy facial expressions. Nature, 383, 812-815. National Institute of Neurological Disorders and Stroke (2001, July 1). Parkinsons disease backgrounder. Retrieved February 9, 2004, from http://www.ninds.nih.gov/health_and_medical/pubs/ parkinson's_disease_backgrounder.htm OGorman, J.R. (1990). Individual differences in the orienting response: Nonresponding in nonclinical samples. Pavlovian Journal of Biological Science, 25(3), 104-108. Ouchi, Y., Yoshikawa, E., Okada, H., Futatsubashi, M., Sekine, Y., Iyo, M., et al. (1999). Alterations in binding site density of dopamine transporter in the striatum, orbitofrontal cortex, and amygdala in early Parkinsons disease: Compartment analysis for -CFT binding with positron emission tomography. Annals of Neurology, 45, 601-610. Peto, V., Jenkinson, C., & Fitzpatrick, R. (1998). PDQ-39: A review of the development, validation and application of a Parkinson's disease quality of life questionnaire and its associated measures. Journal of Neurology, 245(Supplement 1): S10-S14. Phillips, M.L., Young, A.W., Scott, S.K., Calder, A.J., Andrew, C., Giampietro, V., Williams, S.C.R., Bullmore, E.T., Brammer, M., & Gray, J.A. (1998). Neural responses to facial and vocal expressions of fear and disgust. Proceedings of the Royal Society of London, Series B: Biological sciences, 265, 1809-1817. Pluck,G., & Brown, R.G. (2002). Apathy in Parkinson's disease. Journal of Neurology, Neurosurgery, and Psychiatry, 73(6), 636-42. Pogarell, O., & Oertel, W.H. (1999). Parkinsonian syndromes and Parkinsons disease: Diagnosis and differential diagnosis. In P.A. LeWitt & W.H. Oertel (Eds.), Parkinsons disease: The treatment options (pp. 1-10). London, UK: Martin Dunitz.

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53 Ransmayr, G., Poewe, W., Ploerer, S., Birbamer, G., & Gerstenbrand, F. (1987). Psychometric findings in clinical subtypes of Parkinson's disease. Advances in Neurology, 45, 409-411. Ransmayr, G., Poewe, W., Plorer, S., Gerstenbrand, F., Leidlmair, K., & Mayr, U. (1986). Prognostic implications of the motor symptoms of Parkinson's disease with respect to clinical, computertomographic and psychometric parameters. Journal of Neural Transmission, 67(1-2), 1-14. Rosen, J.B., & Davis, M. (1988). Enhancement of acoustic startle by electrical stimulation of the amygdala. Behavioral Neuroscience, 102(2), 195-202, 324. Rosen, J.B., Hitchcock, J.M., Miserendino, M.J., Falls, W.A., Campeau, S., & Davis, M. (1992). Lesions of the perirhinal cortex but not of the frontal, medial prefrontal, visual, or insular cortex block fear-potentiated startle using a visual conditioned stimulus. Journal of Neuroscience, 12(12), 4624-4633. Schienle, A., Stark, B., Walter, C., Blecker, U., Ott, P., Kirsch, G., Sammer, G., & Vaitl, D. (2002). The insula is not specifically involved in disgust processing: A fMRI study. Neuroreport, 13, 2023-2026. Schwab, J.F., & England, A.C. (1969). Unified Parkinson's disease rating scale version 3.0 Schwab and England activities of daily living scale. In F.J. Gillingham & M.C. Donaldson (Eds.): Third Symposium on Parkinson's Disease (pp. 152-157). Edinburgh: Livingstone. Scott, S., Caird, F., & Williams, B. (1984). Evidence for an apparent sensory speech disorder in Parkinsons disease. Journal of Neurology, Neurosurgery, and Psychiatry, 47, 840-843. Seignorel, P., Miller, K., Bowers, D., Okun, M. (2003, October). Startle responses in patients with psychogenic movement disorders. Presented at the Psychogenic Movement Disorders Workshop of the Movement Disorder Society, Atlanta, GA. Shapira, N.A., Liu, Y., He, A.G., Bradley, M.M., Lessig, M.C., James, G.A., Stein, D.J., Lang, P.J., & Goodman, W.K. Brain activation by disgust-inducing pictures in obsessive-compulsive disorder. Biological Psychiatry, 54(7), 751-756. Slomine, B., Bowers, D., & Heilman, K.M. (1999). Dissociation between autonomic responding and verbal report in right and left hemisphere brain damage during anticipatory anxiety. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 12(3), 143-148. Smith, M.C., Smith, M.K., & Ellgring, H. (1996). Spontaneous and posed facial expression in Parkinsons disease. Journal of the International Neuropsychological Society, 2, 383-391.

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54 Sprengelmeyer, R., Rausch, M., Eysel, U.T., & Przuntek, H. (1998). Neural structures associated with recognition of facial expressions of basic emotions. Proceedings of the Royal Society of London, Series B: Biological sciences, 265, 1927-1931. Sprengelmeyer, R., Young, A.W., Mahn, K., Schroeder, U., Woitalla, D., Bttner, T., Kuhn, W., & Przuntek, H. (2003). Facial expression recognition in people with medicated and unmedicated Parkinsons disease. Neuropsychologia, 41, 1047-1057. Starkstein, S.E., Mayberg, H.S., Preziosi, T.J., Andrezejewski, P., Leiguarda, R., & Robinson, R.G. (1992). Reliability, validity, and clinical correlates of apathy in Parkinsons disease. Journal of Neuropsychiatry and Clinical Neuroscience, 4, 134-139. Tessitore, A., Hariri, A.R., Fera, F., Smith, W.G., Chase, T.N., Hyde, T.M., Weinberger, D.R.,& Mattay, V.S. (2002). Dopamine modulates the response of the human amygdala: A study in Parkinsons disease. The Journal of Neuroscience, 22(20), 9099-9103. van Spaendonck, K.P., Berger, H.J., Horstink, M.W., Borm, G.F., & Cools, A.R. (1993). Card sorting performance in Parkinsons disease: A comparison between acquisition and shifting performance. Journal of Clinical Experimental Neuropsychology, 17, 918-925. Vidailhet, M., Rothwell, J.C., Thompson, P.D., Lees, A.J., & Marsden, C.D. (1992). The auditory startle response in the Steele-Richardson-Olszewski syndrome and Parkinsons disease. Brain, 115(4), 1181-1192. Vrana, S.R., Spence, E.L., & Lang, P.J. (1988). The startle probe response: A new measure of emotion? Journal of Abnormal Psychology, 97(4), 487-491. Walker, D.L., & Davis, M. (2002). The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacology, Biochemistry, and Behavior, 71, 379-392. Whalen, P.J., Rauch, S.L, Etcoff, N.L., McInerney, S.C., Lee, M.B., & Jenike, M.A. (1998). Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. Journal of Neuroscience, 18, 411-418. Yip, J.T.H., Lee, T.M.C., Ho, S.-L., Tsang, K.-L., & Li, L.S.W. (2003). Emotion recognition in patients with idiopathic Parkinsons disease. Movement Disorders, 18(10), 1115-1122. Young, A.W., Aggleton, J.P., Hellawell, D.J., Johnson, M., Broks, P., & Hanley, J.R. (1995). Face processing impairments after amygdalotomy. Brain, 118, 15-24.

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55 Zgaljardic, D.J., Borod, J.C., Foldi, N.S., & Mattis, P. (2003). A review of the cognitive and behavioral sequelae of Parkinsons disease: Relationship to frontostriatal circuitry. Cognitive and Behavioral Neurology, 16(4), 193-210.

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BIOGRAPHICAL SKETCH Kimberly Miller was born in San Jose, CA, and received her B.A. in psychology from the University of California, Berkeley. After gaining research experience in cognitive neuroscience at the Martinez V.A., she moved to Gainesville to pursue her doctorate in clinical psychology at the University of Florida, specializing in neuropsychology. Current clinical interests include learning disorders and speech and language disorders. Current research interests include the affective modulation of startle in chronically depressed patients, as well as the effect of psychiatric disorders on cognitive processes. 56


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DIMINISHED AFFECTIVE MODULATION OF STARTLE TO THREATENING
STIMULI IN PARKINSON' S DISEASE














By

KIMBERLY M. MILLER


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


2004
































Copyright 2004

by

Kimberly M. Miller
















ACKNOWLEDGMENTS

I would like to acknowledge my research mentor, Dawn Bowers, for her constant

availability and support. I would like to thank the graduate students and research

assistants in the Cognitive Neuroscience Laboratory who helped in the collection of this

data. I would like to thank Michael Okun and his colleagues at the Movement Disorders

Center for providing access to patients, and the patients themselves who endured many

long hours of testing.




















TABLE OF CONTENTS


page


ACKNOWLEDGMENT S ................. ................. iii...___ ....


LIST OF TABLES ....___ ................ ........___.........v


LI ST OF FIGURE S .............. .................... vii


AB S TRAC T ......_ ................. ..........._..._ viii..


CHAPTER


1 INTRODUCTION ................. ...............1.......... ......


Motor and Cognitive Symptoms in Parkinson's Disease .............. .....................
Emotional Processing in Parkinson's Disease ................. .............. ......... .....4
Mood Disturbance in Parkinson' s Disease ................ .. ............ ................ ..4

Expression and Perception of Emotion in Parkinson' s Disease ................... .........5
Physiologic Reactivity ................. ............. ... .... ........ ..........7
Pathophysiology of Emotional Changes in Parkinson' s Disease ................ ...............9
Neural Circuitry Involved in Emotional Behavior ..........._.._. ........_.. ........10
Amygdala Pathology ........._.._.. ...._... ...............11....
Rationale for the Present Study .............. ...............12....
Hypotheses and Predictions ........._..... ...._... ...............14....
Hypothesis 1 .............. ............... 14....
Hypothesis 2 ........._.._.. ...._... ...............14....
Exploratory Questions ........._..... ...._... ...............15.....


2 METHODS ........._.._.. ...._... ...............17....


Participants .............. ...............17....
Materials ........._.._........ .. ....._... .... .._... .... .. .........1
International Affective Picture System Slides............... ...............19.
Self Assessment Manikin (SAM) ................. ...............21................
Proc edure s ................ ...............21........... ....
Data Collection ................. ........ ........ ... ............. ....................2
Data Reduction of the Eyeblink Component of the Startle Response .................22
Statistical Analyses............... ...............23











3 RE SULT S .............. ...............26....


Startle Eyeblink .............. .. ........... ...........2
Pleasant versus Unpleasant Pictures .....___._ ........_. .....__. ...........2
Threatening versus Other Unpleasant Pictures ....._.__._ ........___ ..............27
Subj ective Ratings: Valence and Arousal ....__ ......_____ ...... ...___.........2
Pleasant versus Unpleasant Pictures ....__ ......_____ .......___ ............2
Threatening versus Other Unpleasant Pictures ....._____ .........__ ...............30
Eyeblink Magnitude and BDI Correlations ................ ...............31......_... ...

4 DI SCUS SSION ....._.._................. ........_.._.........3


Basic Acoustic Startle in PD Patients ........._._. ............. ... ....._. ...........3
Possible Effects of Depression on the Present Findings .................. .. ............ .......3 8
The Role of the Amygdala in Response to Threatening/Fearful Stimuli .................. .39
Dissociation of Subj ective Ratings and Physiological Response ............... ... ............40
Limitations of the Present Study ................. ...............42........... ...
Directions for Future Research ................. ...............44................


LIST OF REFERENCES ................. ...............47........... ....


BIOGRAPHICAL SKETCH .............. ...............56....


















LIST OF TABLES


Table pg

1-1 Patient and Control Characteristics .................._____ ......... ...........2

3-1 Means and SDs of Pleasantness and Arousal Ratings for Unpleasant and
Pleasant Pictures. ........... ..... .._ ...............30......

3-2 Means and SDs of Pleasantness and Arousal Ratings for Threatening and Other
Unpleasant Pictures. ............. ...............3 1....

3-3 Correlations Between Number of Years with Parkinson' s Disease, BDI Score,
Hoehn and Yahr Stage, and UPDRS Motor Subscale Score............... ..................3
















LIST OF FIGURES


Figure pg

1-1 Simplified Direct Loop in the PD patient's Dysfunctional Motor System. ..............3

1-2 Two Hypothesized Striato-Thalamo-Cortical Loops Involved in Emotion. ............11

3-1 Peak Eyeblink Amplitudes for Unpleasant versus Pleasant Pictures ................... ....28

3-2 Peak Eyeblink Amplitude for Threat versus Other Unpleasant Pictures .................29
















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

DIMINISHED AFFECTIVE MODULATION OF STARTLE TO THREATENING
STIMULI IN PARKINSON' S DISEASE


By

Kimberly M. Miller

May 2004

Chair: Dawn Bowers
Major Department: Clinical and Health Psychology

Rationale. Studies of patients with Parkinson's disease have suggested various

deficits in emotional processing. These impairments may be linked to a decrease in

dopamine levels regulating key limbic circuitry, and pathology of the amygdala in

Parkinson's patients. In the present study, the issue as to whether patients with

Parkinson's disease display normal emotional modulation of startle to unpleasant and

pleasant pictures was examined. Furthermore, within the category of unpleasant pictures,

reactivity to threat-eliciting versus other types of aversive pictures was investigated. It

was hypothesized that Parkinson' s patients would show diminished emotional reactivity

in general to the emotional pictures, based on suggestions of amygdala and limbic

circuitry dysfunction. Additionally, it was hypothesized that Parkinson' s patients would

exhibit reduced emotional reactivity, relative to controls, to threat-eliciting pictures

specifically, due to the role of the amygdala in processing of threatening stimuli.









Methods. To test this hypothesis, twenty Parkinson's patients and fifteen age-

matched healthy Controls viewed standard sets of pleasant, unpleasant, and neutral

pictures for six seconds each. During this time white noise bursts were binaurally

presented to elicit startle eyeblinks. Subj ective ratings of valence and arousal were also

obtained. The Parkinson's patients were tested while "on" dopaminergic medication.

Results. Data were analyzed using 2 X 2 repeated measures Analyses of

Variance. Both the Parkinson's patients and Controls showed significantly larger startle

amplitude during unpleasant versus pleasant pictures, which is the normal pattern of

emotion modulation. This effect was significantly weaker and less robust in the

Parkinson's patients than the Controls, as revealed by a Group X Affect interaction.

Specifically, startles to negative pictures were significantly smaller in Parkinson's than

Controls, with no group differences for pleasant pictures. Within the unpleasant pictures,

Controls showed a significantly larger startle amplitude during threatening versus other

types of unpleasant pictures, whereas the Parkinson' s patients did not. The Parkinson' s

and controls rated the emotional pictures similarly.

Conclusions. The current study found that Parkinson' s patients were less

emotionally reactive than controls to aversive pictures, specifically with regards to threat-

eliciting pictures. The basis for this diminished reactivity is unknown, but may reflect

pathological changes in the amygdala of PD patients, a structure consistently implicated

in processing of fearful stimuli, as well as a reduction in dopamine levels within limbic

neural circuitry.















CHAPTER 1
INTTRODUCTION

Parkinson's disease (PD) is the second most common neurodegenerative disorder

next to Alzheimer' s disease, affecting approximately half a million to a million people in

the United States (McDonald, Richard, & DeLong, 2003). About 50,000 new cases are

reported annually, and this figure is rising as the average age of the population increases

(National Institute of Neurological Disorders and Stroke, 2001). Slightly more males than

females suffer from Parkinson's disease. The average age of onset is approximately 60-

65 years old, although a small proportion of PD patients (5-10%) display symptoms

before age 40 (Fahn, 2003; Lang & Lozano, 1998). The likelihood of developing PD

increases with age, with a lifetime risk of about 2% (Fahn, 2003).

Although the motor and cognitive symptoms of Parkinson' s disease have been

well studied over the years, relatively few studies have specifically examined changes in

emotional reactivity. This is surprising in light of the fact that aspects of the neural

circuitry affected by dopaminergic depletion in PD involve "limbic" regions that are

known to be important in emotional behavior (i.e., amygdala, nucleus accumbens,

orbitofrontal region). Thus, the goal of the present study was to investigate emotional

reactivity in Parkinson's disease by using experimental measures that assessed

physiologic reactivity to emotional pictures. To do this, patients' physiological responses

to pictures of varying valence and arousal levels were measured and compared to the

responses of control subj ects. Before turning to a review of the literature on emotional

processing in PD, the core symptoms of Parkinson' s disease will be briefly discussed.









Motor and Cognitive Symptoms in Parkinson's Disease

Behaviorally, Parkinson's disease is characterized by motor symptoms including

resting tremor, bradykinesia (slowed movement), rigidity (increased muscle tone), and

akinesia (difficulty initiating or maintaining a body movement (Hughes, Ben-Shlomo,

Daniel, & Lees, 1992; Hughes, Daniel, Kilford, & Lees, 1992)). Additionally,

Parkinson's patients may experience diminished facial expressivity ("masked facies"),

loss of postural reflexes, and/or motoric "freezing" when attempting to walk (Fahn,

2003). These motoric symptoms are thought to be caused primarily by a depletion of

dopaminergic neurons in the substantial nigra. This dopaminergic depletion then affects a

whole cascade of structures involved in the production of voluntary movement,

particularly the basal ganglia. A diagram of the neural circuitry involved in Parkinson' s

disease is depicted in Figure 1-1. It has been estimated that patients with PD have an

approximately 60-85% loss of dopaminergic neurons in the substantial nigra (Pogarell &

Oertel, 1999). As such, dopamine replacement therapy (using levodopa, a dopamine

precursor that is able to cross the blood-brain barrier) is the maj or medical approach to

treating the motor symptoms of Parkinson' s (Fahn, 2003). Initially, the motor symptoms

of Parkinson's disease are dramatically improved by dopaminergic therapy. Over time,

however, medications become less effective and are associated with dramatic "on" and

"off' fluctuations in symptoms. This has led to recent surgical treatments for Parkinson' s

disease, including the implantation of small stimulating micro-electrodes into specific

brain regions within the basal ganglia (i.e., globus pallidus internus, subthalamic

nucleus). The basic idea behind deep brain stimulation and other surgical treatments for

Parkinson's disease is to change the imbalance of activation and inhibition that results

from dopaminergic depletion (Benabid, 2003).















Striatum



SNC (VA, VL)





MGP




Figure 1-1. Simplified Direct Loop in the PD patient' s Dysfunctional Motor System. The
striatum receives excitatory projections from the cortex, but input from the
SNc is impaired due to a reduction of dopamine. This results in the striatum
not receiving enough excitatory input to exert its inhibitory influence over the
MGP and SNr. The MGP and SNr, free of inhibition from the striatum,
provide inhibitory influence over the thalamus, thus preventing the thalamus
from providing excitatory output to the cortex. The inhibition of the thalamus
and lack of cortical activation results in poverty of movement. (SNc =
substantial nigra pars compact, MGP = medial globus pallidus, SNr =
substantial nigra pars reticularis).

Although the motor symptoms of Parkinson' s disease are the primary focus of

pharmacotherapy and surgical treatments, various nonmotor symptoms also occur and

can be particularly disturbing and disabling. These include insomnia, autonomic

dysfunction, mood disturbance, psychosis, and cognitive changes. Common cognitive

sequalae are slowed thinking (bradyphrenia), impaired "set-shifting," reduced working

memory, and forgetfulness (Cools, Barker, Sahakian, & Robbins, 2001; Dimitrov,

Grafman, Soares, & Clark, 1999; Fahn, 2003; Gauntlett-Gilbert, Roberts, & Brown,

1999; van Spaendonck, Berger, Horstink, Borm, & Cools, 1995). Moreover, about 20%

of Parkinson' s patients develop a frank dementia (Brown & Marsden, 1984), which is









most common in PD patients with a later age of onset. When a patient suffers from both

dementia and PD, they are referred to as having "Parkinson's plus syndrome" (Fahn,

2003).

Myriad studies have investigated the pattern of motoric and cognitive deficits

found in Parkinson's disease. Fewer have delved into the domain of emotional changes

that accompany Parkinson's disease, the focus of the current study. In the following

sections, a brief overview of some of the emotional changes that accompany Parkinson' s

disease will be presented.

Emotional Processing in Parkinson's Disease

Emotional processing can be broadly conceptualized as encompassing four

domains: mood (subjective emotional experience), perception, expression, and

physiology. Research to date suggests that Parkinson's patients may exhibit difficulties in

at least three of these domains. Each of these will be briefly reviewed below.

Mood Disturbance in Parkinson's Disease

A variety of studies have consistently found mood disturbances among patients

with Parkinson' s disease, with an average of 40-50% of PD patients experiencing

depressive symptoms (Cummings, 1992; McDonald et al., 2003; Zgaljardic et al., 2003).

Accumulating evidence over the years suggests that depression in PD may be secondary

to the underlying neuroanatomical degeneration, rather than simply a reaction to

psychosocial stress and disability, although the latter may clearly play a role as well. The

incidence of depression is correlated with changes in central serotonergic function and

neurodegeneration of specific cortical and subcortical pathways (Burn, 2002; Mayberg et

al., 1990). In addition to decreasing quality of life, depression and other psychiatric









disturbance in Parkinson's patients appear to exacerbate motoric symptoms (Cummings,

1992).

Other common psychiatric disturbances in Parkinson's disease are anxiety and

apathy (Fahn, 2003). Apathy refers to diminished emotional reactivity to both positive

and negative events, lack of motivation to engage in goal-directed behavior or cognition,

and a subj ective sense of indifference (Marin, 1991). Between 40 and 50% of Parkinson' s

patients have been described as meeting criteria for apathy, based on various "apathy"

scales (Isella et al., 2002; Starkstein, Mayberg, Preziosi, Andrezejewski, Leiguarda, &

Robinson, 1992), with higher levels of apathy in Parkinson' s patients relative to equally

disabled patients with severe osteoarthritis (Pluck & Brown, 2002). Those patients with

high levels of apathy are not more likely to be depressed or anxious than those with the

lowest levels of apathy (Pluck & Brown, 2002). Instead, apathy has been correlated with

increasing cognitive impairments. Like depression, it has been argued that apathy is

more likely a direct consequence of disease related physiological changes than a

psychological reaction or adaptation to disability (Brown & Pluck, 2000; Pluck & Brown,

2002).

Expression and Perception of Emotion in Parkinson's Disease

In addition to mood disturbances, patients with Parkinson's disease also have

difficulty communicating emotion using various nonverbal signals such as facial

expression and emotional tone of voice (Blonder, Gur, & Gur, 1989; Borod et al., 1990;

Buck & Duffy, 1980; Jacobs, Shuren, Bowers, & Heilman, 1995 Smith, Smith, &

Ellgring, 1996). In fact, one of the common clinical features of Parkinson's disease is

"masked facies," a term that refers to the expressionless facial demeanor of PD patients.

Diminished facial expressivity occurs relatively early in the disease course and is









unrelated to depression (Katiskitis & Pilowsky, 1991; Smith, Smith, & Ellgring, 1996).

Recent studies using sophisticated computer imaging techniques have found that the

facial movements in Parkinson's disease are actually smaller in amplitude, slower to

initiate, occur less frequently, and correlate with other motor symptoms of Parkinson' s

disease such as bradykinesia (Bowers et al., in press). Unfortunately, diminished use of

nonverbal communication signals by Parkinson patients poses significant problems,

ranging from misdiagnosis of depression to the misattribution of negative emotion states

by family members and health care providers.

The research literature regarding the perception of emotional information (faces,

scenes, prosody) is inconsistent at best. Some investigators have found that Parkinson' s

disease patients are impaired when asked to identify emotional faces, emotional prosody,

or emotional scenes (Blonder et al., 1989; Jacobs et al., 1995; Scott, Caird & Williams,

1984; Sprengelmeyer et al., 2003). Others, however, have not documented differences

between Parkinson's disease patients and healthy controls (Adolphs, Schul and Tranel,

1998; Madeley, Ellis, & Mindham, 1995). Some possibilities that may account for these

discrepancies are methodologic inconsistencies regarding the stage of severity of

Parkinson' s disease, whether patients are tested on versus off medications, and the extent

of co-existing cognitive impairment or mood disturbance.

Recently, a particular interest has emerged with respect to the possibility that

Parkinson's patients may have difficulties with processing of specific emotions such as

"fear" or "disgust" relative to other emotions. Some researchers have found that PD

patients appear to be more impaired at recognizing aversive facial expressions (i.e.,

anger, disgust, fear) than other expressions. For example, Kan and colleagues (Kan,









Kawamura, Hasegawa, Mochizuki, & Nakamura, 2002) found that PD patients were

selectively impaired at recognizing fear and disgust facial expressions. However, not all

researchers have found impairments in recognition of emotional facial expressions

(Adolphs et al., 1998; Madeley et al., 1995).

Physiologic Reactivity

Another approach for examining emotional behavior involves monitoring

patients' physiological reactivity to emotional materials. To date, there are no published

studies of psychophysiologic reactivity to emotional materials in patients with

Parkinson's disease. This is surprising, since using physiology as an index of emotional

reactivity in a Parkinson's sample has several advantages. First, it does not require a

voluntary motor response (as measurements of facial expressivity or vocal prosody do),

thereby eliminating the confounding problem that the movements being used as an index

of expressivity may be affected by the motor symptoms of PD. Secondly, measurement

of physiological reaction does not depend on self-report (as many paper-and-pencil

measures of mood do), and thus the demand characteristics associated with it are

minimal. Finally, because the response that is being measured is near impossible to

voluntarily control, it does not rely on the subj ect' s attention, motivation, or cooperation

(Bradley, 2000).

Skin conductance. One type of physiological reaction frequently measured in

psychological research is skin conductance response (SCR) to emotional stimuli. This is

accomplished by applying electrodes that essentially measure "palm sweat" to the inside

of the hands. The larger the SCR, the larger the physiological arousal the subject has

experienced in response to the emotional stimuli. Although measurement of SCR can be

useful, it does have serious limitations. First, individuals vary considerably in how their









SCR to emotional stimuli habituates over time. Some individuals habituate after a few

trials, whereas others do not appear to habituate much at all. Secondly, 15-20% of

healthy people are "nonresponders;" that is, they to do not exhibit a discernable

difference in SCR to varying types of stimuli (Bradley, 2000; O'Gorman, 1990). Finally,

excess motor activity (such as tremor in the hands) can dramatically interfere with skin

conductance recordings (Bradley, 2000). For these reasons, SCR data do not always

produce consistent results, may not detect subtle between-groups differences in

physiological responding, and may not be the most appropriate physiologic measure for

patients with a movement disorder.

Startle eyeblink response. Another widely used index of emotional reactivity is

the affective modulation of the startle eyeblink response (Lang, Bradley, & Cuthbert,

1990; Vrana, Spence, & Lang, 1988). It is this measure that was chosen to serve as the

index of emotional reactivity in the present study. In order to understand the mechanism

of this phenomenon, it is first necessary to describe the basic startle response and how it

is neurally mediated. In mammals, an automatic startle response occurs at the abrupt

onset of a stimulus, such as a jarring noise or flash of light. It is characterized by limb

and trunk movements of the body, as well as a reflexive eyeblink (Bradley & Vrana,

1993). A variety of studies over the past decade have documented that size of the startle

eyeblink is directly modulated by an individual's affective state (i.e., negative, positive).

In humans, startle response magnitude (as indexed by reflexive eyeblink) is augmented

during emotionally aversive tasks and attenuated during more pleasant tasks. This

valence modulation of startle is observed across a variety of tasks involving slide

viewing, imagining emotional situations, and anticipation of shock (Bradley, Cuthbert, &










Lang, 1990, 1991; Grillon, Ameli, Woods, & Merikangas, 1991; Lang, Bradley, &

Cuthbert, 1990). Lang et al. (1990) proposed that startle response magnitude reflects the

valence of the individual's central motivational state (appetitive versus aversive), rather

than being a tactical response in a specific affective context.

The neural circuitry underlying the startle response has been exquisitely mapped

out by Mike Davis and colleagues (Davis, 1992; Davis, Gendelman, Tischler, &

Gendelman, 1982). Davis' group has shown that the basic startle circuitry is mediated

entirely subcortically (at the level of the brainstem-spinal cord), and can be directly

modulated by the amydal (at least in rodents) via its proj section to the brainstem.

Electrical stimulation of the amygdala in rats facilitates startle (Rosen & Davis, 1988),

while lesions of the amygdala diminish fear potentiated and shock sensitized startle

responses while leaving the basic startle intact (Hitchcock & Davis, 1991; Hitchcock,

Sananes, & Davis, 1989). Further, lesions at some cortical sites that relay information to

the amygdala appear to attenuate fear potentiated startle in rodents (Rosen, Hitchcock,

Miserendino, Falls, Campeau, & Davis, 1992). In humans, temporal lobe ablations

involving the amygdala are associated with reduced startle potentiation during the

viewing unpleasant pictures.

Taken together, these findings suggest that increases in the startle response during

negative emotional states may reflect the amygdala's role in both threat detection and in

modulating subcortical startle circuitry.

Pathophysiology of Emotional Changes in Parkinson's Disease

Before turning to the rationale for the current study, the question arises as to the

basis for changes in emotional behavior in Parkinson's disease. There appears to be at

least two possible mechanisms that might potentially affect emotional processing in









Parkinson's disease. First, the reduction in nigrostriatal dopamine found in PD influence

neural circuits that have been implicated in emotion. Secondly, evidence has been found

that the amygdala, a key limbic structure, exhibits significant pathological changes in

Parkinson's disease. Each of these possible mechanisms will be discussed below.

Neural Circuitry Involved in Emotional Behavior

The deficits in emotional processing described previously may be linked to limbic

circuitry subserved by the neurotransmitter dopamine. There are three main systems

through which dopamine may affect emotional processing in PD: the striato-thalamo-

cortico loops, the mesolimbic circuit, and the mesocortical circuit. Beginning with the

first of these, Alexander, DeLong, & Strick (1986) proposed a network of Hyve parallel

striato-thalamo-cortical circuits that allow frontal cortical activity to be modulated by

ascending input from the basal ganglia/thalamus through direct and indirect pathways.

Two of these circuits involve key limbic areas such as the orbitofrontal cortex (OFC), the

anterior cingulate cortex (ACC), and the nucleus accumbens. General schematas of these

two circuits are depicted in Figure 1-2.

Outside of these striato-thalamo-cortical circuits, the dopamine-mediated

mesolimbic pathway is implicated in emotional processing as well. The ventral

tegmental area has dopaminergic connections to the ventral striatum (which consists of

the nucleus accumbens and olfactory tubercle) of the basal ganglia. Changes in

dopaminergic input to the ventral striatum can then affect the associated striato-thalamo-

cortical circuits, and thus depletion of dopamine may affect the ability of limbic

structures to influence frontal cortical activity. Finally, the mesocortical circuit connects

the ventral tegmental area to the cortex, and provides yet another way in which dopamine












A) B) Lateral
Anterior Cingulate Cortex ObtfotlCre



Ventral Striatum Caudate
(Nucleus Accumbens) (ventromedial)



G.P. rostrolateral/ G.P. mdm/
SNr SNr



SThalamus I Thalamus
MD & VA AID



Figure 1-2. Two Hypothesized Striato-Thalamo-Cortical Loops Involved in Emotion. A)
ACC loop, B) OFC loop. G.P.= globus pallidus, SNr = substantial nigra pars
reticulata, mdm = medial dorsomedial.

depletion may affect emotional functioning. Cortical dopamine release modulates the

descending cortico-striatal fibers, potentially influencing the activity of the striato-

thalamo-cortico circuits (Brown & Pluck, 2000).

In summary, there are myriad hypothesized dopamine-mediated circuits that

connect the limbic system to the frontal cortex and thus allow for emotional modulation

of cognitive processes. The depletion of dopamine that characterizes Parkinson's disease

may affect regulation of these circuits, potentially leading to dysfunction in emotional

processing.

Amygdala Pathology

One of the key limbic structures involved in emotion is the amygdala, a small

almond-shaped structure located within the anterior temporal lobe. The amygdala has

consistently been implicated in the recognition of fearful stimuli and responding to









threatening situations. Monkeys with lesions of the amygdala do not display normal fear

reactions to threatening stimuli, such as snakes (Amaral, 2003; Kltiver & Bucy, 1939). In

humans, lesions of the amygdala have been associated with behavioral placidity,

diminished physiologic reactivity, and impairments in recognizing fearful faces

(Aggleton, 1992; Calder, Young, Rowland, Perrett, Hodges, & Etcoff, 1996; Young,

Aggleton, Hellawell, Johnson, Broks, & Hanley, 1995). Electrical stimulation of the

amygdala elicits many of the behaviors used to define the state of "fear," such as

tachycardia, increased galvanic skin response, corticosteroid release, and increased startle

(Davis, 1992).

Recently, several investigators have found evidence of pathological changes in

the amygdala of Parkinson' s patients. In a post-mortem study, Harding and colleagues

(Harding, Stimson, Henderson, & Halliday, 2002) found a 20% reduction in the

amygdala volumes of PD patients compared to normal controls. Ouchi and colleagues

(1999) found a 30-45% reduction of dopamine agonist binding in the amygdala of PD

patients, which they speculated might be due to a loss of pre-synaptic dopamine terminals

in this region. Additionally, post-mortem studies have found the presence of Lewy

bodies in the amygdala of PD patients (Braak & Braak, 2000).

The fact that the amygdala has been shown to exhibit neuropathology in PD

brings up the issue as to whether Parkinson's patients might have a diminished emotional

reactivity to threatening stimuli, or difficulty interpreting expressions of fear in others.

The findings thus far with respect to these questions are reviewed below.

Rationale for the Present Study

To date, there are no published studies that have used psychophysiology as a

marker of emotional responsiveness in Parkinson' s disease. Because of the symptoms of









PD include motor rigidity and slowing, using facial expressivity or vocal prosody as an

index of emotional reactivity (as has been done in past studies) may potentially confound

motoric deficits with emotional deficits. Thus, measurement of affective startle eyeblink

magnitude may provide a clearer methodological approach to investigating emotional

reactivity in this patient group. Seignorel and colleagues (Seignorel, Miller, Bowers, &

Okun, 2003) found no significant differences in either latency or magnitude of startle

eyeblink responses in a group of PD patients compared to controls, suggesting that

despite motor impairments, basic eyeblink startle startle remain intact in Parkinson's

patients. Similar findings with respect to the magnitude of basic startle responses have

also been described by other researchers (Koffer et al., 2001; Vidailhet, Rothwell,

Thompson, Lees, & Marsden, 1992).

The primary purpose of the present study was twofold: 1) To determine if PD

patients and controls differ in degree of startle modulation produced by positive and

negative stimuli; and 2) To determine if PD patients exhibit less startle potentiation to

threatening stimuli, relative to controls. To date, no studies have investigated PD

patients' reaction (as opposed to ability to recognize) to non-facial threat-evoking

stimuli. For this reason, the issue of whether PD patients exhibit a normal response to

threatening stimuli is unknown, although observations of amygdala pathology raise the

possibility that threat responding may potentially be disrupted. The only existing studies

that address threat processing in PD patients have focused on the ability to recognize

fearful facial expressions. Findings from these studies have been mixed. In a task

involving recognition of prototypical emotional facial expressions, Sprengelmeyer et al.

(2003) found that medicated PD patients were specifically impaired at recognizing anger









and fear, compared to controls. However, when these same patients were tested on a

different emotion recognition task (involving morphed images of emotional expressions),

they demonstrated no deficit. Kan et al. (2003) found that PD patients were impaired in

the recognition of fear and disgust when moving facial stimuli were used. Thus, these

studies raise the possibility that recognition of fearful faces may be impaired in PD

patients, but do not address the issue of whether an abnormal reaction to a threat-eliciting

stimulus exists at the physiologic or subj ective level in Parkinson' s.

Hypotheses and Predictions

In healthy subjects, unpleasant stimuli are consistently associated with larger blinks

compared to pleasant stimuli. Keeping this in mind, the following hypotheses were

made:

Hypothesis 1

Parkinson's disease patients will display diminished emotional reactivity relative to

normal controls, as indexed by startle modulation during affective pictures. Thus, it was

predicted that PD patients would exhibit a significantly smaller eyeblink magnitude than

controls while viewing unpleasant slides, and a significantly larger eyeblink magnitude

than controls while viewing pleasant slides. This prediction is based on the observations

that PD patients show 1) reduced striatal dopamine, which may affect dopamine-

mediated limbic circuits; and 2) amygdala neuropathology, which may affect the ability

of the amygdala to modulate the basic startle response.

Hypothesis 2

Parkinson's patients will show a more diminished emotional response to

threatening pictures as compared to other categories of unpleasant pictures. Specifically,

it was predicted that PD patients would display a significantly smaller eyeblink










magnitude than controls in response to threatening slides, whereas their eyeblink

magnitude during other unpleasant pictures would not significantly differ from that of

controls. This prediction is based on the fact that the amygdala is known to play a key

role in responding to threatening stimuli, is implicated in the fear-potentiated startle, and

exhibits pathology in PD patients.

Exploratory Questions

In addition to the maj or hypotheses described above, several exploratory questions

were addressed. For example, would Parkinson patients rate the affective pictures as

intensely emotional as the controls in terms of valence? This is an important question for

several reasons. First, if PD patients rated the emotional pictures as less intense, then this

might be due to perceptual problems in appraising the stimuli, which could potentially

influence emotional reactivity. Alternatively, reduced ratings might be due to some

alteration in emotional appraisal. As mentioned previously, approximately 40% of PD

patients experience apathy (Marin, 1996). One component of apathy is diminished

emotional response to both positive and negative events. Whether this holds true for

positive and negative pictures in an experimental setting, which is obviously much

different from the natural environment, is unknown. If it does indeed hold true, then

patients with PD should find unpleasant pictures less unpleasant than controls, and

pleasant pictures should be rated as less pleasant than control' ratings. On the other hand,

Smith et al. (1996) found that PD patients rated emotional scenes from movies no

differently from healthy controls. This raises the possibility that patients in the current

study might rate pictures similarly to controls, yet nevertheless show differences in

emotional reactivity as indexed by startle. This situation would suggest a decouplingg"

between appraisal and the translation of the results of this appraisal into a motivational









state. The amygdala is thought to play a pivotal role in this translational process based

on lesion studies of patients who have undergone resection of the mesial temporal region

including the amygdala (Bowers et al., 1998). Should a decoupling be found in

Parkinson's patients, this finding would be consistent with some abnormality in the

translationall" process, possibly related to alterations in amygdala functioning. An

additional question was whether controls and PD patients would find the pictures

similarly arousing. If PD patients are experiencing emotional "blunting", one might

expect them to find the emotional stimuli less arousing than controls. Finally, it was

important to determine if any differences between patients' and controls' emotional

startle modulation could be attributed to differences in level of depression. Therefore, an

additional exploratory goal was to investigate any possible association between

depressive symptoms and startle eyeblink magnitude.















CHAPTER 2
METHOD S

Participants

Participants included twenty patients with idiopathic Parkinson's disease and

fifteen healthy age-matched controls. The Parkinson's patients were recruited through

the Movement Disorders Center of the University of Florida and had been evaluated

within the preceding three months by a movement disorders neurologist (Dr. Okun or Dr.

Fernandez). As part of their routine workup in the Movement Disorders Clinic, the

Parkinson' s patients received standard measures for staging the severity of their motor

symptoms and disease course. These included: the thrited'Parkinson Disease Rating

Scale-ThirdEdition' (motor subscale [Fahn & Elton, 1987]), a modified Hoehn-Y ahrYYYY~~~~~~YYYYY

scale (Hoehn & Yahr, 1967), and the Scinvab andEnglandActivities ofDaily Living3

(Schwab & England, 1969). Patients were evaluated on these scales "off" medication (12

hours after last levodopa dose) and again one hour after taking their medication ("on"

state). During this clinical evaluation, PD patients were also screened for dementia

(M~ini-M~entalState Exam [Folstein, Folstein, & McHugh, 2001]), depressed mood (Beck



SThis is a rating tool designed to assess the severity of various motor symptoms over the course of the
disease. Higher scores indicate greater severity. Patients were assessed while on and off dopaminergic
medication.

2 This scale is used to rate the "stage" of severitv/disability in the PD patient. Stages range from 1-5, with
five being the most severe (cannot walk without assistance, or is confined to wheelchair). Patients were
assessed while on and off dopaminergic medication.

3 This rating scale is an index of the PD patient' s level of functioning in activities of daily life. Scores
range from 0-100%, with 100% indicating complete independence, and 0% indicating that the patient is
bedridden.










Depression Inventory [Beck, 1978]), and decreased quality of life (Parkinson Disease

Quality of Life Scale-39 [Peto, Jenkinson, & Fitzpatrick, 1998]).

To be included in the PD group, patients had to meet stringent diagnostic criteria

for Parkinson' s disease, be free of other neurologic or medical illness that would

compromise their participation (or interpretation of findings), and be free of dementia and

significant psychological distress (i.e., a psychiatric disorder). The clinical diagnosis of

idiopathic PD was based on: (a) the presence of at least two of four cardinal motor

signals (i.e., akinesia, bradykinesia, resting tremor, rigidity [Hughes, Ben-Shlomo, et al.,

1992; Hughes, Daniel, et al., 1992]); and (b) a demonstrated therapeutic response to

dopamine replacement therapy, as defined by a marked improvement in Parkinsonian

motor signs, based on the motor subscore of the United Parkinson Disease Rating Scale

(UPDRS) following administration of levodopa during their screening neurologic

examination. A demonstrated good response to levodopa therapy was required in order

to exclude patients with Parkinson's plus syndromes (e.g., Shy-Drager, multiple system

atrophy, Lewy body disease, corticobasal degeneration). Only Parkinson patients who

scored in the nondemented range on the Mini-Mental State Exam (>26) were invited to

participate in the present study.

The PD patients included sixteen men and four women, who ranged in age from 43

to 85 (X = 61.9, SD = 10.0). As a group, they had been treated for Parkinson' s disease

for eleven years and were in the mid-stages of their disease, based on staging criteria

from the Hoehn and Yahr scale. This information is depicted in Table 1-1. In order to

assess depressive symptomatology, all patients received the Beck Depression Inventory

(BDI) on the same day they received the experimental emotional tasks. The BDI scores









for the PD patients included in the present study ranged from two to nineteen (means and

standard deviations are shown in Table 1-1). Two patients met criteria for Mild

Depression (BDIs = 14 and 19), as defined by Beck, Steer, & Brown (1996).

Control participants included fifteen healthy individuals (ten men, five women)

who had been recruited from the community. Any control participant with reported

psychiatric disorder, head previous head injury, learning disability, or neurological

disorder was excluded. Controls were also given the BDI. There were no instances in

which Control participants produced BDI scores that exceeded thirteen (the

recommended cutoff score for Mild Depression; Beck et al., 1996).

A comparison of patient and control demographic variables is presented in Table 1-

1. As shown, the PD and Control groups did not significantly differ with respect to age

(t(33)= 1.90, p = .40), although the mean age of the PD patients was about ten years

greater than that of the controls. The reason for this discrepancy related to the young age

of two of the control subj ects (these subj ects were twenty-five and twenty-nine years old,

respectively). Additionally, the PD patients were slightly more educated than the controls

(t (28.7)= 2.04, p = .05). The PD patients had a mean of fifteen years of education,

whereas controls had a mean of 13.5 years of education. Finally, PD patients and

controls significantly differed with respect to their mean BDI scores (t(31) = 3.06, p<

005), with BDI scores of the PD group (X = 8.5) being significantly higher than those of

the Controls (X = 4. 1).

Materials

International Affective Picture System Slides

Participants viewed a subset of forty-four pictures (twelve pleasant, twelve

unpleasant, twelve neutral, and eight "filler") taken from the International Affective









Table 1-1. Patient and Control Characteristics
PD patients Controls
(N = 2 0) (N- = 5)
Men: Women 16:4 10: 5
Age 62.9 (10) 53.8 (15.2) ns
Yrs. Ed 15. (2.9) 13.5 (1.3) p =.05
Hoehn-Yahr* 2.7 (.52) -
UPDRS motor* 27.2 (10.2) -
Yrs. with PD 10.8 (6.0) -
BDI 8.5 (4.0) 4.1 (4.0) p .005
* Assessed while on dopaminergic medication.

Picture System (Lang, Bradley, & Cuthbert, 2001a). Efforts were made to equate

the pleasant and unpleasant pictures on the basis of normative ratings of arousal (Lang,

Bradley, & Cuthbert, 2001Ib); however, a t-test revealed that the normative sample of men

and women found the unpleasant pictures to be more arousing on average than the

pleasant pictures, t(1 1) = 2.73, p < .05 (mean of Unpleasant pictures = 6.6, SD = .664;

mean of Pleasant pictures = 5.8, SD = 1.03 [ratings range from one to nine, with nine

being the most arousing]).4 The experiment began with two filler slides for practice,

followed by six blocks of seven trials. Each block contained two unpleasant slides, two

pleasant slides, two neutral slides, and one filler slide, presented in randomized order.

In order to investigate the impact of threatening pictures on emotional reactivity,

the negative pictures were further divided into two additional categories: "Threat" versus

"other unpleasant" pictures. "Threat" slides were defined as any slide suggesting

imminent attack, such as a snake preparing to bite, a gun pointed at the viewer, or a dog

with saliva-dripping fangs spread open. All remaining unpleasant pictures were then



SThese normative ratings were obtained from a large sample of college students, and thus may not be
applicable to older participants. Additionally, the male to female ratio of the normative sample differs from
that of the current study.










categorized as "other unpleasant" pictures. This post-hoc division resulted in seven

"threat" pictures and Hyve "other unpleasant" pictures. The IAPS numbers for the threat

pictures are: 1090, 2120, 1300, 3000, 3530, 6230, 6370). The IAPS numbers for the

"other unpleasant" pictures are: 3010, 3100, 3130, 9040, 9050). "Threat" pictures had a

mean normative arousal rating of 6.40 (SD = 0.862) and "other unpleasant" pictures had a

mean normative arousal rating of 6.56 (SD = 0.52 [Lang, Bradley, & Cuthbert, 2001b]).

Self Assessment Manikin (SAM)

Each participant rated the pictures for valence (pleasant, unpleasant) and arousal

using the Self Assessment Manikin (SAM). SAM is a graphic display depicting a

cartoon Eigure that varies along the dimensions of valence and arousal (Greenwald, Cook,

& Lang, 1989; Lang, 1980). For valence, nine versions of the cartoon Eigure were shown,

ranging from positive to neutral to negative. For arousal, nine versions of the cartoon

Eigure were shown ranging, from sleepy to neutral to highly excited. During the

experiment, participants were asked to rate their reactions to each IAPS picture

immediately after viewing it by referring to the SAM figures. The SAM Eigures were

vertically displayed on a computer screen in front of the participants. The participants

verbally gave their valence and arousal ratings which were heard, via an intercom, by an

investigator in an adj acent room.

Procedures

Data Collection

Prior to beginning the study, informed consent was obtained from each participant

according to University and Federal guidelines. All testing took place in the Cognitive

Neuroscience Laboratory of the UF Brain Institute. The session began with completion

of various questionnaires, including the BDI. This was followed by a detailed









description of the study and attachment of electrodes over the face and hands. (For the

purpose of the present study, only the startle component will be described). After

cleaning the area under the eye, two 3 mm Ag/AgCl electrodes were filled with a

conducting gel (Medical Associates, Inc., Stock # TD-40, Lot # 70204) and were

positioned under the left and right eyes to record EMG activity from the orbicularis oculi

muscle. Electrodes were affixed to the skin surface with adhesive collars. During the

experiment, participants sat in a reclining chair that was located in a sound-attenuated and

electrically shielded 12'xl2' room. Visual stimuli were displayed on a 21" computer

monitor located directly in front of the participant. After the participant was taught how

to use SAM and practiced with two sample slides, the experiment commenced. Each trial

began by presentation of the picture for six seconds. During this time, startle eyeblinks

were elicited by a 50 ms burst of white noise (95dB, instantaneous rise time) that was

delivered binaurally via Telephonics (TD-591c) headphones. A Colbourn S81-02

module generated the white noise bursts that were gated through a Colbourn S82-24

amplifier. These white noise bursts (startle probes) were randomly presented at various

points following picture onset (i.e., 4200, 5000, or 5800 ms) and counterbalanced across

valence category. Following each picture, the SAM figure appeared on the computer

screen and the participant verbally rated his/her subj ective level of valence and arousal.

Data Reduction of the Eyeblink Component of the Startle Response

The eyeblink component of the startle response was measured by recording EMG

activity from the orbicularis oculi muscle beneath each eye. The raw EMG signal was

amplified and frequencies below 90 Hz and above 1000 Hz were filtered using a

Colbourn bioamplifier. Amplification of acoustic startle was set at 30,000. The raw

signal was then rectified and integrated using a Colbourn Contour Following Integrator









with a time constant of 200 ms. This information was sent to a Scientific Solutions A/D

board interconnected with a custom personal computer. Digital sampling at 1000 Hz

began 50ms prior to startle probe onset and continued at this rate for 250 ms after the

probe onset. The startle data were reduced off-line using custom software programs.

These programs automatically eliminate trials with an unstable baseline and derive

baseline, peak, and blink amplitude values in arbitrary A-D units for each trial. Each trial

was scored for amplitude (i.e., peak baseline in microvolts) during the 25-130 ms

interval following startle onset. Trials that failed to reach peak during this interval were

rej ected. Latency to peak blink magnitude (in ms) was also derived on a trial-by-trial

basis.

Statistical Analyses

To test the first prediction (PD patients will exhibit a significantly smaller

eyeblink magnitude than controls while viewing unpleasant slides, and a significantly

larger eyeblink magnitude than controls while viewing pleasant slides), valence-

modulation of startle was evaluated by conducting a 2 (PDs, controls) X 2 (pleasant,

unpleasant) Repeated Measures Analysis of Variance with eyeblink magnitude T-scores

as the dependent variable. The eyeblink magnitudes in response to neutral pictures were

not included in the analysis for several reasons. First, although the neutral pictures have

normative subjective valence ratings that fall midway between ratings of pleasant and

unpleasant pictures, individuals' physiologic responses to these pictures vary widely.

One subj ect may respond to an ostensibly neutral picture as if it is somewhat negative in

valence, while another may respond to the same picture as if it is positive in valence.

Furthermore, research suggests that individual differences in current state anxiety levels

can affect startle modulation while viewing emotionally valenced pictures (Grillon,









Ameli, & Davis, 1993). Potentially, the same subject could respond differently to the

same "neutral" picture on two separate occasions, depending on factors such as the

individual's mood and the situation. Finally, the inclusion of only strongly valenced

pictures in the analysis, as opposed to more ambivalent pictures, increased the chances of

detecting any potential differences between the PD and Control groups.

To test the second prediction (PD patients will display a significantly smaller

eyeblink magnitude than controls in response to threatening slides), a 2 (PDs, controls) X

2 (threat, other unpleasant) Repeated Measures Analysis of Variance was conducted, with

eyeblink magnitude as the dependent variable once again.

Next, to investigate whether PD patients and controls rated pleasant and

unpleasant slides similarly with respect to valence, a 2 (PDs, controls) X 2 (pleasant,

unpleasant) Repeated Measures ANOVA was conducted, with subj ective valence ratings

as the dependent variable. This analysis was then repeated with "threat" and "other

unpleasant" pictures as the independent variables.

To investigate whether PD patients and controls differed in their arousal ratings of

pleasant and unpleasant pictures, a 2 (PDs, controls) X 2 (pleasant pictures, unpleasant

pictures) Repeated Measures ANOVA was conducted with subj ective arousal ratings as

the dependent variable. This analysis was then repeated with "threat" and "other

unpleasant" pictures as the independent variables.

A final set of analyses examined the relationship between emotional reactivity, as

indexed by startle magnitude, and scores on the Beck Depression Inventory. Although

only two of the PD patients scored below the clinical cutoff for depression on the Beck

Depression Inventory, the PD patients did obtain significantly higher scores on the BDI










(X = 8.5) than the Controls (X = 4.1). Thus, correlational analyses were performed in

order to learn whether BDI scores varied in any systematic way with emotional reactivity,

as indexed by startle. A startle reactivity index score was derived using the following

formula: [Unpleasant T-score] [Pleasant T-score]. This index score is a measure of

overall emotional reactivity; the larger the difference between the eyeblink peak

magnitudes for pleasant and unpleasant pictures, the greater reactivity to the stimuli the

participant is displaying. A second correlational analysis was performed using an index

score derived from the Threat and Other Unpleasant pictures (i.e., [Threat T-score] -

[Other Unpleasant T-score]).















CHAPTER 3
RESULTS

Startle Eyeblink

Startle eyeblink responses were converted to T-scores (X=50, SD=10) following

the procedures of Bradley & Vrana (1993). This was done order to minimize between-

subj ect variability in the absolute size of startle responses that might otherwise obfuscate

the pattern of the relationship among pleasant, neutral, and unpleasant conditions. For

each participant an overall mean startle magnitude (and standard deviation) was derived

from the values of that subj ect' s individual trials. T-scores for each subj ect were

computed on a trial-by-trial basis, based on the unique array of values for a particular

subject. From these data, average startle responses (T-scores) were derived for the

unpleasant, neutral and pleasant pictures. Because startle values were similar for the left

and right eyes, a composite score was created (by averaging the left and right eye T-

scores) and used as the dependent value in the analyses described below. Since left and

right eye startle values did not significantly differ, for instances in which one eye

contained greater than 50% invalid trials, values from the other eye were used instead of

a composite score. Valid trials were defined as blinks that reached peak amplitude during

the 25-130 ms interval following startle onset.

Pleasant versus Unpleasant Pictures

The initial analysis examined whether Parkinson patients differed from Controls in

their emotional reactivity during pleasant versus unpleasant pictures. A repeated

measures Analysis of Variance (ANOVA) was conducted, with Group (PDs, Controls) as









the between-subj ects factor and Type Affect (pleasant, unpleasant) as the within-subj ects

factor. Results revealed a significant main effect for Type Affect (F(1, 33) = 31.39,

p<.001). Consistent with previous findings (Bradley & Vrana, 1993), startle eyeblinks

during unpleasant pictures (X = 51.4, SD = 2.41) were significantly larger than those

during pleasant pictures (X = 48.1, SD = 2.10). Additionally, there was significant Type

Affect X Group interaction (F(1,33)= 4.60, p<.05). This is depicted in Figure 3-1. Post

hoc t-tests indicated that: (a) for the PD group, startle eyeblinks were significantly larger

during unpleasant (X = 50.62, SD = 2.67) than pleasant pictures (X = 48.60, SD = 2.23;

t(19) = 2.35, p < .05); (b) for the Control group, startle eyeblinks were significantly

larger during unpleasant (X = 52.17, SD = 1.71) than pleasant pictures (X = 47.67, SD =

1.80; t(14) = 6.43, p < .001); (c) for unpleasant pictures, the Controls (X = 52.17, SD =

1.71) exhibited significantly larger eyeblinks than the Parkinson's patients (X = 50.62,

SD = 2.67; t(33) = -2. 11, p < .05; (d) for pleasant pictures, Controls (X = 47.67, SD =

1.80) and Parkinson's patients (X = 48.60, SD = 2.23) did not significantly differ with

respect to peak eyeblink amplitude (t(33) = 1.33, p > .19).

In summary, these findings indicate that both groups displayed greater emotional

reactivity, as indexed by startle modulation, during unpleasant versus pleasant picture

viewing. However, the Controls' reactivity was significantly greater than the Parkinson's

patients' during presentation of unpleasant pictures.

Threatening versus Other Unpleasant Pictures

A second ANOVA was conducted in order to determine whether Parkinson' s

patients were less reactive to "threat" versus other types of unpleasant emotional pictures.

One control and four PD patients were excluded from this analysis due to the fact that





55 f I U pleasant rlctures
CIPleasant Pictures








4i50



Parkinson's Controls


Figure 3-1. Peak Eyeblink Amplitudes for Unpleasant versus Pleasant Pictures

these participants had less than 50% valid trials for either the "threat"or"other

unpleasant" category.A repeated measures ANOVA was conducted with Group (PD,

Controls) as the between-subject factor and Type Affect (Threat, Other unpleasant) as the

within-subj ect factor. Results of this ANOVA revealed a significant main effect for Type

Affect (F(1, 28)= 15.4, p<.001), indicating that startle eyeblink responses were larger

during threatening pictures (X = 53.36, SD = .612) as compared to other types of

unpleasant pictures (X = 49.21, SD = .696). Again, the Condition X Group interaction

was significant (F(1, 28)= 5.31, p<.05). Post hoc t-tests indicated that: (a) for the PD

group, startle eyeblinks did not significantly differ with respect to peak eyeblink

amplitude for "threat" (X = 51.91, SD = 4.10; t(15) = -1.05, p >.30) versus "other

unpleasant" pictures (X = 50.20, SD = 3.84); (b) for the Control group, startle eyeblinks

were significantly larger while viewing "threat" (X = 54.80, SD = 2. 17) versus "other

unpleasant" pictures (X = 48.22, SD = 3.76; t(13) = -5.13, p <.001); (c) for "threat"










pictures, the Controls exhibited significantly larger eyeblinks (X = 54.80, SD = 2. 17) than

the Parkinson's patients (X = 51.91, SD = 4.10; t(30) = -2.74, p < .05); (d) for "other

unpleasant" pictures, Controls (X = 48.22, SD = 3.76) and Parkinson's patients (X =

50.20, SD = 3.84) did not significantly differ with respect to peak eyeblink amplitude

(t(30) = 1.20, p >.20).




60 M Threat Pictures
O Other Unpleasant Pictures














Parkinson's Controls



Figure 3-2. Peak Eyeblink Amplitude for Threat versus Other Unpleasant Pictures

In summary, Controls demonstrated greater emotional reactivity to "threat" pictures

in comparison to the "other unpleasant" pictures, where as the Parkinson's patients did

not. However, both groups responded similarly to the "other unpleasant" pictures.

Subjective Ratings: Valence and Arousal

Pleasant versus Unpleasant Pictures

A third set of analyses was conducted to examine subj ective ratings of the

emotional pictures by the Parkinson's patients and Controls. The mean valence and









arousal ratings for the pleasant and unpleasant pictures are depicted in Table 3-1. Two

PD patients and two controls were excluded due to missing data. The valence ratings and

the arousal ratings were independently analyzed in separate Group X Type Affect

(Pleasant, Unpleasant) repeated measures ANOVAs. Results of the valence ANOVA

indicated a main effect for Type Affect (F(1,29) = 54.2, p<.001). Namely, unpleasant

pictures (X = 2.85, SD = 1.68) were rated as significantly more negative than the pleasant

pictures (X = 6.80, SD = 1.48). The Group X Type Affect interaction was not

significant, F(1,29) = 2.08, p = .16. Results of the ANOVA for the arousal ratings

revealed no significant main effects or interactions. Taken together, these findings

indicate that the pleasant and unpleasant pictures elicited ratings that differed in terms of

Table 3-1. Means and SDs of Pleasantness and Arousal Ratings for Unpleasant and
Pleasant Pictures.
Unpleasant Pleasant Unpleasant Pleasant
Valence* Valence* Arousal~ Arousal~

PD Patients 2.57 (1.70) 7.14 (1.16) 5.22 (2.01) 6.10 (1.36)

Controls 3.24 (1.65) 6.32 (1.77) 5.78 (1.66) 5.47 (1.67)
* Valence ratings ranged from 1 (highly negative) to 9 (highly pleasant).
SArousal ratings ranged from 1 (low arousal) to 9 (high arousal)

valence. However, both the Controls and PD groups found the negative and positive

pictures to be similar in terms of how "arousing" they found them.

Threatening versus Other Unpleasant Pictures

A fourth set of analyses was conducted to examine subj ective ratings of the "threat"

and "other unpleasant" pictures by the Parkinson' s patients and Controls. The mean

valence and arousal ratings for these categories are shown in Table 3-1. As with the

analyses of subj ective ratings for pleasant and unpleasant pictures, two PD patients and

two controls were excluded from the analyses due to missing data. The valence ratings









and the arousal ratings were independently analyzed in separate Group X Type Affect

(Pleasant, Unpleasant) repeated measures ANOVAs. Results of the valence ANOVA

indicated a main effect for Type Affect, F(1,29) = 10.3, p<.005. Suprisingly, participants

subjectively found the "other unpleasant" pictures (X = 2.49, SD = 1.93) to be more

unpleasant than the "threatening" pictures (X = 3.11, SD = 1.62), even though both

groups showed greater startle eyeblink potentiation for the threatening pictures. The

Group X Type Affect interaction was not significant, F(1,29) = 0.308, p= .58. Results of

the ANOVA for the arousal ratings revealed no significant main effects or interactions.

Taken together, these findings indicate that both groups found the "other unpleasant"

pictures more unpleasant the "threat" pictures, although greater startle potentiation was

Table 3-2. Means and SDs of Pleasantness and Arousal Ratings for Threatening and
Other Unpleasant Pictures.
Threatening Other Unpleasant Threatening Other Unpleasant
Valence* Valence* Arousal+ Arousal+

PD Patients 2.86 (1.71) 2.16 (1.80) 5.42 (2.15) 4.94 (2.33)


Controls 3.45 (1.47) 2.95 (2.01) 5.76 (1.74) 5.80 (1.89)
* Valence ratings ranged from 1 (highly negative) to 9 (highly pleasant).
SArousal ratings ranged from 1 (low arousal) to 9 (high arousal)

demonstrated for "threat" pictures. However, participants did not find the two categories

of pictures to differ in terms of level of arousal they evoked.

Eyeblink Magnitude and BDI Correlations

A final set of analyses examined the relationship between emotional reactivity, as

indexed by startle magnitude, and scores on the Beck Depression Inventory. Although all

but two Parkinson' s patients and none of the Controls scored below the cutoff for Mild

Depression on the BDI, the PD patients did obtain significantly higher scores (X = 8.5)

than the Controls (X = 4.1). Thus, correlational analyses were performed in order to










learn whether BDI scores varied in any systematic way with emotional reactivity, as

indexed by startle. A "startle reactivity index score" was computed ([Unpleasant T-

score] [Pleasant T-score], see Chapter 2 for an explanation of this formula) to serve as a

measure of overall emotional reactivity. The Pearson's product-moment correlation

between this index score and the BDI score was nonsignifieant (r = -0. 167, p = .3 52).

Two control subjects were excluded from the analysis due to missing BDI scores. A

second correlational analysis was performed using an index score derived from the

"threat" and "other unpleasant" pictures (i.e., [Threat T-score] [Other Unpleasant] T-

score). The results of this analysis indicated that the Pearson' s correlation between this

difference score and BDI scores was again nonsignifieant (r = -0.304, p = .102). In

summary, these Eindings suggest that level of depressive symptomatology, as indexed by

the BDI, does not vary in any systematic fashion with emotional modulation of startle.

Next, correlational analyses were performed in the Parkinson's disease group to

examine the relationships among the Hoehn and Yahr stage (assessed while on

medication), UPDRS motor subscale score (assessed while on medication), duration of

illness, and BDI score. These analyses were performed in order to determine if severity or

duration of Parkinson' s disease is associated with depression symptomatology. The

correlations between these variables are displayed in Table 3-3. The correlation between

Hoehn and Yahr stage and BDI score was nonsignifieant (r = -.008, p > .97), as was the

correlation between number of years with Parkinson' s disease and BDI score (r = .089, p

> .62). However, UPDRS score and BDI score were significantly positively correlated,

r= .518, p < .05. Although the UPDRS and Hoehn and Yahr both measure level of motor

impairment, the UPDRS assesses impairment at the level of highly specific motor










symptoms and has a greater range of possible scores. This may be why a significant

correlation was found between the UPDRS and the BDI, but not Hoehn and Yahr Stage

and BDI. Finally, UPDRS score and Hoehn and Yahr stage were highly significantly

correlated in the positive direction (as would be expected since they both assess level of

motor impairment in the PD patient), r = 67, p < .005, and Hoehn and Yahr stage and

years with PD were significantly positively correlated, r = .44, p = .05. In sum, these

analyses demonstrate that a) degree of motor impairment (as assessed by Hoehn and Yahr

stage) increases with duration of illness; and b) greater motor limitation is associated with

greater depression severity.

Correlational analyses were also performed between the general index of startle

reactivity ([Unpleasant T-score] [Pleasant T-score]) and UPDRS motor subscale score,

Hoehn and Yahr stage, and years with PD in order to determine if severity or duration of

Parkinson's disease is associated with reduced startle reactivity. Hoehn and Yahr stage

and startle reactivity index were significantly negatively correlated, r = -0.70, p < .005, as

Table 3-3. Correlations Between Number of Years with Parkinson's Disease, BDI Score,
Hoehn and Yahr Stage, and UPDRS Motor Subscale Score.
Yrs. PD BDI Hoehn &Yahr UPDRS
motor subcale

Yrs. PD 1.00 0.089 0.444* 0.107

BDI -- 1.00 -.008 .518*

Hoehn & Yahr -- -- 1.00 .665**

UPDRS motor subcale -- -- -- 1.00

*. Correlation is significant at the .05 level (two-tailed).
**. Correlation is significant at the .01 level (two-tailed).

were number of years with illness and startle reactivity index, r = -0.36, p < .05.

Additionally, the correlation between UPDRS score and startle reactivity approached










significance, r = -0.48, p = .053. Taken together, these findings suggest that greater

motor impairment and longer disease duration in Parkinson's patients are associated with

reduced emotional reactivity, as indexed by startle modulation.















CHAPTER 4
DISCUSSION

The present study sought to examine two hypotheses. The first hypothesis was that

Parkinson's patients would show diminished emotional reactivity to effectively valenced

pictures. This led to the specific prediction that PD patients would exhibit a significantly

smaller eyeblink magnitude than controls while viewing unpleasant slides, and a

significantly larger eyeblink magnitude than controls while viewing pleasant slides. This

prediction was based on previous findings that PD patients show reduced striatal

dopamine, which may affect dopamine-mediated limbic circuits; as well as amygdala

neuropathology, which may affect the amygdala' s modulation of the basic startle

response. The second hypothesis was that Parkinson's patients would exhibit greater

emotional blunting for threatening pictures, as opposed to other categories of negative

pictures. Specifically, it was predicted that PD patients would display a significantly

smaller eyeblink response than controls in response to threatening slides, whereas their

eyeblink responses during other unpleasant pictures would not differ from that of

controls. This prediction was based on the fact that the amygdala is known to play a key

role in responding to threatening stimuli, is implicated in fear-potentiated startle, and

exhibits pathology in PD patients.

Hypothesis 1 was partially supported by the data. Parkinson's patients exhibited

significantly smaller eyeblink responses than controls while viewing the unpleasant

pictures; however, their eyeblink responses during pleasant pictures did not differ from









those of controls. Thus, the PD patients demonstrated diminished emotional reactivity to

negatively valenced pictures but not positively valenced pictures.

Hypothesis 2 was also supported by the data. That is, PD patients exhibited

significantly smaller eyeblink responses while viewing threatening pictures relative to

controls. The patients and controls did not differ significantly with respect to eyeblink

responses during other types of unpleasant pictures.

In summary, PD patients demonstrated diminished emotional reactivity to

unpleasant pictures compared to healthy controls (as indexed by startle eyeblink

modulation), but did not differ from controls in terms of emotional reactivity to pleasant

pictures. Furthermore, this effect seems to be driven by the PD patients' diminished

emotional reactivity towards threatening stimuli specifically.

Basic Acoustic Startle in PD Patients

Before discussing some possible explanations for the present Eindings, an obvious

question concerns whether the Parkinson's patients might have a basic defect in startle

eyeblink reactivity per se. Conceivably, Parkinson's patients could have motor

abnormalities that might reduce or minimize the size of the eyeblink response itself.

This, in turn, would result in reduced size of startle eyeblink responses during negative

emotional pictures, giving rise to the impression of diminished emotional reactivity to

unpleasant and threatening stimuli. To explore this, it is necessary to look at past

research on the basic startle response in patients with Parkinson's disease. Vidailhet and

colleagues (1992) examined startle eyeblink responses elicited by an abrupt noise in

eleven patients with idiopathic PD and a group of controls. Both the magnitude of the

startle eyeblink response and the pattern of muscles recruited were similar in the PD

patients and controls. However, the latency of the eyeblink response was significantly










delayed in the Parkinson's patients. Similar findings were described by Koffer and

coworkers (2001). In contrast, Seignorel and colleagues (2003) found no significant

differences in either latency or magnitude of startle eyeblink responses in PD patients and

controls.

In the present study, basic startle data were available from ten controls and ten

Parkinson's patients. Basic startle eyeblink responses were obtained immediately prior to

presentation of the emotional pictures. These data consisted of twelve startle eyeblink

responses that had been elicited in response to a burst of white noise delivered through

headphones. The results of a one-way ANOVA revealed no significant differences

between the PD and Control groups in terms of latency to peak startle eyeblink, (F(1,18)

= 1.62, p >.20 [Control mean = 73.3 ms, SD = 8.27; PD mean = 66.9 ms, SD = 13.5]).

Similarly, there was no significant difference between the PD patients and Controls with

regard to the magnitude of the startle eyeblink response (F(1,18) = 2.50, p>. 10 [Control

mean = .0170 mV, SD = .009; PD mean = .0113 mV, SD = .008])

Taken together, some inconsistency exists with respect to latency of basic startle

eyeblink responses described in the literature. Some studies report slowed startle

eyeblink responses in Parkinson' s patients (Kofler et al., 2001; Vidailhet et al., 1992),

whereas others have found no difference between PD patients and Controls (Bowers,

Miller, Springer, Foote, & Okun, submitted; Seignorel et al., 2003). Importantly,

however, all studies are consistent with respect to magnitude of startle responses in

Parkinson patients and controls. Specifically, the PD patients appear normal with regards

to the absolute size of the startle eyeblink peak. This, of course, is the variable of interest

in the current study.









Possible Effects of Depression on the Present Findings

One possible explanation for the present findings is that the PD patients had

diminished potentiation of startle eyeblink in response to unpleasant pictures due to

depression and/or apathy. Every attempt was made to exclude PD patients that may be

depressed from the study by only including patients that did not meet criteria for Maj or

Depression. However, two of the twenty PD patients did meet criteria for "mild

depression" as determined by BDI score, and PD patients and controls did significantly

differ with respect to mean BDI scores. Another possibility is that some of the patients

may have experienced depression in the past and abnormal emotional reactivity may have

persisted (even though they were asymptomatic at the time of testing). Findings from a

recent study with depressed patients suggest that this is an unlikely explanation. Using

pictures from the International Affective Picture System, Allen and coworkers (Allen,

Trinder, & Brennan, 1999) found that moderate to severely depressed subjects (BDI

scores ranging from 19 to 29) showed normal emotional startle modulation. Patients who

were extremely depressed (i.e., BDI scores greater than 30) showed a larger startle

potentiation for pleasant versus unpleasant pictures (i.e., they responded to the pleasant

pictures as if they were aversive). Although this study involved a small sample size, it

suggests that abnormal startle modulation is not exhibited by depressed subj ects unless

they are severely depressed; furthermore, the pattern of startle potentiation found was

opposite to that of the current study. Namely, the PD patients in the present study

demonstrated normal startle modulation for pleasant pictures, but diminished startle

modulation for unpleasant pictures.

Similarly, the pattern of responding in the current study does not appear to be due

to a generalized apathy. Since apathy is the diminished reaction to all stimuli, both









positive and negative (Marin, 1996), one would expect a diminished reaction to

emotional pictures of all valence categories if apathy were indeed the driving force

behind the observed responses in PD patients. However, the present study did not

formally test level of apathy by use of standard scales, and thus this possibility cannot be

addressed by the current data.

The Role of the Amygdala in Response to Threatening/Fearful Stimuli

The Einding of reduced emotional responsivity to unpleasant pictures, and more

specifically, threatening pictures, is consistent with previous reports of pathological

changes in the amygdala of patients with Parkinson' s disease (Braak & Braak, 2000;

Harding et al., 2002; Ouchi et al., 1999). Several studies of patients with lesions that

include the amygdala have reported impaired identification of fear facial expressions

(Adophs et al. 1994, 1995; Calder et al. 1996; Young et al. 1995;). Additionally, fMRI

studies have found that the viewing of facial expressions of fear is associated with robust

amygdala activation (Breiter et al., 1996; Davidson & Irwin, 1999; Davis & Whalen,

2001; Morris et al., 1996; Whalen et al., 1998). Importantly, however, amygdala

activation is sometimes found for other negative facial expressions of emotion as well,

including disgust (Schienle et al., 2002) and anger (Tessitore et al., 2002). In an

experiment utilizing threatening pictures from the IAPS series (similar to the current

study), Hariri et al. (2003) found a significant bilateral amygdala BOLD response when

healthy subjects were asked to simply match a picture to a picture identical to it. In light

of this evidence implicating the amygdala in the processing of threatening stimuli, it is

possible that the PD patients in the present study suffer from significant amygdala

pathology that is causing a diminished emotional reactivity to threat-evoking stimuli. The

Parkinson's patients in the current study each received head MRI scans; however, at this









time volumetric measurements of the amygdala have not been performed, and thus this

prediction remains speculative. Additionally, Tessitore et al. (2001) have found evidence

that dopamine may modulate the functioning of the amygdala. The implication of this

finding with regards to the current study is that dopamine modulation of the amygdala

may be disrupted in PD patients due to loss of striatal dopamine.

An alternative or additional explanation for the current findings is that reduced

dopaminerigic innervation (i.e., nigrostriatal, mesolimbic, and/or mesocortical) in PD

patients may be disrupting the neural circuitry involved in emotion processing. Although

the patients in the present study were tested while on dopaminergic medication, it is

unlikely that this makes them similar to healthy people with respect to dopamine levels.

For example, Ouchi and coworkers (1999) found a reduction of dopamine (DA) agonist

binding in the amygdala, striatum, and orbitofrontal cortex of unmedicated PD patients.

The authors suggested that this might be due to a loss of presynaptic DA terminals in

these regions. To relate this back to the present study, a loss of dopaminergic terminals

would decrease levadopa binding in the medicated patients, leaving them with

abnormally low DA levels even when on medication. Additionally, the results from

Ouchi and colleagues' laboratory suggest an alteration in the mesocortical, mesolimbic,

and striato-thalamo-cortico orbitofrontal dopaminergic systems' functioning in PD

patients. As mentioned previously, these are circuits thought to be involved in emotional

processing.

Dissociation of Subjective Ratings and Physiological Response

Interestingly, although the PD patients showed diminished modulation of startle in

response to negative stimuli (particularly threatening stimuli) compared to controls, the

two groups did not differ with respect to their subj ective ratings of valence and arousal









levels in response to the pictures. Although the literature is sparse, there is evidence that

decouplingg" of subj ective emotional experience and physiological response can occur in

patients following brain damage. For example, a dissociation between skin conductance

responses (SCRs) and verbal report during anticipatory anxiety of electric shock was

reported by Slomine et al. (1999). Patients with both right and left hemisphere brain

damage exhibited smaller SCRs than healthy controls while anticipating the shock, yet all

groups reported feeling less pleasant, less in control, and more aroused while awaiting

shock as opposed to during a no-shock condition. In contrast, Meadows & Kaplan (1994)

reported that patients with right hemisphere damage showed diminished SCRs to

emotional and neutral slides relative to controls, while patients with left hemisphere brain

damage exhibited increased SCRs to both emotional and neutral slides. The groups did

not differ with respect to subj ective ratings of the slides, or in orienting and habituation to

loud tones.

Decoupling of physiological and subj ective emotional responses in Parkinson' s

disease patients has not been discussed in the literature, and is certainly an area towards

which future research should be directed. Although the mechanism underlying this

decouplingg" is unknown, one possibility is that subj ective emotional experience

typically incorporates feedback from the body's physiological pattern of response. In

Parkinson's disease as well as other neurological disorders, brain abnormalities can cause

a functional disconnect between the two (Slomine et al., 1999). Alternatively, it may be

that patients know the typical valence rating that is expected from them for each slide

(i.e., mutilation pictures should be rated as very unpleasant, puppies as pleasant) and are

conforming to experimenter demand characteristics.










Limitations of the Present Study

Several limitations of the current study must be acknowledged. First, the study

suffers from a small sample size, and thus it is uncertain whether these findings would be

replicated in a larger sample. Secondly, women and men were included together,

although men and women are generally regarded as responding to emotional stimuli

differently, and expressing emotional reactivity to different degrees.' The study also

utilized a rather homogeneous sample of Parkinson patients who were highly educated

and who had moderate motor impairments (mean Hoehn-Yahr stage of 2.7). Further

research is needed to determine whether the same pattern of affective startle modulation

exits in patients with milder or more severe PD.

Turning to a methodological critique of the study, one limitation is the fact that the

analysis of eyeblink magnitude to threatening versus other types of fearful stimuli was

conducted post-hoc. Thus, the original set of forty-four pictures was designed to measure

emotional reactivity to neutral, pleasant, and unpleasant stimuli; later, pictures depicting

imminent attack were grouped together and labeled as "threatening," and all other

remaining unpleasant pictures were grouped together and labeled "other unpleasant

pictures." Ideally, a larger sample of pictures should be used, expressing a variety of

threatening situations, and designed explicitly to assess startle modulation during viewing

of threatening stimuli versus other specific types of aversive stimuli (for example,

disgust-eliciting pictures).




SHowever, separate t-tests conducted on PD and control data yielded no significant differences between
men and women for unpleasant or pleasant blink magnitudes (controls unpleasant: t(13) = -0.038, p >.9;
controls pleasant: t(13) = 0.31, p > .7; PD unpleasant: t(18) = -0.089, p > .9; PD pleasant: t(18) = 0.56, p >









Another limitation of the current study is that startle eyeblink modulation to

unpleasant and pleasant stimuli was assumed to reflect emotional reactivity to the valence

of the pictures. However, the arousal level of a picture also affects startle modulation by

intensifying the magnitude of the eyeblink in the direction of the individual's

motivational activation (i.e., appetitive/pleasant or defensive/unpleasant). Namely, the

more arousing an unpleasant picture is to a participant, the greater the startle potentiation.

Similarly, the more arousing a pleasant picture is to a participant, the more attenuated the

startle eyeblink (Bradley, Codispoti, Cuthbert, & Lang, 2001). It may be that Parkinson's

patients display an overall pattern of "hypoarousal" in response to emotional materials. If

this is true, than Parkinson's patients might have shown a smaller difference between

unpleasant and pleasant picture eyeblink magnitudes relative to controls because they did

not exhibit a level of arousal that would serve to intensify the magnitude of their eyeblink

in line with the direction of the picture valence. Although PD patients reported

experiencing levels of arousal equivalent to those of Controls, they also rated picture

valences similar to Controls, suggesting that their subjective experience and physiologic

reactions are not necessarily congruent. Thus, the possibility that the findings of the

current study were due to a general diminished psychophysiologic reactivity to emotional

material in Parkinson's patients cannot be ruled out.

A further limitation is that analyses in the present study used T-scores, as opposed

to raw eyeblink magnitudes, as a way to measure emotional startle modulation. This was

done to minimize individual differences in eyeblink magnitude modulation, such that all

subjects could be compared on a common metric. However, it is possible that converting

raw scores to T-scores could obscure differences between the PD group and Controls. In









the future, raw startle data should be analyzed as well, to check that it exhibits the same

pattern as the transformed data.

Finally, the current study did not use a manipulation check to determine whether

participants subj ectively felt threatened during presentation of slides categorized as

"threatening." Although PD patients did exhibit diminished startle eyeblink potentiation

for threatening pictures compared to controls, this assumes that threat was indeed the

emotion subj ectively experienced by participants, which may or may not have been the

case. This issue is further confounded by the fact that both groups rated the "other

unpleasant stimuli" as being more unpleasant than the "threatening" stimuli, yet they

displayed larger eyeblink potentiation during viewing of the threatening pictures.

Directions for Future Research

Future directions for research include an exploration as to whether different

subtypes of PD are associated with differential patterns of affective startle eyeblink

modulation. For example, some researchers classify PD patients as either akinetic/rigid

or tremor predominant, depending on the key symptoms of the individual patient

(Ransmayr, Poewe, Ploerer, Birbamer, & Gerstenbrand, 1987; Ransmayr, Poewe, Plorer,

Gerstenbrand, Leidlmair, & Mayr, 1986). It is thought that the akinetic/rigid type

involves greater involvement of the mesolimbic and mesocortical pathways, and thus

these patients may display more aberrant patterns of startle modulation. The emotional

modulation of startle paradigm could also be used in different groups of patients with

basal ganglia disorders, such as those with essential tremor, Progressive Supranuclear

Palsy, and Huntington's Disease, as a way to measure emotional reactivity in these

patient groups without the confounding variable of motor output abnormalities. It may be

that disorders that often appear clinically similar on the behavioral level (such as essential









tremor and PD) may be distinguished from one another by their pattern of emotional

startle modulation.

Another important future line of research will be to determine if diminished

reactivity to threatening pictures correlates with measures of amygdala pathology, such as

decreased amygdala volume or decreased BOLD signal (relative to controls) during fMLRI

with concurrent presentation of threatening pictures. The results of the current study,

supported by past literature, suggest that reduced emotional reactivity to threatening

stimuli may be linked to amygdala abnormalities, but this hypothesis is purely

speculative as of now. Additionally, PD patients should be tested off their dopaminergic

medications using the emotional startle modulation paradigm, in order to determine how

dopamine levels affect emotional reactions as assessed by the startle paradigm.

An idea for a future study might include threatening pictures from the IAPS series

intermixed with disgusting pictures. Previous investigators have used pictures such as

body excrement, food contamination, and unsanitary conditions in an attempt to evoke

disgust in participants (e.g., Schienle et al., 2002; Shapira et al., 2003;). Studies have

implicated several structures that are part of the nigrostriatal loop affected in PD as being

involved in the recognition of disgust. For example, in an fMLRI study, Sprengelmeyer

and coworkers (1998) found that viewing pictures of facial expressions of disgust caused

activation of the left anterior insula, right anterior globus pallidus, and putamen in

healthy subjects. Activation of the left anterior insula, bilateral putamen, and right globus

pallidus and caudate nucleus was reported by Phillips et al. (1997), who presented images

of faces depicting different degrees of disgust intensity to normal controls. As such, one

might predict that PD patients presented with disgust-evoking pictures would exhibit









diminished startle potentiation, much as they displayed a diminished startle potentiation

in response to threat-evoking stimuli in the present study.

To conclude, the Einding of reduced emotional reactivity to negative stimuli in PD

patients, and threatening stimuli specifically, does not appear to be an artifact of a motor

output problem or depressive symptomatology. For these reasons, it offers a unique

advantage compared to other measures of emotionality in PD (such as facial expressivity

or vocal prosody), which are wrought with the confounding problem that these

movements may be affected by the motor symptoms of PD. Furthermore, the acoustic

startle is an involuntary physiological reaction that is very difficult, if not impossible, to

inhibit or voluntarily control, and thus does not rely on the participant' s attention or

motivation (Bradley, 2000). These characteristics make measurement of affective

modulation of eyeblink amplitude a paradigm that may afford a purer, more obj ective

method of exploring emotional reactivity in patients with basal ganglia disorders.
















LIST OF REFERENCES


Adolphs, R., Schul, R., & Tranel, D. (1998). Intact recognition of facial emotion in
Parkinson's disease. Neuropsychology, 12(2), 253-258.

Adolphs, R., Tranel, D., Damasio, H., & Damasio, A. (1994). Impaired recognition of
emotion in facial expressions following bilateral damage to the human amygdala.
Nature, 372(6507), 669-772.

Adolphs, R., Tranel, D., Damasio, H., & Damasio, A.R. (1995). Fear and the human
amygdala. The Journal ofNeuroscience, 15, 5879-5892.

Alexander, G.E., DeLong, M.R., & Strick, P.L. (1986). Parallel organization of
functionally segregated circuits linking basal ganglia and cortex. Annual Review of
Neuroscience, 9, 3 57-3 81.

Allen, N.B., Trinder, J., & Brennan, C. (1999). Affective startle modulation in clinical
depression: Preliminary findings. Biological Psychiatry, 46, 542-550.

Amaral, D.G. (2003). The amygdala, social behavior, and danger detection. Annals of the
New York Academy of Sciences, 1000, 337-347.

Beck, A.T. (1978). Beck depression inventory. San Antonio, TX: The Psychological
Corporation.

Beck, A.T., Steer, R.A., & Brown, G.K. (1996). Beck depression inventory-Second
edition manual. San Antonio, TX: The Psychological Corporation.

Benabid, A.L. (2003). Deep brain stimulation for Parkinson's disease. Current Opinion in
Neurobiology, 13(6), 696-706.

Blender, L.X., Gur, R.E., & Gur, R.C. (1989). The effects of right and left
hemiparkinsonism on prosody. Brain and Language, 36, 193-207.

Borod, J.C., Welkowitz, J., Alpert, M., Brozgold, A.Z., Martin, C., Peselow, E., & Diller,
L. (1990). Parameters of emotional processing in neuropsychiatric disorders:
Conceptual issues and a battery of tests. Journal of Conanunication Disorders, 23,
247-271.










Bowers, D., Bosch, W., Gokcay, D., Peden, C., Pedraza, O., Miller, K., Bongiolatti, S.,
Springer, U., Okun, M. (in press). Faces of emotion in Parkinson's disease: Micro-
expressivity and bradykinesia during voluntary facial expressions. Journal of
Cognitive Neuroscience.

Bowers, D. Gilmore, R. Bauer, R., Rogish, M., Kortenkamp, S., Gokay, D., Bradley, M.
& Roper, S. (1998, November) Affect modulation of startle is disrupted by right,
but not left, temporal resections involving the amygdala. Poster session presented at
the meeting of the Society for Neuroscience, Los Angeles, 1998.

Bowers, D., Miller, K., Springer, U., Foote, K., Okun, M. (2003). Startling facts about
emotion in ParkinsonP~~PPP~~~PP~~~PP 's disease. Manuscript submitted for publication.

Braak, H., & Braak, E. (2000). Pathoanatomy of Parkinson' s disease. Journal of
Neurology, 247(Suppl. 2), II/3-II/10.

Bradley, M. (2000). Emotion and motivation. In L. Tassinary, J. Cacioppo, & G.
Berntson (Eds.), Handbook ofpsychophysiology. New York, NY: Cambridge
University Press.

Bradley, M.M., Codispoti, M., Cuthbert, B.N., & Lang, P.J. (2001). Emotion and
motivation I: Defensive and appetitive reactions in picture processing. Emotion,
1(3), 276-298.

Bradley, M.M., Cuthbert, B.N., & Lang, P.J. (1990). Startle reflex: Emotion or attention?
Psychophysiology, 27, 513-522.

Bradley, M.M., Cuthbert, B.N., & Lang, P.J. (1991). Startle and emotion: Lateral acoustic
probes and the bilateral blink. Psychophysiology, 28, 285-295.

Bradley, M.M., & Vrana, S.R. (1993). In N. Birbaumer, & A. Ohman (Eds.), The
structure of emotion: Psychophysiological, cognitive, and clinical aspects (pp. 270-
287). Seattle, WA: Hogrefe & Huber.

Breiter, H.C., Etcoff, N.L., Whalen, P.J., Kennedy, W.A., Rauch, S.L., Buckner, R.L.,
Strauss, M.M., Hyman, S.E., & Rosen, B.R. (1996). Response and habituation of
the human amygdala during visual processing of facial expression. Neuron, 1 7,
875-887.

Brown, R.G., & Marsden, C.D. (1984). How common is dementia in Parkinson's
disease? Lancet, 2, 1262-1265.

Brown, R.G., & Pluck, G. (2000). Negative symptoms: The "pathology" of motivation
and goal-directed behaviour. Trends in Neuroscience, 23, 412-417.

Buck, R., & Duffy, R.J. (1980). Nonverbal communication of affect in brain-damaged
patients. Cortex, 16, 351-362.










Burn DJ. (2002). Beyond the iron mask: Towards better recognition and treatment of
depression associated with Parkinson's disease. M~ovenzentDisorders, 1 7(3), 445-
454.

Calder, A.J., Young, A.W., Rowland, D., Perrett, D.I., Hodges, J.R., & Etcoff, N.L.
(1996). Facial emotion recognition after bilateral amygdala damage: Differentially
severe impairment of fear. Cognitive Neuropsychology, 13, 699-745.

Cools, R., Barker, R.A., Sahakian, B.J., & Robbins, T.W. (2001). Mechanisms of
cognitive set flexibility in Parkinson's disease. Brain, 124, 2503-2512.

Cummings, J.L. (1992). Depression and Parkinson's disease: A review. American
Journal ofPsychiatry, 149, 443-454.

Davidson, R.J., Irwin, W. (1999). The functional neuroanatomy- of emotion and affective
style. Trends in Cognitive Science, 3(1), 11-21.

Davis, M. (1992). The role of the amygdala in conditioned fear. In J. Aggleton (Ed.), The
anzygdala: Neurobiological aspects of emotion, zentory, and mental dys~i~nction
(pp. 255-305). New York, NY: Wiley Publishers.

Davis, M., Genderlman, D.S., Tischler, M.D., & Gendelman, P.M. (1982). A primary
acoustic startle circuit: lesion and stimulation studies. Journal ofNeuroscience,
2(6), 791-805.

Davis, M., Whalen, P.J. (2001). The amygdala: Vigilance and emotion. Molecular
Psychiatry, 6(1), 13-34.

Dimitrov, M, Grafman, J., Soares, A.H., Clark, K. (1999). Concept formation and
concept shifting in frontal lesion and Parkinson's disease patients assessed with the
California card sorting task. Neuropsychology, 13, 135-143.

Fahn, S. (2003). Description of Parkinson's disease as a clinical syndrome. AnnualNew
York Academy ofSciences, 991, 1-14.

Fahn, S., Elton, R.L. (1987). Unified Parkinsons disease rating scale. In S. Fahn, C.D.
Marsden, M. Goldstein, D.B. Calne (Eds.), Recent developments in ParkinsonPP~~~PPP~~~PPP~~'s
disease, Voumle 2 (pp. 153-163). Florham Park, NJ: Macmillan Healthcare
Information.

Folstein, M.F., Folstein, S.E., & McHugh, P.R. (2001). M~ini-M~entalstate examination.
Odessa, FL: Psychological Assessment Resources.

Gauntlett-Gilbert, J., Roberts, R.C., Brown, V.J. (1999). Mechanisms underlying
attentional set-shifting in Parkinson's disease. Neuropsychologia, 37, 605-616.










Greenwald, M., Cook, E., & Lang, P. (1989). Affective judgment and
psychophysiological response dimensional covariation in the evaluation of pictorial
stimuli. Journal ofPsychophysiology, 3, 51-64.

Grillon, C., Ameli, R., Foot, M., & Davis, M. (1993). Fear-potentiated startle:
Relationship to the level of state/trait anxiety in healthy subj ects. Biological
Psychiatry, 33(8-9), 566-574.

Grillon, C., Ameli, R., Woods, S.W., Merikangas, K., & Davis, M. (1991). Fear-
potentiated startle in humans: Effects of anticipatory anxiety on the acoustic blink
reflex. Psychophysiology, 28(5), 588-595.

Harding, A.J., Stimson, E., Henderson, J.M., & Halliday, G.H. (2002). Clinical correlates
of selective pathology in the amygdala of patients with Parkinson's disease. Brain,
125, 2431-2445.

Hariri, A.R., Mattay, V.S., Tessitore, A., Fera, F., & Weinberger, D.R. (2003).
Neocortical modulation of the amygdala response to fearful stimuli. Biological
Psychiatry, 53, 494-501.

Hitchcock, J.M., & Davis, M. (1991). Efferent pathway of the amygdala involved in
conditioned fear as measured with the fear-potentiated startle paradigm. Behavioral
Neuroscience, 105(6), 826-842.

Hitchcock, J.M., Sananes, C.B., Davis, M. (1989). Sensitization of the startle reflex by
footshock: Blockade by lesions of the central nucleus of the amygdala or its
efferent pathway to the brainstem. Behavioral Neuroscience, 103(3), 509-518.

Hoehn, M., & Yahr, M. (1967). Parkinsonism: Onset, progression, and mortality.
Neurology, 17, 427-442.

Hughes, A.J., Ben-Shlomo, Y., Daniel, S.E., & Lees, A.J. (1992). What features improve
the accuracy of clinical diagnosis in Parkinson's disease: A clinicopathologic study.
Neurology, 42, 1142-1146.

Hughes, A.J., Daniel, S.E., Kilford, L., & Lees, A.J. (1992). Accuracy of clinical
diagnosis of idiopathic Parkinson's disease: A clinicopathological study of 100
cases. Journal ofNeurology, Neurosurgery, and Psychiatry, 55, 181-184.

Isella, V., Melzi, P., Grimaldi, M., lurlaro, S., Piolti, R., Ferrarese, C., Frattola, L., &
Appollonio, I. (2002). Clinical, neuropsychological, and morphometric correlates
of apathy in Parkinson' s disease.M2ovement Disorders, 1 7(2), 366-371.

Jacobs, D.H., Shuren, J., Bowers, D., & Heilman, K.M. (1995). Emotional facial
imagery, perception, and expression in Parkinson's disease. Neurology, 45, 1696-
1702.










Kan, Y., Kawamura, M., Hasegawa, Y., Mochizuki, S., & Nakamura, K. (2002).
Recognition of emotion from facial, prosodic, and written verbal stimuli in
Parkinson's disease. Cortex, 38(4), 623-630.

Katsikitis, B.A., & Pilowsky, M.D. (1988). A study of facial expression in Parkinson's
disease using a novel microcomputer-based method. Journal ofNeurology,
Neurosurgery, andPsychiatry, 51, 362-366.

Katsikitis, B.A., & Pilowsky, M.D. (1991). A controlled quantitative study of facial
expression in Parkinson's disease and depression. The Journal of Nervous and
Mental Disease, 1 79(1 1), 683-688.

Kltiver, H., & Bucy, P.C. (1939). Preliminary analysis of the temporal lobes in monkeys.
Archives ofNeurology and Psychiatry, 42, 979-1000.

Koffer, M., Muller, J., Wenning, G.K. Reggiani, L., Hollosi, P., Bosch, S., Ransmayr,
G., Valls-Sole, J., & Poewe, W. (2001). The auditory startle reaction in
parkinsonian disorders. Movement Disorders, 16(1), 62-71.

Lang, P.J. (1980). Behavioral treatment and biobehavioral assessment: Computer
applications. In J.B. Sidowski, J.H. Johnson, & T.A. Williams (Eds.). Technology
in nzental health care delivery. Norwood, NJ: Albex Publishing Corp.

Lang, P.J., Bradley, M.M., & Cuthbert, B.N. (1990). Emotion, attention, and the startle
reflex. Psychological Review, 9 7(3), 3 77-3 95.

Lang, P., Bradley, M., & Cuthbert, B. (2001a). The international affective picture system
(photographic slides). Gainesville, FL: The Center for Research in
Psychophysiology, University of Florida.

Lang, P., Bradley, M., & Cuthbert, B. (2001Ib). International affective picture system
(IAPS): Instruction manual and affective ratings: Technical Report A-5.
Gainesville, FL: The Center for Research in Psychophysiology, University of
Florida.

Lang, A.E, & Lozano, A.M. (1998). Parkinson's disease: First of two parts. The New
Englan2dJournal of2~edicine, 339(15), 1044-1053.

Madeley, P., Ellis, A.W., & Mindham, R.H.S. (1995). Facial expressions and Parkinson's
disease. Behavioural Neurology, 8, 115-119.

Marin, R.S. (1991). Apathy: A neuropsychiatric syndrome. Journal ofNeuropsychiatry
and Clinical Neuroscience, 3, 243-254.

Marin, R.S., (1996). Apathy: Concept, syndrome, neural mechanisms, and treatment.
Seminars in Clinical Neuropsychiatry, 1, 3 04-3 14.










Mayberg, H.S., Starkstein, S.E., Sadzot, B., Preziosi, T., Andrezejewski, P.L., Dannals,
R.F., Wagner, H.N. Jr., & Robinson R.G. (1990). Selective hypometabolism in the
inferior frontal lobe in depressed patients with Parkinson's disease. Annals of
Neurology, 28(1), 57-64.

McDonald, W.M., Richard, I.H., & DeLong, M.R. (2003). Prevalence, etiology, and
treatment of depression in Parkinson's disease. Biological Psychiatry, 54(3), 363-
75.

Meadows, M.E., & Kaplan, R.F. (1994). Dissociation of autonomic and subj ective
responses to emotional slides in right hemisphere damaged patients.
Neuropsychologia, 32(7), 847-56.

Morris, J.S., Frith, C.D., Perrett, D.I., Rowland, D., Young, A.W., Calder, A.J., & Dolan,
R.J. (1996). A differential neural response in the human amygdala to fearful and
happy facial expressions. Nature, 383, 812-815.

National Institute of Neurological Disorders and Stroke (2001, July 1). Parkinson's
disease backgrounder. Retrieved February 9, 2004, from
http://www.ninds.nih.gov/health_and~medica/us
p arki nson' s_di seas e~backgrounder. htm

O'Gorman, J.R. (1990). Individual differences in the orienting response: Nonresponding
in nonclinical samples. Pavlovian Journal of Biological Science, 25(3), 104-108.

Ouchi, Y., Yoshikawa, E., Okada, H., Futatsubashi, M., Sekine, Y., lyo, M., et al. (1999).
Alterations in binding site density of dopamine transporter in the striatum,
orbitofrontal cortex, and amygdala in early Parkinson's disease: Compartment
analysis for P-CFT binding with positron emission tomography. Annals of
Neurology, 45, 601-610.

Peto, V., Jenkinson, C., & Fitzpatrick, R. (1998). PDQ-39: A review of the development,
validation and application of a Parkinson's disease quality of life questionnaire and
its associated measures. Journal ofNeurology, 245(Supplement 1): S10-S14.

Phillips, M.L., Young, A.W., Scott, S.K., Calder, A.J., Andrew, C., Giampietro, V.,
Williams, S.C.R., Bullmore, E.T., Brammer, M., & Gray, J.A. (1998). Neural
responses to facial and vocal expressions of fear and disgust. Proceedings of the
Royal Society ofLondon, Series B: Biological sciences, 265, 1809-18 17.

Pluck,G., & Brown, R.G. (2002). Apathy in Parkinson's disease. Journal ofNeurology,
Neurosurgery, and Psychiatry, 73(6), 636-42.

Pogarell, O., & Oertel, W.H. (1999). Parkinsonian syndromes and Parkinson's disease:
Diagnosis and differential diagnosis. In P.A. LeWitt & W.H. Oertel (Eds.),
Parkinson 's disease: The treatment options (pp. 1-10). London, UK: Martin
Dunitz.










Ransmayr, G., Poewe, W., Ploerer, S., Birbamer, G., & Gerstenbrand, F. (1987).
Psychometric findings in clinical subtypes of Parkinson's disease. Advances in
Neurology, 45, 409-411.

Ransmayr, G., Poewe, W., Plorer, S., Gerstenbrand, F., Leidlmair, K., & Mayr, U.
(1986). Prognostic implications of the motor symptoms of Parkinson's disease with
respect to clinical, computertomographic and psychometric parameters. Journal of
Neural Transmission, 67(1-2), 1-14.

Rosen, J.B., & Davis, M. (1988). Enhancement of acoustic startle by electrical
stimulation of the amygdala. Behavioral Neuroscience, 102(2), 195-202, 324.

Rosen, J.B., Hitchcock, J.M., Miserendino, M.J., Falls, W.A., Campeau, S., & Davis, M.
(1992). Lesions of the perirhinal cortex but not of the frontal, medial prefrontal,
visual, or insular cortex block fear-potentiated startle using a visual conditioned
stimulus. Journal ofNeuroscience, 12(12), 4624-4633.

Schienle, A., Stark, B., Walter, C., Blecker, U., Ott, P., Kirsch, G., Sammer, G., & Vaitl,
D. (2002). The insula is not specifically involved in disgust processing: A fMLRI
study. Neuroreport, 13, 2023-2026.

Schwab, J.F., & England, A.C. (1969). Unified Parkinson's disease rating scale version
3.0 Schwab and England activities of daily living scale. In F.J. Gillingham & M.C.
Donaldson (Eds.): Third Symposium on Parkinson'sPP~~PP~~~PP~~PP Disease (pp. 152-157).
Edinburgh: Livingstone.

Scott, S., Caird, F., & Williams, B. (1984). Evidence for an apparent sensory speech
disorder in Parkinson's disease. Journal ofNeurology, Neurosurgery, and
Psychiatry, 47, 840-843.

Seignorel, P., Miller, K., Bowers, D., Okun, M. (2003, October). Startle responses in
patients nI ithr psychogenic movement disorders. Presented at the Psychogenic
Movement Disorders Workshop of the Movement Disorder Society, Atlanta, GA.

Shapira, N.A., Liu, Y., He, A.G., Bradley, M.M., Lessig, M.C., James, G.A., Stein, D.J.,
Lang, P.J., & Goodman, W.K. Brain activation by disgust-inducing pictures in
obsessive-compulsive disorder. Biological Psychiatry, 54(7), 751-756.

Slomine, B., Bowers, D., & Heilman, K.M. (1999). Dissociation between autonomic
responding and verbal report in right and left hemisphere brain damage during
anticipatory anxiety. Neuropsychiatry, Neuropsychology, and Behavioral
Neurology, 12(3), 143-148.

Smith, M.C., Smith, M.K., & Ellgring, H. (1996). Spontaneous and posed facial
expression in Parkinson' s disease. Journal of the International Neuropsychological
Society, 2, 383-391.










Sprengelmeyer, R., Rausch, M., Eysel, U.T., & Przuntek, H. (1998). Neural structures
associated with recognition of facial expressions of basic emotions. Proceedings of
the Royal Society ofLondon, Series B: Biological sciences, 265, 1927-193 1.

Sprengelmeyer, R., Young, A.W., Mahn, K., Schroeder, U., Woitalla, D., Biittner, T.,
Kuhn, W., & Przuntek, H. (2003). Facial expression recognition in people with
medicated and unmedicated Parkinson's disease. Neuropsychologia, 41, 1047-
1057.

Starkstein, S.E., Mayberg, H.S., Preziosi, T.J., Andrezejewski, P., Leiguarda, R., &
Robinson, R.G. (1992). Reliability, validity, and clinical correlates of apathy in
Parkinson' s disease. Journal ofNeuropsychiatry and Clinical Neuroscience, 4,
134-139.

Tessitore, A., Hariri, A.R., Fera, F., Smith, W.G., Chase, T.N., Hyde, T.M., Weinberger,
D.R.,& Mattay, V. S. (2002). Dopamine modulates the response of the human
amygdala: A study in Parkinson's disease. The Journal ofNeuroscience, 22(20),
9099-9103.

van Spaendonck, K.P., Berger, H.J., Horstink, M.W., Borm, G.F., & Cools, A.R. (1993).
Card sorting performance in Parkinson's disease: A comparison between
acquisition and shifting performance. Journal of Clinical Experimental
Neuropsychology, 17, 918-925.

Vidailhet, M., Rothwell, J.C., Thompson, P.D., Lees, A.J., & Marsden, C.D. (1992). The
auditory startle response in the Steele-Richardson-Olszewski syndrome and
Parkinson's disease. Brain, 115(4), 1181-1192.

Vrana, S.R., Spence, E.L., & Lang, P.J. (1988). The startle probe response: A new
measure of emotion? Journal ofAbnormal Psychology, 97(4), 487-491.

Walker, D.L., & Davis, M. (2002). The role of amygdala glutamate receptors in fear
learning, fear-potentiated startle, and extinction. Pharmacology, Biochemistry, and
Behavior, 71, 379-392.

Whalen, P.J., Rauch, S.L, Etcoff, N.L., McInerney, S.C., Lee, M.B., & Jenike, M.A.
(1998). Masked presentations of emotional facial expressions modulate amygdala
activity without explicit knowledge. Journal ofNeuroscience, 18, 411-418.

Yip, J.T.H., Lee, T.M.C., Ho, S.-L., Tsang, K.-L., & Li, L.S.W. (2003). Emotion
recognition in patients with idiopathic Parkinson's disease. Movement Disorders,
18(10), 1115-1122.

Young, A.W., Aggleton, J.P., Hellawell, D.J., Johnson, M., Broks, P., & Hanley, J.R.
(1995). Face processing impairments after amygdalotomy. Brain, 118, 15-24.










Zgaljardic, D.J., Borod, J.C., Foldi, N.S., & Mattis, P. (2003). A review of the cognitive
and behavioral sequelae of Parkinson' s disease: Relationship to frontostriatal
circuitry. Cognitive and Behavioral Neurology, 16(4), 193-210.
















BIOGRAPHICAL SKETCH

Kimberly Miller was born in San Jose, CA, and received her B.A. in psychology

from the University of California, Berkeley. After gaining research experience in

cognitive neuroscience at the Martinez V.A., she moved to Gainesville to pursue her

doctorate in clinical psychology at the University of Florida, specializing in

neuropsychology. Current clinical interests include learning disorders and speech and

language disorders. Current research interests include the affective modulation of startle

in chronically depressed patients, as well as the effect of psychiatric disorders on

cogmitive processes.