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The effects of cortisol on emotion

ProQuest Dissertations and Theses, 2009
Dissertation
Author: Keith Daniel Sudheimer
Abstract:
Release of the hormone cortisol is normally tightly regulated. However, when regulation fails and cortisol is hypersecreted (as in Cushing's disease), significant emotional changes occur, including depression, raising the question of whether cortisol effects on the brain could be generating depressive symptoms. Dysregulation leading to cortisol hypersecretion is also observed in depression, where emotion changes compose the core symptoms. However, cortisol as a causative agent in generating emotional changes in depression has rarely been investigated despite evidence that cortisol impacts emotional states and the neurophysiology of brain regions that process emotion. To explore the effects of cortisol on processes impacted by depression we administered exogenous cortisol to healthy subjects and observed its effects on the subjective experience of emotion, on brain activity patterns elicited by emotional stimuli, and on early perceptual processing of emotional stimuli. In a large neuroimaging study (N=60) we examined the effects of cortisol on brain activity induced by viewing emotionally evocative pictures (measured using fMRI) and on the cerebral hemodynamic response function, as a verification that cortisol's physiological effects do not invalidate fMRI measures of brain activity. In this study we administered placebos to a control group and either a single dose regimen of cortisol administration (100 mg) or an extended dose cortisol regimen (25 mg/day, 5 days) (N=20/group) to experimental groups. In a separate behavioral study of early perceptual processing (N=33), we examined the effects of cortisol on detection and identification of emotional faces. Cortisol administration did not affect the cerebral hemodynamic response, but did significantly increased feelings of arousal during sadness and simultaneously inhibited subgenual cingulate (Brodmann area 25) activity, a region implicated in normal sadness and pathological sadness in depression. In the behavioral study, cortisol did not influence detection or identification of emotional faces. In summary, we demonstrate that cortisol, a hormone often hypersecreted in depression, influences the experience of emotions relevant to depression and activity in brain regions associated with depression, but it does not alter early perceptual processing of emotional stimuli. Further study of cortisol's influence on these processes in healthy and depressed populations may provide insights into the pathophysiology of depression.

Table of Contents Dedication ii Acknowledgements iii List of Figures viii List of Tables xi List of Abbreviations xii Chapter 1: Introduction 1 Physiology of Cortisol 1 Cortisol and Stress 4 Depression Neurophysiology, and Hypercortisolemia 5 Emotion and Hypercortisolemia 7 Neurophysiology of Emotion and Cortisol 8 Purpose of this Dissertation 9 Chapter 2: Cortisol Administration and the Hemodynamic Response 14 Introduction 14 Methods 15 Subjects 15 Cortisol Administration 16 MRI image acquisition 16 iv

fMRI Tasks 17 fMRI Analysis 18 Measures of the HRF 19 Results 19 Discussion 21 Limitations 23 Chapter 3: The Effect of Cortisol Administration on the Neural Correlates of Emotion 24 Introduction 24 Methods 27 Subjects 27 Cortisol Administration 28 fMRI Task 28 Measurement of Emotional States 29 Measurement of Cortisol 30 MRI Image Acquisition 30 Ratings of Emotion induced by Stimuli Presented During Scanning 31 fMRI Analysis 31 Results 33 Experimental Blinding 33 Circulating Cortisol Levels Elevated by Cortisol Administration 34 Cortisol Produces a Trend Level Increase in Sad Mood 36 Cortisol Increases Arousal Ratings of Sad Stimuli 36 Emotional Stimuli Robustly Activate Subcortical and Cortical Brain Regions 37 v

Cortisol Modulates Brain Activity Elicited by Emotional Stimuli 39 Discussion 54 Limitations 57 Chapter 4: The Effect of Cortisol Administration on the Time Course of Early Detection and Identification of Emotional Facial Expressions 60 Introduction 60 Methods 62 Subjects 62 Cortisol administration and Measurement: 63 Measurement of Emotional States 63 Equipment , 64 Stimuli 64 Design 65 Analysis 68 Results 69 Experimental Blinding 69 Cortisol Administration does not affect Overall Emotional State 69 Circulating Cortisol Levels Elevated by Cortisol Administration 70 Type of Emotional Facial Expression Affects Detection Accuracy and Sensitivity But Cortisol Administration Does Not 70 Type of Emotional Facial Expression Affects Identification Accuracy and Sensitivity But Cortisol Administration Does Not 74 Discussion VI 80

Effects of Cortisol on Detection and Identification 80 Happy Faces Detected and Identified Better Than Sad or Neutral Faces 81 Learning across sessions 82 Limitations 84 Chapter 5: Conclusion 87 Limitations 89 Significance & Future Directions 92 Bibliography 95 vn

List of Figures Figure 1 Estimates of the time course of the visual cortex (Brodmann areas 17/18) HRF in subjects administered Placebo, a single dose of lOOmg of hydrocortisone, or a extended dose of 25mg/day of hydrocortisone 20 Figure 2 Average time to achieve peak BOLD response in the visual cortex in response to a 1 second visual stimulation for subjects administered placebo, a single dose of lOOmg of hydrocortisone, or a split dose of 25mg/day of hydrocortisone/day over 5 days 21 Figure 3 Average magnitude of the peak BOLD response in the visual cortex in response to a 1 second visual stimulation for subjects administered placebo, a single dose of lOOmg of hydrocortisone, or a split dose of 25mg/day of hydrocortisone/day over 5 days 21 Figure 4 Circulating Cortisol concentrations as measured in saliva. The single dose group was administered lOOmg oral hydrocortisone at time 0. The extended dose group was administered 25mg hydrocortisone/day over 5 days, ending 6 hours prior to time 0 35 Figure 5 Average circulating Cortisol during fMRI scanning was robustly elevated in the single dose group. 36 Figure 6 Arousal ratings in reaction to viewing sad stimuli were significantly elevated in the extended dose group but not the single dose group 37 Figure 7 Brain Activity Changes Resulting from the Viewing of Happy (Row A), Neutral (Row B), and Sad (Row C) stimuli. All emotion condition activations/deactivations are relative to fixation cross for the placebo group only 39 Figure 8 Subgenual cingulate suppression by a single dose (A) and an extended dose (B) of Cortisol relative vni

to the placebo group 40 Figure 9 Cortisol induced subgenual cingulate activity suppression is observed only during the sadness condition 41 Figure 10 Sadness induced subgenual cingulate activity in the single dose group is negatively correlated with circulating Cortisol levels at the time of scanning 41 Figure 11 Cortisol induced VMPFC activity suppression is observed only during the sadness condition. The single dose produces only trend level suppression, whereas, the extended dose produces significant suppression 42 Figure 12 Amygdala activity in response to emotional stimuli is not significantly altered by either the single dose or the extended dose of Cortisol 43 Figure 13 Parahippocampal/perimamygdala activity is increased in the single dose group during sadness (A) and the extended dose group during sadness (B), neutrality (C), and happiness (D) 44 Figure 14 Extended dose induced suppression of SLEA activity during sadness 44 Figure 15 Superior colliculus and thalamus activity is suppressed by a single dose of Cortisol 45 Figure 16 Presentation time course of noise (Row A) and signal (Row B) trials in the face detection task. Each target face was preceded by a blank screen with a 3 00-5 00ms duration and then followed by a 100ms perceptual mask 67 Figure 17 Presentation time course of identification trials. Each target face was preceded by a blank screen with a 300-500ms duration and then followed by a 100ms perceptual mask 68 Figure 18 Cortisol administration does not significantly alter any of the 11 PANAS mood subscales 69 Figure 19 Circulating Cortisol levels are significantly elevated 2 hours after Cortisol administration 70 Figure 20 Detection accuracy curve for happy and sad facial expressions 71 Figure 21 Accuracy of detecting happy facial expression across sessions for the placebo and Cortisol groups. 72 ix

Figure 22 Change in accuracy of detecting happy facial expression across sessions for the placebo and Cortisol groups 73 Figure 23 Accuracy of detecting sad facial expression across sessions for the placebo and Cortisol groups. 73 Figure 24 Change in accuracy of detecting sad facial expression across sessions for the placebo and Cortisol groups 74 Figure 25 Identification accuracy curve for happy, neutral and sad facial expressions 75 Figure 26 Change in detection and identification accuracy across sessions for each type of emotional facial expression 76 Figure 27 Accuracy of identifying happy facial expressions across sessions for the placebo and Cortisol groups 77 Figure 28 Change in accuracy of identifying happy facial expressions across sessions for the placebo and Cortisol groups 77 Figure 29 Accuracy of identifying neutral facial expressions across sessions for the placebo and Cortisol groups 78 Figure 30 Change in accuracy of identifying neutral facial expressions across sessions for the placebo and Cortisol groups 78 Figure 31 Accuracy of identifying sad facial expressions across sessions for the placebo and Cortisol groups. 79 Figure 32 Change in accuracy of identifying sad facial expressions across sessions for the placebo and Cortisol groups 79 x

List of Tables Table 1 Confusion matrix table indicates that subjects were poor at distinguishing between taking hydrocortisone and taking a placebo. Columns indicate the group assignment. Rows indicate the group the subject thought they were in. Cells indicate the rate of correct identification of group (diagonals) or misidentification of group (off diagonals) 34 Table 2 Table of significant group differences in brain activity while viewing sad stimuli. a Stereotactic coordinates from MNI152 reference, left/right, anterior/posterior and superior/inferior, respectively. b Cluster size in voxels. c All foci meet min threshold of p< 0.005, uncorrected; Extend threshold k=5 voxels 46 Table 3 Table of significant group differences in brain activity while viewing happy stimuli. a Stereotactic coordinates from MNI152 reference, left/right, anterior/posterior and superior/inferior, respectively. b Cluster size in voxels. c All foci meet min threshold of p< 0.005, uncorrected; Extend threshold k=5 voxels 48 Table 4 Table of significant group differences in brain activity while viewing neutral stimuli. a Stereotactic coordinates from MNI152 reference, left/right, anterior/posterior and superior/inferior, respectively. b Cluster size in voxels. c All foci meet min threshold of p< 0.005, uncorrected; Extend threshold k=5 voxels 51 Table 5 The confusion matrix of emotional facial expression. Columns indicate the emotion presented. Rows indicate the response. Cells indicate the rate of correct identification (diagonals) or misidentification (off diagonals) 80

List of Abbreviations 3AFC ACTH ANOVA BA BOLD CBG cm CRH CRT d' dL fMRI FOV GB GHz GLM GR HPA HRF Hz Three Alternative Forced Choice Adrenocorticotropic Hormone Analysis of Variance Brodmann Area Blood Oxygen Level Dependant Corticosteroid Binding Globulin Centimeter Corticotropin Releasing Hormone Cathode Ray Tube D prime Deciliter Functional Magnetic Resonance In Field of View Gigabyte Gigahertz General Linear Model Glucocorticoid Receptor Hypothalamic-Pituitary-Adrenal Hemodynamic Response Function Hertz Xll

IAPS K Hg mg mm MINI MM MR mRNA ms PANAS RAM SLEA SPGR SPM SPSS TE TR VMPFC International Affective Picture System Cluster Microgragms Milligrams Millimeter Mini International Neuropsychiatric Interview Montreal Neurological Institute Mineralcorticoid Receptor Messanger Ribonucleic acid Millisecond Positive And Negative Affect Schedule Random Access Memory Sublenticular Extended Amygdala Spoiled Gradient Echo Pulse Sequence Statistical Parametric Mapping Statistical Package for the Social Sciences Echo Time Repetition Time Ventral Medial Prefrontal Cortex xm

Chapter 1: Introduction There is long standing evidence linking depression and the hormone Cortisol. A large amount of previous research has focused on establishing measures of Cortisol secretion and Cortisol regulation as biomarkers of depression. However, comparatively little work has been to investigate if Cortisol is a contributing factor to the development or maintenance of depression. In this body of work we outline several studies designed to elucidate the physiological effects of Cortisol administration on brain and behavioral processes relevant to depression. Physiology of Cortisol Cortisol is a steroid hormone, often secreted in response to stress (Selye, 1971). It is classified as a corticosteroid, due to its biosyntheses in the adrenal cortex. It is also classified as a glucocorticoid, due to early observations of its functions in glucose regulation and metabolism. Cortisol is produced in vivo from cholesterol and is secreted principally from the adrenal cortex. Endogenous Cortisol has many known physiological effects including anti-inflammatory, energy regulatory, glucose regulatory, and immunosuppressive effects. The synthetic equivalent of endogenous Cortisol is known as hydrocortisone, which is produced commercially from various plant sterols, and marketed in creams and as oral capsules to treat common inflammatory autoimmune 1

conditions. Other glucocorticoids such as prednisone and dexamethasone are also used for these purposes, with increased potency relative to Cortisol. Cortisol is the major output hormone of the hypothalamic-pituitary-adrenal (HPA) axis in humans, whereas in rodents a closely related hormone called corticosterone serves this purpose. Cortisol secretion also maintains a regulated circadian rhythm. Activation of the HPA axis beyond the normal circadian rhythm and the subsequent release of Cortisol are often associated with stress (Selye, 1985). However, Cortisol secretion is not inextricably coupled with the subjective feelings of stress, and subjective feelings of stress do not always translate into high Cortisol levels (Curtis et al., 1978). Thus, high levels of Cortisol do not directly cause subjective feelings of stress. Cortisol has two known types of principal intracellular receptors, the glucocorticoid receptor (GR) and the mineralcorticoid receptor (MR) which are distributed widely in the brain and periphery (Watzka et al., 2000b; Rashid and Lewis, 2005) and at least one additional cell membrane bound receptor (Orchinik et al., 1991; Borski, 2000). Activation of these receptors can produce a wide variety of physiological and psychological effects through gene transcription changes, mediated by glucocorticoid response elements, within hours of exposure to Cortisol (Karst et al., 2002). Glucocorticoid hormones can also produce effects within seconds through membrane mediated mechanisms and through other unknown mechanisms that can affect neurotransmission and even complex behaviours. (Orchinik et al., 1991; ffrench-Mullen, 1995; Rose, 2000; Mikics et al., 2005; de Kloet et al., 2008a) (for a review see (Dallman, 2005)). 2

The amount of circulating Cortisol that is free to exert effects on receptors in the brain or periphery is tightly regulated. Two known isoforms of the enzyme 11-beta-hydroxysteroid dehydrogenase serve to interconvert Cortisol and its much less active form cortisone (for review see (Tomlinson and Stewart, 2001)). In the blood the vast majority of Cortisol is bound and inactivated by a protein called corticosteroid binding globulin (CBG/transcortin) (Westphal, 1983). Cortisol release is also regulated at multiple levels by redundant feedback inhibition within the HPA axis. When the HPA axis is activated brain mediated signals prompt the release of corticotropin releasing hormone (CRH) at the level of the hypothalamus. CRH then prompts the release of a second hormone known as adrenocorticotropic hormone (ACTH) at the level of the pituitary gland. ACTH is released into the general circulation and serves to prompt the release of Cortisol from the adrenal cortex. When Cortisol is released into circulation, it serves to inhibit its own release by providing inhibitory signals at the level of the pituitary, hypothalamus, and hippocampus. These inhibitory signals are achived extremely rapidly at the level of the hypothalamus (paraventricular nucleus) and hippocampus (cornu ammonis 1 cells) through non-genomic mechanisms that affects glutamate neurotransmission and subsequent miniature excitatory postsynaptic currents. Intermediated and slower delayed negative feedback mechanisms also occur on the level of the hypothalamus, pituitary, and hippocampus acting predominantly via cytosolic GR, which affect the structure and function of neurons in these and other subcortical and cortical brain regions (for reviews see (Jacobson, 2005; de Kloet et al., 2008b)). Failure to regulate Cortisol production can result in serious pathological conditions. Addison's disease, which is characterized by underproduction of Cortisol brought on by 3

insufficient production of Cortisol in the adrenal cortex, results in chronic and worsening fatigue over time, muscle weakness and loss of weight and appetite. Cushing's syndrome, characterized by overproduction of Cortisol (hypercortisolemia), is often caused by pituitary or adrenal tumors and results in severe fatigue, muscle weakness, high blood pressure, high blood glucose, upper body obesity and, notably, increases in anxiety and depression (Haskett, 1985; Nieman and Ilias, 2005). Cortisol and Stress The release of glucocorticoids in humans and animals is triggered by a wide variety of stimuli that are often conceptualized as stressful or threatening to the integrity or homeostasis of an organism. These triggers include physical stressors such as bodily injury and also psychological stressors which may predict such injury. For example, invasive surgical procedures result in massive increases in circulating glucocorticoid levels (Naito et al., 1992). Less invasive procedures such as electric shocks (Bassett et al., 1973) and exposure to extreme cold (Edelson and Robertson, 1986) also produce a significant glucocorticoid response. Exposure to physically threatening stimuli which could predict injury can also elicit a similarly robust glucocorticoid response. For example, in animals, exposure to the smell of predators can causes robust increases in glucocorticoid responses, even when the predator inflicts no physical harm (for a review see (Apfelbach et al., 2005)). Similarly, physical restraint in animals can also produce a large glucocorticoid response (Keim and Sigg, 1976) without producing any physical harm. In human studies, potentially physically threatening situations that do not result in physical harm also generate a robust increase in Cortisol secretion. For example, 4

novice skydivers performing their first jump show marked increases in Cortisol secretion (Chatterton et al., 1997). In humans recent evidence suggests that psychosocial stress or threats to the social self (social value, esteem, status, worth etc.) can generate a robust glucocorticoid response (Dickerson and Kemeny, 2004). Laboratory studies employing the Trier social stress test (TSST) (Kirschbaum et al., 1993), which involves subjects delivering a speech and performing mental arithmetic in front of an audience, demonstrate a robust and reliable increase in Cortisol secretion and seem to support psychosocial stress theories. In addition, a meta-analysis of studies attempting to induce stress via cognitive tasks, public speaking tasks, noise exposure and emotion induction suggests that Cortisol is most reactive to social evaluative/psychosocial stress. It also suggests that amongst psychosocial stressors the Cortisol response is the greatest when subjects are in experimental contexts that involve dimensions of social evaluation threat and uncontrollability (Dickerson and Kemeny, 2004). Depression Neurophysiology, and Hypercortisolemia Depression is a psychiatric disorder characterized by symptoms that include low mood, decreased interest in pleasurable activities, changes in appetite or weight, insomnia/hypersomnia, psychomotor agitation/retardation, fatigue, inappropriate guilt, difficulties with cognition, and thoughts of suicide (American Psychiatric Association., 2000). Some investigations have reported that over 17% of the population will develop major depression in their lifetime (Blazer et al., 1994) and the World Health Organization 5

estimates that depression is the second leading cause of potential years of life lost to disability for both men and women between the ages of 15 and 44, making the global burden of depression immense. Hypercortisolemia has been observed in large portions of depressed patients (Carroll et al., 1976; Young et al., 2001). Hypercortisolemia is accompanied by increases in the size of the adrenal cortex (Rubin et al., 1995). This hypercortisolemia is thought to arise from decreased sensitivity to inhibitory feedback (Kolebinov et al., 1975; Carroll, 1980; Greden et al., 1980; Carroll, 1982a, b; Holsboer et al., 1982; Carroll, 1984; Zobel et al., 2001). Amelioration of the hypercortisolemic state in depression is associated with recovery from depression, resistance to relapse (Greden et al., 1980; Holsboer et al., 1982; Zobel et al., 1999; Zobel et al., 2001) and normalization of the adrenal gland size(Rubin et al., 1995). However, it is currently unknown if this hypercortisolemia is a consequence of depression, or if Cortisol may be actively contributing to the maintenance or etiology of depressive symptomatology through its effects on the brain. Several brain functional, volumetric, and histological abnormalities have been documented in depression (See (Drevets et al., 2008) for a current review). Among these the subgenual cingulate cortex is most notable in that it demonstrates reduced volume, cell counts and glucose metabolism in depression. However, once the reduce volume of the subgenual cingulate is accounted for activity within this region appears to increase in depression relative to healthy controls. Reductions in volume, cell counts, and markers of functionality (glucose metabolism or cerebral blood flow) have also been observed in the dorsal medial prefrontal cortex, pregenual anterior cingulate, vental 6

lateral prefrontal cortex, and parahippocampal cortex. Decreased volume in the hippocampus of depressed patients has also been observed in multiple studies and correlates with time spent untreated (Sheline et al., 1999; Sheline et al., 2003). However, there are not consistent observations of decreased hippocampal functional activity to accompany this reduced volume. In the amygdala the literature is mixed with respect to volume and functional activity, both increases and decreases in these measures have been observed. The ventral striatum is another region that has reduced grey matter volume and functional activity. Also notable amongst these findings is that the medial thalamus demonstrates decreased functional activity in depressed patients relative to healthy controls. Emotion and Hypercortisolemia Some evidence suggests that hypercortisolemia could be contributing to mood changes in depression. For example, patients with Cushing's disease often have high rates of co-morbid depression (up to 80%). Exogenous hydrocortisone administration in large doses can also directly induce severe mood dysregulation, including both depression and mania (Ling et al., 1981), with depression the more common outcome. Measures of endogenous Cortisol levels in humans have been shown to correlate with depressed mood (Van Honk et al., 2003). Animal studies also support this notion by demonstrating that corticosterone administration increases depression-like behaviors (Kalynchuk et al., 2004), and anxiety in rats (Mitra and Sapolsky, 2008). 7

Neurophysiology of Emotion and Cortisol Consistent findings across studies of the neurophysiology of emotion are rare due to heterogeneity of laboratory tasks designed to evoke emotion and the highly subjective nature of measurements of emotion induction magnitude. However, some patterns of brain activity seem to associate strongly with certain emotions. Fear is strongly associated with amygdala activity, sadness with subgenual cingulate activity and happiness with basal ganglia activity (Phan et al., 2002). These regions however do not respond exclusively to these emotions, and these emotions involve additional brain regions. The amygdala for example responds most robustly to fear (Aggleton, 1992) but it also responds to many other additional emotions (Fitzgerald et al., 2006). The subgenual cingulate, while less extensively studied than the amygdala, shows strong associations with negative mood and sadness. Critically, this subgenual cingulate responsiveness seems to overlap between sadness in healthy subjects and the pathological sadness central to depression (Mayberg et al., 1999). Moreover, early evidence from clinical trials of deep brain stimulation aiming to modulate subgenual cingulate activity for use in treatment resistant depression has demonstrated promising results (Lozano et al., 2008; McNeely et al., 2008). Further evidence suggests that Cortisol can influence emotion and the structure and physiology of neurons in brain regions thought to underlie emotional responses. Animal studies have demonstrated that corticosterone has direct modulatory effects on the physiological responsiveness of neurons in neural structures associated with emotion, such as the hippocampus (Birnstiel et al., 1995; De Kloet et al., 1998), amygdala (Karst et al., 2002; Mitra and Sapolsky, 2008), and ventral tegmental area (Cho and Little, 1999). 8

High levels of corticosterone in animals also causes dendritic reorganization of the hippocampus (Woolley et al., 1990) and prefrontal cortex (Wellman, 2001). In humans, MR and GR are expressed in high levels in brain regions associated with emotional processing such as the hippocampus (Watzka et al., 2000a), amygdala (Sarrieau et al., 1986), and in both the frontal and temporal lobes (Watzka et al., 2000b). Endogenous Cortisol levels in humans have been shown to correlate with activity in a variety of subcortical brain regions thought to process emotion, such as the amygdala (Drevets et al., 2002), insula and subgenual cingulate cortex (Liberzon et al., 2007). Furthermore, Cortisol administration has been shown to enhance memory for selective types of emotional material (Buchanan and Lovallo, 2001), and is capable of blunting emotional responses to some stimuli (Reuter, 2002). Purpose of this Dissertation Despite long-standing evidence that Cortisol is associated with depression, alters emotional behaviors, and affects brain regions involved in emotion, to date, little work has been done to explore what influence Cortisol may be having on emotional processes relevant to depression. Understanding how Cortisol may be altering emotional processes and the brain activity underlying those processes may be a critical step in understanding the root causes of emotional and brain activity changes that are observed in depression. Furthermore, identifying neurophysiological effects that explain the core symptoms of depression would be a critical step forward in the progression towards informed treatments, and could potentially speed development of novel pharmaceuticals. 9

The general approach used in this dissertation is to begin to uncover the effects of Cortisol on emotion and brain activity associated with emotion by actively manipulating circulating Cortisol levels. In contrast, the majority of previous studies have relied on correlating circulating endogenous Cortisol levels with measures of emotion and brain activity. The approach that we use here decreases the inherent ambiguity in correlation studies, as it allows directionality of effects to be inferred. Are emotional changes driving changes in Cortisol levels or are Cortisol levels driving emotional changes? Since we are administering Cortisol, the possibility of emotional changes driving up Cortisol levels is all but eliminated, allowing inferences about the effects of Cortisol on emotion. In chapter 2 we present a necessary prerequisite study to determine if Cortisol alters brain hemodynamic responses, which are used to make inferences about emotion related brain activity. The advent of neuroimaging techniques in recent decades has provided a method of studying the neurophysiology of emotion in humans, opening realms of knowledge almost entirely inaccessible previously. However, successful implementation of these techniques requires obsequious recognition of the underlying assumptions and limitations of the technique being utilized. The incorporation of pharmacology in fMRI studies presents a potent example of this principle. The fMRI signal is particularly reliant on the dynamics of oxygenated and deoxygenated blood within the cerebral vasculature, which is closely correlated with local neural activity. Therefore any pharmacological agent that impacts the dynamics of the cerebral vasculature could lead to atypical fMRI signal from the underlying neural activity. This would then require adapted models of the fMRI signal to be used to infer functioning of 10

the underlying neural activity. Chapter 2 aims to address this issue directly by empirically deriving the shape of the hemodynamic response function derived from the visual cortex of subjects administered placebo or various dose regimens of exogenous Cortisol. A novel characterization of shape changes in the hemodynamic response function would allow for individualized hemodynamic models to be built accounting for Cortisol differences. Alternatively, verification of a typical hemodynamic response function would allow for the use of standard hemodynamic models to infer neural activity patterns. Chapter 3 aims to determine if Cortisol administration produces changes in subjective emotional experience, and the neural correlates of that experience. Furthermore, in this chapter we aim to be sensitive to subjective emotional changes and brain activity changes that are relevant to depression, such as Cortisol induced increases in measures of sadness, decreases in measures of happiness, and changes in subgenual cingulate and amygdala activity during emotional processes. In Chapter 3 we are informed by the results of Chapter 2, which allow valid inferences to be made in Chapter 3 regarding the effects of Cortisol on brain activity associated with emotion. In service of the aims of Chapter 3 we incorporate two different types of measures of subjective emotional experience. The first is a measurement of emotional states (see page 29) and the second measures the magnitude of the emotional reaction elicited by a stimulus (see page 31). We also utilize both happiness and sadness conditions within the fMRI scanning session to allow sensitivity to observe Cortisol induced changes relevant to sadness or anhedonia symptoms in depression. Results from Chapter 3 provide several findings potentially relevant to the pathophysiology of depression and additional unexpected effects of 11

Cortisol administration. Chapter 4 seeks to test if Cortisol administration produces changes in the perceptual processing of emotional stimuli. This study was informed by unexpected results in Chapter 3 (see Figure 15 on page 45), indicating that Cortisol affects brain activity in regions traditionally associated with sensory processing of visual stimuli, regions such as the superior colliculus, thalamus, and the visual cortex. Each of these brain regions is also thought to be a critical node in the expeditious visual processing of emotional stimuli which drive amygdala based behavioral responses (LeDoux, 1994). In Chapter 4 we use these findings to generate a hypothesis that Cortisol might be affecting early sensory processes in such a way as to constitute a perceptual bias. Such a perceptual bias could theoretically drive emotional changes such as those observed in Chapter 3. In order to test this hypothesis we assess the effects of Cortisol on perception by utilizing two measures of emotional perception, a test of ability to detect emotional facial expression (see Figure 16 on page 68) and a test of ability to identify emotional facial expression (see Figure 17 on page 68). Both of these tests make use of a perceptual "masking" technique called backwards masking where a mask image is presented immediately after a target image in order to interfere with the subjective awareness of the target image. In the study outlined in Chapter 4 we use a swirl mask to interfere with the subjective awareness of emotional facial expressions. We hypothesized that Cortisol administration would lead to greater accuracy and sensitivity to sad facial expressions and lower accuracy and sensitivity to happy facial expression under conditions that limit the subjective awareness of the faces. We characterize the majority of the psychophysical response curve associated with the detection of emotional facial expression and the curve 12

associated with identification of emotional facial expressions. We characterize the response curves of detection of happy and sad facial expressions, and the response curves of the identification of happy, sad and neutral facial expressions. The results of experiments in Chapter 4 suggest that Cortisol does not affect aspects of the perception of emotional stimuli, such as detection and identification. These results can be used to shape inferences drawn in Chapter 3 regarding the nature of the effects of Cortisol on emotion, suggesting that Cortisol may affect emotional processing that occurs subsequent to an unmodified perceptual experience. The experiments chronicled in Chapter 2, Chapter 3, and Chapter 4 fit together as an overall approach to characterize depression relevant emotional processes that are affected by Cortisol administration. The central focus of this approach provides insight that could help to explain the emotional, neurophysiological, and perceptual consequences of endogenous hypercortisolemia, and how those consequences could theoretically manifest themselves in components of the symptom profiles of depressed patients. 13

Full document contains 125 pages
Abstract: Release of the hormone cortisol is normally tightly regulated. However, when regulation fails and cortisol is hypersecreted (as in Cushing's disease), significant emotional changes occur, including depression, raising the question of whether cortisol effects on the brain could be generating depressive symptoms. Dysregulation leading to cortisol hypersecretion is also observed in depression, where emotion changes compose the core symptoms. However, cortisol as a causative agent in generating emotional changes in depression has rarely been investigated despite evidence that cortisol impacts emotional states and the neurophysiology of brain regions that process emotion. To explore the effects of cortisol on processes impacted by depression we administered exogenous cortisol to healthy subjects and observed its effects on the subjective experience of emotion, on brain activity patterns elicited by emotional stimuli, and on early perceptual processing of emotional stimuli. In a large neuroimaging study (N=60) we examined the effects of cortisol on brain activity induced by viewing emotionally evocative pictures (measured using fMRI) and on the cerebral hemodynamic response function, as a verification that cortisol's physiological effects do not invalidate fMRI measures of brain activity. In this study we administered placebos to a control group and either a single dose regimen of cortisol administration (100 mg) or an extended dose cortisol regimen (25 mg/day, 5 days) (N=20/group) to experimental groups. In a separate behavioral study of early perceptual processing (N=33), we examined the effects of cortisol on detection and identification of emotional faces. Cortisol administration did not affect the cerebral hemodynamic response, but did significantly increased feelings of arousal during sadness and simultaneously inhibited subgenual cingulate (Brodmann area 25) activity, a region implicated in normal sadness and pathological sadness in depression. In the behavioral study, cortisol did not influence detection or identification of emotional faces. In summary, we demonstrate that cortisol, a hormone often hypersecreted in depression, influences the experience of emotions relevant to depression and activity in brain regions associated with depression, but it does not alter early perceptual processing of emotional stimuli. Further study of cortisol's influence on these processes in healthy and depressed populations may provide insights into the pathophysiology of depression.