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Stress represents a significant problem for Western societies inducing costs as high as 3-4 % of the European gross national products, a burden that is continually increasing (WHO Briefing, EUR/04/5047810/B6). The classical stress response system is the hypothalamic-pituitary-adrenal (HPA) axis which acts to restore homeostasis after disturbances. Two major components within the HPA axis system are the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Cortisol, released from the adrenal glands at the end of the HPA axis, binds to MRs and with a 10 fold lower affinity to GRs. Both, impairment of the HPA axis and an imbalance in the MR/GR ratio enhances the risk for infection, inflammation and stress related psychiatric disorders. Major depressive disorder (MDD) is characterised by a variety of symptoms, however, one of the most consistent findings is the hyperactivity of the HPA axis. This may be the result of lower numbers or reduced activity of GRs and MRs. The GR gene consists of multiple alternative first exons resulting in different GR mRNA transcripts whereas for the MR only two first exons are known to date. Both, the human GR promoter 1F and the homologue rat Gr promoter 1.7 seem to be susceptible to methylation during stressful early life events resulting in lower 1F/1.7 transcript levels. It was proposed that this is due to methylation of a NGFI-A binding site in both, the rat promoter 1.7 and the human promoter 1F. The research presented in this thesis was undertaken to determine the differential expression and methylation patterns of GR and MR variants in multiple areas of the limbic brain system in the healthy and depressed human brain. Furthermore, the transcriptional control of the GR transcript 1F was investigated as expression changes of this transcript were associated with MDD, childhood abuse and early life stress. The role of NGFI-A and several other transcription factors on 1F regulation was studied in vitro and the effect of Ngfi-a overexpression on the rat Gr promoter 1.7 in vivo. The susceptibility to epigenetic programming of several GR promoters was investigated in MDD. In addition, changes in methylation levels have been determined in response to a single acute stressor in rodents. Our results showed that GR and MR first exon transcripts are differentially expressed in the human brain, but this is not due to epigenetic programming. We showed that NGFI-A has no effect on endogenous 1F/1.7 expression in vitro and in vivo. We provide evidence that the transcription factor E2F1 is a major element in the transcriptional complex necessary to drive the expression of GR 1F transcripts. In rats, highly individual methylation patterns in the paraventricular nucleus of the hypothalamus (PVN) suggest that this is not related to the stressor but can rather be interpreted as pre-existing differences. In contrast, the hippocampus showed a much more uniform epigenetic status, but still is susceptible to epigenetic modification even after a single acute stress suggesting a differential "state‟ versus "trait‟ regulation of the GR gene in different brain regions. The results of this thesis have given further insight in the complex transcriptional regulation of GR and MR first exons in health and disease. Epigenetic programming of GR promoters seems to be involved in early life stress and acute stress in adult rats; however, the susceptibility to methylation in response to stress seems to vary between brain regions.
The glucocorticoid (GC) cortisol, main mediator of the hypothalamic-pituitary-adrenal axis, has many implications in metabolism, stress response and the immune system. GC function is mediated mainly via the glucocorticoid receptor (GR) which binds as a transcription factor to glucocorticoid response elements (GREs). GCs are strong immunosuppressants and used to treat inflammatory and autoimmune diseases. Long-term usage can lead to several irreversible side effects which make improved understanding indispensable and warrant the adaptation of current drugs. Several large scale gene expression studies have been performed to gain insight into GC signalling. Nevertheless, studies at the proteomic level have not yet been made. The effects of cortisol on monocytes and macrophages were studied in the THP-1 cell line using 2D fluorescence difference gel electrophoresis (2D DIGE) combined with MALDI-TOF mass spectrometry. More than 50 cortisol-modulated proteins were identified which belonged to five functional groups: cytoskeleton, chaperones, immune response, metabolism, and transcription/translation. Multiple GREs were found in the promoters of their corresponding genes (+10 kb/-0.2 kb promoter regions including all alternative promoters available within the Database for Transcription Start Sites (DBTSS)). High quality GREs were observed mainly in cortisol modulated genes, corroborating the proteomics results. Differential regulation of selected immune response related proteins were confirmed by qPCR and immuno-blotting. All immune response related proteins (MX1, IFIT3, SYWC, STAT3, PMSE2, PRS7) which were induced by LPS were suppressed by cortisol and belong mainly to classical interferon target genes. Mx1 has been selected for detailed expression analysis since new isoforms have been identified by proteomics. FKBP51, known to be induced by cortisol, was identified as the strongest differentially expressed protein and contained the highest number of strict GREs. Genomic analysis of five alternative FKBP5 promoter regions suggested GC inducibility of all transcripts. 2D DIGE combined with 2D immunoblotting revealed the existence of several previously unknown FKBP51 isoforms, possibly resulting from these transcripts. Additionally multiple post-translational modifications were found, which could lead to different subcellular localization in monocytes and macrophages as seen by confocal microscopy. Similar results were obtained for the different cellular subsets of human peripheral blood mononuclear cells (PBMCs). FKBP51 was found to be constitutively phosphorylated with up to 8 phosphosites in CD19+ B lymphocytes. Differential Co-immunoprecipitation for cytoplasm and nucleus allowed us to identify new potential interaction partners. Nuclear FKBP51 was found to interact with myosin 9, whereas cytosolic FKBP51 with TRIM21 (synonym: Ro52, Sjögren`s syndrome antigen). The GR has been found to interact with THOC4 and YB1, two proteins implicated in mRNA processing and transcriptional regulation. We also applied proteomics to study rapid non-genomic effects of acute stress in a rat model. The nuclear proteome of the thymus was investigated after 15 min restraint stress and compared to the non-stressed control. Most of the identified proteins were transcriptional regulators found to be enriched in the nucleus probably to assist gene expression in an appropriate manner. The proteomic approach allowed us to further understand the cortisol mediated response in monocytes/macrophages. We identified several new target proteins, but we also found new protein variants and post-translational modifications which need further investigation. Detailed study of FKBP51 and GR indicated a complex regulation network which opened a new field of research. We identified new variants of the anti-viral response protein MX1, displaying differential expression and phosphorylation in the cellular compartments. Further, proteomics allowed us to follow the very early effects of acute stress, which happen prior to gene expression. The nuclear thymocyte proteome of restraint stressed rats revealed an active preparation for subsequent gene expression. Proteomics was successfully applied to study differential protein expression, to identify new protein variants and phosphorylation events as well as to follow translocation. New aspects for future research in the field of cortisol-mediated immune modulation have been added.
Attitudes are "the most distinctive and indispensable concept in contemporary social psychology" (Allport, 1935, p. 798). This outstanding position of the attitude concept in social cognitive research is not only reflected in the innumerous studies focusing on this concept but also in the huge number of theoretical approaches that have been put forth since then. Yet, it is still an open question, what attitudes actually are. That is, the question of how attitude objects are represented in memory cannot be unequivocally answered until now (e.g., Barsalou, 1999; Gawronski, 2007; Pratkanis, 1989, Chapter 4). In particular, researchers strongly differ with respect to their assumptions on the content, format and structural nature of attitude representations (Ferguson & Fukukura, 2012). This prevailing uncertainty on what actually constitutes our likes and dislikes is strongly dovetailed with the question of which processes result in the formation of these representations. In recent years, this issue has mainly been addressed in evaluative conditioning research (EC). In a standard EC-paradigm a neutral stimulus (conditioned stimulus, CS) is repeatedly paired with an affective stimulus (unconditioned stimulus, US). The pairing of stimuli then typically results in changes in the evaluation of the CS corresponding to the evaluative response of the US (De Houwer, Baeyens, & Field, 2005). This experimental approach on the formation of attitudes has primarily been concerned with the question of how the representations underlying our attitudes are formed. However, which processes operate on the formation of such an attitude representation is not yet understood (Jones, Olson, & Fazio, 2010; Walther, Nagengast, & Trasselli, 2005). Indeed, there are several ideas on how CS-US pairs might be encoded in memory. Notwithstanding the importance of these theoretical ideas, looking at the existing empirical work within the research area of EC (for reviews see Hofmann, De Houwer, Perugini, Baeyens, & Crombez, 2010; De Houwer, Thomas, & Baeyens, 2001) leaves one with the impression that scientists have skipped the basic processes. Basic processes hereby especially refer to the attentional processes being involved in the encoding of CSs and USs as well as the relation between them. Against the background of this huge gap in current research on attitude formation, the focus of this thesis will be to highlight the contribution of selective attention processes to a better understanding of the representation underlying our likes and dislikes. In particular, the present thesis considers the role of selective attention processes for the solution of the representation issue from three different perspectives. Before illustrating these different perspectives, Chapter 1 is meant to envision the omnipresence of the representation problem in current theoretical as well as empirical work on evaluative conditioning. Likewise, it emphasizes the critical role of selective attention processes for the representation question in classical conditioning and how this knowledge might be used to put forth the uniqueness of evaluative conditioning as compared to classical conditioning. Chapter 2 then considers the differential influence of attentional resources and goal-directed attention on attitude learning. The primary objective of the presented experiment was thereby to investigate whether attentional resources and goal-directed attention exert their influence on EC via changes in the encoding of CS-US relations in memory (i.e., contingency memory). Taking the findings from this experiment into account, Chapter 3 focuses on the selective processing of the US relative to the CS. In particular, the two experiments presented in this chapter were meant to explore the moderating influence of the selective processing of the US in its relation to the CS on EC. In Chapter 4 the important role of the encoding of the US in relation to the CS, as outlined in Chapter 3, is illuminated in the context of different retrieval processes. Against the background of the findings from the two presented experiments, the interplay between the encoding of CS-US contingencies and the moderation of EC via different retrieval processes will be discussed. Finally, a general discussion of the findings, their theoretical implications and future research lines will be outlined in Chapter 5.
Magnet Resonance Imaging (MRI) and Electroencephalography (EEG) are tools used to investigate the functioning of the working brain in both humans and animal studies. Both methods are increasingly combined in separate or simultaneous measurements under the assumption to benefit from their individual strength while compensating their particular weaknesses. However, little attention has been paid to how statistical analyses strategies can influence the information that can be retrieved from a combined EEG fMRI study. Two independent studies in healthy student volunteers were conducted in the context of emotion research to demonstrate two approaches of combining MRI and EEG data of the same participants. The first study (N = 20) applied a visual search paradigm and found that in both measurements the assumed effects were absent by not statistically combining their results. The second study (N = 12) applied a novelty P300 paradigm and found that only the statistical combination of MRI and EEG measurements was able to disentangle the functional effects of brain areas involved in emotion processing. In conclusion, the observed results demonstrate that there are added benefits of statistically combining EEG-fMRI data acquisitions by assessing both the inferential statistical structure and the intra-individual correlations of the EEG and fMRI signal.
Although it has been demonstrated that nociceptive processing can be modulated by heterotopically and concurrently applied noxious stimuli, the nature of brain processes involved in this percept modulation in healthy subjects remains elusive. Using functional magnetic resonance imaging (fMRI) we investigated the effect of noxious counter-stimulation on pain processing. FMRI scans (1.5 T; block-design) were performed in 34 healthy subjects (median age: 23.5 years; range: 20-31 yrs.) during combined and single application (duration: 15 s; ISI=36 s incl. 6 s rating time) of noxious interdigital-web pinching (intensity range: 6-15 N) and contact-heat (45-49 -°C) presented in pseudo-randomized order during two runs separated by approx. 15 min with individually adjusted equi-intense stimuli. In order to control for attention artifacts, subjects were instructed to maintain their focus either on the mechanical or on the thermal pain stimulus. Changes in subjective pain intensity were computed as percent differences (∆%) in pain ratings between single and heterotopic stimulation for both fMRI runs, resulting in two subgroups showing a relative pain increase (subgroup P-IN, N=10) vs. decrease (subgroup P-DE, N=12). Second level and Region of Interest analysis conducted for both subgroups separately revealed that during heterotopic noxious counter-stimulation, subjects with relative pain decrease showed stronger and more widespread brain activations compared to subjects with relative pain increase in pain processing regions as well as a fronto-parietal network. Median-split regression analyses revealed a modulatory effect of prefrontal activation on connectivity between the thalamus and midbrain/pons, supporting the proposed involvement of prefrontal cortex regions in pain modulation. Furthermore, the mid-sagittal size of the total corpus callosum and five of its subareas were measured from the in vivo magnetic resonance imaging (MRI) recordings. A significantly larger relative truncus size (P=.04) was identified in participants reporting a relative decrease of subjective pain intensity during counter-stimulation, when compared to subjects experiencing a relative pain increase. The above subgroup differences observed in functional and structural imaging data are discussed with consideration of potential differences in cognitive and emotional aspects of pain modulation.
Aggression is one of the most researched topics in psychology. This is understandable, since aggression behavior does a lot of harm to individuals and groups. A lot is known already about the biology of aggression, but one system that seems to be of vital importance in animals has largely been overlooked: the hypothalamic-pituitary-adrenal (HPA) axis. Menno Kruk and Jószef Haller and their research teams developed rodent models of adaptive, normal, and abnormal aggressive behavior. They found the acute HPA axis (re)activity, but also chronic basal levels to be causally relevant in the elicitation and escalation of aggressive behavior. As a mediating variable, changes in the processing of relevant social information is proposed, although this could not be tested in animals. In humans, not a lot of research has been done, but there is evidence for both the association between acute and basal cortisol levels in (abnormal) aggression. However, not many of these studies have been experimental of nature. rnrnOur aim was to add to the understanding of both basal chronic levels of HPA axis activity, as well as acute levels in the formation of aggressive behavior. Therefore, we did two experiments, both with healthy student samples. In both studies we induced aggression with a well validated paradigm from social psychology: the Taylor Aggression Paradigm. Half of the subjects, however, only went through a non-provoking control condition. We measured trait basal levels of HPA axis activity on three days prior. We took several cortisol samples before, during, and after the task. After the induction of aggression, we measured the behavioral and electrophysiological brain response to relevant social stimuli, i.e., emotional facial expressions embedded in an emotional Stroop task. In the second study, we pharmacologically manipulated cortisol levels 60min before the beginning of the experiment. To do that, half of the subjects were administered 20mg of hydrocortisone, which elevates circulating cortisol levels (cortisol group), the other half was administered a placebo (placebo group). Results showed that acute HPA axis activity is indeed relevant for aggressive behavior. We found in Study 1 a difference in cortisol levels after the aggression induction in the provoked group compared to the non-provoked group (i.e., a heightened reactivity of the HPA axis). However, this could not be replicated in Study 2. Furthermore, the pharmacological elevation of cortisol levels led to an increase in aggressive behavior in women compared to the placebo group. There were no effects in men, so that while men were significantly more aggressive than women in the placebo group, they were equally aggressive in the cortisol group. Furthermore, there was an interaction of cortisol treatment with block of the Taylor Aggression Paradigm, in that the cortisol group was significantly more aggressive in the third block of the task. Concerning basal HPA axis activity, we found an effect on aggressive behavior in both studies, albeit more consistently in women and in the provoked and non-provoked groups. However, the effect was not apparent in the cortisol group. After the aggressive encounter, information processing patterns were changed in the provoked compared to the non-provoked group for all facial expressions, especially anger. These results indicate that the HPA axis plays an important role in the formation of aggressive behavior in humans, as well. Importantly, different changes within the system, be it basal or acute, are associated with the same outcome in this task. More studies are needed, however, to better understand the role that each plays in different kinds of aggressive behavior, and the role information processing plays as a possible mediating variable. This extensive knowledge is necessary for better behavioral interventions.
The brain is the central coordinator of the human stress reaction. At the same time, peripheral endocrine and neural stress signals act on the brain modulating brain function. Here, three experimental studies are presented demonstrating this dual role of the brain in stress. Study I shows that centrally acting insulin, an important regulator of energy homeostasis, attenuates the stress related cortisol secretion. Studies II and III show that specific components of the stress reaction modulate learning and memory retrieval, two important aspects of higher-order brain function.
The complicated human alternative GR promoter region plays a pivotal role in the regulation of GR levels. In this thesis, both genomic and environmental factors linked with GR expression are covered. This research showed that GR promoters were susceptible to silencing by methylation and the activity of the individual promoters was also modulated by SNPs. E2F1 is a major element to drive the expression of GR 1F transcripts and single CpG dinucleotide methylation cannot mediate the inhibition of transcription in vitro. Also, the distribution of GR first exons and 3" splice variants (GRα and GR-P) is expressed throughout the human brain with no region-specific alternative first exon usage. These data mirrored the consistently low levels of methylation in the brain, and the observed homogeneity throughout the studied regions. Taken together, the research presented in this thesis explored several layers of complexity in GR transcriptional regulation.
Background and rationale: Changing working conditions demand adaptation, resulting in higher stress levels in employees. In consequence, decreased productivity, increasing rates of sick leave, and cases of early retirement result in higher direct, indirect, and intangible costs. Aims of the Research Project: The aim of the study was to test the usefulness of a novel translational diagnostic tool, Neuropattern, for early detection, prevention, and personalized treatment of stress-related disorders. The trial was designed as a pilot study with a wait list control group. Materials and Methods: In this study, 70 employees of the Forestry Department Rhineland-Palatinate, Germany, were enrolled. Subjects were block-randomized according to the functional group of their career field, and either underwent Neuropattern diagnostics immediately, or after a waiting period of three months. After the diagnostic assessment, their physicians received the Neuropattern Medical Report, including the diagnostic results and treatment recommendations. Participants were informed by the Neuropattern Patient Report, and were eligible to an individualized Neuropattern Online Counseling account. Results: The application of Neuropattern diagnostics significantly improved mental health and health-related behavior, reduced perceived stress, emotional exhaustion, overcommitment and possibly, presenteeism. Additionally, Neuropattern sensitively detected functional changes in stress physiology at an early stage, thus allowing timely personalized interventions to prevent and treat stress pathology. Conclusion: The present study encouraged the application of Neuropattern diagnostics to early intervention in non-clinical populations. However, further research is required to determine the best operating conditions.
Objective: Only 20-25% of the variance for the two to four-fold increased risk of developing breast cancer among women with family histories of the disease can be explained by known gene mutations. Other factors must exist. Here, a familial breast cancer model is proposed in which overestimation of risk, general distress, and cancer-specific distress constitute the type of background stress sufficient to increase unrelated acute stress reactivity in women at familial risk for breast cancer. Furthermore, these stress reactions are thought to be associated with central adiposity, an independent well-established risk factor for breast cancer. Hence, stress through its hormonal correlates and possible associations with central adiposity may play a crucial role in the etiology of breast cancer in women at familial risk for the disease. Methods: Participants were 215 healthy working women with first-degree relatives diagnosed before (high familial risk) or after age 50 (low familial risk), or without breast cancer in first-degree relatives (no familial risk). Participants completed self-report measures of perceived lifetime breast cancer risk, intrusive thoughts and avoidance about breast cancer (Impact of Event Scale), negative affect (Profile of Mood States), and general distress (Brief Symptom Inventory). Anthropometric measurements were taken. Urine samples during work, home, and sleep were collected for assessment of cortisol responses in the naturalistic setting where work was conceptualized as the stressful time of the day. Results: A series of analyses indicated a gradient increase of cortisol levels in response to the work environment from no, low, to high familial risk of breast cancer. When adding breast cancer intrusions to the model with familial risk status predicting work cortisol levels, significant intrusion effects emerged rendering the familial risk group non-significant. However, due to a lack of association between intrusions and cortisol in the low and high familial risk group separately, as well as a significant difference between low and high familial risk on intrusions, but not on work cortisol levels, full mediation of familial risk group effects on work cortisol by intrusions could not be established. A separate analysis indicated increased levels of central but not general adiposity in women at high familial risk of breast cancer compared to the low and no risk groups. There were no significant associations between central adiposity and cortisol excretion. Conclusion: A hyperactive hypothalamus-pituitary-adrenal axis with a more pronounced excretion of its end product cortisol, as well as elevated levels of central but not overall adiposity in women at high familial risk for breast cancer may indicate an increased health risk which expands beyond that of increased breast cancer risk for these women.
The startle response in psychophysiological research: modulating effects of contextual parameters
(2013)
Startle reactions are fast, reflexive, and defensive responses which protect the body from injury in the face of imminent danger. The underlying reflex is basic and can be found in many species. Even though it consists of only a few synapses located in the brain stem, the startle reflex offers a valuable research method for human affective, cognitive, and psychological research. This is because of moderating effects of higher mental processes such as attention and emotion on the response magnitude: affective foreground stimulation and directed attention are validated paradigms in startle-related research. This work presents findings from three independent research studies that deal with (1) the application of the established "affective modulation of startle"-paradigm to the novel setting of attractiveness and human mating preferences, (2) the question of how different components of the startle response are affected by a physiological stressor and (3) how startle stimuli affect visual attention towards emotional stimuli. While the first two studies treat the startle response as a dependent variable by measuring its response magnitude, the third study uses startle stimuli as an experimental manipulation and investigates its potential effects on a behavioural measure. The first chapter of this thesis describes the basic mechanisms of the startle response as well as the body of research that sets the foundation of startle research in psychophysiology. It provides the rationale for the presented studies, and offers a short summary of the obtained results. Chapter two to four represent primary research articles that are published or in press. At the beginning of each chapter the contribution of all authors is explained. The references for all chapters are listed at the end of this thesis. The overall scope of this thesis is to show how the human startle response is modulated by a variety of factors, such as the attractiveness of a potential mating partner or the exposure to a stressor. In conclusion, the magnitude of the startle response can serve as a measure for such psychological states and processes. Beyond the involuntary, physiological startle reflex, startle stimuli also affect intentional behavioural responses, which we could demonstrate for eye movements in a visual attention paradigm.
Stress has been considered one of the most relevant factors promoting aggressive behavior. Animal and human pharmacological studies revealed the stress hormones corticosterone in rodents and cortisol in humans to constitute a particularly important neuroendocrine determinate in facilitating aggression and beyond that, assumedly in its continuation and escalation. Moreover, cortisol-induced alterations of social information processing, as well as of cognitive control processes, have been hypothesized as possible influencing factors in the stress-aggression link. So far, the immediate impact of a preceding stressor and thereby stress-induced rise of cortisol on aggressive behavior as well as higher-order cognitive control processes and social information processing in this context have gone mostly unheeded. The present thesis aimed to extend the hitherto findings of stress and aggression in this regard. For this purpose two psychophysiological studies with healthy adults were carried out, both using the socially evaluated-cold pressor test as an acute stress induction. Additionally to behavioral data and subjective reports, event related potentials were measured and acute levels of salivary cortisol were collected on the basis of which stressed participants were divided into cortisol-responders and "nonresponders. Study 1 examined the impact of acute stress-induced cortisol increase on inhibitory control and its neural correlates. 41 male participants were randomly assigned to the stress procedure or to a non-stressful control condition. Beforehand and afterwards, participants performed a Go Nogo task with visual letters to measure response inhibition. The effect of acute stress-induced cortisol increase on covert and overt aggressive behavior and on the processing of provoking stimuli within the aggressive encounter was investigated in study 2. Moreover, this experiment examined the combined impact of stress and aggression on ensuing affective information processing. 71 male and female participants were either exposed to the stress or to the control condition. Following this, half of each group received high or low levels of provocation during the Taylor Aggression Paradigm. At the end of the experiment, a passive viewing paradigm with affective pictures depicting positive, negative, or aggressive scenes with either humans or objects was realized. The results revealed that men were not affected by a stress-induced rise in cortisol on a behavioral level, showing neither impaired response inhibition nor enhanced aggressive behavior. In contrast, women showed enhanced overt and covert aggressive behavior under a surge of endogenous cortisol, confirming previous results, albeit only in case of high provocation and only up to the level of the control group. Unlike this rather moderate impact on behavior, cortisol showed a distinct impact on neural correlates of information processing throughout inhibitory control, aggression-eliciting stimuli, and emotional pictures for both men and women. At this, stress-induced increase of cortisol resulted in enhanced N2 amplitudes to Go stimuli, whereas P2 amplitudes to both and N2 to Nogo amplitudes retained unchanged, indicating an overcorrection and caution of the response activation in favor of successful inhibitory control. The processing of aggression-eliciting stimuli during the aggressive encounter was complexly altered by stress differently for women and men. Under increased cortisol levels, the frontal or parietal P3 amplitude patterns were either diminished or reversed in the case of high provocation compared to the control group and to cortisol-nonresponders, indicating a desensitization towards aggression-eliciting stimuli in males, but a more elaborate processing of those in women. Moreover, stress-induced cortisol and provocation jointly altered subsequent affective information processing at early as well as later stages of the information processing stream. Again, increased levels of cortisol led opposite directed amplitudes in the case of high provocation relative to the control group and cortisol-nonresponders, with enhanced N2 amplitudes in men and reduced P3 and LPP amplitudes in men and women for all affective pictures, suggesting initially enhanced emotional reactivity in men, but ensuing reduced motivational attention and enhanced emotion regulation in both, men and women. As a result, these present findings confirm the relevance of HPA activity in the elicitation and persistence of human aggressive behavior. Moreover, they reveal the significance of compensatory and emotion regulatory strategies and mechanisms in response to stress and provocation, indorsing the relevance of social information and cognitive control processes. Still, more research is needed to clarify the conditions which lead to the facilitation of aggression and by which compensatory mechanisms this is prevented.
In this study, candidate loci for periodic catatonia (SCZD10, OMIM #605419) on chromosome 15q15 and 22q13.33 have been fine mapped and investigated. Previously, several studies found evidences for a major susceptibility locus on chromosome 15q15 and a further potential locus on 22q13.33 pointing to genetic heterogeneity. Fine mapping was done in our multiplex families through linkage and mutational analysis using genomic markers selected from public databases. Positional candidate genes like SPRED1 and BRD1, and ultra-conserved elements were investigated by direct sequencing in these families. The results narrow down the susceptibility locus on chromosome 15q14-15q15.1 to a region between markers D15S1042 and D15S968, as well as exclusion of SPRED1 and ultra-conserved elements as susceptibility candidates. Fine mapping for two chromosome 23q13.33-linked families showed that the recombination events would place the disease-causing gene to a telomeric ~577 Kb interval and SNP rs138880 investigation revealed an A-allele in the affected person, therefore excludes BRD1 as well as confirmed MLC1 to be the candidate gene for periodic catatonia.
The influence of the dopamine agonist Ritalin-® on performance in a card sorting task involving a monetary reward component was tested in 43 healthy male participants. It was investigated whether Ritalin-® would have differential behavioral effects as a function of the participants' parental bonding experiences and the personality variable "Novelty Seeking". When activity and performance accuracy were stimulated my monetary reward, Ritalin-® reduced activity in response to reward and added to the reward-induced increase in performance accuracy. However, performance accuracy after drug challenge was improved only in the low care participants. In the high care participants, it was contrarily impaired. This observation suggests that the successful therapeutic administration of Ritalin-® in ADHD may be influenced by early life parental care. Suggesting an association between the personality dimension of "Novelty Seeking" and the dopamine system, high "Novelty Seeking" scores positively correlated with sensitivity to Ritalin-® challenge.
The stress hormone cortisol as the end-product of the hypothalamic-pituitary-adrenal (HPA) axis has been found to play a crucial role in the release of aggressive behavior (Kruk et al., 2004; Böhnke et al., 2010). In order to further explore potential mechanisms underlying the relationship between stress and aggression, such as changes in (social) information processing, we conducted two experimental studies that are presented in this thesis. In both studies, acute stress was induced by means of the Socially Evaluated Cold Pressor Test (SECP) designed by Schwabe et al. (2008). Stressed participants were classified as either cortisol responders or nonresponders depending on their rise in cortisol following the stressor. Moreover, basal HPA axis activity was measured prior to the experimental sessions and EEG was recorded throughout the experiments. The first study dealt with the influence of acute stress on cognitive control processes. 41 healthy male participants were assigned to either the stress condition or the non-stressful control procedure of the SECP. Before as well as after the stress induction, all participants performed a cued task-switching paradigm in order to measure cognitive control processes. Results revealed a significant influence of acute and basal cortisol levels, respectively, on the motor preparation of the upcoming behavioral response, that was reflected in changes in the magnitude of the terminal Contingent Negative Variation (CNV). In the second study, the effect of acute stress and subsequent social provocation on approach-avoidance motivation was examined. 72 healthy students (36 males, 36 females) took part in the study. They performed an approach-avoidance task, using emotional facial expressions as stimuli, before as well as after the experimental manipulation of acute stress (again via the SECP) and social provocation realized by means of the Taylor Aggression Paradigm (Taylor, 1967). Additionally to salivary cortisol, testosterone samples were collected at several points in time during the experimental session. Results indicated a positive relationship between acute testosterone levels and the motivation to approach social threat stimuli in highly provoked cortisol responders. Similar results were found when the testosterone-to-cortisol ratio at baseline was taken into account instead of acute testosterone levels. Moreover, brain activity during the approach-avoidance task was significantly influenced by acute stress and social provocation, as reflected in reductions of early (P2) as well as of later (P3) ERP components in highly provoked cortisol responders. This may indicate a less accurate, rapid processing of socially relevant stimuli due to an acute increase in cortisol and subsequent social provocation. In conclusion, the two studies presented in this thesis provide evidence for significant changes in information processing due to acute stress, basal cortisol levels and social provocation, suggesting an enhanced preparation for a rapid behavioral response in the sense of a fight-or-flight reaction. These results confirm the model of Kruk et al. (2004) proposing a mediating role of changed information processes in the stress-aggression-link.
Every day we are exposed to a large set of appetitive food cues, mostly of high caloric, high carbohydrate content. Environmental factors like food cue exposition can impact eating behavior, by triggering anticipatory endocrinal responses and reinforcing the reward value of food. Additionally, it has been shown that eating behavior is largely influence by neuroendocrine factors. Energy homeostasis is of great importance for survival in all animal species. It is challenged under the state of food deprivation which is considered to be a metabolic stressor. Interestingly, the systems regulating stress and food intake share neural circuits. Adrenal glucocorticoids, as cortisol, and the pancreatic hormone insulin have been shown to be crucial to maintain catabolic and anabolic balance. Cortisol and insulin can cross the blood-brain barrier and interact with receptors distributed throughout the brain, influencing appetite and eating behavior. At the same time, these hormones have an important impact on the stress response. The aim of the current work is to broaden the knowledge on reward related food cue processing. With that purpose, we studied how food cue processing is influenced by food deprivation in women (in different phases of the menstrual cycle) and men. Furthermore, we investigated the impact of the stress/metabolic hormones, insulin and cortisol, at neural sites important for energy metabolism and in the processing of visual food cues. The Chapter I of this thesis details the underlying mechanisms of the startle response and its application in the investigation of food cue processing. Moreover, it describes the effects of food deprivation and of the stress-metabolic hormones insulin and cortisol in reward related processing of food cues. It explains the rationale for the studies presented in Chapter II-IV and describes their main findings. A general discussion of the results and recommendations for future research is given. In the study described in Chapter II, startle methodology was used to study the impact of food deprivation in the processing of reward related food cues. Women in different phases of the menstrual cycle and men were studied, in order to address potential effects of sex and menstrual cycle. All participants were studied either satiated or food deprived. Food deprivation provoked enhanced acoustic startle (ASR) response during foreground presentation of visual food cues. Sex and menstrual cycle did not influence this effect. The startle pattern towards food cues during fasting can be explained by a frustrative nonreward effect (FNR), driven by the impossibility to consume the exposed food. In Chapter III, a study is described, which was carried out to explore the central effects of insulin and cortisol, using continuous arterial spin labeling to map cerebral blood flow patterns. Following standardized periods of fasting, male participants received either intranasal insulin, oral cortisol, both, or placebo. Intranasal insulin increased resting regional cerebral blood flow in the putamen and insular cortex, structures that are involved in the regulation of eating behavior. Neither cortisol nor interaction effects were found. These results demonstrate that insulin exerts an action in metabolic centers during resting state, which is not affected by glucocorticoids. The study described in Chapter IV uses a similar pharmacological manipulation as the one presented in Chapter III, while assessing processing of reward related food cues through the startle paradigm validated in Chapter II. A sample of men was studied during short-term food deprivation. Considering the importance of both cortisol and insulin in glucose metabolism, food pictures were divided by glycemic index. Cortisol administration enhanced ASR during foreground presentation of "high glycemic" food pictures. This result suggests that cortisol provokes an increase in reward value of high glycemic food cues, which is congruent with previous research on stress and food consumption. This thesis gives support to the FNR hypothesis towards food cues during states of deprivation. Furthermore, it highlights the potential effects of stress related hormones in metabolism-connected neuronal structures, and in the reward related mechanisms of food cue processing. In a society marked by increased food exposure and availability, alongside with increased stress, it is important to better understand the impact of food exposition and its interaction with relevant hormones. This thesis contributes to the knowledge in this field. More research in this direction is needed.
During pregnancy every eighth woman is treated with glucocorticoids. Glucocorticoids inhibit cell division but are assumed to accelerate the differentiation of cells. In this review animal models for the development of the human fetal and neonatal hypothalamic-pituitary-adrenal (HPA) axis are investigated. It is possible to show that during pregnancy in humans, as in most of the here-investigated animal models, a stress hyporesponsive period (SHRP) is present. In this period, the fetus is facing reduced glucocorticoid concentrations, by low or absent fetal glucocorticoid synthesis and by reduced exposure to maternal glucocorticoids. During that phase, sensitive maturational processes in the brain are assumed, which could be inhibited by high glucocorticoid concentrations. In the SHRP, species-specific maximal brain growth spurt and neurogenesis of the somatosensory cortex take place. The latter is critical for the development of social and communication skills and the secure attachment of mother and child. Glucocorticoid treatment during pregnancy needs to be further investigated especially during this vulnerable SHRP. The hypothalamus and the pituitary stimulate the adrenal glucocorticoid production. On the other hand, glucocorticoids can inhibit the synthesis of corticotropin-releasing hormone (CRH) in the hypothalamus and of adrenocorticotropic hormone (ACTH) in the pituitary. Alterations in this negative feedback are assumed among others in the development of fibromyalgia, diabetes and factors of the metabolic syndrome. In this work it is shown that the fetal cortisol surge at the end of gestation is at least partially due to reduced glucocorticoid negative feedback. It is also assumed that androgens are involved in the control of fetal glucocorticoid synthesis. Glucocorticoids seem to prevent masculinization of the female fetus by androgens during the sexual gonadal development. In this work a negative interaction of glucocorticoids and androgens is detectable.
Evaluative conditioning (EC) refers to changes in liking that are due to the pairing of stimuli, and is one of the effects studied in order to understand the processes of attitude formation. Initially, EC had been conceived of as driven by processes that are unique to the formation of attitudes, and that occur independent of whether or not individuals engage in conscious and effortful propositional processes. However, propositional processes have gained considerable popularity as an explanatory concept for the boundary conditions observed in EC studies, with some authors going as far as to suggest that the evidence implies that EC is driven primarily by propositional processes. In this monograph I present research which questions the validity of this claim, and I discuss theoretical challenges and avenues for future EC research.
There is ample evidence that the personality trait of extraversion is associated with frequent experiences of positive affect whereas introversion is associated with less frequent experiences of positive affect. According to a theory of Watson et al. (1997), these findings demonstrate that positive affect forms the conceptual core of extraversion. In contrast, several other researchers consider sociability - and not positive affect - as the core of extraversion. The aim of the present work is to examine the relation between extraversion and dispositional positive affect on the neurobiological level. In 38 participants resting cerebral blood flow was measured with continuous arterial spin labeling (CASL). Each participant was scanned on two measurement occasions separated by seven weeks. In addition, questionnaire measures of extraversion and dispositional positive affect were collected. To employ CASL for investigating the biological basis of personality traits, the psychometric properties of CASL blood flow measurements were examined in two studies. The first study was conducted to validate the CASL technique. Using a visual stimulation paradigm, the expected pattern of activity was found, i.e. there were specific differences in blood flow in the primary and secondary visual areas. Moreover, the results in the first measurement occasion could be reproduced in the second. Thus, these results suggest that CASL blood flow measurements have a high degree of validity. The aim of the second psychometric study was to examine whether resting blood flow measurements are characterized by a sufficient trait stability to be used as a marker for personality traits. Employing the latent state-trait theory developed by Steyer and colleagues, it was shown that about 70 % of the variance of regional blood flow could be explained by individual differences in a latent trait. This suggests that blood flow measurements have sufficient trait stability for investigating the biological basis of personality traits. In the third study, the relation between extraversion and dispositional positive affect was investigated on the neurobiological level. Voxel-based analyses showed that dispositional positive affect was correlated with resting blood flow in the ventral striatum, i.e. a brain structure that is associated with approach behavior and reward processing. This biological basis was also found for extraversion. In addition, when extraversion was statistically controlled, the association between dispositional positive affect and blood flow in the ventral striatum was still present. However, when dispositional positive affect was statistically controlled, the relation between extraversion and the ventral striatum disappeared. Taken together, these results suggest that positive affect forms a core of extraversion on the neurobiological level. The present findings thus add psychophysiological evidence to the theory of Watson et al. (1997), which suggests that positive affect forms the conceptual core of extraversion.
Fibromyalgia is a disorder of unknown etiology characterized by widespread, chronic musculoskeletal pain of at least three month duration and pressure hyperalgesia at specific tender points on clinical examination. The disorder is accompanied by a multitude of additional symptoms such as fatigue, sleep disturbances, morning stiffness, depression, and anxiety. In terms of biological disturbances, low cortisol concentrations have been repeatedly observed in blood and urine samples of fibromyalgia patients, both under basal and stress-induced conditions. The aim of this dissertation was to investigate the presence of low cortisol concentrations (hypocortisolism) and potential accompanying alterations on sympathetic and immunological levels in female fibromyalgia patients. Beside the expected hypocortisolism, a higher norepinephrine secretion and lower natural killer cell levels were found in the patient group compared to a control group consisting of healthy, age-matched women. In addition, an increased activity of some pro-inflammatory markers was observed thus leading to alterations in the balance of pro-/anti-inflammatory activity. The results underline the relevance of simultaneous investigations of interacting bodily systems for a better understanding of underlying biological mechanisms in stress-related disorders.