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Institut
- Psychologie (94) (entfernen)
The overall objective of this thesis was to gain a deeper understanding of the antecedents, processes, and manifestations of uniqueness-driven consumer behavior. To achieve this goal, five studies have been conducted in Germany and Switzerland with a total of 1048 participants across different demographic and socio-economic backgrounds. Two concepts were employed in all studies: Consumer need for uniqueness (CNFU) and general uniqueness perception (GUP). CNFU (Tian, Bearden, & Hunter, 2001), a mainly US"based consumer research concept, measures the individual need, and thus the motivation to acquire, use, and dispose consumer goods in order to develop a unique image. GUP, adapted from the two-component theory of individuality (Kampmeier, 2001), represents a global and direct measure of self-ascribed uniqueness. Study #1 looked at the interrelation of the uniqueness-driven concepts. Therefore, GUP and CNFU were employed in the study as potential psychological factors that influence and predict uniqueness-driven consumer behavior. Different behavioral measures were used: The newly developed possession of individualized products (POIP), the newly developed products for uniqueness display (PFUD), and the already established uniqueness-enhancing behaviors (UEB). Analyses showed that CNFU mediates the relationship between GUP and the behavioral measures in a German speaking setting. Thus, GUP (representing self-perception) was identified as the driver behind CNFU (representing motivation) and the actual consumer behavior. Study #2 examined further manifestations of uniqueness-driven consumer behavior. For this purpose, an extreme form of uniqueness-increasing behavior was researched: Tattooing. The influence of GUP and CNFU on tattooing behavior was investigated using a sample derived from a tattoo exhibition. To do so, a newly developed measure to determine the percentage of the body covered by tattoos was employed. It was revealed that individuals with higher GUP and CNFU levels indeed have a higher tattooing degree. Study #3 further explored the predictive possibilities and limitations of the GUP and CNFU concepts. On the one hand, study #3 specifically looked at the consumption of customized apparel products as mass customization is said to become the standard of the century (Piller & Müller, 2004). It was shown that individuals with higher CNFU levels not only purchased more customized apparel products in the last six months, but also spend more money on them. On the other hand, uniqueness-enhancing activities (UEA), such as travel to exotic places or extreme sports, were investigated by using a newly developed 30-item scale. It was revealed that CNFU partly mediates the GUP and UEA relationship, proving that CNFU indeed predicts a broad range of consumer behaviors and that GUP is the driver behind the need and the behavior. Study #4, entered a new terrain. In contrast to the previous three studies, it explored the so termed "passive" side of uniqueness-seeking in the consumer context. Individuals might feel unique because business companies treat them in a special way. Such a unique customer treatment (UCT) involves activities like customer service or customer relationship management. Study #4 investigated if individuals differ in their need for such a treatment. Hence, with the need for unique customer treatment (NFUCT) a new uniqueness-driven consumer need was introduced and its impact on customer loyalty examined. Analyses, for example, revealed that individuals with high NFUCT levels receiving a high unique customer treatment (UCT) showed the highest customer loyalty, whereas the lowest customer loyalty was found among those individuals with high NFUCT levels receiving a low unique customer treatment (UCT). Study #5 mainly examined the processes behind uniqueness-driven consumer behavior. Here, not only the psychological influences, but also situational influences were examined. This study investigated the impact of a non-personal "indirect" uniqueness manipulation on the consumption of customized apparel products by simultaneously controlling for the influence of GUP and CNFU. Therefore, two equal experimental groups were created. Afterwards, these groups either received an e-mail with a "pro-individualism" campaign or a "pro-collectivism" campaign especially developed for study #5. The conducted experiment revealed that, individuals receiving a "pro-individualism" poster campaign telling the participants that uniqueness is socially appropriate and desired were willing to spend more money on customization options compared to individuals receiving a "pro-collectivism" poster campaign. Hence, not only psychological antecedents such as GUP and CNFU influence uniqueness-driven consumer behavior, but also situational factors.
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 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.
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.
Cortisol is a stress hormone that acts on the central nervous system in order to support adaptation and time-adjusted coping processes. Whereas previous research has focused on slow emerging, genomic effects of cortisol likely mediated by protein synthesis, there is only limited knowledge about rapid, non-genomic cortisol effects on in vivo neuronal cell activity in humans. Three independent placebo-controlled studies in healthy men were conducted to test effects of 4 mg cortisol on central nervous system activity, occurring within 15 minutes after intravenous administration. Two of the studies (N = 26; N = 9) used continuous arterial spin labeling as a magnetic resonance imaging sequence, and found rapid bilateral thalamic perfusion decrements. The third study (N = 14) revealed rapid cortisol-induced changes in global signal strength and map complexity of the electroencephalogram. The observed changes in neuronal functioning suggest that cortisol may act on the thalamic relay of non-relevant background as well as on task specific sensory information in order to facilitate the adaptation to stress challenges. In conclusion, these results are the first to coherently suggest that a physiologically plausible amount of cortisol profoundly affects functioning and perfusion of the human CNS in vivo by a rapid, non-genomic mechanism.
By rodent studies it has been shown that the mineralocorticoid receptor (MR) is a candidate gene for the investigation of cognitive functions comparable to human executive function. The present work addresses the question if polymorphisms in the MR gene can act as a "probe" to explain a part of the interindividual variance of human executive functions. For this purpose, 72 healthy young participants were assigned to four equally sized groups, concerning their particular MR genotype for two common MR polymorphisms. They were investigated in an electroencephalogram (EEG) test session, accomplishing two cognitive tests while delivering saliva samples for subsequent cortisol measures. The two tests chosen for the assessment of executive functions were the Attention Network Task (ANT) and a modified version of the Wisconsin Card Sorting Test (WCST).Chapter 1 of the present work reports of the rational bases for the empirical approach, which were built up on a broad theoretical background presented in Chapter 2. In the third chapter, the investigation and results of the statistical analysis for behavioral data (i.e. reaction times, accuracy/error rates) are presented. No association with MR polymorphisms was found for the reaction times of both tests. For the accuracy rate, differences between genotype groups were found for ANT and WCST, indicating an association of MR polymorphisms and accuracy in the Alertness and Executive Control network of the ANT and during the detection of an intradimensional shift in the WCST. Data acquisition and the results for EEG data analyses are presented in Chapter 4. The results show that groups differing for MR genotype show different activity over prefrontal motor areas during the process of answering to the ANT. Those group differences again were prominent for the Alertness and Executive Control network. A tendency for further significant group differences was found for activity on frontopolar positions in extradimensional rule switching. Chapter 5 summarizes the findings for the analysis of salivary free cortisol, showing a tendency for an association between MR polymorphisms and a mildly stimulated Hypothalamus-pituitary-adrenal (HPA) axis during the test situation. The results of the different measures are integrated and discussed in Chapter 6 within the scope of novel findings in investigating the functionality of the chosen MR polymorphisms. Finally, Chapter 7 gives an outlook on the methodology and constraints of future research strategies to further describe the role of the MR in human cognitive function.
On the Influence of Ignored Stimuli: Generalization and Application of Distractor-Response Binding.
(2011)
In selection tasks where target stimuli are accompanied by distractors, responses to target stimuli, target stimuli and the distractor stimuli can be encoded together as one episode in memory. Subsequent repetition of any aspect of such an episode can lead to the retrieval of the whole episode including the response. Thus, repeating a distractor can retrieve responses given to previous targets; this mechanism was labeled distractor-response binding and has been evidenced in several visual setups. Three experiments of the present thesis implemented a priming paradigm with an identification task to generalize this mechanism to auditory and tactile stimuli as well as to stimulus concepts. In four more experiments the possible effect of distractor-response binding on drivers' reactions was investigated. The same paradigm was implemented using more complex stimuli, foot responses, go/no-go responses, and a dual task setup with head-up and head-down displays. The results indicate that distractor-response binding effects occur with auditory and tactile stimuli and that the process is mediated by a conceptual representation of the distractor stimuli. Distractor-response binding effects also revealed for stimuli, responses, and framework conditions likely to occur in a driving situation. It can be concluded that the effect of distractor-response binding needs to be taken into account for the design of local danger warnings in driver assistance systems.
In addition to the well-recognised effects of both, genes and adult environment, it is now broadly accepted that adverse conditions during pregnancy contribute to the development of mental and somatic disorders in the offspring, such as cardiovascular disorders, endocrinological disorders, metabolic disorders, schizophrenia, anxious and depressive behaviour and attention deficit hyperactivity disorder (ADHD). Early life events may have long lasting impact on tissue structure and function and these effects appear to underlie the developmental origins of vulnerability to chronic diseases. The assumption that prenatal adversity, such as maternal emotional states during pregnancy, may have adverse effects on the developing infant is not new. Accordant references can be found in an ancient Indian text (ca. 1050 before Christ), in biblical texts and in documents originating during the Middle Ages. Even Hippocrates stated possible effects of maternal emotional states on the developing fetus. Since the mid-1950s, research examining the effects of maternal psychosocial stress during pregnancy appeared in the literature. Extensive research in this field has been conducted since the early 1990s. Thus, the relationship between early life events and long-term health outcomes was already postulated over 20 years ago. David Barker and colleagues demonstrated that children of lower birth weight - which represents a crude marker of an adverse intrauterine environment - were at increased risk of high blood pressure, cardiovascular disorders, and type-2 diabetes later in life. These provocative findings led to a large amount of subsequent research, initially focussing on the role of undernutrition in determining fetal outcomes. The phenomenon of prenatal influences that determine in part the risk of suffering from chronic disease later in life has been named the "fetal origins of health and disease" paradigm. The concept of "prenatal programming" has now been extended to many other domains, such as the effects of prenatal maternal stress, prenatal tobacco exposure, alcohol intake, medication, toxins, as well as maternal infection and diseases. During the process of prenatal programming, environmental agents are transmitted across the placenta and act on specific fetal tissues during sensitive periods of development. Thus, developmental trajectories are changed and the organisation and function of tissue structure and organ system is altered. The biological purpose of those "early life programming" may consist in evolutionary advantages. The offspring adapts its development to the expected extrauterine environment which is forecast by the clues available during fetal life. If the fetus receives signals of a challenging environment, e.g. due to maternal stress hormones or maternal undernutrition, its survival may be promoted due to developmental adaptation processes. However, if the expected environment does not match with the real environment, maladapation and later disease risk may result. For example, a possible indicator of a "response ready" trait, such as hyperactivity/inattention may have been advantageous in an adverse ancient environment. However, it is of disadvantage when the postnatal environment demands oppositional skills, such as attention and concentration " e.g. in the classroom, at school, to achieve academic success. Borderline personality disorder (BPD) is a prevalent psychiatric disorder, characterized by impulsivity, affective instability, dysfunctional interpersonal relationships and identity disturbance. Although many studies report different risk factors, the exact etiologic mechanisms are not yet understood. In addition to the well-recognised effects of genetic components and adverse childhood experiences, BPD may potentially be co-determined by further environmental influences, acting very early in life: during pre- and perinatal period. There are several hints that may suggest possible prenatal programming processes in BPD. For example, patients with BPD are characterized by elevated stress sensitivity and reactivity and dysfunctions of the neuroendocrine stress system, such as the hypothalamic pituitary adrenal (HPA) axis. Furthermore, patients with BPD show a broad range of somatic comorbidities " especially those disorders for which prenatal programming processes have been described. During infancy and childhood, BPD patients already show behavioural and emotional abnormalities as well as pronounced temperamental traits, such as impulsivity, emotional dysregulation and inattention that may potentially be co-determined by prenatal programming processes. Such temperamental traits - similar to those, seen in patients with ADHD - have been described to be associated with low birthweight which indicates a suboptimal intrauterine environment. Moreover, the functional and structural alterations in the central nervous system (CNS) in patients with BPD might also be mediated in part by prenatal agents, such as prenatal tobacco exposure. Prenatal adversity may thus constitute a further, additional component in the multifactorial genesis of BPD. The association between BPD and prenatal risk factors has not yet been studied in such detail. We are not aware of any further study that assessed pre- and perinatal risk factors, such as maternal psychoscocial stress, smoking, alcohol intake, obstetric complications and lack of breastfeeding in patients with BPD.
The role of cortisol and cortisol dynamics in patients after aneurysmal subarachnoid hemorrhage
(2011)
Spontaneous aneurysmal subarachnoid hemorrhage (SAH) is a form of stroke which constitutes a severe trauma to the brain and often leads to serious long-term medical and psychosocial sequels which persist for years after the acute event. Recently, adrenocorticotrophic hormone deficiency has been identified as one possible consequence of the bleeding and is assumed to occur in around 20% of all survivors. Additionally, a number of studies report a high prevalence of post-SAH symptoms such as lack of initiative, fatigue, loss of concentration, impaired quality of life and psychiatric symptoms such as depression. The overlap of these symptoms and those of patients with untreated partial or complete hypopituitarism lead to the suggestion that neuroendocrine dysregulations may contribute to the psychosocial sequels of SAH. Therefore, one of the aims of this work is to gain insights into the role of neuroendocrine dysfunction on quality of life and the prevalence of psychiatric sequels in SAH-patients. Additionally, as data on cortisol dynamics after SAH are scarce, diurnal cortisol profiles are investigated in patients in the acute and chronic phase, as well as the cortisol awakening response and feedback sensitivity in the chronic phase after SAH. As a result, it can be shown that some SAH patients exhibit lower serum cortisol levels but at the same time a higher cortisol awakening response in saliva than healthy controls. Also, patients in the chronic phase after SAH do have a stable diurnal cortisol rhythm while there are disturbances in around 50% of all patients in the acute phase, leading to the conclusion that a single baseline measurement of cortisol is of no substantial use for diagnosing cortisol dysregulations in the acute phase after SAH. It is assumed that in SAH patients endocrine changes occur over time and that a combination of adrenal exhaustion and a subsequent downregulation of corticosteroid binding globulin may be the most probable causes for the dissociation of serum cortisol concentrations and salivary cortisol profiles in the investigated SAH patients. These changes may be an emergency response after SAH and, as elevated free cortisol levels are connected to a better psychosocial outcome in patients in the chronic phase after SAH, this reaction may even be adaptive.
Psychiatric/Behavioral disorders/traits are usually polygenic in nature, where a particular phenotype is the manifestation of multiple genes. However, the existence of large families with numerous members who are affected by these disorders/traits steers us towards a Mendelian (or monogenic) possibility, where the phenotype is caused by a single gene. In order to better understand the genetic architecture of general psychiatric/behavioral disorders/traits, this thesis investigates large pedigrees that display a Mendelian pattern for attention-deficit/hyperactivity disorder, schizophrenia and bipolar disorder. Numerous challenges in the field of psychiatric and behavioral sciences have impeded the genetic investigation of such disorders/traits. Examples include frequent cross-disorders, genetic heterogeneity across subjects as well as the use of diagnostic tools that can be subjective at times. To overcome these challenges, this thesis investigates large multi-generational pedigrees, which comprise a significant number of members who exhibit specific psychiatric/behavioral phenotypes. These pedigrees provide high-resolution experimental setups that can dissect the genetic complexities of psychiatric/behavioral disorders/traits. This thesis adopts a classical two-stage genetic approach to investigate the various psychiatric/behavioral disorders/traits in large pedigrees. The classical two-stage genetic approach is commonly used by many human geneticists to study a wide spectrum of human physiological disorders but is only being applied to the field of psychiatric and behavioral genetics recently. Through the study of large pedigrees, this thesis discovers the genomic regions that may play a causative role in the expression of certain psychiatric/behavioral disorders/traits within the vast genome.
There is a lot of evidence for the impact of acute glucocorticoid treatment on hippocampus-dependent explicit learning and memory (memory for facts and events). But there have been few studies, investigating the effect of glucocorticoids on implicit learning and memory. We conducted three studies with different methodology to investigate the effect of glucocorticoids on different forms of implicit learning. In Study 1, we investigated the effect of cortisol depletion on short-term habituation in 49 healthy subjects. 25 participants received oral metyrapone (1500 mg) to suppress endogenous cortisol production, while 24 controls received oral placebo. Eye blink electromyogram (EMG) responses to 105 dB acoustic startle stimuli were assessed. Effective endogenous cortisol suppression had no effect on short-term habituation of the startle reflex, but startle eye blink responses were significantly increased in the metyrapone group. The latter findings are in line with previous human studies, which have shown that excess cortisol, sufficient to fully occupy central nervous system (CNS) corticosteroid receptors, may reduce startle eye blink. This effect may be mediated by CNS mechanisms controlling cortisol feedback. In Study 2, we investigated delay or trace eyeblink conditioning in a patient group with a relative hypocortisolism (30 patients with fibromyaligia syndrome/FMS) compared to 20 healthy control subjects. Conditioned eyeblink response probability was assessed by EMG. Morning cortisol levels, ratings of depression, anxiety and psychosomatic complaints as well as general symptomatology and psychological distress were assessed. As compared to healthy controls FMS patients showed lower morning cortisol levels, and trace eyeblink conditioning was facilitated whereas delay eyeblink conditioning was reduced. Cortisol measures correlate significantly only with trace eyeblink conditioning. Our results are in line with studies of pharmacologically induced hyper- and hypocortisolism, which affected trace eyeblink conditioning. We suggest that endocrine mechanisms affecting hippocampus-mediated forms of associative learning may play a role in the generation of symptoms in these patients.rnIn Study 3, we investigated the effect of excess cortisol on implicit sequence learning in healthy subjects. Oral cortisol (30 mg) was given to 29 participants, whereas 31 control subjects received placebo. All volunteers performed a 5-choice serial reaction time task (SRTT). The reaction speed of every button-press was determined and difference-scores were calculated as a proof of learning. Compared to the control group, we found a delayed learning in the cortisol group at the very beginning of the task. This study is the first human investigation, indicating impaired implicit memory function after exogenous administration of the stress hormone cortisol. Our findings support a previous neuroimaging study, which suggested that the medial temporal lobe (including the hippocampus) is also active in implicit sequence learning, but our results may also depend on the engagement of other brain structures.
Stress and pain are common experiences in human lives. Both, the stress and the pain system have adaptive functions and try to protect the organism in case of harm and danger. However, stress and pain are two of the most challenging problems for the society and the health system. Chronic stress, as often seen in modern societies, has much impact on health and can lead to chronic stress disorders. These disorders also include a number of chronic pain syndromes. However, pain can also be regarded as a stressor itself, especially when we consider how much patients suffer from long-lasting pain and the impact of pain on life quality. In this way, the effects of stress on pain can be fostered. For the generation and manifestation of chronic pain symptoms also learning processes such as classical conditioning play an important role. Processes of classical conditioning can also be influenced by stress. These facts illustrate the complex and various interactions between the pain and the stress systems. Both systems communicate permanently with each other and help to protect the organism and to keep a homeostatic state. They have various ways of communication, for example mechanisms related to endogenous opioids, immune parameters, glucocorticoids and baroreflexes. But an overactivation of the systems, for example caused by ongoing stress, can lead to severe health problems. Therefore, it is of great importance to understand these interactions and their underlying mechanisms. The present work deals with the relationship of stress and pain. A special focus is put on stress related hypocortisolism and pain processing, stress induced hypoalgesia via baroreceptor related mechanisms and stress related cortisol effects on aversive conditioning (as a model of pain learning). This work is a contribution to the wide field of research that tries to understand the complex interactions of stress and pain. To demonstrate the variety, the selected studies highlight different aspects of these interactions. In the first chapter I will give a short introduction on the pain and the stress systems and their ways of interaction. Furthermore, I will give a short summary of the studies presented in Chapter II to V and their background. The results and their meaning for future research will be discussed in the last part of the first chapter. Chronic pain syndromes have been associated with chronic stress and alterations of the HPA axis resulting in chronic hypocortisolism. But if these alterations may play a causal role in the pathophysiology of chronic pain remains unclear. Thus, the study described in Chapter II investigated the effects of pharmacological induced hypocortisolism on pain perception. Both, the stress and the pain system are related to the cardiovascular system. Increase of blood pressure is part of the stress reaction and leads to reduced pain perception. Therefore, it is important for the usage of pain tests to keep in mind potential interferences from activation of the cardiovascular system, especially when pain inhibitory processes are investigated. For this reason we compared two commonly and interchangeably used pain tests with regard to the triggered autonomic reactions. This study is described in chapter III. Chapter IV and V deal with the role of learning processes in pain and related influences of stress. Processes of classical conditioning play an important role for symptom generation and manifestation. In both studies aversive eyeblink conditioning was used as a model for pain learning. In the study described in Chapter IV we compared classical eyeblink conditioning in healthy volunteers to patients suffering from fibromyalgia, a chronic pain disorder. Also, differences of the HPA axis, as part of the stress system, were taken in account. The study of Chapter V investigated effects of the very first stress reaction, particularly rapid non-genomic cortisol effects. Healthy volunteers received an intravenous cortisol administration immediately before the eyeblink conditioning. Rapid effects have only been demonstrated on a cellular level and on animal behavior so far. In general, the studies presented in this work may give an impression of the broad variety of possible interactions between the pain and the stress system. Furthermore, they contribute to our knowledge about theses interactions. However, more research is needed to complete the picture.
Stress is a common phenomenon for animals living in the wild, but also for humans in modern societies. Originally, the body's stress response is an adaptive reaction to a possibly life-threatening situation, and it has been shown to impact on energy distribution and metabolism, thereby increasing the chance of survival. However, stress has also been shown to impact on mating behaviour and reproductive strategies in animals and humans. This work deals with the effect of stress on reproductive behavior. Up to now, research has only focused on the effects of stress on reproduction in general. The effects of stress on reproduction may be looked at from two points of view. First, stress affects reproductive functioning by endocrine (e.g. glucocorticoid) actions on the reproductive system. However, stress can also influence reproductive behavior, i.e. mate choice and mating preferences. Animals and humans do not mate randomly, but exhibit preferences towards mating partners. One factor by which animals and humans choose their mating partners is similarity vs. dissimilarity: Similar mates usually carry more of one's own genes and the cooperation between similar mates is, at least theoretically, less hampered by expressing diverse behaviors. By mating with dissimilar mates on the other hand one may acquire new qualities for oneself, but also for one's offspring, useful to cope with environmental challenge. In humans we usually find a preference for similar mates. Due to the high costs of breeding, variables like cooperation and life-long partnerships may play a greater role than the acquaintance of new qualities.The present work focuses on stress effects on mating preferences of humans and will give a first answer to the question whether stress may affect our preference for similar mates. Stress and mating preferences are at the centre of this work. Thus, in the first Chapter I will give an introduction on stress and mating preferences and link these topics to each other. Furthermore, I will give a short summary of the studies described in Chapter II - Chapter IV and close the chapter with a general discussion of the findings and directions for further research on stress and mating preferences. Human mating behavior is complex, and many aspects of it may not relate to biology but social conventions and education. This work will not focus on those aspects but rather on cognitive and affective processing of erotic and sexually-relevant stimuli, since we assume that these aspects of mating behaviour are likely related to psychobiological stress mechanisms. Therefore, a paradigm is needed that measures such aspects of mating preferences in humans. The studies presented in Chapter II and Chapter III were performed in order to develop such a paradigm. In these studies we show that affective startle modulation may be used to indicate differences in sexual approach motivation to potential mating partners with different similarity levels to the participant. In Chapter IV, I will describe a study that aimed to investigate the effects of stress on human mating preferences. We showed that stress reverses human mating preferences: While unstressed individuals show a preference for similar mates, stressed individuals seem to prefer dissimilar mates. Overall, the studies presented in this work showed that affective startle modulation can be employed to measure mating preferences in humans and that these mating preferences are influenced by stress.
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.
In this thesis, three studies investigating the impact of stress on the protective startle eye blink reflex are reported. In the first study a decrease in prepulse inhibition of the startle reflex was observed after intravenous low dose cortisol application. In the second study a decrease in reflex magnitude of the startle reflex was observed after pharmacological suppression of endogenous cortisol production. In the third study, a higher reflex magnitude of the startle reflex was observed at reduced arterial and central venous blood pressure. These results can be interpreted in terms of an adaption to hostile environments.
This thesis presents a study of the visual change detection mechanism. This mechanism is thought to be responsible for the detection of sudden and unexpected changes in our visual environment. As the brain is a capacity limited system and has to deal with a continuous stream of information from its surroundings only a part of the vast amount of information can be completely processed and be brought to conscious awareness. This information, which passes through attentional filters, is used for goal-directed behaviour. Therefore, the change detection mechanism is a very useful aid to cope with important information which is outside the focus of our attention. rnIt is thought that a neural memory trace of repetitive visual information is stored. Each new information input is compared to this existing memory trace by a so-called change or mismatch detection system. Following a sudden change, the comparison process leads to a mismatch and the detection system elicits a warning signal, to which an orienting response can follow. This involves a change in the focus of attention towards this sudden environmental change which can then be evaluated for potential danger and allows for a behavioural adaptation to the new situation. rnTo this purpose a paradigm was developed combining a 2-choice response time task with in the background a mismatch detection task of which the subjects were not aware. This paradigm was implemented in an ERP and an fMRI study and was used to study the the change detection mechanism and its relationship with impulsivity.rnIn previous studies a change detection system for auditory information had already been established. As the brain is a very efficient system it was thought to be unlikely that this change detection system is only available for the processing of auditory information. rnIndeed, a modality specific mismatch response at the sensory specific occipital cortex and a more general response at the frontocentral midline, both resembling the components shown in auditory research, were found in the ERP study.rnAdditionally, magnetic resonance imaging revealed a possible functional network of regions, which responded specifically to the processing of a deviant. These regions included the occipital gyrus, premotor cortex, inferior frontal cortex, thalamas, insula, and parts of the cingular cortex. rnThe relationship between impulsivity measures and visual change detection was established in an additional study. More impulsive subjects showed less detection of deviant stimuli, which was most likely due to too fast and imprecise information processing.rnIn summary it can be said, that the work presented in this thesis demonstrates that visual mismatch negativity was established, a number of regions could be associated with change detection and additionally the relevance of change detection in information processing was shown.rn
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.
One mechanism underlying the acquisition of interpersonal attitudes is the formation of an association between a valenced unconditioned stimulus (US) and an affectively neutral conditioned stimulus (CS). However, a stimulus (e.g., a person) is not always and necessarily perceived to be unambiguously positive or negative. An individual can be negative regarding abstract (trait) information but at the same time display a positive (concrete) behavior. The present research deals with the question of whether the valence of abstract or concrete information about a US is encoded and subsequently transferred to an associated CS. The central assumptions are that the valence of the concrete information is more important for the evaluation of the US, whereas the abstract information is more important for the evaluation of the CS. The rationale behind these assumptions is that the US is a psychologically proximal stimulus because it elicits a more direct affective reaction. The CS, however, is psychologically more distal because it is merely associated with the US and is therefore only experienced indirectly. It is postulated that the associative relation between US and CS constitutes a dimension of psychological distance. In four studies, the valence of abstract and concrete information about a number of USs was manipulated. Within an evaluative learning paradigm, these stimuli were associated with affectively neutral CSs. As predicted, ambivalent USs were evaluated according to the valence of the concrete information. The evaluation of CSs, however, was influenced more strongly by the valence of the abstract information. Moreover, in a subsequent lexical decision task, participants were faster to categorize abstract (vs. concrete) stimuli when the stimuli were preceded by a CS prime as compared to a US prime. The results provide first evidence that perceived psychological distance influences the evaluations of US and CS in an associative evaluative learning paradigm.
Interoception - the perception of bodily processes - plays a crucial role in the subjective experience of emotion, consciousness and symptom genesis. As an alternative to interoceptive paradigms that depend on the participants" active cooperation, five studies are presented to show that startle methodology may be employed to study visceral afferent processing. Study 1 (38 volunteers) showed that startle responses to acoustic stimuli of 105 dB(A) intensity were smaller when elicited during the cardiac systole (R-wave +230 ms) as compared to the diastole (R +530 ms). In Study 2, 31 diabetic patients were divided into two groups with normal or diminished (< 6 ms/mmHg) baroreflex sensitivity (BRS) of heart rate control. Patients with normal BRS showed a startle inhibition during the cardiac systole as was found for healthy volunteers. Diabetic patients with diminished BRS did not show this pattern. Because diminished BRS is an indicator of impaired baro-afferent signal transmission, we concluded that cardiac modulation of startle is associated with intact arterial baro-afferent feedback. Thus, pre-attentive startle methodology is feasible to study visceral afferent processing. rnVisceral- and baro-afferent information has been found to be mainly processed in the right hemisphere. To explore whether cardiac modulation of startle eye blink is lateralized as well, in Study 3, 37 healthy volunteers received 160 unilateral acoustic startle stimuli presented to both ears, one at a time (R +0, 100, 230, 530 ms). Startle response magnitude was only diminished at R +230 ms and for left-ear presentation. This lateralization effect in the cardiac modulation of startle eye blink may reflect the previously described advantages of right-hemispheric brain structures in relaying viscero- and baro-afferent signal transmission. rnThis lateralization effect implies that higher cognitive processes may also play a role in the cardiac modulation of startle. To address this question, in Study 4, 25 volunteers responded first by 'fast as possible' button pushes (reaction time, RT), and second, rated perceived intensity of 60 acoustic startle stimuli (85, 95, or 105 dB; R +230, 530 ms). RT was divided into evaluation and motor response time. Increasing stimulus intensity enhanced startle eye blink, intensity ratings, and RT components. Eye blinks and intensity judgments were lower when startle was elicited at a latency of R +230 ms, but RT components were differentially affected. It is concluded that the cardiac cycle affects the attentive processing of acoustic startle stimuli. rnBeside the arterial baroreceptors, the cardiopulmonary baroreceptors represent another important system of cardiovascular perception that may have similar effects on startle responsiveness. To clarify this issue, in Study 5, Lower Body Negative Pressure at gradients of 0, -10, -20, and -30 mmHg was applied to unload cardiopulmonary baroreceptors in 12 healthy males, while acoustic startle stimuli were presented (R +230, 530 ms). Unloading of cardiopulmonary baroreceptors increased startle eye blink responsiveness. Furthermore, the effect of relative loading/unloading of arterial baroreceptors on startle eye blink responsiveness was replicated. These results demonstrate that the loading status of cardiopulmonary baroreceptors also has an impact on brainstem-based CNS processes. rnThus, the cardiac modulation of acoustic startle is feasible to reflect baro-afferent signal transmission of multiple neural sources, it represents a pre-attentive method that is independent of active cooperation, but its modulatory effects also reach higher cognitive, attentive processes.rn
The catechol-O-methyltransferase gene (COMT) plays a crucial role in the metabolism of catecholamines in the frontal cortex. A single nucleotide polymorphism (Val158Met SNP, rs4680) leads to either methionine (Met) or valine (Val) at codon 158, resulting in a three- to fourfold reduction in COMT activity. The aim of the present study was to assess the COMT Val158Met SNP as a risk factor for attention-deficit/hyperactivity disorder (ADHD), ADHD symptom severity and co-morbid conduct disorder (CD) in 166 children with ADHD. The main finding of the present study is that the Met allele of the COMT Val158Met SNP was associated with ADHD and increased ADHD symptom severity. No association with co-morbid CD was observed. In addition, ADHD symptom severity and early adverse familial environment were positive predictors of lifetime CD. These findings support previous results implicating COMT in ADHD symptom severity and early adverse familial environment as risk factors for co-morbid CD, emphasizing the need for early intervention to prevent aggressive and maladaptive behavior progressing into CD, reducing the overall severity of the disease burden in children with ADHD.
The aim of the thesis was to investigate the role of the immune system in fibromyalgia (FM), as part of a dynamic co-regulation between different bodily systems. FM is a chronic musculoskeletal disorder characterized by widespread pain and specific tender points, combined with other symptoms including fatigue, sleep disturbances, morning stiffness and anxiety. The main goal of the work was to identify possible dysregulation of peripheral immune and endocrine parameters in patients with FM compared to matched healthy controls. Moreover, the possible relation between symptom complaints and the specific parameters measured was also evaluated. A first approach was to investigate possible differences between FM patients and controls in the expression of cytokines, as they have been implicated in the occurrence of several of the symptoms associated with FM. Furthermore, adhesion molecules which are involved in cell-to-cell communication and immune cell trafficking were also studied. The latter are known to be regulated by both cytokines and glucocorticoids (GCs) and their expression is often found altered in patients with immune dysregulation. It was expected that subjects with FM would have an increased production of proinflammatory cytokines and/or a reduced antiinflammatory cytokine production and that certain cytokines and/or adhesion molecules would be differently regulated by dexamethasone (DEX). Unstimulated blood was used in the analysis of adhesion molecule expression by flow cytometry while stimulated whole blood cell cultures were used in cytokine flow cytometry assays. Peripheral blood mononuclear cells (PBMCs) were also cultured and the supernatants collected to determine the concentration of cytokines by biochip protein array. In addition, serum samples were used in enzyme-linked immunosorbent assays (ELISA) for quantification of soluble adhesion molecules. L-selectin was found elevated on monocytes and neutrophils of FM patients. A bias toward lower IL-4 levels was observed in FM patients. Based on studies showing differences in glucocorticoid receptor (GR) affinity and disturbances associated with loss of hypothalamic-pituitary-adrenal (HPA) axis resiliency in FM, it was hypothesized whether FM would be associated with abnormalities in glucocorticoid sensitivity. Total plasma cortisol and salivary free cortisol were quantified by ELISA and time-resolved fluorescence immunoassay, respectively. GR sensitivity through DEX inhibition of IL-6, in stimulated whole blood, was evaluated after cytokine quantification by ELISA. The corticosteroid receptors, GR alpha and mineralocorticoid receptor (MR), as well as the glucocorticoid-induced leucine zipper (GILZ) and the FK506 binding protein 5 mRNA expression were assessed in PBMCs by real-time reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, sequencing of RT-PCR products and/or genomic DNA was used for mutational analysis of the corticosteroid receptors. We observed lower basal plasma cortisol levels (borderline statistical significance) and a lower expression of corticosteroid receptors and GILZ in FM patients when compared to healthy controls. The minor allele of the MR single nucleotide polymorphism (SNP) rs5522 was found more often in FM patients than in controls. In addition, female carriers of this SNP seemed to have reduced salivary cortisol responses to a strong psychological stressor (Trier Social Stress Test) compared to non-carriers. FM patient carriers of an MR intronic SNP (rs17484245), before exon 3, were associated with significantly higher scores of depression symptoms compared to patient non-carriers. The thesis includes also a comprehensive analysis of the complexity of GR regulation and the role of alternative mRNA splicing. It focuses on the differential expression of the untranslated GR first exons, their high sequence homology among different species and how genetic determinants, without apparent relevance, may have implications in health and disease. In FM patients, GR exon 1-C expression was found lower and a significant difference was observed when comparing GR 1-C expression between antidepressant-free and patients who had taken antidepressants until two weeks before sample collection. In summary, the study shows a slight disturbance of some components of the innate immune system of FM patients and suggests an enhanced adhesion and possible recruitment of leukocytes to inflammatory sites. The reduced expression of corticosteroid receptors and possibly the reduced MR function may be associated with an impaired function of the HPA axis in these patients. A hyporesponsiveness of the HPA axis under stress or disturbances of the stress response could make these patients more vulnerable to cytokines and inflammation which, compounded by lower antiinflammatory mediators, may sustain some of the symptoms that contribute to the clinical picture of FM.
During the last decade, anatomic and physiological neuroscience research has yielded extensive information on the physiological regulators of short-term satiety, visceral and interoceptive sensation. Distinct neural circuits regulate the elements of food ingestion physiologically. The general aim of the current studies is to elucidate the peripheral neural pathways to the brain in healthy subjects to establish the groundwork for the study of the pathophysiology of bulimia nervosa (BN). We aimed to define the central activation pattern during non-nutritive gastric distension in humans, and aimed to define the cognitive responses to this mechanical gastric distension. We estimated regional cerebral blood flow with 15O-water positron emission tomography during intragastric balloon inflation and deflation in 18 healthy young women of normal weight. The contrast between inflated minus deflated in the exploratory analysis revealed activation in more than 20 brain regions. The analysis confirmed several well known areas in the central nervous system that contribute to visceral processing: the inferior frontal cortex, representing a zone of convergence for food related stimuli; the insula and operculum referred to as "visceral cortex"; the anterior cingulate gyrus (and insula), processing affective information; and the brainstem, a site of vagal relay for visceral afferent stimuli. Brain activation in the left ventrolateral prefrontal cortex was reproducible. This area is well known for higher cognitive processing, especially reward-related stimuli. The ventrolateral prefrontal cortex with the insular regions may provide a link between the affective and rewarding components of eating and disordered eating as observed in BN and binge-eating obesity. Gastric distension caused a significant rapid, reversible, and reproducible increase in the feelings of fullness, sleepiness, and gastric discomfort as well as a significant rapid, reversible, and reproducible decrease in the feeling of hunger. We showed that mechanical activation of the neurocircuitry involved in meal termination led to the described phenomena. The current brain activation studies of non-painful, proximal gastric distension could provide groundwork in the field of abnormal eating behavior by suggesting a link between visceral sensation and abnormal eating patterns. A potential treatment for disordered eating and obesity could alter the conscious and unconscious perception and interoceptive awareness of gastric distension contributing to meal termination.
The human brain is characterised by two apparently symmetrical cerebral hemispheres. However, the functions attributed to each half of the brain are very distinct with a relative specialisation of the left hemisphere for language processing. Most laterality research has been performed on a behavioural level, using techniques such as visual half-field presentation. The visual half-field technique involves the presentation of stimuli in the left or right visual field for a very short time (about 200 ms). During the presentation of lateralized stimuli, the gaze of the participants is fixated on a centrally presented fixation cross. This technique takes advantage of the anatomy of the visual pathway as the temporal hemiretinae project ipsilateral, while the nasal hemiretinae project contralateral. Thus, stimuli presented in the left or right visual field are initially processed in the contralateral hemisphere. Language organisation can also be directly investigated using functional magnetic resonance imaging (fMRI). Both behavioural and neuroimaging studies showed that about 95% of right-handed men have a left hemispheric specialisation for language. In contrast, data on language organisation in women are ambiguous. It is supposed that this ambivalent picture might be associated with changes in gonadal steroid levels in blood during the menstrual cycle. However, gonadal steroid effects are complex and their role in functional cerebral lateralization is still open to discussion. The aim of this PhD project was to investigate, using fMRI: (1) the processing of linguistic information initially received in the specialised, non-specialised or both hemispheres; (2) linking the associated brain activation pattern with progesterone levels during the menstrual cycle. Firstly, brain activation was measured in 16 right-handed, healthy males during processing of different components of language (orthography, phonology and semantics) after reception in the left, right or both hemispheres. Secondly, to investigate changes in language organisation during the menstrual cycle, we conducted an event-related fMRI study during semantic and phonological processing also using visual half-field and central presentation of linguistic stimuli. Our results revealed higher BOLD signal intensity change in the visual cortex contralateral to the visual field of stimulus presentation compared to the ipsilateral visual cortex reflecting the crossing of visual pathways. We also found support for the hypothesis that the superiority of word recognition in the left VWFA is the result of a reduced activity in the right VWFA under left hemispheric control. Further, linguistic information received in the subdominant RH, is interhemispheric transferred to the left hemisphere for phonological processing. Semantic processing in contrast occurs in the specialised and in the non-specialised hemisphere. For the group of women, data analysis revealed that during semantic processing, salivary progesterone levels correlated positively with brain activity of the left superior frontal gyrus, left middle and inferior occipital gyri and bilateral fusiform gyrus. In contrast, the brain activation pattern for phonological processing did not change significantly across the menstrual cycle. In conclusion, the effect of serum progesterone levels on brain activity is task and region specific.
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.
In this psycho-neuro-endocrine study the molecular basis of different variants of steroid receptors as well as highly conserved non steroidal receptors was investigated. These nuclear receptors (NRs) are important key regulators of a wide variety of different physiological and pathophysiological challenges ranging from inflammation and stress to complex behaviour and disease. NRs control gene transcription in a ligand dependent manner and are embedded in the huge interaction network of the neuroendocrine and immune system. Two receptors, the glucocorticoid receptor (GR) and the chicken ovalbumin upstream promoter-transcription factorII (Coup-TFII), both expressed in the immune and nervous system, were investigated regarding possible splice variants and their implication in the control of gene transcription. Both NRs are known to interact and modulate each other- target gene regulation. This study could be shown that both NRs have different splice variants that are expressed in a tissue specific manner. The different 5-´alternative transcript variants of the human GR were in silico identified in other species and evidence for a highly conserved and tightly controlled function was provided. Investigations of the N-terminal transactivation domain of the GR showed a deletion suggesting an altered glucocorticoid-dependent transactivation profile. The newly identified alternative transcript variant of Coup-TFII leads to a DNA binding deficient Coup-TFII isoform that is highly expressed in the brain. This Coup-TFII isoform alters Coup-TFII target gene expression and is suggested to interact with GR via its ligand binding domain resulting in an impaired GR target gene regulation in the nervous system. In this thesis it was demonstrated that NR variants are important for the understanding of the enormous regulatory potential of this receptor family and have to be taken into account for the development of therapeutic strategies for complex diseases such as stress related and neurodegenerative disorders.
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 midcingulate cortex has become the focus of scientific interest as it has been associated with a wide range of attentional phenomena. This survey found evidence indicating the relevance of gender and handedness for measures of regional cortical morphology. Although gender was associated with structural variations concerning the neuroanatomy of the midcingulum bundle as well, handedness did not emerge in the analyses of white matter characteristics as significant factor. Hemispheric differences were found at the level of both gray and white matter. Turning to the functional implications of neuroanatomical variations and comparing subjects with a pronounced and a low degree of midcingulate folding, which indicates differential expansions of cytoarchitectural areas, behavioral and electrophysiological differences in the processing of interference became evident. A high degree of leftward midcingulate fissurization was associated with better behavioral performance, presumably caused by a more effective conflict-monitoring system triggering fast and automatic attentional filtering mechanisms. Subjects exhibiting a lower degree of midcingulate fissurization rather seem to rely on more effortful control processes. These results carry implications not only concerning neuronal representations of individual differences in attentional processes, but might also be of relevance for the refinement of models for mental disorders.
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.
Memory consists of multiple anatomically and functionally distinct systems. Animal studies suggest that stress modulates multiple memory systems in a manner that favors nucleus caudatus-based stimulus-response learning at the expense of hippocampus-based spatial learning. The present work aimed (i) to translate these findings to humans, (ii) to determine the involvement of the stress hormone cortisol in this effect, and (iii) to assess whether the use of stimulus-response and spatial strategies is a long lasting person characteristic. To address these issues we developed a new paradigm that differentiates the use of spatial and stimulus-response learning in humans. Our findings indicate that (i) psychosocial stress (Trier Social Stress Test) modulates the use of spatial and stimulus-response learning in humans, (ii) cortisol plays a key role in this modulatory effect of stress, and (iii) the use of spatial and stimulus-response learning is affected by situational rather than long lasting person factors.
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.
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.
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.
Software and interactive systems that adapt their behavior to the user are often referred to as Adaptive Systems. These systems infer the user's goals, knowledge or preferences by observing the user's actions. A synposis of 43 published studies demonstrated that only few of the existing systems are evaluated empirically. Most studies failed to show an advantage of the user model. A new framework is proposed that categorizes existing studies and defines an evaluation procedure which is able to uncover failures and maladaptations in the user model. It consists of four layers: evaluation of input data, evaluation of inference, evaluation of adaptation decision and evaluation of total interaction. Exemplary, the framework has been applied to the HTML-Tutor, an online-course that adapts to the learners' knowledge. Several empirical studies are described that test the accuracy of the user models, and explore the effects of adaptation to knowledge respectively prior knowledge. Generalization issues of the approach are discussed.
There is considerable evidence for an association between chronic dysregulation of the hypothalamus-pituitary adrenal (HPA) axis, atrophy of the hippocampus (HC) and cognitive and mood changes in clinical populations and in aging. The present thesis investigated this relationship in young healthy male subjects. Special emphasis was put on measures of HC volume and function derived from structural and functional magnetic resonance imaging (MRI). Higher cortisol levels after awakening were observed in subjects with higher levels of depressive symptomatology. Larger HC volume was associated with higher cortisol levels after awakening and in response to acute stress, whereas cognitive performance was impaired in subjects with larger HC volumes. Hippocampal activation during picture encoding was reduced after stress induction, and positive associations between activation and cognitive performance before stress were not present anymore afterwards. The present findings underscore the importance of structural and functional brain imaging for psychoneuroendocrinological research. The investigation of the association between cortisol levels and hippocampal integrity in young healthy subjects elicited unexpected results and adds to the understanding of HPA dysfunction and HC atrophy in clinical and aged populations.