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- Psychologie (15) (entfernen)
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.
Die Einführung leistungsorientierter Entgeltsysteme stellt Mitarbeiter und Unternehmen vor besondere Herausforderungen. Dabei verändert sich vor allem die Rolle des Mitarbeiters. War er vormals Ausführender der ihm übertragenen Arbeitsaufgaben, wird er zunehmend zum eigenverantwortlichen Gestalter und Mitunternehmer. Im Rahmen einer multiplen Fallstudie wird zunächst der Frage nachgegangen, wie die Mitarbeiter in drei karitativen Einrichtungen die Einführung einer leistungsorientierten Vergütungskomponente erleben. Dazu werden inhaltliche Gestaltungsmerkmale der Entgeltsysteme, Merkmale des Einführungsprozesses und ihre Auswirkungen untersucht. Die Ergebnisse zeigen, dass die Mitarbeiter in allen Einrichtungen dem Aspekt der Finanzierung des variablen Vergütungsanteils eine wesentliche Bedeutung beimessen. Wird dieser Anteil durch die Variabilisierung bisher garantierter, fixer Vergütungsanteile finanziert, entstehen unsichere Gehalts-anteile und es erhöht sich das Risiko von möglichen Gehaltsverlusten. In der Einrichtung mit dem höchsten Entgeltrisiko führte dieser Umstand dazu, dass Mitarbeiter und Vorgesetzte durch informelle Absprachen versucht haben, mögliche Verluste zu vermeiden. Wird der variable Entgeltanteil durch die Einrichtungen mitfinanziert, erhöhen sich hingegen die Chancen auf Einkommensgewinne, was auch zu einer höheren Akzeptanz der neuen Entgeltsysteme beiträgt. Aufbauend auf den Ergebnissen der Fallstudie werden in einer quantitativen Analyse die Auswirkungen eines erhöhten Entgeltrisikos auf die Zufriedenheit der Mitarbeiter mit ihrem variablen Vergütungsanteil (Bonuszufriedenheit) untersucht. Dabei wird das Entgeltrisiko durch drei konzeptuelle Facetten operationalisiert: die Variabilität der Entlohnung, das Ausmaß möglicher Verluste und das Verhältnis von Risiko und Chance (RCV). Entgegen der bisherigen Annahme in der Forschungsliteratur, dass vor allem die Variabilität der Entlohnung ausschlaggebend für die Auswirkungen von Entgeltrisiko ist, zeigen regressionsanalytische Ergebnisse, dass in der Einführungsphase neuer Entgeltsysteme vor allem das RCV einen signifikanten Effekt auf die Bonuszufriedenheit der Mitarbeiter hat. Die Ergebnisse einer multiplen Mediationsanalyse legen nahe, dass der Effekt von RCV auf die Bonuszufriedenheit zum Teil von Einstellungen der distributiven und prozeduralen Gerechtigkeit vermittelt wird. Wei-terführende Analysen ergeben, dass der Zusammenhang zwischen dem RCV und der Bonuszufriedenheit durch zwei moderierende Variablen beeinflusst wird: zum einen durch die partizipative Beteiligung der Mitarbeiter am Einführungsprozess und zum anderen durch die individuelle Präferenz für leistungsorientierte Entlohnung. Vor allem bei hoher partizipativer Beteiligung wirkt sich ein günstiges RCV positiv auf die Bonuszufriedenheit der Mitarbeiter aus. Außerdem sind jene Mitarbeiter unzufriedener mit einem risiko-reichen Entgeltsystem, die eine stark ausgeprägte Präferenz für leistungsorientierte Entlohnung besitzen.
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.
Monatelange Wartezeiten auf einen ambulanten Psychotherapieplatz sind der Regelfall im deutschen Gesundheitssystem. Die Veränderung der Symptombelastung der Patienten in der Wartezeit ist bislang allerdings kaum empirisch untersucht worden. In der vorliegenden Arbeit wurden an einer Stichprobe ambulanter Psychotherapiepatienten die Ausprägungen und Veränderungen der allgemeinen psychischen Symptombelastung während der durchschnittlich sechsmonatigen Wartezeit auf den Psychotherapieplatz untersucht. Zudem wurde überprüft, mit welchen Merkmalen die Symptombelastungen zum Zeitpunkt der Anmeldung zur Therapie und zum Zeitpunkt des Erstgesprächs sowie ihre Veränderungen in der Wartezeit zusammenhängen. Die dabei untersuchten Persönlichkeitsmerkmale wurden aus theoretischen Rahmenmodellen abgeleitet. Hierzu gehören die aktionale Entwicklungspsychologie, das handlungstheoretische Partialmodell der Persönlichkeit mit der darin eingeordneten Vertrauens-Trias und das Androgynie-Modell der psychischen Gesundheit. Nach einem direkten Veränderungskriterium zeigten 48 % der Patienten in der Wartezeit keine bedeutsame Veränderung, 29 % eine Verbesserung und 23 % eine Verschlechterung. Durch die bei der Anmeldung erfassten Persönlichkeitsmerkmale konnten Verbesserungen, Verschlechterungen und gleichbleibende Symptombelastungen in der Wartezeit anhand einer multinomialen logistischen Regressionsanalyse für 60 % der Patienten korrekt vorausgesagt werden. Eine traditionelle normative Geschlechtsrollen-Orientierung stellt einen negativen Prädiktor für eine Verbesserung dar. Soziales Vertrauen konnte Verschlechterungen negativ vorhersagen. Bei Hoffnungslosigkeit handelt es sich um einen marginal negativen Prädiktor für eine Verbesserung. Ein hoch ausgeprägtes Selbstkonzept eigener Fähigkeiten ist ein positiver Prädiktor für eine Verschlechterung. Hinsichtlich der soziodemografischen und störungsbezogenen Merkmale konnten das Alter, das Geschlecht und die Anzahl der Diagnosen die Veränderungen der Symptombelastung in der Wartezeit zu 54 % korrekt vorhersagen. Das Alter ist ein positiver Prädiktor für eine Verschlechterung. Weibliches Geschlecht und die Anzahl an Diagnosen sind negative Prädiktoren für eine Verbesserung. Darüber hinaus wurden differenzierte Zusammenhänge zwischen den Persönlichkeitsmerkmalen und der Symptombelastung exploratorisch untersucht.
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.
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.
Die Vertrauens-Trias erlaubt salutogentische Aussagen über personale Ressourcen. Die kulturvergleichende Anwendung der Vertrauens-Trias wurde bei Jugendlichen in drei Ländern (Deutschland, Luxemburg, Spanien) überprüft. Dabei wurde die Konstruktvalidität der Vertrauens-Trias als auch Zusammenhänge zu symptomatischen Belastungen insgesamt bestätigt. Vergleiche zwischen den Kulturen zeigen keine Unterschiede zwischen deutschen und luxemburgischen Schülern, jedoch zwischen deutschen und spanischen Schülern.
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.