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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.
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.
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.
Fast and Slow Effects of Cortisol on Several Functions of the Central Nervous System in Humans
(2014)
Cortisol is one of the key substances released during stress to restore homeostasis. Our knowledge of the impact of this glucocorticoid on cognition and behavior in humans is, however, still limited. Two modes of action of cortisol are known, a rapid, nongenomic and a slow, genomic mode. Both mechanisms appear to be involved in mediating the various effects of stress on cognition. Here, three experiments are presented that investigated fast and slow effects of cortisol on several functions of the human brain. The first experiment investigated the interaction between insulin and slow, genomic cortisol effects on resting regional cerebral blood flow (rCBF) in 48 young men. A bilateral, locally distinct increase in rCBF in the insular cortex was observed 37 to 58 minutes after intranasal insulin admission. Cortisol did not influence rCBF, neither alone nor in interaction with insulin. This finding suggests that cortisol does not influence resting cerebral blood flow within a genomic timeframe. The second experiment examined fast cortisol effects on memory retrieval. 40 participants (20 of them female) learned associations between neutral male faces and social descriptions and were tested for recall one week later. Cortisol administered intravenously 8 minutes before retrieval influenced recall performance in an inverted U-shaped dose-response relationship. This study demonstrates a rapid, presumably nongenomic cortisol effect on memory retrieval in humans. The third experiment studied rapid cortisol effects on early multisensory integration. 24 male participants were tested twice in a focused cross-modal choice reaction time paradigm, once after cortisol and once after placebo infusion. Cortisol acutely enhanced the integration of visual targets and startling auditory distractors, when both stimuli appeared in the same sensory hemi-field. The rapidity of effect onset strongly suggests that cortisol changes multisensory integration by a nongenomic mechanism. The work presented in this thesis highlights the essential role of cortisol as a fast acting agent during the stress response. Both the second and the third experiment provide new evidence of nongenomic cortisol effects on human cognition and behavior. Future studies should continue to investigate the impact of rapid cortisol effects on the functioning of the human brain.
Fostering positive and realistic self-concepts of individuals is a major goal in education worldwide (Trautwein & Möller, 2016). Individuals spend most of their childhood and adolescence in school. Thus, schools are important contexts for individuals to develop positive self-perceptions such as self-concepts. In order to enhance positive self-concepts in educational settings and in general, it is indispensable to have a comprehensive knowledge about the development and structure of self-concepts and their determinants. To date, extensive empirical and theoretical work on antecedents and change processes of self-concept has been conducted. However, several research gaps still exist, and several of these are the focus of the present dissertation. Specifically, these research gaps encompass (a) the development of multiple self-concepts from multiple perspectives regarding stability and change, (b) the direction of longitudinal interplay between self-concept facets over the entire time period from childhood to late adolescence, and (c) the evidence that a recently developed structural model of academic self-concept (nested Marsh/Shavelson model [Brunner et al., 2010]) fits the data in elementary school students, (d) the investigation of structural changes in academic self-concept profile formation within this model, (e) the investigation of dimensional comparison processes as determinants of academic self-concept profile formation in elementary school students within the internal/external frame of reference model (I/E model; Marsh, 1986), (f) the test of moderating variables for dimensional comparison processes in elementary school, (g) the test of the key assumptions of the I/E model that effects of dimensional comparisons depend to a large degree on the existence of achievement differences between subjects, and (h) the generalizability of the findings regarding the I/E model over different statistical analytic methods. Thus, the aim of the present dissertation is to contribute to close these gaps with three studies. Thereby, data from German students enrolled in elementary school to secondary school education were gathered in three projects comprising the developmental time span from childhood to adolescence (ages 6 to 20). Three vital self-concept areas in childhood and adolescence were in-vestigated: general self-concept (i.e., self-esteem), academic self-concepts (general, math, reading, writing, native language), and social self-concepts (of acceptance and assertion). In all studies, data were analyzed within a latent variable framework. Findings are discussed with respect to the research aims of acquiring more comprehensive knowledge on the structure and development of significant self-concept in childhood and adolescence and their determinants. In addition, theoretical and practical implications derived from the findings of the present studies are outlined. Strengths and limitations of the present dissertation are discussed. Finally, an outlook for future research on self-concepts is given.
The Role of Dopamine and Acetylcholine as Modulators of Selective Attention and Response Speed
(2015)
The principles of top-down and bottom-up processing are essential to cognitive psychology. At their broadest, most general definition, they denote that processing can be driven either by the salience of the stimulus input or by individual goals and strategies. Selective top-down attention, specifically, consists in the deliberate prioritizing of stimuli that are deemed goal-relevant, while selective bottom-up attention relies on the automatic allocation of attention to salient stimuli (Connor, Egeth, & Yantis, 2004; Schneider, Schote, Meyer, & Frings, 2014). Variations within neurotransmitter systems can modulate cognitive performance in a domain-specific fashion (Greenwood, Fossella, & Parasuraman, 2005). Noudoost and Moore (2011a) proposed that the influence of the dopaminergic neurotransmitter system on selective top-down attention might be greater than the influence of this system on selective bottom-up attention; likewise, they assumed that the cholinergic neurotransmitter system might be more important for selective bottom-up than top-down attention. To test this hypothesis, naturally occurring variations within the two neurotransmitter systems were assessed. Five polymorphisms were selected; two of the dopaminergic system (the COMT Val158Met polymorphism and the DAT1 polymorphism) and three of the cholinergic system (the CHRNA4 rs1044396 polymorphism, the CHRNA5 rs3841324 polymorphism, and the CHRNA5 rs16969968 polymorphism). It was tested whether these polymorphisms modulated the performance in tasks of selective top-down attention (a Stroop task and a Negative priming task) and in a task of selective bottom-up attention (a Posner-Cuing task). Indeed, the dopaminergic polymorphisms influenced selective top-down attention, but exerted no effects on bottom-up attention. This aligned with the hypothesis proposed by Noudoost and Moore (2011a). In contrast, the cholinergic polymorphisms were not found to modulate selective bottom-up attention. The three cholinergic polymorphisms, however, affected the general response speed in the Stroop task, Negative priming task, and Posner-Cuing task (irrespective of attentional processing). In sum, the findings of this study provide strong indications that the dopaminergic system modulates selective top-down attention, while the cholinergic system is highly relevant for the general speed of information processing.
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.
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 present thesis addresses the validity of Binge Eating Disorder (BED) as well as underlying mechanisms of BED from three different angles. Three studies provide data discriminating obesity with BED from obesity without BED. Study 1 demonstrates differences between obese individuals with and without BED regarding eating in the natural environment, psychiatric comorbidity, negative affect as well as self reported tendencies in eating behavior. Evidence for possible psychological mechanisms explaining increased intake of BED individuals in the natural environment was given by analyzing associations of negative affect, emotional eating, restrained eating and caloric intake in obese BED compared to NBED controls. Study 2 demonstrated stress-induced changes in the eating behavior of obese individuals with BED. The impact of a psychosocial stressor, the Trier Social Stress Test (TSST, Kirschbaum, Pirke, &amp;amp; Hellhammer, 1993), on behavioral patterns of eating behavior in laboratory was investigated. Special attention was given to stress-induced changes in variables that reflect mechanisms of appetite regulation in obese BED individuals compared to controls. To further explore by which mechanisms stress might trigger binge eating, study 3 investigated differences in stress-induced cortisol secretion after a socially evaluated cold pressure test (SECPT, Schwabe, Haddad, &amp;amp; Schachinger, 2008) in obese BED as compared to obese NBED individuals.
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.
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 search for relevant determinants of knowledge acquisition has a long tradition in educational research, with systematic analyses having started over a century ago. To date, a variety of relevant environmental and learner-related characteristics have been identified, providing a wide body of empirical evidence. However, there are still some gaps in the literature, which are highlighted in the current dissertation. The dissertation includes two meta-analyses summarizing the evidence on the effectiveness of electrical brain stimulation and the effects of prior knowledge on later learning outcomes and one empirical study employing latent profile transition analysis to investigate the changes in conceptual knowledge over time. The results from the three studies demonstrate how learning outcomes can be advanced by input from the environment and that they are highly related to the students" level of prior knowledge. It is concluded that the effects of environmental and learner-related variables impact both the biological and cognitive processes underlying knowledge acquisition. Based on the findings from the three studies, methodological and practical implications are provided, followed by an outline of four recommendations for future research on knowledge acquisition.
At any given moment, our senses are assaulted with a flood of information from the environment around us. We need to pick our way through all this information in order to be able to effectively respond to that what is relevant to us. In most cases we are usually able to select information relevant to our intentions from what is not relevant. However, what happens to the information that is not relevant to us? Is this irrelevant information completely ignored so that it does not affect our actions? The literature suggests that even though we mayrnignore an irrelevant stimulus, it may still interfere with our actions. One of the ways in which irrelevant stimuli can affect actions is by retrieving a response with which it was associated. An irrelevant stimulus that is presented in close temporal contiguity with a relevant stimulus can be associated with the response made to the relevant stimulus " an observation termed distractor-response binding (Rothermund, Wentura, & De Houwer, 2005). The studies presented in this work take a closer look at such distractor-response bindings, and therncircumstances in which they occur. Specifically, the study reported in chapter 6 examined whether only an exact repetition of the distractor can retrieve the response with which it was associated, or whether even similar distractors may cause retrieval. The results suggested that even repeating a similar distractor caused retrieval, albeit less than an exact repetition. In chapter 7, the existence of bindings between a distractor and a response were tested beyond arnperceptual level, to see whether they exist at an (abstract) conceptual level. Similar to perceptual repetition, distractor-based retrieval of the response was observed for the repetition of concepts. The study reported in chapter 8 of this work examined the influence of attention on the feature-response binding of irrelevant features. The results pointed towards a stronger binding effects when attention was directed towards the irrelevant feature compared to whenrnit was not. The study in chapter 9 presented here looked at the processes underlying distractor-based retrieval and distractor inhibition. The data suggest that motor processes underlie distractor-based retrieval and cognitive process underlie distractor inhibition. Finally, the findings of all four studies are also discussed in the context of learning.
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
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.
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.
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.
Cortisol exhibits typical ultradian and circadian rhythm and disturbances in its secretory pattern have been described in stress-related pathology. The aim of this thesis was to dissect the underlying structure of cortisol pulsatility and to develop tools to investigate the effects of this pulsatility on immune cell trafficking and the responsiveness of the neuroendocrine system and GR target genes to stress. Deconvolution modeling was set up as a tool for investigation of the pulsatile secretion underlying the ultradian cortisol rhythm. This further allowed us to investigate the role of the single cortisol pulses on the immune cell trafficking and the role of induced cortisol pulses on the kinetics of expression of GR target genes. The development of these three tools, would allow to induce and investigate in future the significance of single cortisol pulses for health and disease.
In this thesis, in order to shed light on the biological function of the membrane-bound Glucocorticoid Receptor (mGR), proteomic changes induced by 15 min in vivo acute stress and by short in vitro activation of the mGR were analyzed in T-lymphocytes. The numerous overlaps between the two datasets suggest that the mGR mediates physiologically relevant actions and participates in the early stress response, triggering rapid early priming events that pave the way for the slower genomic GC activities. In addition, a new commercially available method with suitable sensitivity to detect the human mGR is reported and the transcriptional origin of this protein investigated. Our results indicates that specific GR-transcripts, containing exon 1C and 1D, are associated with the expression of this membrane isoform.
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.