TY - THES A1 - Schiele, Miriam T1 - Interaction of 5-HTT/NPSR1 variants with distal and acute stress on dimensional and neuroendocrine anxiety endophenotypes – A multi-dimensional model of anxiety risk T1 - Interaktion von 5-HTT/NPSR1 Varianten mit distalem und akutem Stress bei dimensionalen und neuroendokrinen Endophänotypen von Angst – Ein multidimensionales Modell der Angstentstehung N2 - The etiology of anxiety disorders is multifactorial with contributions from both genetic and environmental factors. Several susceptibility genes of anxiety disorders or anxiety-related intermediate phenotypes have been identified, including the serotonin transporter gene (5-HTT) and the neuropeptide S receptor gene (NPSR1), which have been shown to modulate responses to distal and acute stress experiences. For instance, gene-environment interaction (GxE) studies have provided evidence that both 5-HTT and NPSR1 interact with environmental stress, particularly traumatic experiences during childhood, in the moderation of anxiety traits, and both 5-HTT and NPSR1 have been implicated in hypothalamic-pituitary-adrenal (HPA) axis reactivity – an intermediate phenotype of mental disorders – in response to acute stress exposure. The first part of this thesis aimed to address the interplay of variations in both 5-HTT and NPSR1 genes and distal stress experiences, i.e. childhood trauma, in the moderation of anxiety-related traits, extended by investigation of the potentially protective effect of positive influences, i.e. elements of successful coping such as general self-efficacy (GSE), on a GxE risk constellation by introducing GSE as an indicator of coping ability (“C”) as an additional dimension in a GxExC approach conferring – or buffering – vulnerability to anxiety. Increased anxiety was observed in 5-HTTLPR/rs25531 LALA genotype and NSPR1 rs324981 AA genotype carriers, respectively, with a history of childhood maltreatment but only in the absence of a person’s ability to cope with adversity, whereas a dose-dependent effect on anxiety traits as a function of maltreatment experiences irrespective of coping characteristics was observed in the presence of at least one 5-HTT S/LG or NSPR1 T allele, respectively. The second part of this thesis addressed the respective impact of 5-HTT and NPSR1 variants on the neuroendocrine, i.e. salivary cortisol response to acute psychosocial stress by applying the Maastricht Acute Stress Test (MAST). A direct effect of NPSR1 – but not 5-HTT – on the modulation of acute stress reactivity could be discerned, with carriers of the more active NPSR1 T allele Summary III displaying significantly higher overall salivary cortisol levels in response to the MAST compared to AA genotype carriers. In summary, study 1 observed a moderating effect of GSE in interaction with childhood maltreatment and 5-HTT and NPSR1, respectively, in an extended GxExC model of anxiety risk, which may serve to inform targeted preventive interventions mitigating GxE risk constellations and to improve therapeutic interventions by strengthening coping ability as a protective mechanism to promote resilient functioning. In study 2, a modulation of HPA axis function, considered to be an endophenotype of stress-related mental disorders, by NPSR1 gene variation could be discerned, suggesting neuroendocrine stress reactivity as an important potential intermediate phenotype of anxiety given findings linking NPSR1 to dimensional and categorical anxiety. Results from both studies may converge within the framework of a multi-level model of anxiety risk, integrating neurobiological, neuroendocrine, environmental, and psychological factors that act together in a highly complex manner towards increasing or decreasing anxiety risk. N2 - Die Entstehung von Angsterkrankungen ist multifaktoriell bedingt durch sowohl genetische als auch umweltbezogene Faktoren. Verschiedene Suszeptibilitätsgene von Angsterkrankungen und angstbezogenen Phänotypen konnten identifiziert werden, darunter das Serotonintransportergen (5-HTT) und das Neuropeptid S Rezeptorgen (NPSR1). Für beide Gene konnte gezeigt werden, dass sie die Reaktion auf sowohl distale als auch akute Stresserlebnisse beeinflussen können. Unter anderem legen Befunde aus Gen-Umwelt-Interaktionsstudien (GxE) nahe, dass sowohl 5-HTT also auch NPSR1 mit Umwelteinflüssen interagieren, insbesondere mit traumatischen Kindheitserlebnissen, und somit unterschiedliche Ausprägungen der Angst mitbedingen. Weiterhin konnten sowohl 5-HTT als auch NPSR1 in Bezug zu veränderter Reaktivität der Hypothalamus-Hypophysen- Nebennierenrinden-Achse (HPA-Achse) auf psychosozialen Stress hin gebracht werden, deren Funktion einen intermediären Phänotyp von psychischen Erkrankungen darstellt. Im ersten Teil dieser Arbeit wurde das Zusammenwirken von Varianten in sowohl dem 5-HTT als auch dem NPSR1 Gen mit distalen Stresserlebnissen, d.h. Kindheitstraumata, unter Einbezug der möglicherweise protektiven Funktion von positiven Einflussfaktoren im Sinne von erfolgreichen Bewältigungsstrategien (engl. Coping) wie der generellen Selbstwirksamkeitserwartung (GSE) untersucht. Dazu wurde GSE als Indikator für Coping-Eigenschaften („C“) als zusätzliche Ebene in einem erweiterten GxExCAnsatz eingeführt, welche je nach Ausprägung die Vulnerabilität für Angst zusätzlich mitbedingen oder aber abschwächen kann. Es zeigten sich jeweils erhöhte Angstwerte in Trägern des 5-HTTLPR/rs25531 LALA Genotyps sowie des NPSR1 rs324981 AA Genotyps, welche traumatische Ereignisse während der Kindheit erlebt hatten, aber nur bei gleichzeitig vorliegender niedriger Coping-Fähigkeit. Das Vorliegen von mindestens einem 5-HTT S/LG-Allel beziehungsweise einem NSPR1 T-Allel war hingegen mit einem Anstieg der Angstmaße mit steigender Zahl erlebter Zusammenfassung V Kindheitstraumata assoziiert unabhängig von der Ausprägung von Bewältigungsmöglichkeiten. Der zweite Teil dieser Arbeit behandelte den jeweiligen Einfluss von 5-HTT beziehungsweise NPSR1 Varianten bezüglich der neuroendokrinen, d.h. Speichelkortisol-Stressantwort auf einen akuten psychosozialen Stressor im Rahmen des Maastricht Acute Stress Tests (MAST). Es konnte ein direkter Einfluss von NPSR1, aber nicht von 5-HTT, auf die Veränderung der akuten Stressreaktivität gezeigt werden. Träger des höher aktiven NPSR1 T-Allels waren gekennzeichnet durch höhere Speichelkortisollevel in Reaktion auf den MAST im Vergleich zu Trägern des AA Genotyps. Zusammenfassend konnte in der ersten Studie ein moderierender Einfluss von GSE in Interaktion mit Kindheitstrauma und 5-HTT beziehungsweise NPSR1 im Sinne eines erweiterten GxExC-Modells des Angstrisikos gezeigt werden. Dies kann zum einen zur Entwicklung gezielter präventiver Maßnahmen und zum anderen zur Verbesserung therapeutischer Interventionen beitragen, durch welche jeweils Bewältigungsfähigkeiten im Sinne eines protektiven, resilienzfördernden Mechanismus gestärkt werden. In der zweiten Studie zeigte sich eine veränderte Funktion der HPA-Achse, welche einen Endophänotyp von stressbezogenen psychischen Erkrankungen darstellt, in Abhängigkeit von einer NPSR1 Genvariante, was die neuroendokrine Stressreaktivität als möglichen intermediären Angstphänotyp im Zusammenhang von NPSR1 Variation und dimensionaler bzw. kategorialer Angst nahelegt. Ausblickend können die Ergebnisse aus beiden Studien im Rahmen eines Mehrebenenmodells des Angstrisikos zusammenfließen, welches neurobiologische, neuroendokrine, umweltbezogene und psychologische Faktoren integriert, die auf hochkomplexe Art zusammenwirken und somit das Angstrisiko erhöhen oder herabsetzen können. KW - Angst KW - Genetik KW - Gen-Umwelt Interaktion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148600 ER - TY - JOUR A1 - Volkert, Julia A1 - Zierhut, Kathrin C. A1 - Schiele, Miriam A. A1 - Wenzel, Martina A1 - Kopf, Juliane A1 - Kittel-Schneider, Sarah A1 - Reif, Andreas T1 - Predominant polarity in bipolar disorder and validation of the polarity index in a German sample N2 - Background: A large number of patients with bipolar disorder (BD) can be characterized by predominant polarity (PP), which has important implications for relapse prevention. Recently, Popovic et al. (EUR NEUROPSYCHOPHARM 22(5): 339–346, 2012) proposed the Polarity Index (PI) as a helpful tool in the maintenance treatment of BD. As a numeric expression, it reflects the efficacy of drugs used in treatment of BD. In the present retrospective study, we aimed to validate this Index in a large and well characterized German bipolar sample. Methods: We investigated 336 bipolar patients (BP) according to their PP and calculated the PI for each patient in order to prove if maintenance treatment differs according to their PP. Furthermore, we analysed whether PP is associated with demographic and clinical characteristics of BP. Results: In our sample, 63.9% of patients fulfilled criteria of PP: 169 patients were classified as depressive predominant polarity (DPP), 46 patients as manic predominant polarity (MPP). The two groups differed significantly in their drug regime: Patients with DPP were more often medicated with lamotrigine and antidepressants, patients with MPP were more often treated with lithium, valproate, carbamazepine and first generation antipsychotics. However, patients with DPP and MPP did not differ significantly with respect to the PI, although they received evidence-based and guideline-driven treatment. Conclusion: The reason for this negative finding might well be that for several drugs, which were used frequently, no PI value is available. Nevertheless we suggest PP as an important concept in the planning of BD maintenance treatment. KW - Bipolar disorder KW - Predominant polarity KW - Polarity index KW - Maintenance treatment KW - Depression KW - Mania KW - EBM Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111042 ER - TY - JOUR A1 - Schiele, Miriam A. A1 - Ziegler, Christiane A1 - Kollert, Leonie A1 - Katzorke, Andrea A1 - Schartner, Christoph A1 - Busch, Yasmin A1 - Gromer, Daniel A1 - Reif, Andreas A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Herrmann, Martin J. A1 - Domschke, Katharina T1 - Plasticity of Functional MAOA Gene Methylation in Acrophobia JF - International Journal of Neuropsychopharmacology N2 - Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction. KW - monoamine oxidase A KW - anxiety KW - extinction KW - epigenetics KW - DNA methylation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228571 VL - 21 IS - 9 ER - TY - JOUR A1 - Herzog, Katharina A1 - Andreatta, Marta A1 - Schneider, Kristina A1 - Schiele, Miriam A. A1 - Domschke, Katharina A1 - Romanos, Marcel A1 - Deckert, Jürgen A1 - Pauli, Paul T1 - Reducing Generalization of Conditioned Fear: Beneficial Impact of Fear Relevance and Feedback in Discrimination Training JF - Frontiers in Psychology N2 - Anxiety patients over-generalize fear, possibly because of an incapacity to discriminate threat and safety signals. Discrimination trainings are promising approaches for reducing such fear over-generalization. Here we investigated the efficacy of a fear-relevant vs. a fear-irrelevant discrimination training on fear generalization and whether the effects are increased with feedback during training. Eighty participants underwent two fear acquisition blocks, during which one face (conditioned stimulus, CS+), but not another face (CS−), was associated with a female scream (unconditioned stimulus, US). During two generalization blocks, both CSs plus four morphs (generalization stimuli, GS1–GS4) were presented. Between these generalization blocks, half of the participants underwent a fear-relevant discrimination training (discrimination between CS+ and the other faces) with or without feedback and the other half a fear-irrelevant discrimination training (discrimination between the width of lines) with or without feedback. US expectancy, arousal, valence ratings, and skin conductance responses (SCR) indicated successful fear acquisition. Importantly, fear-relevant vs. fear-irrelevant discrimination trainings and feedback vs. no feedback reduced generalization as reflected in US expectancy ratings independently from one another. No effects of training condition were found for arousal and valence ratings or SCR. In summary, this is a first indication that fear-relevant discrimination training and feedback can improve the discrimination between threat and safety signals in healthy individuals, at least for learning-related evaluations, but not evaluations of valence or (physiological) arousal. KW - fear generalization KW - feedback KW - discrimination training KW - fear-relevant training KW - classical conditioning Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239970 SN - 1664-1078 VL - 12 ER - TY - JOUR A1 - Ziegler, Georg C. A1 - Ehlis, Ann-Christine A1 - Weber, Heike A1 - Vitale, Maria Rosaria A1 - Zöller, Johanna E. M. A1 - Ku, Hsing-Ping A1 - Schiele, Miriam A. A1 - Kürbitz, Laura I. A1 - Romanos, Marcel A1 - Pauli, Paul A1 - Kalisch, Raffael A1 - Zwanzger, Peter A1 - Domschke, Katharina A1 - Fallgatter, Andreas J. A1 - Reif, Andreas A1 - Lesch, Klaus-Peter T1 - A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD JF - Genes N2 - The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD. KW - ADHD KW - CDH13 KW - neurodevelopment KW - executive functions KW - working memory KW - Big Five KW - agreeableness Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245220 SN - 2073-4425 VL - 12 IS - 9 ER - TY - JOUR A1 - Schiele, Miriam A. A1 - Reinhard, Julia A1 - Reif, Andreas A1 - Domschke, Katharina A1 - Romanos, Marcel A1 - Deckert, Jürgen A1 - Pauli, Paul T1 - Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults JF - Developmental Psychobiology N2 - Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. KW - fear conditioning KW - fear generalization KW - development KW - skin conductance KW - maturation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189488 VL - 58 IS - 4 ER - TY - JOUR A1 - Kuhn, Manuel A1 - Scharfenort, Robert A1 - Schümann, Dirk A1 - Schiele, Miriam A. A1 - Münsterkötter, Anna L. A1 - Deckert, Jürgen A1 - Domschke, Katharina A1 - Haaker, Jan A1 - Kalisch, Raffael A1 - Pauli, Paul A1 - Reif, Andreas A1 - Romanos, Marcel A1 - Zwanzger, Peter A1 - Lonsdorf, Tina B. T1 - Mismatch or allostatic load? Timing of life adversity differentially shapes gray matter volume and anxious temperament JF - Social Cognitive and Affective Neuroscience N2 - Traditionally, adversity was defined as the accumulation of environmental events (allostatic load). Recently however, a mismatch between the early and the later (adult) environment (mismatch) has been hypothesized to be critical for disease development, a hypothesis that has not yet been tested explicitly in humans. We explored the impact of timing of life adversity (childhood and past year) on anxiety and depression levels (N = 833) and brain morphology (N = 129). Both remote (childhood) and proximal (recent) adversities were differentially mirrored in morphometric changes in areas critically involved in emotional processing (i.e. amygdala/hippocampus, dorsal anterior cingulate cortex, respectively). The effect of adversity on affect acted in an additive way with no evidence for interactions (mismatch). Structural equation modeling demonstrated a direct effect of adversity on morphometric estimates and anxiety/depression without evidence of brain morphology functioning as a mediator. Our results highlight that adversity manifests as pronounced changes in brain morphometric and affective temperament even though these seem to represent distinct mechanistic pathways. A major goal of future studies should be to define critical time periods for the impact of adversity and strategies for intervening to prevent or reverse the effects of adverse childhood life experiences. KW - VBM KW - childhood maltreatment KW - adversity KW - stressful life events KW - mismatch KW - allostatic load Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189645 VL - 11 IS - 4 ER -