TY - JOUR A1 - Weber, Heike A1 - Scholz, Claus Jürgen A1 - Domschke, Katharina A1 - Baumann, Christian A1 - Klauke, Benedikt A1 - Jacob, Christian P. A1 - Maier, Wolfgang A1 - Fritze, Jürgen A1 - Bandelow, Borwin A1 - Zwanzger, Peter Michael A1 - Lang, Thomas A1 - Fehm, Lydia A1 - Ströhle, Andreas A1 - Hamm, Alfons A1 - Gerlach, Alexander L. A1 - Alpers, Georg W. A1 - Kircher, Tilo A1 - Wittchen, Hans-Ulrich A1 - Arolt, Volker A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Reif, Andreas T1 - Gender Differences in Associations of Glutamate Decarboxylase 1 Gene (GAD1) Variants with Panic Disorder N2 - Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype6gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype6gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75830 ER - TY - JOUR A1 - Rayner, Christopher A1 - Coleman, Jonathan R. I. A1 - Purves, Kirstin L. A1 - Hodsoll, John A1 - Goldsmith, Kimberley A1 - Alpers, Georg W. A1 - Andersson, Evelyn A1 - Arolt, Volker A1 - Boberg, Julia A1 - Bögels, Susan A1 - Creswell, Cathy A1 - Cooper, Peter A1 - Curtis, Charles A1 - Deckert, Jürgen A1 - Domschke, Katharina A1 - El Alaoui, Samir A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Grocholewski, Anja A1 - Hahlweg, Kurt A1 - Hamm, Alfons A1 - Hedman, Erik A1 - Heiervang, Einar R. A1 - Hudson, Jennifer L. A1 - Jöhren, Peter A1 - Keers, Robert A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lavebratt, Catharina A1 - Lee, Sang-hyuck A1 - Lester, Kathryn J. A1 - Lindefors, Nils A1 - Margraf, Jürgen A1 - Nauta, Maaike A1 - Pané-Farré, Christiane A. A1 - Pauli, Paul A1 - Rapee, Ronald M. A1 - Reif, Andreas A1 - Rief, Winfried A1 - Roberts, Susanna A1 - Schalling, Martin A1 - Schneider, Silvia A1 - Silverman, Wendy K. A1 - Ströhle, Andreas A1 - Teismann, Tobias A1 - Thastum, Mikael A1 - Wannemüller, Andre A1 - Weber, Heike A1 - Wittchen, Hans-Ulrich A1 - Wolf, Christiane A1 - Rück, Christian A1 - Breen, Gerome A1 - Eley, Thalia C. T1 - A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders JF - Translational Psychiatry N2 - Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits. KW - Human behaviour KW - Personalized medicine KW - Prognostic markers KW - Psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225048 VL - 9 IS - 150 ER - TY - JOUR A1 - Biehl, Stefanie C. A1 - Merz, Christian J. A1 - Dresler, Thomas A1 - Heupel, Julia A1 - Reichert, Susanne A1 - Jacob, Christian P. A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty? JF - International Journal of Neuropsychopharmacology N2 - Background: Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap. Methods: Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients. Results: There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients. Conclusions: Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes. KW - working memory KW - clinical trial KW - child memory KW - short-term methylphenidate brain KW - methylphenidate KW - adult attention deficit/hyperactivity disorder KW - fMRI KW - functional magnetic resonance imaging Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147551 VL - 19 IS - 10 ER - TY - JOUR A1 - Biehl, Stefanie C. A1 - Dresler, Thomas A1 - Reif, Andreas A1 - Scheuerpflug, Peter A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Dopamine Transporter (DAT1) and Dopamine Receptor D4 (DRD4) Genotypes Differentially Impact on Electrophysiological Correlates of Error Processing JF - PLoS One N2 - Recent studies as well as theoretical models of error processing assign fundamental importance to the brain's dopaminergic system. Research about how the electrophysiological correlates of error processing—the error-related negativity (ERN) and the error positivity (Pe)—are influenced by variations of common dopaminergic genes, however, is still relatively scarce. In the present study, we therefore investigated whether polymorphisms in the DAT1 gene and in the DRD4 gene, respectively, lead to interindividual differences in these error processing correlates. One hundred sixty participants completed a version of the Eriksen Flanker Task while a 26-channel EEG was recorded. The task was slightly modified in order to increase error rates. During data analysis, participants were split into two groups depending on their DAT1 and their DRD4 genotypes, respectively. ERN and Pe amplitudes after correct responses and after errors as well as difference amplitudes between errors and correct responses were analyzed. We found a differential effect of DAT1 genotype on the Pe difference amplitude but not on the ERN difference amplitude, while the reverse was true for DRD4 genotype. These findings are in line with predictions from theoretical models of dopaminergic transmission in the brain. They furthermore tie results from clinical investigations of disorders impacting on the dopamine system to genetic variations known to be at-risk genotypes. KW - haplotypes KW - electroencephalography KW - basal ganglia KW - reaction time KW - dopaminergics KW - dopamine KW - ADHD KW - research errors Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137930 VL - 6 IS - 12 ER - TY - JOUR A1 - Klauke, Benedikt A1 - Winter, Bernward A1 - Gajewska, Agnes A1 - Zwanzger, Peter A1 - Reif, Andreas A1 - Herrmann, Martin J. A1 - Dlugos, Andrea A1 - Warrings, Bodo A1 - Jacob, Christian A1 - Mühlberger, Andreas A1 - Arolt, Volker A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Domschke, Katharina T1 - Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma JF - PLoS One N2 - The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system - partly conferred by catechol-O-methyltransferase (COMT) gene variation - for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders. KW - COMT VAL(158)MET polymorphism KW - serotonin transporter gene KW - life events KW - community sample KW - acoustic startle KW - prepulse inhibition KW - panic disorder KW - caffeine-induced anxiety KW - fear-potentiated startle KW - posttraumatic-stress-disorder Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132184 VL - 7 IS - 6 ER - TY - JOUR A1 - Hohoff, Christa A1 - Gorji, Ali A1 - Kaiser, Sylvia A1 - Willscher, Edith A1 - Korsching, Eberhard A1 - Ambrée, Oliver A1 - Arolt, Volker A1 - Lesch, Klaus-Peter A1 - Sachser, Norbert A1 - Deckert, Jürgen A1 - Lewejohann, Lars T1 - Effect of Acute Stressor and Serotonin Transporter Genotype on Amygdala First Wave Transcriptome in Mice JF - PLoS ONE N2 - The most prominent brain region evaluating the significance of external stimuli immediately after their onset is the amygdala. Stimuli evaluated as being stressful actuate a number of physiological processes as an immediate stress response. Variation in the serotonin transporter gene has been associated with increased anxiety- and depression-like behavior, altered stress reactivity and adaptation, and pathophysiology of stress-related disorders. In this study the instant reactions to an acute stressor were measured in a serotonin transporter knockout mouse model. Mice lacking the serotonin transporter were verified to be more anxious than their wild-type conspecifics. Genome-wide gene expression changes in the amygdala were measured after the mice were subjected to control condition or to an acute stressor of one minute exposure to water. The dissection of amygdalae and stabilization of RNA was conducted within nine minutes after the onset of the stressor. This extremely short protocol allowed for analysis of first wave primary response genes, typically induced within five to ten minutes of stimulation, and was performed using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. RNA profiling revealed a largely new set of differentially expressed primary response genes between the conditions acute stress and control that differed distinctly between wild-type and knockout mice. Consequently, functional categorization and pathway analysis indicated genes related to neuroplasticity and adaptation in wild-types whereas knockouts were characterized by impaired plasticity and genes more related to chronic stress and pathophysiology. Our study therefore disclosed different coping styles dependent on serotonin transporter genotype even directly after the onset of stress and accentuates the role of the serotonergic system in processing stressors and threat in the amygdala. Moreover, several of the first wave primary response genes that we found might provide promising targets for future therapeutic interventions of stress-related disorders also in humans. KW - plasticity KW - corticotropin releasing factor KW - primary response genes KW - spatial memory KW - knockout mice KW - rat brain KW - in vivo KW - expression KW - anxiety KW - emotion Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131040 VL - 8 IS - 3 ER - TY - JOUR A1 - Guhn, Anne A1 - Dresler, Thomas A1 - Andreatta, Marta A1 - Müller, Laura D. A1 - Hahn, Tim A1 - Tupak, Sara V. A1 - Polak, Thomas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Medial prefrontal cortex stimulation modulates the processing of conditioned fear N2 - The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS−) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS− discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT). KW - fear conditioning KW - memory consolidation and extinction KW - learning KW - transcranial magnetic stimulation (TMS) KW - medial prefrontal cortex (mPFC) Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111309 ER - TY - JOUR A1 - Pauli, Paul A1 - Glotzbach-Schoon, Evelyn A1 - Andreatta, Marta A1 - Reif, Andreas A1 - Ewald, Heike A1 - Tröger, Christian A1 - Baumann, Christian A1 - Deckert, Jürgen A1 - Mühlberger, Andreas T1 - Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle JF - Frontiers in Behavioral Neuroscience N2 - The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT−). During extinction no US was administered. Anxiety responses were quantified by fear-potentiated startle and ratings. Most importantly, we found a gene × gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT−. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT−. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders. KW - 5HTTLPR KW - NPSR1 KW - gene × gene interaction KW - contextual fear conditioning KW - fear-potentiated startle Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96516 ER - TY - JOUR A1 - Manish, Asthana A1 - Nueckel, Katharina A1 - Mühlberger, Andreas A1 - Neueder, Dorothea A1 - Polak, Thomas A1 - Domschke, Katharina A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Effects of transcranial direct current stimulation on consolidation of fear memory JF - Frontiers in Neuropsychiatric Imaging and Stimulation N2 - It has been shown that applying transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) influences declarative memory processes. This study investigates the efficacy of tDCS on emotional memory consolidation, especially experimental fear conditioning. We applied an auditory fear-conditioning paradigm, in which two differently colored squares (blue and yellow) were presented as conditioned stimuli (CS) and an auditory stimulus as unconditioned stimulus (UCS). Sixty-nine participants were randomly assigned into three groups: anodal, cathodal, and sham stimulation. The participants of the two active groups (i.e., anodal and cathodal) received tDCS over the left DLPFC for 12 min after fear conditioning. The effect of fear conditioning and consolidation (24 h later) was measured by assessing the skin conductance response (SCR) to the CS. The results provide evidence that cathodal stimulation of the left DLPFC leads to an inhibitory effect on fear memory consolidation compared to anodal and sham stimulation, as indicated by decreased SCRs to CS+ presentation during extinction training at day 2. In conclusion, current work suggests that cathodal stimulation interferes with processes of fear memory consolidation. KW - transcranial direct current stimulation KW - dorsolateral prefrontal cortex KW - fear conditioning KW - fear memory consolidation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97294 ER - TY - JOUR A1 - Hebestreit, Helge A1 - Zeidler, Cornelia A1 - Schippers, Christopher A1 - de Zwaan, Martina A1 - Deckert, Jürgen A1 - Heuschmann, Peter A1 - Krauth, Christian A1 - Bullinger, Monika A1 - Berger, Alexandra A1 - Berneburg, Mark A1 - Brandstetter, Lilly A1 - Deibele, Anna A1 - Dieris-Hirche, Jan A1 - Graessner, Holm A1 - Gündel, Harald A1 - Herpertz, Stephan A1 - Heuft, Gereon A1 - Lapstich, Anne-Marie A1 - Lücke, Thomas A1 - Maisch, Tim A1 - Mundlos, Christine A1 - Petermann-Meyer, Andrea A1 - Müller, Susanne A1 - Ott, Stephan A1 - Pfister, Lisa A1 - Quitmann, Julia A1 - Romanos, Marcel A1 - Rutsch, Frank A1 - Schaubert, Kristina A1 - Schubert, Katharina A1 - Schulz, Jörg B. A1 - Schweiger, Susann A1 - Tüscher, Oliver A1 - Ungethüm, Kathrin A1 - Wagner, Thomas O. F. A1 - Haas, Kirsten T1 - Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study JF - Orphanet Journal of Rare Diseases N2 - Background In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design This multi-center, prospective controlled study has a two-phase cohort design. Methods Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach. Conclusions This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease. KW - rare diseases KW - multi‑center cohort study KW - dual guidance Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300440 VL - 17 IS - 1 ER -