TY - JOUR A1 - Prelog, Martina A1 - Hilligardt, Deborah A1 - Schmidt, Christian A. A1 - Przybylski, Grzegorz K. A1 - Leierer, Johannes A1 - Almanzar, Giovanni A1 - El Hajj, Nady A1 - Lesch, Klaus-Peter A1 - Arolt, Volker A1 - Zwanzger, Peter A1 - Haaf, Thomas A1 - Domschke, Katharina T1 - Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder? JF - PLoS ONE N2 - Immunological abnormalities associated with pathological conditions, such as higher infection rates, inflammatory diseases, cancer or cardiovascular events are common in patients with panic disorder. In the present study, T cell receptor excision circles (TRECs), Forkhead-Box-Protein P3 gene (FOXP3) methylation of regulatory T cells (Tregs) and relative telomere lengths (RTLs) were investigated in a total and subsamples of 131 patients with panic disorder as compared to 131 age- and sex-matched healthy controls in order to test for a potential dysfunction and premature aging of the immune system in anxiety disorders. Significantly lower TRECs (p = 0.004) as well as significant hypermethylation of the FOXP3 promoter region (p = 0.005) were observed in female (but not in male) patients with panic disorder as compared to healthy controls. No difference in relative telomere length was discerned between patients and controls, but significantly shorter telomeres in females, smokers and older persons within the patient group. The presently observed reduced TRECs in panic disorder patients and FOXP3 hypermethylation in female patients with panic disorder potentially reflect impaired thymus and immunosuppressive Treg function, which might partly account for the known increased morbidity and mortality of anxiety disorders conferred by e.g. cancer and cardiovascular disorders. KW - DNA methylation KW - antidepressants KW - regulatory T cells KW - panic disorder KW - treatment guidelines KW - telomere length KW - inflammatory diseases KW - anxiety disorders Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179684 VL - 11 IS - 6 ER - TY - JOUR A1 - Neueder, Dorothea A1 - Andreatta, Marta A1 - Pauli, Paul T1 - Contextual fear conditioning and fear generalization in individuals with panic attacks JF - Frontiers in Behavioral Neuroscience N2 - Context conditioning is characterized by unpredictable threat and its generalization may constitute risk factors for panic disorder (PD). Therefore, we examined differences between individuals with panic attacks (PA; N = 21) and healthy controls (HC, N = 22) in contextual learning and context generalization using a virtual reality (VR) paradigm. Successful context conditioning was indicated in both groups by higher arousal, anxiety and contingency ratings, and increased startle responses and skin conductance levels (SCLs) in an anxiety context (CTX+) where an aversive unconditioned stimulus (US) occurred unpredictably vs. a safety context (CTX−). PA compared to HC exhibited increased differential responding to CTX+ vs. CTX− and overgeneralization of contextual anxiety on an evaluative verbal level, but not on a physiological level. We conclude that increased contextual conditioning and contextual generalization may constitute risk factors for PD or agoraphobia contributing to the characteristic avoidance of anxiety contexts and withdrawal to safety contexts and that evaluative cognitive process may play a major role. KW - contextual fear conditioning KW - anxiety generalization KW - startle response KW - panic disorder KW - virtual reality Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201318 VL - 13 ER - TY - JOUR A1 - Leibold, NK A1 - van den Hove, DLA A1 - Viechtbauer, W A1 - Buchanan, GF A1 - Goossens, L A1 - Lange, I A1 - Knuts, I A1 - Lesch, KP A1 - Steinbusch, HWM A1 - Schruers, KRJ T1 - CO\(_{2}\) exposure as translational cross-species experimental model for panic JF - Translational Psychiatry N2 - The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral–emotional and bodily response to CO\(_{2}\) exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO\(_{2}\) exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO\(_{2}\), demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies. KW - translational panic model KW - CO\(_{2}\) exposure KW - humans KW - mice KW - panic disorder KW - cross-species comparison KW - fear response Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168308 VL - 6 IS - e885 ER - TY - JOUR A1 - Kleint, Nina I. A1 - Wittchen, Hans-Ulrich A1 - Lueken, Ulrike T1 - Probing the interoceptive network by listening to heartbeats: an fMRI study JF - PLoS ONE N2 - Exposure to cues of homeostatic relevance (i.e. heartbeats) is supposed to increase the allocation of attentional resources towards the cue, due to its importance for self-regulatory, interoceptive processes. This functional magnetic resonance imaging (fMRI) study aimed at determining whether listening to heartbeats is accompanied by activation in brain areas associated with interoception, particularly the insular cortex. Brain activity was measured with fMRI during cue-exposure in 36 subjects while listening to heartbeats vs. sinus tones. Autonomic markers (skin conductance) and subjective measures of state and trait anxiety were assessed. Stimulation with heartbeat sounds triggered activation in brain areas commonly associated with the processing of interoceptive information, including bilateral insular cortices, the inferior frontal operculum, and the middle frontal gyrus. A psychophysiological interaction analysis indicated a functional connectivity between the middle frontal gyrus (seed region) and bilateral insular cortices, the left amygdala and the supplementary motor area. The magnitude of neural activation in the right anterior insular cortex was positively associated with autonomic arousal. The present findings indicate that listening to heartbeats induced activity in areas of the interoception network as well as changes in psychophysiological arousal and subjective emotional experience. As this approach constitutes a promising method for studying interoception in the fMRI environment, a clinical application in anxiety prone populations should be addressed by future studies. KW - inferior parietal lobule KW - brain activation KW - cortex KW - awareness KW - perception KW - cardiovascular arousal KW - panic disorder KW - humans KW - anterior insula KW - emotional experience Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148330 VL - 10 IS - 7 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 - Wölk, Julian A1 - Sütterlin, Stefan A1 - Koch, Stefan A1 - Vögele, Claus A1 - Schulz, Stefan M. T1 - Enhanced cardiac perception predicts impaired performance in the Iowa Gambling Task in patients with panic disorder JF - Brain and Behavior N2 - OBJECTIVE: Somatic marker theory predicts that somatic cues serve intuitive decision making; however, cardiovascular symptoms are threat cues for patients with panic disorder (PD). Therefore, enhanced cardiac perception may aid intuitive decision making only in healthy individuals, but impair intuitive decision making in PD patients. METHODS: PD patients and age-and sex-matched volunteers without a psychiatric diagnosis (n=17, respectively) completed the Iowa Gambling Task (IGT) as a measure of intuitive decision making. Interindividual differences in cardiac perception were assessed with a common mental-tracking task. RESULTS: In line with our hypothesis, we found a pattern of opposing associations (Fisher's Z=1.78, P=0.04) of high cardiac perception with improved IGT-performance in matched control-participants (r=0.36, n=14) but impaired IGT-performance in PD patients (r=-0.38, n=13). CONCLUSION: Interoceptive skills, typically assumed to aid intuitive decision making, can have the opposite effect in PD patients who experience interoceptive cues as threatening, and tend to avoid them. This may explain why PD patients frequently have problems with decision making in everyday life. Screening of cardiac perception may help identifying patients who benefit from specifically tailored interventions. KW - panic disorder KW - somatic marker hypothesis KW - cardiac perception KW - Iowa Gambling Task KW - decision making KW - interoception Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119865 SN - 2162-3279 VL - 4 IS - 2 ER - TY - JOUR A1 - Straube, B. A1 - Reif, A. A1 - Richter, J. A1 - Lueken, U. A1 - Weber, H. A1 - Arolt, V. A1 - Jansen, A. A1 - Zwanzger, P. A1 - Domschke, K. A1 - Pauli, P. A1 - Konrad, C. A1 - Gerlach, A. L. A1 - Lang, T. A1 - Fydrich, T. A1 - Alpers, G. W. A1 - Stroehle, A. A1 - Wittmann, A. A1 - Pfleiderer, B. A1 - Wittchen, H.-U. A1 - Hamm, A. A1 - Deckert, J. A1 - Kircher, T. T1 - The functional - 1019C/G HTR1A polymorphism and mechanisms of fear JF - Translational Psychiatry N2 - Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n = 185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n = 245; after CBT: n = 171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n = 39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders. KW - randomized-controlled trial KW - panic disorder KW - 5-HT1A receptor KW - defensive reactivity KW - major depression KW - cognitive-behavioral therapy KW - receptor gene polymorphism KW - C(-1019)G polymorphism KW - anxiety disorders KW - serotonin(1A) receptor Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114369 SN - 2158-3188 VL - 4 ER -