@article{StraubeReifRichteretal.2014, author = {Straube, B. and Reif, A. and Richter, J. and Lueken, U. and Weber, H. and Arolt, V. and Jansen, A. and Zwanzger, P. and Domschke, K. and Pauli, P. and Konrad, C. and Gerlach, A. L. and Lang, T. and Fydrich, T. and Alpers, G. W. and Stroehle, A. and Wittmann, A. and Pfleiderer, B. and Wittchen, H.-U. and Hamm, A. and Deckert, J. and Kircher, T.}, title = {The functional - 1019C/G HTR1A polymorphism and mechanisms of fear}, series = {Translational Psychiatry}, volume = {4}, journal = {Translational Psychiatry}, issn = {2158-3188}, doi = {10.1038/tp.2014.130}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114369}, pages = {e490}, year = {2014}, abstract = {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.}, language = {en} } @phdthesis{Schwarzmeier2023, author = {Schwarzmeier, Hanna}, title = {From fear extinction to exposure therapy: neural mechanisms and moderators of extinction}, doi = {10.25972/OPUS-22330}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223304}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Emotional-associative learning processes such as fear conditioning and extinction are highly relevant to not only the development and maintenance of anxiety disorders (ADs), but also to their treatment. Extinction, as the laboratory analogue to behavioral exposure, is assumed a core process underlying the treatment of ADs. Although exposure-based treatments are highly effective for the average patient suffering from an AD, there remains a gap in treatment efficacy with over one third of patients failing to achieve clinically significant symptom relief. There is ergo a pressing need for intensified research regarding the underlying neural mechanisms of aberrant emotional-associative learning processes and the neurobiological moderators of treatment (non-)response in ADs. The current thesis focuses on different applications of the fundamental principles of fear conditioning and extinction by using two example cases of ADs from two different multicenter trials. First, we targeted alterations in fear acquisition, extinction, and its recall as a function of psychopathology in panic disorder (PD) patients compared to healthy subjects using fMRI. Second, exposure-based therapy and pre-treatment patient characteristics exerting a moderating influence on this essential learning process later on (i.e. treatment outcome) were examined using multimodal functional and structural neuroimaging in spider phobia. We observed aberrations in emotional-associative learning processes in PD patients compared to healthy subjects indicated by an accelerated fear acquisition and an attenuated extinction recall. Furthermore, pre-treatment differences related to defensive, regulatory, attentional, and perceptual processes may exert a moderating influence on treatment outcome to behavioral exposure in spider phobia. Although the current results need further replication, on an integrative meta level, results point to a hyperactive defensive network system and deficient emotion regulation processes (including extinction processes) and top-down control in ADs. This speaks in favor of transdiagnostic deficits in important functional domains in ADs. Deficits in transdiagnostic domains such as emotion regulation processes could be targeted by enhancing extinction learning or by means of promising tools like neurofeedback. The detection of pre-treatment clinical response moderators, for instance via machine learning frameworks, may help in supporting clinical decision making on individually tailored treatment approaches or, respectively, to avoid ineffective treatment and its related financial costs. In the long run, the identification of neurobiological markers which are capable of detecting non-responders a priori represents an ultimate goal.}, subject = {Extinktion}, language = {en} } @article{PrelogHilligardtSchmidtetal.2016, author = {Prelog, Martina and Hilligardt, Deborah and Schmidt, Christian A. and Przybylski, Grzegorz K. and Leierer, Johannes and Almanzar, Giovanni and El Hajj, Nady and Lesch, Klaus-Peter and Arolt, Volker and Zwanzger, Peter and Haaf, Thomas and Domschke, Katharina}, title = {Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder?}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0157930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179684}, year = {2016}, abstract = {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.}, language = {en} } @article{PittigHeinigGoerigketal.2021, author = {Pittig, Andre and Heinig, Ingmar and Goerigk, Stephan and Thiel, Freya and Hummel, Katrin and Scholl, Lucie and Deckert, J{\"u}rgen and Pauli, Paul and Domschke, Katharina and Lueken, Ulrike and Fydrich, Thomas and Fehm, Lydia and Plag, Jens and Str{\"o}hle, Andreas and Kircher, Tilo and Straube, Benjamin and Rief, Winfried and Koelkebeck, Katja and Arolt, Volker and Dannlowski, Udo and Margraf, J{\"u}rgen and Totzeck, Christina and Schneider, Silvia and Neudeck, Peter and Craske, Michelle G. and Hollandt, Maike and Richter, Jan and Hamm, Alfons and Wittchen, Hans-Ulrich}, title = {Efficacy of temporally intensified exposure for anxiety disorders: A multicenter randomized clinical trial}, series = {Depression and Anxiety}, volume = {38}, journal = {Depression and Anxiety}, number = {11}, doi = {10.1002/da.23204}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257331}, pages = {1169-1181}, year = {2021}, abstract = {Background The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions. Methods This multicenter randomized controlled trial compared two variants of prediction error-based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx-I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx-S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6-months follow-up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression. Results Both treatments resulted in substantial improvements at post (PeEx-I: d\(_{within}\) = 1.50, PeEx-S: d\(_{within}\) = 1.78) and follow-up (PeEx-I: d\(_{within}\) = 2.34; PeEx-S: d\(_{within}\) = 2.03). Both groups showed formally equivalent symptom reduction at post and follow-up. However, time until response during treatment was 32\% shorter in PeEx-I (median = 68 days) than PeEx-S (108 days; TR\(_{PeEx-I}\)-I = 0.68). Interestingly, drop-out rates were lower during intensified exposure. PeEx-I was also superior in reducing disability days and improving quality of life at follow-up without increasing relapse. Conclusions Both treatment variants focusing on the transdiagnostic exposure-based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop-out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.}, language = {en} } @article{DiemerAlpersPeperkornetal.2015, author = {Diemer, Julia and Alpers, Georg W. and Peperkorn, Henrik M. and Shiban, Youssef and M{\"u}hlberger, Andreas}, title = {The impact of perception and presence on emotional reactions: a review of research in virtual reality}, series = {Frontiers in Psychology}, volume = {6}, journal = {Frontiers in Psychology}, number = {26}, doi = {10.3389/fpsyg.2015.00026}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144200}, year = {2015}, abstract = {Virtual reality (VR) has made its way into mainstream psychological research in the last two decades. This technology, with its unique ability to simulate complex, real situations and contexts, offers researchers unprecedented opportunities to investigate human behavior in well controlled designs in the laboratory. One important application of VR is the investigation of pathological processes in mental disorders, especially anxiety disorders. Research on the processes underlying threat perception, fear, and exposure therapy has shed light on more general aspects of the relation between perception and emotion. Being by its nature virtual, i.e., simulation of reality, VR strongly relies on the adequate selection of specific perceptual cues to activate emotions. Emotional experiences in turn are related to presence, another important concept in VR, which describes the user's sense of being in a VR environment. This paper summarizes current research into perception of fear cues, emotion, and presence, aiming at the identification of the most relevant aspects of emotional experience in VR and their mutual relations. A special focus lies on a series of recent experiments designed to test the relative contribution of perception and conceptual information on fear in VR. This strand of research capitalizes on the dissociation between perception (bottom up input) and conceptual information (top-down input) that is possible in VR. Further, we review the factors that have so far been recognized to influence presence, with emotions (e.g., fear) being the most relevant in the context of clinical psychology. Recent research has highlighted the mutual influence of presence and fear in VR, but has also traced the limits of our current understanding of this relationship. In this paper, the crucial role of perception on eliciting emotional reactions is highlighted, and the role of arousal as a basic dimension of emotional experience is discussed. An interoceptive attribution model of presence is suggested as a first step toward an integrative framework for emotion research in VR. Gaps in the current literature and future directions are outlined.}, language = {en} }