GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation : a potential neurogenetic pathway to panic disorder

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG - related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1,370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, p=3.3x10-8; rs191260602, p=3.9x10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2,547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3,845) and a case control sample with the categorical phenotype PD/AG (Ncombined =1,012) obtaining highly significant p-values also for GLRB single nucleotide variants rs17035816 (p=3.8x10-4) and rs7688285 (p=7.6x10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout-mice demonstrated an agoraphobic phenotype. In conjunction withthe clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, though functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.PostprintPeer reviewe

Soziales Kompetenztraining in Virtueller Realität bei sozialer Angst

Background: Social skills training is an important tool in psychotherapy for social anxiety disorder. The implementation of virtual reality (VR) could increase its availability and effectiveness, but there is a need for validated VR scenarios. Objective: We examined the validity of two VR scenarios according to the group training of social skills by Hinsch and Pfingsten (2015). We hypothesize that the subjective, psychophysiological, and cognitive components of social anxiety triggered by the scenario significantly differentiate between higher (HSA) and lower (NSA) socially anxious persons. Method: A sample of N = 55 HSA and NSA students underwent two VR scenarios for the training of assertiveness. Additionally, the duration of eye contact by the virtual interaction partner was varied experimentally. The main outcome measure was experienced anxiety. In addition, heart rate, electrodermal activity, as well as the assessment of own's own competence were recorded. Results: In both scenarios, HSA compared with NSA reported significantly higher anxiety as well as negative distortions regarding the assessment of one's own competency. With regard to physiology, there was activation but no differentiation between groups. Both VR scenarios were perceived as realistic. Conclusion: Virtual interaction scenarios can be used for training purposes, and social skills training in VR has great potential as a psychotherapeutic intervention for social anxiety disorder

Fear, psychophysiological arousal, and cognitions during a virtual social skills training in social anxiety disorder while manipulating gaze duration

The use of virtual reality (VR) is an option for social skills training and exposure in Social Anxiety Disorder (SAD). In addition, virtual social situations are an ideal tool to study the influence of a counterpart's social behavior, e. g. eye contact. We developed two scenarios in VR that enable users to practice to assert their rights. The participants' tasks were to ask a passenger to release their reserved seat in a virtual train and to cancel a trip in a virtual travel agency. In a randomized, crossover design, we compared the effect of a large (during 80% of the conversation time) and a small (20%) amount of direct gaze by the virtual conversational partners in 41 patients with SAD and 21 healthy controls (HCs). We expected fear and psychophysiological arousal to be higher in patients than in HCs and higher in the 80% eye contact condition. The scenarios provoked an increase of fear and psychophysiological arousal over baseline in patients and in HCs. Gaze duration of the virtual agent had no influence on fear and psychophysiological arousal, but affected the experience of presence. Our results suggest a suitability of our scenarios for social skills training and exposure therapy in SAD. The lack of influence of gaze duration on parameters of fear might be explained by the fact that participants did not consciously detect the differences in gaze duration. However, the impact on some parameters (e. g. presence) suggests that participants noticed differences in gaze duration on a subliminal level

Neurobiological and clinical effects of fNIRS-controlled rTMS in patients with panic disorder/agoraphobia during cognitive-behavioural therapy

Background: A relevant proportion of patients with panic disorder (PD) does not improve even though they receive state of the art treatment for anxiety disorders such as cognitive-behavioural therapy (CBT). At the same time, it is known, that from a neurobiological point of view, PD patients are often characterised by prefrontal hypoactivation. Intermittent Theta Burst Stimulation (iTBS) is a non-invasive type of neurostimulation which can modulate cortical activity and thus has the potential to normalise prefrontal hypoactivity found in PD. We therefore aimed at investigating the effects of iTBS as an innovative add-on to CBT in the treatment for PD. Methods: In this double-blind, bicentric study, 44 PD patients, randomised to sham or verum stimulation, received 15 sessions of iTBS over the left prefrontal cortex (PFC) in addition to 9weeks of group CBT. Cortical activity during a cognitive as well as an emotional (Emotional Stroop) paradigm was assessed both at baseline and post-iTBS treatment using functional near-infrared spectroscopy (fNIRS) and compared to healthy controls. Results: In this manuscript we only report the results of the emotional paradigm; for the results of the cognitive paradigm please refer to Deppermann et al. (2014).During the Emotional Stroop test, PD patients showed significantly reduced activation to panic-related compared to neutral stimuli for the left PFC at baseline. Bilateral prefrontal activation for panic-related stimuli significantly increased after verum iTBS only. Clinical ratings significantly improved during CBT and remained stable at follow-up. However, no clinical differences between the verum- and sham-stimulated group were identified, except for a more stable reduction of agoraphobic avoidance during follow-up in the verum iTBS group. Limitations: Limitations include insufficient blinding, the missing control for possible state-dependent iTBS effects, and the timing of iTBS application during CBT. Conclusion: Prefrontal hypoactivity in PD patients was normalised by add-on iTBS. Clinical improvement of anxiety symptoms was not affected by iTBS. Keywords: Panic disorder, Functional near-infrared spectroscopy, Cognitive-behavioural therapy, Intermittent Theta Burst Stimulation, Emotion regulatio