ObjectivesEmbedded in the Collaborative Research Center “Fear, Anxiety, Anxiety Disorders” (CRC‐TRR58), this bicentric clinical study aims at identifying biobehavioral markers of treatment (non‐)response by applying machine learning methodology with an external cross‐validation protocol. We hypothesize that a priori prediction of treatment (non‐)response is possible in a second, independent sample based on multimodal markers.MethodsOne‐session virtual reality exposure treatment (VRET) with patients with spider phobia was conducted on two sites. Clinical, neuroimaging, and genetic data were assessed at baseline, post‐treatment and after 6 months. The primary and secondary outcomes defining treatment response are as follows: 30% reduction regarding the individual score in the Spider Phobia Questionnaire and 50% reduction regarding the individual distance in the behavioral avoidance test.ResultsN = 204 patients have been included (n = 100 in Würzburg, n = 104 in Münster). Sample characteristics for both sites are comparable.DiscussionThis study will offer cross‐validated theranostic markers for predicting the individual success of exposure‐based therapy. Findings will support clinical decision‐making on personalized therapy, bridge the gap between basic and clinical research, and bring stratified therapy into reach. The study is registered at ClinicalTrials.gov (ID: NCT03208400).

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As overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pre-treatment levels of fear generalization in spider-phobic patients are associated with their response to exposure-based treatment, in order to identify pre-treatment correlates of treatment success. Ninety patients with spider phobia completed pre-treatment clinical and magnetoencephalography (MEG) assessments, one session of virtual reality exposure therapy, and a post-treatment clinical assessment. Based on the primary outcome (30% symptom reduction in self-reported symptoms from pre- to post-treatment) they were categorized as responders or non-responders. In a pre-treatment MEG fear generalization paradigm involving fear conditioning with two unconditioned stimuli (UCS), we obtained fear ratings, UCS-expectancy ratings, and event-related fields to conditioned stimuli (CS+, CS-) and 7 different generalization stimuli (GS) on a perceptual continuum from CS+ to CS-. Prior to treatment, non-responders showed behavioral overgeneralization indicated by more linear generalization gradients in fear ratings. Analyses of MEG source estimations revealed that non-responders showed a decline of their (inhibitory) frontal activations to safety-signaling CS- and GS compared to CS+ over time, while responders maintained these activations at early (<300ms) and late processing stages. Results provide initial evidence that pre-treatment differences of behavioral and neural markers of fear generalization are associated with later responses to behavioral exposure. Findings demonstrate the relevance of inhibitory learning functions and their spatio-temporal neural reflections in this interplay. Findings stimulate research on mechanism-based augmentation strategies for behavioral therapies.

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