Disruption of fear reconsolidation using rTMS in the treatment of anxiety disorders

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With a lifetime prevalence of more than 15%, anxiety disorders represent the most common mental disorder and are even more common than affective disorders (Jacobi et al., 2015). In addition to pharmacological treatment, cognitive behavioral therapy (CBT) represents the therapy with the highest evidence base for anxiety disorders (Carpenter et al., 2018), but not all patients benefit sufficiently. Pittig et al. (2021), for example, showed that in up to 21% of patients with anxiety disorders successfully treated at the end of therapy, anxiety symptoms returned to a clinically relevant level after six months. Currently, it is assumed that extinction learning of a previously conditioned fear response (CS-UCS), as a model of exposure-based psychotherapy, does not erase the original fear memory trace but forms an additional memory trace (CS-NoUCS) that inhibits the expression of the original CS-UCS association. Thus, the two memory traces persist simultaneously and compete in their influence on experience and behavior. Accordingly, clinically relevant anxiety symptoms may return after successful therapy either when patients re-experience an aversive fear-related situation or extinction memory weakens over time (Spontaneous Recovery; Kindt, 2018). A landmark laboratory study (Borgomaneri et al., 2020, replicated and extended by Su et al., 2022) recently demonstrated that inhibitory transcranial magnetic stimulation (TMS) after fear memory activation can disrupt fear memory retrieval (reconsolidation) and lead to fear reduction. The aim of this requested feasibility study is to translate the new and promising laboratory results (Borgomaneri et al., 2020; Su et al., 2022) into a therapeutic study while investigating the underlying neurobiological mechanisms. In this project, we will examine for the first time in a placebo-controlled double-blind study whether inhibitory rTMS of the right dlPFC after fear memory activation leads to a greater decrease in anxiety symptoms (SPQ questionnaire) in specific phobia (spider) at 3-month follow-up compared to placebo stimulation, and thus might provide a new therapeutic approach. Functional brain activity measurements will be used to test the hypothesis that TMS intervention will result in a greater decrease in amygdala activity and functional coupling of the amygdala with other fear-processing areassuch as the anterior cingulate cortex, bilateral insulae, and hippocampus from pre to post, whichunderlie the therapeutic effect.