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

焦虑症的终生患病率超过15%，是最常见的精神障碍，甚至比情感性障碍更常见（Jacobi et al., 2015）。除了药物治疗外，认知行为疗法（CBT）是治疗焦虑症的证据基础最高的疗法（Carpenter et al., 2018），但并非所有患者都能充分受益。例如，Pittig等人（2021）表明，在治疗结束时成功治疗的焦虑症患者中，多达21%的患者在六个月后焦虑症状恢复到临床相关水平。目前，人们认为前条件恐惧反应的消退学习（CS-UCS）作为暴露心理治疗的一种模式，不会消除原始的恐惧记忆痕迹，而是形成额外的记忆痕迹（CS-NoUCS），抑制原始CS-UCS关联的表达。因此，这两种记忆痕迹同时存在，并在对经验和行为的影响方面相互竞争。因此，临床相关的焦虑症状可能会在治疗成功后复发，要么是患者重新经历与恐惧相关的厌恶情境，要么是消退记忆随着时间的推移而减弱（自发恢复；Kindt, 2018）。一项具有里程碑意义的实验室研究（Borgomaneri et al., 2020，由Su et al.， 2022复制和扩展）最近表明，恐惧记忆激活后的抑制性经颅磁刺激（TMS）可以破坏恐惧记忆检索（再巩固）并导致恐惧减少。这项可行性研究的目的是将新的和有希望的实验室结果（Borgomaneri等人，2020；Su等人，2022）转化为治疗性研究，同时调查潜在的神经生物学机制。在本项目中，我们将首次在安慰剂对照双盲研究中检验恐惧记忆激活后右侧dlPFC的抑制性rTMS是否比安慰剂刺激在3个月的随访中导致特定恐惧症（蜘蛛）焦虑症状（SPQ问卷）的更大减少，从而可能提供一种新的治疗方法。脑功能活动测量将被用于验证颅磁刺激干预将导致杏仁核活动和杏仁核与其他恐惧处理区域（如前扣带皮层、双侧脑岛和海马体）的功能耦合从前到后的更大减少的假设，这是治疗效果的基础。

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.