Cerebellar Neuromodulation to Enhance Fear extinction and Predict Response to Exposure Therapy

项目摘要 尽管在焦虑症的功能神经成像研究上投入了巨大的财力和人力，但 这些研究的结果对临床实践的可操作影响有限。特别是，几乎没有人 研究的目的是预测哪些患者将从特定的干预中受益，这可能 从而在提供精神卫生保健方面节省了大量成本并提高了效率。的目标是 基于暴露的焦虑症疗法是在安全的环境下向患者呈现诱发恐惧的刺激。 为了消除(恐惧消退)之前的条件反射(恐惧条件反射)。中的异常现象 恐惧消退的过程是许多焦虑症的特征，如社交恐惧症、恐慌症和 创伤后应激障碍。对焦虑个体的恐惧条件作用研究表明，增强的和 过度泛化的条件性恐惧反应以及恐惧消退学习的缺陷。我们假设 急性干预，如经颅磁刺激(TMS)，可能能够探测到 神经网络与暴露治疗的结果相关，并有助于帮助确定谁是最危险的早期决策点 可能会从暴露疗法中受益。动物和人类的研究都支持了一个重要的 小脑在恐惧条件反射和恐惧消退中的作用，小脑外侧半球受累 在联想和情感方面，以及小脑蠕虫参与感觉和自主神经 一个。小脑和大脑半球之间的功能连接表明，大脑 TMS患者大脑皮质难以到达的结构可能可以通过小脑连接到达，a 这种关系正在慢慢得到认可。经TMS可触及小脑外侧半球， 在功能上方便地连接到内侧前额叶皮质。腹内侧前额叶皮质(VmPFC) 激活是有效消除恐惧的关键组成部分。因此，vmpfc在恐惧消退过程中不活跃。 在焦虑的个体中学习，这一发现明确地确定了那些有恐惧症的人。探索的机会 可能通过调节vmPFC活动增强恐惧消退的神经通路的作用 保持大范围开放，通过小脑进行调制是一个未被充分探索的问题。我们的调查模式使用 害怕公开演讲，这是一种普遍的社交恐惧症，可以接受基于暴露的治疗，这是 与其他焦虑症相比，合并症的并发症通常较少。这项研究将是第一批 清楚地描绘了小脑在消除恐惧中的作用。阐明小脑的特殊功能 之所以重要，是因为1]它使人能够调节可使用TMS和其他方法访问的大脑结构 神经调节工具，以及2]它可以提供一个严重性指标来帮助识别患有 与恐惧消亡有关的严重困难。这项研究的结果可能会导致一项旨在 将神经调节与行为疗法相结合以提高治疗效果。

PROJECT ABSTRACT Despite enormous financial and person-power investments into functional neuroimaging studies in anxiety, the results from these investigations have had limited actionable impact on clinical practice. In particular, few studies have been designed to predict which patients will benefit from a particular intervention, which could result in enormous cost-savings and increased efficiency in delivering mental health care. The goal of exposure-based therapies for anxiety is to present the fear inducing stimulus to the patient in a safe setting in order to extinguish (fear extinction) the previously conditioned (fear conditioned) association. Abnormalities in the fear extinction process characterize many anxiety disorders such as social phobias, panic disorder, and post-traumatic stress disorder. Fear conditioning studies in anxious individuals implicate both enhanced and overgeneralized conditioned fear responses as well as deficits in fear extinction learning. We hypothesize that an acute intervention such as transcranial magnetic stimulation (TMS) may be able to probe the plasticity of a neural network relevant to exposure therapy outcome and help aid early decision points regarding who is most likely to benefit from exposure therapy. Both animals and human investigations have supported an important role for the cerebellum in fear conditioning and fear extinction, with the lateral cerebellar hemispheres involved in the associative and emotional aspects and the cerebellar vermis involved in the sensory and autonomic ones. Functional connectivity between the cerebellum and cerebral hemispheres suggests that cerebral structures too difficult to reach by the cortex with TMS may be accessible via their cerebellar connectivity, a relationship that is slowly becoming recognized. The lateral cerebellar hemisphere is accessible by TMS and is conveniently functionally connected to the medial prefrontal cortex. Ventromedial prefrontal cortex (vmPFC) activation is a key component to effective fear extinction. Accordingly, vmPFC is hypoactive in fear extinction learning in anxious individuals, a finding explicitly determined for those with phobias. Opportunities to explore the contribution of neural pathways that may enhance fear extinction through modulation of vmPFC activity remain wide open and modulation via the cerebellum is an underexplored one. Our investigative model uses fear of public speaking, a prevalent social phobia that is amenable to exposure based therapy and which is typically less complicated by comorbidities than other anxiety disorders. This study will be among the first to clearly delineate the role of the cerebellum in fear extinction. Clarifying the particular function of the cerebellum is important because 1] it enables one to modulate a brain structure that is accessible using TMS and other neuromodulation tools, and 2] it may provide a severity indicator to help identify subsets of individuals with severe difficulties with fear extinction. The results from this study may lead to a program of research aimed at synergizing neuromodulation with behavioral therapy to increase treatment efficacy.