Transcranial Direct Current Stimulation (tDCS) as a Treatment for Acute Fear

 描述（由申请人提供）：本申请响应RFA-MH-15-300（精神障碍新型干预措施的探索性临床试验[R21/R33]），提出将神经科学发现转化为急性恐惧的新型非药物治疗，这是许多DSM定义的焦虑症常见的研究领域标准（RDoC）结构。作为这项工作基础的神经科学发现是一个广泛的临床前文献，记录了脑干中被称为蓝斑（LC）的区域在调节急性恐惧症状中起着关键作用。我们利用的证据表明，LC活动可以用瞳孔测量法进行非侵入性测量，我们的试点数据表明，我们可以通过连接到皮肤/头皮的电极施加经颅直流电刺激（tDCS）来调节LC活动。我们的方法是开发tDCS作为抑制LC活性的手段，然后确定这是否会减轻急性恐惧的症状。 我们的转化工作将包括两个阶段，一个为期2年的R21阶段，在此阶段，我们建立了可行性、耐受性、安全性和概念验证（POC），以确定神经靶点的能力，然后是一个为期3年的R33平行组、双盲、对照试验。在R21阶段，我们将采用迭代方法，其中我们使用具有真实头部模型的电场建模来识别有希望的治疗电极放置，我们将在3个健康对照队列中测试一系列电剂量，以尝试识别tDCS治疗电极配置，通过该配置，我们可以识别每个受试者的剂量：（1）可耐受（5分Likert评级为无 超过轻度不适）;和（2）通过短暂抑制LC活动来接合目标神经回路，这反映在防止听觉古怪任务（AOT）中对罕见刺激的瞳孔扩张反应中，这可靠地激活了LC。如果成功，我们将进行3年R33平行组试验，其中将60名健康志愿者随机分配至电剂量个性化活性tDCS与活性对照疗法（tDCS递送与活性相同的皮肤电流密度，但不影响LC），其中通过吸入7.5%CO2引起临床症状急性恐惧（主要结局）。如果有初步证据表明，参与目标（抑制LC）安全地减少临床急性恐惧症状，未来的开发可行性将被假定。 我们广泛的科学目标是评估目标脑回路的参与，LC的抑制，是否是治疗急性恐惧的可行目标。这是高度的公共卫生重要性，因为急性恐惧是非常普遍和衰弱的问题，目前的治疗选择是相当有限的。

 DESCRIPTION (provided by applicant): This application responds to RFA-MH-15-300 (Exploratory Clinical Trials of Novel Interventions for Mental Disorders [R21/R33]) by proposing to translate neuroscience findings into a novel non-pharmacologic treatment for Acute Fear, a Research Domain Criteria (RDoC) construct common to many DSM defined anxiety disorders. The neuroscience findings which serve as the basis for this effort are an extensive pre- clinical literature documenting that the region of the brainstem known as the locus coeruleus (LC) plays a key role in mediating symptoms of Acute Fear. We capitalize on evidence that LC activity can be non-invasively measured with pupillometry and our pilot data indicating that we can modulate LC activity with transcranial direct current stimulation (tDCS) applied via electrodes attached to the skin/scalp. Our approach is to develop tDCS as a means of inhibiting LC activity and then determine if this diminishes symptoms of Acute Fear. Our translational effort will consist of two stages, a 2 year R21 phase where we establish feasibility, tolerability, safety, and proof-of-concept (POC) in terms of capacity to engage the neural target, followed by a 3 year R33 parallel-group, double-blind, controlled trial. In the R21 phase we will employ an iterative approach where we use electric field modeling with a realistic head model to identify promising treatment electrode placements which we will test across a series of electrical doses in 3 cohorts of healthy controls to attempt to identify a tDCS treatment electrode configuration with which we can identify a dosage in each subject that is: (1) tolerable (5-point Likert ratings of no more than mild discomfort); and (2) engages the target neural circuitry by transiently inhibiting LC activity as reflected in prevention of the pupil dilation response to rare stimuli in the auditoy oddball task (AOT), which reliably activates LC. If successful we will proceed to a 3 year R33 parallel- group trial where 60 healthy volunteers are randomized to electrical dose-personalized active tDCS vs an active control therapy (tDCS that delivers the same skin current density as the active but does not affect LC) where clinical symptoms Acute Fear, the primary outcome, are elicited by inhalation of 7.5% CO2. Future development viability will be assumed if there is preliminary evidence that engaging the target (inhibiting LC) safely diminishes clinical Acute Fear symptoms. Our broad scientific goal is to evaluate if engagement of the target brain circuitry, inhibition of LC, is a viable target for treating Acute Fear. This is of high public heath importance as Acute Fear is extremely widespread and debilitating problem and current treatment options are quite limited.