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(精神疾病新型干预措施的探索性临床试验[R21/R33])，建议将神经科学的发现转化为急性恐惧的新的非药物治疗，这是许多DSM定义的焦虑症共同的研究领域标准(RDoC)构建。作为这一努力的基础的神经科学发现是一篇广泛的临床前文献，记录了脑干被称为蓝斑(LC)的区域在调节急性恐惧症状方面发挥的关键作用。我们利用经颅直流电刺激(TDC)通过连接到皮肤/头皮上的电极来调节LC活动的证据，该证据表明LC活动可以通过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施加TDC来调节LC活动。我们的方法是开发tdcs作为一种抑制LC活动的方法，然后确定这是否可以减轻急性恐惧的症状。我们的转化工作将包括两个阶段，为期2年的R21阶段，在此阶段，我们就参与神经靶点的能力确定可行性、耐受性、安全性和概念验证(POC)，随后是为期3年的R33平行分组双盲对照试验。在R21阶段，我们将使用迭代方法，其中我们使用电场建模和逼真的头部模型来确定有希望的治疗电极放置，我们将在3个健康对照组的一系列电剂量上进行测试，试图确定tDCS治疗电极配置，利用该配置，我们可以在每个受试者中识别如下剂量：(1)可耐受(5分Likert评分NO 不仅是轻微的不适)；和(2)通过瞬时抑制LC活动来参与靶神经回路，这反映在防止听觉奇怪任务(AOT)中对稀有刺激的扩大反应，这可靠地激活LC。如果成功，我们将继续进行为期3年的R33平行组试验，其中60名健康志愿者被随机分成电剂量个性化主动tdcs和主动对照疗法(tdcs提供与主动tdcs相同的皮肤电流密度，但不影响LC)，其中临床症状急性恐惧，即主要结果，是吸入7.5%二氧化碳引起的。如果有初步证据表明，使用靶点(抑制LC)可以安全地减轻临床急性恐惧症状，则可以假定未来的开发可行性。我们广泛的科学目标是评估靶向大脑回路的参与，即LC的抑制，是否是治疗急性恐惧的可行靶点。这对公众健康具有高度重要性，因为急性恐惧非常普遍，使人虚弱的问题和目前的治疗选择相当有限。

 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.