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

经颅直流电刺激 (tDCS) 治疗急性恐惧

• 批准号: 8874641
• 负责人: ANDREW D KRYSTAL
• 金额: $ 46.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874641
• 关键词: Acute; Adverse event; Affect; Anxiety Disorders; Auditory; Brain; Brain Stem; Breathing; Caliber; Carbon Dioxide; Clinical; Clinical Trials; Cross-Over Studies; Data; Development; Diagnostic and Statistical Manual of Mental Disorders; Dose; Double-Blind Method; Electrodes; Fright; Future; Genetic Crossing Over; Goals; Head; Individual; Intervention; Literature; Measures; Mediating; Mental disorders; Methods; Modeling; Mydriasis; Neurosciences; Phase; Pilot Projects; Play; Prevention; Public Health; Pupil; Randomized; Randomized Controlled Trials; Research Domain Criteria; Safety; Scalp structure; Series; Severities; Skin; Staging; Stimulus; Symptoms; Testing; Translating; active control; active method; anxiety treatment; base; brain circuitry; cohort; control trial; density; dosage; electric field; healthy volunteer; improved; locus ceruleus structure; neural circuit; novel; pre-clinical; prevent; primary outcome; public health relevance; relating to nervous system; response; treatment effect

 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.

 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]），提议将神经科学发现转化为针对急性恐惧的新型非药物治疗方法是许多 DSM 焦虑定义障碍所共有的研究领域标准 (RDoC) 构建。作为这项工作基础的神经科学发现是大量的临床前文献。记录了被称为蓝斑 (LC) 的脑干区域在调节急性恐惧症状中发挥着关键作用，我们利用了可以通过瞳孔测量法非侵入性测量 LC 活动的证据，并且我们的试点数据表明我们可以进行调节。通过附着在皮肤/头皮上的电极施加经颅直流电刺激 (tDCS) 的 LC 活性我们的方法是开发 tDCS 作为抑制 LC 活性的方法，然后确定是否会出现这种情况。我们的转化工作将包括两个阶段，一个为期 2 年的 R21 阶段，我们在参与神经目标的能力方面建立可行性、耐受性、安全性和概念验证 (POC)，然后是为期 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，使用电场建模和真实的头部模型来确定有希望的治疗电极放置位置，我们将在整个过程中进行测试。在 3 组健康对照中进行一系列电剂量，试图确定 tDCS 治疗电极配置，通过该配置，我们可以确定每个受试者的剂量：(1) 可耐受（5 点李克特评级为无） （不仅仅是轻微的不适）；（2）通过暂时抑制 LC 活动来参与目标神经回路，这反映在听觉奇怪任务（AOT）中防止瞳孔扩张反应，这会可靠地激活 LC。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配接受电剂量个性化主动 tDCS 与主动对照疗法（tDCS 提供与主动治疗相同的皮肤电流密度，但不影响 LC），其中临床症状急性恐惧（主要结果）是通过吸入 7.5% CO2 引起的，如果有初步证据表明参与目标（抑制 LC）可以安全地减轻临床急性恐惧症状，则可以假定未来的发展可行性。我们广泛的科学目标是评估目标大脑回路的参与（LC 的抑制）是否是治疗急性恐惧的可行目标，这对于公共健康具有很高的重要性，因为急性恐惧是一种极其普遍且令人衰弱的问题和当前的治疗方法。选择非常有限。