Frontal stimulation to modulate threat sensitivity in anxious depression

额部刺激调节焦虑抑郁症的威胁敏感性

• 批准号: 10377706
• 负责人: Maria Ironside
• 金额: $ 27.41万
• 依托单位: LAUREATE INSTITUTE FOR BRAIN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-24 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377706
• 关键词: Frontal; stimulation; modulate; threat; sensitivity

Over 50% of patients with major depressive disorder (MDD) do not respond to initial treatment and relapse is common [1]. In particular, comorbid depression and anxiety disorders are associated with more treatment resistance [2]. Thus, there is a great need for novel, more targeted treatments. Transcranial direct current stimulation (tDCS) is a novel intervention that can be used to causally target neural excitability and plasticity in brain regions/circuits implicated in regulating mood and anxiety and emerging evidence suggests that it reduces threat sensitivity. Here we propose to use tDCS to target threat sensitivity as a core symptom of anxious depression to determine if we can engage the neural circuits that are treatment targets. Following the administration of a single dose of anxiolytic or antidepressant treatment, early changes in emotional processing have been observed in healthy people and clinical groups. Among patients, acute cognitive effects – such as a reduction in threat sensitivity – have been shown to predict response to drug [3] and behavioral [4] treatments. Functional magnetic resonance imaging (fMRI) studies have confirmed hyperactive amygdala and/or hypoactive prefrontal activity in patients, indicating an imbalance of activity within this cortico-limbic circuit that sub-serves threat identification (amygdala) and top-down control (prefrontal). Specifically, treatments aiming to remediate prefrontal/ amygdala dysfunction could be a critical target in patients exhibiting these deficits. Several clinical trials have shown that administration of frontal cortex tDCS is a potentially effective treatment for MDD [5]. However, underlying mechanisms of action are unclear. To meet this gap, we propose an experimental medicine study (target identification and initial target engagement paths) where 120 volunteers with anxious MDD will be randomized to receive a single session of active or sham tDCS in a parallel design. Threat sensitivity will be measured using task and resting state fMRI and potentiated startle electrophysiology. Preliminary data suggest reductions in behavioral threat sensitivity from a single session of frontal tDCS [6]. This was followed up with an fMRI study which found that a single session of active vs sham frontal tDCS reduced amygdala response to fearful faces whilst simultaneously increasing frontal attentional control signals [7]. This provides evidence that modulating activity in the frontal cortex inhibits amygdala response to threat, highlighting a potential neural mechanism for the behavioral reduction in threat sensitivity. In addition, this offers initial mechanistic insights into the efficacy of tDCS in clinical trials for the treatment of MDD and anxiety disorders, suggesting that threat sensitivity may be a suitable cognitive target. The current proposal builds on this to establish acute effects of frontal tDCS on amygdala response to threat (primary aim), frontoparietal response to threat (secondary aim), startle response under threat (secondary aim), approach-avoidance-conflict (exploratory aim) and model-based learning (exploratory aim). The ultimate aim is to apply these multi-level acute findings to mechanistic clinical trials of tDCS, to test their prediction of treatment response (full model path) and improve patient outcomes

超过50%的重度抑郁症（MDD）患者对初始治疗无反应， 常见的[1]。特别是抑郁症和焦虑症的共病者，治疗更多 阻力[2]。因此，非常需要新的、更有针对性的治疗方法。经颅直流电 刺激（tDCS）是一种新的干预措施，可用于因果靶向神经兴奋性和可塑性， 参与调节情绪和焦虑的大脑区域/回路，新出现的证据表明， 威胁敏感度在这里，我们建议使用tDCS来瞄准威胁敏感性作为焦虑的核心症状 抑郁症来确定我们是否可以参与作为治疗目标的神经回路。后 给予单剂量抗焦虑药或抗抑郁药治疗，情绪处理的早期变化 已在健康人群和临床人群中观察到。在患者中，急性认知效应-如 威胁敏感性的降低-已被证明可以预测对药物[3]和行为[4]治疗的反应。 功能性磁共振成像（fMRI）研究已经证实杏仁核过度活跃和/或活动减退 患者的前额叶活动，表明皮质边缘回路内的活动不平衡， 威胁识别（杏仁核）和自上而下的控制（前额叶）。具体而言，旨在补救 前额叶/杏仁核功能障碍可能是表现出这些缺陷的患者的关键目标。几项临床 试验表明，给予额叶皮层tDCS是治疗MDD的潜在有效方法[5]。 然而，潜在的作用机制尚不清楚。为了填补这一空白，我们提出了一种实验性药物， 研究（目标识别和初始目标参与路径），其中120名患有焦虑MDD的志愿者将 在平行设计中随机接受单次活性或假tDCS。威胁敏感度将是 使用任务和静息状态功能磁共振成像和增强惊吓电生理学测量。初步数据表明 从正面tDCS的单次会话中降低行为威胁敏感度[6]。随后， 一项fMRI研究发现，一个单一的活动与假额叶tDCS会议减少杏仁核反应， 恐惧的面孔，同时增加正面注意力控制信号[7]。这证明 调节额叶皮层的活动会抑制杏仁核对威胁的反应，这突出了一个潜在的神经系统。 威胁敏感性的行为降低机制。此外，这提供了初步的机械见解， tDCS在治疗MDD和焦虑症的临床试验中的疗效表明， 敏感性可以是合适的认知目标。目前的建议是在此基础上建立的， 额叶tDCS对杏仁核对威胁的反应（主要目标），额顶叶对威胁的反应（次要目标）， 威胁下惊吓反应（次要目标）、接近-回避-冲突（探索目标）和基于模型 探索性目标（Exploratory Aim）最终目的是将这些多水平急性发现应用于机械临床 tDCS试验，以测试其对治疗反应的预测（完整模型路径）并改善患者结局