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: 10390276
• 负责人: Maria Ironside
• 金额: $ 28.9万
• 依托单位: LAUREATE INSTITUTE FOR BRAIN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390276
• 关键词: Acute; Amygdaloid structure; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Behavioral; Behavioral Mechanisms; Brain region; Clinical; Clinical Treatment; Clinical Trials; Cognitive; Data; Dose; Electrophysiology (science); Emotional; Exhibits; Face; Functional Magnetic Resonance Imaging; Functional disorder; Future; Hyperactivity; Intervention; Learning; Major Depressive Disorder; Measures; Medicine; Mental Depression; Mental Health; Mental disorders; Modeling; Moods; Neurosciences; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Prediction of Response to Therapy; Public Health; Randomized; Relapse; Rest; Signal Transduction; Startle Reaction; Testing; anxiety symptoms; anxious; approach avoidance behavior; attentional control; base; cognitive neuroscience; comorbid depression; cortico-limbic circuits; design; effective therapy; follow-up; frontal lobe; health assessment; imaging study; improved; insight; neural circuit; neuromechanism; novel; predicting response; relating to nervous system; response; response biomarker; targeted treatment; therapy resistant; volunteer

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％的重度抑郁症患者（MDD）对初始治疗没有反应，并且可以缓解 常见[1]。特别是合并症抑郁症和焦虑症与更多治疗有关 电阻[2]。那非常需要新颖，更具针对性的治疗方法。经颅直流电流 刺激（TDC）是一种新颖的干预措施，可用于引起靶向神经令人兴奋和可塑性 在调节情绪和动画和新兴证据中实施的大脑区域/电路表明它会减少 威胁敏感性。在这里，我们建议使用TDC靶向威胁敏感性作为焦虑的核心症状 抑郁症以确定我们是否可以参与治疗靶标的神经循环。跟随 给药单剂量的抗焦虑药或抗抑郁药，情绪处理的早期变化 在健康的人和临床组中已经观察到。在患者中，急性认知作用 - 例如 降低威胁敏感性 - 已被证明可以预测对药物的反应[3]和行为[4]治疗。 功能磁共振成像（fMRI）研究已经证实了多活跃杏仁核和/或触发性 患者的前额叶活性，表明该皮质膜电路中的活性失衡 威胁识别（杏仁核）和自上而下的控制（前额叶）。特别是旨在补救的治疗方法 对于表现出这些缺陷的患者，前额叶/杏仁核功能障碍可能是关键目标。几个临床 试验表明，额叶皮层TDC的给药是对MDD的潜在有效治疗方法[5]。 但是，尚不清楚基本的作用机制。为了满足这一差距，我们提出了一种实验医学 研究（目标识别和初始目标参与路径），其中120名焦虑的MDD志愿者将 随机将平行设计中的单个活动或假TDC接收。威胁敏感性将是 使用任务和静止状态fMRI以及潜在的惊吓电生理学测量。初步数据建议 额叶TDC的单个会话的行为威胁敏感性降低[6]。随后是 fMRI研究发现，单个活动与假的额叶TDC会减少对杏仁核的反应 可怕的面孔同时增加了额叶注意控制信号[7]。这提供了证据表明 调节额叶皮层中的活动抑制杏仁核对威胁的反应，突出了潜在的中性 威胁敏感性行为降低的机制。此外，这提供了最初的机械洞察力 TDC在治疗MDD和动画障碍的临床试验中的效率，这表明威胁 灵敏度可能是一个合适的认知靶标。当前的提案以此为基础，以建立 额叶TDC关于杏仁核对威胁的反应（主要目的），额叶对威胁的反应（次要目标）， 威胁下的惊吓反应（次要目的），避免进场冲突（探索目的）和基于模型 学习（探索目的）。最终目的是将这些多级急性发现应用于机械临床 TDC的试验，以测试其治疗反应的预测（完整模型路径）并改善患者的预后