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

基本信息

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
项目类别：
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

项目摘要

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) 患者对初始治疗没有反应，且复发率很高特别是，共病抑郁症和焦虑症与更多治疗相关。因此，非常需要新颖的、更有针对性的经颅直流电治疗。刺激（tDCS）是一种新颖的干预措施，可用于因果性地针对神经兴奋性和可塑性与调节情绪和焦虑有关的大脑区域/回路，新出现的证据表明它可以减少在这里，我们建议使用 tDCS 将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按照治疗目标参与神经回路。单剂量抗焦虑或抗抑郁治疗，情绪处理的早期变化在健康人群和临床群体中已经观察到急性认知效应——例如认知障碍。威胁敏感性降低——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) 研究已证实杏仁核过度活跃和/或功能减退患者的前额叶活动，表明该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）特别是旨在补救的治疗。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。试验表明，额叶皮层 tDCS 治疗是 MDD 的潜在有效治疗方法 [5]。然而，潜在的作用机制尚不清楚，为了弥补这一差距，我们提出了一种实验药物。研究（目标识别和初始目标参与路径），其中 120 名患有焦虑 MDD 的志愿者将被将在并行设计中随机接受单次主动或假 tDCS。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进行测量，初步数据表明。单次额叶 tDCS 可以降低威胁行为敏感性 [6]。功能磁共振成像研究发现，单次主动额叶 tDCS 与假额 tDCS 会降低杏仁核对恐惧的面孔同时增加额叶注意力控制信号[7]。调节额叶皮层的活动抑制杏仁核对威胁的反应，突出了潜在的神经元此外，这还提供了对威胁敏感性行为降低的初步机制见解。 tDCS 在治疗 MDD 和焦虑症的临床试验中的功效，表明威胁敏感性可能是一个合适的认知目标，当前的提议以此为基础来确定敏感性的急性影响。额叶 tDCS 检测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）、威胁下的惊吓反应（次要目标）、接近-避免-冲突（探索性目标）和基于模型学习（探索性目标）的最终目的是将这些多层次的急性发现应用于机械临床。 tDCS 试验，测试其对治疗反应的预测（完整模型路径）并改善患者治疗结果