Frontal stimulation to modulate threat sensitivity in anxious depression

超过50%的重度抑郁障碍(MDD)患者对最初的治疗没有反应，复发是 Common[1]。特别是，抑郁症和焦虑症的共病与更多的治疗有关。 抗性[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。 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 威胁敏感度。在这里，我们建议使用tDC将威胁敏感度作为焦虑的核心症状 以确定我们是否可以激活作为治疗目标的神经回路。紧随其后的是 单次服用抗焦虑或抗抑郁药治疗，情绪处理的早期变化 已在健康人和临床人群中观察到。在患者中，急性认知影响--例如 威胁敏感度的降低--已被证明可以预测药物[3]和行为[4]治疗的反应。 功能性磁共振成像(FMRI)研究证实杏仁核过度活跃和/或活动不足。 患者的前额叶活动，表明次级服务的皮质-边缘环路内的活动失衡 威胁识别(杏仁核)和自上而下的控制(前额叶)。具体地说，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靶点。几个临床案例 试验表明，额叶皮质tDCs是治疗MDD的一种潜在有效方法[5]。 然而，潜在的行动机制尚不清楚。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名患有焦虑性MDD的志愿者将 随机接受平行设计中的活动或假TDC的单次会话。威胁敏感度将是 使用任务和静息状态功能磁共振成像进行测量，并增强惊厥电生理学。初步数据显示 通过一次正面tDC会议降低行为威胁敏感性[6]。在此之后，又发布了一个 FMRI研究发现，单次活动与假手术的额叶TDCs可降低杏仁核对 恐惧的面孔同时增加正面注意控制信号[7]。这提供了证据表明 额叶皮质的调节活动抑制杏仁核对威胁的反应，突出了潜在的神经 降低威胁敏感度的行为机制。此外，这提供了对以下方面的初步机械见解 Tdcs在治疗MDD和焦虑症的临床试验中的有效性，表明威胁 敏感度可能是一个合适的认知目标。目前的提案建立在此基础上，以建立 额叶TDC关于杏仁核对威胁的反应(主要目的)，额顶顶叶对威胁的反应(次要目的)， 威胁下的惊吓反应(次要目标)、接近-回避-冲突(探索性目标)和基于模型的反应 学习(探索性目标)。最终目的是将这些多层次的急性发现应用于机械性临床。 TDCs试验，以测试其对治疗反应的预测(全模型路径)并改善患者结果

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