Imaging-guided tDCS therapy in major depression

项目摘要 治疗重度抑郁症（MDD）的一线药物治疗仅取得中等程度的成功。带阳极 刺激左背外侧前额叶皮层（DLPFC），经颅直流电刺激（tDCS）， 低强度神经调节技术的风险最小，可能会引起抗抑郁作用，并改善 MDD患者的认知控制。先前的证据表明，前额叶边缘电路，包括 DLPFC和背内侧前扣带皮层（dACC）参与情绪和情绪的调节。 因此，它们通过tDCS的调节可能有助于抗抑郁作用。然而，在多大程度上，这些 区域参与tDCS，其招募如何促进临床反应尚不清楚。响应 在个体水平上，刺激的大小、位置和强度可能 解释了不同的治疗效果。最近，已经开发了高清晰度（HD）tDCS，其允许 更多的局部神经刺激在本探索性临床试验的R61阶段，我们的目标是应用和 在中重度MDD患者中比较HD-tDCS、传统tDCS（C-tDCS）和假tDCS （N = 60，每组n = 20），以测试情绪调节DLPFC和dACC参与的差异 使用随机化、双盲设计的条件之间的区域。我们会用核磁共振引导的立体定向术 优化和标准化DLPFC电极放置和新型MRI技术，同时进行tDCS测试 不同刺激强度下tDCS电流的区域分布。我们将使用3D GRASE伪 连续动脉自旋标记（pCASL）MRI，比较受试者完成12天30次之前和之后 2 mA刺激的10分钟会话，以测试局部脑血流量（rCBF）中与tDCS相关的变化， 前额叶回路tDCS诱导DLPFC中的显著磁场变化和rCBF中的显著变化 对于任一活性tDCS，在DLPFC和dACC中基线和tDCS试验结束之间 与假手术相比的条件将构成进入R33阶段的go-no-go标准。使用 主动tDCS模式显示更大的靶点接合和神经生理学效应，而无外周 R33期将随机分配中度至重度MDD患者（N = 100，每组n = 50）， 组）至活动或假手术左侧阳极DLPFC tDCS。患者将再次完成MRI扫描，包括tDCS- 电流映射和pCASL以及两个功能成像任务，探索认知控制和情绪 负性偏见，招募前额叶边缘系统电路，在完成为期12天的30分钟试验之前和之后， tDCS会话。证明目标与主动tDCS的接触与改进的 情绪（主要结局）、认知功能和任务相关脑激活的变化（次要结局） 将构成继续R01研究的标准。这项试验的结果预计将导致 优化MRI引导的tDCS治疗MDD并加深对MDD生理机制的了解 tDCS治疗。

PROJECT SUMMARY First-line pharmacotherapies for major depressive disorder (MDD) are only moderately successful. With anodal stimulation of the left dorsolateral prefrontal cortex (DLPFC), transcranial direct current stimulation (tDCS), a low-intensity neuromodulation technique of minimal risk, may elicit antidepressant effects and improve cognitive control in individuals with MDD. Prior evidence suggests that prefrontal-limbic circuits, including the DLPFC and dorsomedial anterior cingulate cortex (dACC), are involved in the regulation of mood and emotion. Their modulation by tDCS may thus contribute to antidepressant effects. However, the extent to which these regions are engaged by tDCS and how their recruitment contributes to clinical response is unknown. Response to tDCS also remains mixed at the individual level where the size, location and intensity of stimulation might account for varied therapeutic effects. Recently, high definition (HD) tDCS has been developed that allows for more focal neural stimulation. During the R61 phase of this Exploratory Clinical Trial we aim to apply and compare HD-tDCS, conventional tDCS (C-tDCS) and sham tDCS in patients with moderate to severe MDD (N=60, n=20 in each group) to test for differences in the engagement of mood regulating DLPFC and dACC regions between conditions using a randomized, double blind design. We will use MRI-guided stereotaxy to optimize and standardize DLPFC electrode placement and novel MRI techniques with concurrent tDCS to test the regional distribution of tDCS current at different stimulation intensities. We will use 3D GRASE pseudo- continuous arterial spin labeling (pCASL) MRI, compared before and after subjects complete 12 daily 30 minute sessions of 2 mA stimulation, to test for tDCS-related changes in regional cerebral blood flow (rCBF) in prefrontal circuitry. Significant tDCS induced magnetic field changes in DLPFC and significant changes in rCBF between baseline and the end of the tDCS trial in the DLPFC and dACC for either of the active tDCS conditions compared to sham will constitute the go-no-go criterion for proceeding to the R33 Phase. Using the active tDCS modality showing greater target engagement and neurophysiological effects without peripheral side effects, the R33 Phase will randomize patients with moderate to severe MDD (N=100, n=50 in each group) to active or sham left anodal DLPFC tDCS. Patients will again complete MRI scans including tDCS- current mapping and pCASL as well as two functional imaging tasks probing cognitive control and emotion negativity bias, recruiting prefrontal-limbic circuitry, before and after completing a 12-day trial of 30-minute tDCS sessions. Demonstration that target engagement with active tDCS varies in association with improved mood (primary outcome), cognitive function and changes in task-related brain activation (secondary outcomes) will constitute the criterion for continued R01 investigation. Results of this trial are expected to lead to an optimized MRI guided tDCS treatment of MDD and deepen understanding of the physiological mechanisms of tDCS therapy.