Repetitive transcranial magnetic stimulation (rTMS) is a commonly- used treatment for major depressive disorder (MDD). However, our understanding of the mechanism by which TMS exerts its antidepressant effect is minimal. Furthermore, we lack brain signals that can be used to predict and track clinical outcome. Such signals would allow for treatment stratification and optimization. Here, we performed a randomized, sham-controlled clinical trial and measured electrophysiological, neuroimaging, and clinical changes before and after rTMS. Patients (N = 36) were randomized to receive either active or sham rTMS to the left dorsolateral prefrontal cortex (dlPFC) for 20 consecutive weekdays. To capture the rTMS-driven changes in connectivity and causal excitability, resting fMRI and TMS/EEG were performed before and after the treatment. Baseline causal connectivity differences between depressed patients and healthy controls were also evaluated with concurrent TMS/fMRI. We found that active, but not sham rTMS elicited (1) an increase in dlPFC global connectivity, (2) induction of negative dlPFC-amygdala connectivity, and (3) local and distributed changes in TMS/EEG potentials. Global connectivity changes predicted clinical outcome, while both global connectivity and TMS/EEG changes tracked clinical outcome. In patients but not healthy participants, we observed a perturbed inhibitory effect of the dlPFC on the amygdala. Taken together, rTMS induced lasting connectivity and excitability changes from the site of stimulation, such that after active treatment, the dlPFC appeared better able to engage in top-down control of the amygdala. These measures of network functioning both predicted and tracked clinical outcome, potentially opening the door to treatment optimization.

中文翻译：

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全局连通性和局部兴奋性变化是重复经颅磁刺激的抗抑郁作用的基础。

重复经颅磁刺激（rTMS）是重度抑郁症（MDD）的常用治疗方法。但是，我们对TMS发挥其抗抑郁作用机理的了解很少。此外，我们缺乏可用于预测和跟踪临床结果的大脑信号。这样的信号将允许治疗分层和优化。在这里，我们进行了一个随机的，假手术对照的临床试验，并测量了rTMS前后的电生理，神经影像和临床变化。患者（N = 36）被随机分配接受连续20个工作日的活动或假rTMS到左背外侧前额叶皮层（dlPFC）。为了捕获rTMS驱动的连接性和因果兴奋性变化，在治疗前后进行了静息fMRI和TMS / EEG。并发TMS / fMRI还评估了抑郁症患者与健康对照组之间的基线因果联系差异。我们发现主动但不是假的rTMS引发了（1）dlPFC全局连接性的增加，（2）负dlPFC-杏仁核连接性的诱导，以及（3）TMS / EEG电位的局部和分布式变化。全局连通性变化预测了临床结果，而全局连通性和TMS / EEG变化均跟踪了临床结果。在患者而非健康参与者中，我们观察到dlPFC对杏仁核的抑制作用。两者合计，rTMS诱导了刺激部位的持久连通性和兴奋性变化，因此在积极治疗后，dlPFC似乎能够更好地自上而下地控制杏仁核。