Eshel Neir, Keller Corey J, Wu Wei, Jiang Jing, Mills-Finnerty Colleen, Huemer Julia, Wright Rachael, Fonzo Gregory A, Ichikawa Naho, Carreon David, Wong Melinda, Yee Andrew, Shpigel Emmanuel, Guo Yi, McTeague Lisa, Maron-Katz Adi, Etkin Amit
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA.
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, 94305, USA.
Neuropsychopharmacology. 2020 May;45(6):1018-1025. doi: 10.1038/s41386-020-0633-z. Epub 2020 Feb 13.
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.
重复经颅磁刺激（rTMS）是治疗重度抑郁症（MDD）的常用方法。然而，我们对TMS发挥抗抑郁作用的机制了解甚少。此外，我们缺乏可用于预测和跟踪临床结果的脑信号。这些信号将有助于进行治疗分层和优化。在此，我们进行了一项随机、假对照临床试验，并测量了rTMS前后的电生理、神经影像学和临床变化。36名患者被随机分为两组，连续20个工作日接受左侧背外侧前额叶皮质（dlPFC）的主动或假rTMS治疗。为了捕捉rTMS驱动的连通性和因果兴奋性变化，在治疗前后进行了静息态功能磁共振成像（fMRI）和TMS/脑电图（EEG）检查。同时，还通过TMS/fMRI评估了抑郁症患者与健康对照之间的基线因果连通性差异。我们发现，主动rTMS而非假rTMS引发了：（1）dlPFC全局连通性增加；（2）dlPFC与杏仁核之间负性连通性的诱导；（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受到干扰。综上所述，rTMS诱导了刺激部位的持久连通性和兴奋性变化，使得主动治疗后，dlPFC似乎更能对杏仁核进行自上而下的控制。这些网络功能测量指标既预测又跟踪了临床结果，可能为治疗优化打开了大门。
