Targeted modulation of symptom-specific brain circuits with transcranial magnetic stimulation

项目总结 经颅磁刺激(TMS)是FDA批准的治疗难治性抑郁症的方法，但 临床结果各不相同。我们最近表明，通过针对不同的目标，TMS结果可能会得到优化 用于治疗不同症状的电路(Siddiqi等人，Am J精神病学2020)。在接受临床治疗的患者中 TMS至左侧背侧前额叶皮质治疗抑郁症，烦躁不安症状的改善 与TMS有关的一个大脑回路，而“焦虑”症状的改善与 TMS连接到不同的大脑回路。然而，这项研究无法调查生物标记物和机制。 目标是不同的大脑回路。 使用这个队列的子集中的静息状态fMRI数据，我们现在已经生成了初步数据，表明 治疗诱导的每个回路内的连通性改变可以作为哪个回路被 刺激以及哪些症状群得到改善。此外，患者之间的个性化连接 TMS部位和这些回路中的每一个与TMS诱导的连通性变化共同变化，提示潜在的 机制。然而，这些初步结果受到回溯性设计样本量小的限制。 这依赖于TMS部位的偶然变化，而不是这两个大脑回路的定向刺激。在……里面 目前的项目，我们将前瞻性地针对TMS，以便清楚地评估其针对目标的影响 功能连接。 在目标1中，我们将测试我们对两个电路的预期目标是否会导致选择性连接 这些环路内的变化。在目标2中，我们将测试这些连接变化的幅度是否可以 根据TMS站点到底层电路的个性化连接的强度来预测。一起， 这项工作将确定静息状态fMRI是否可以作为靶点参与的可靠生物标记物 寻求调节患者特定的大脑回路。此外，它还将使人们深入了解 先前观察到的症状特异性神经调节效应。这项工作是迈向 机械驱动的临床试验集中在症状特异性和回路特异性神经调节上 抑郁症，长期目标是个性化和跨诊断电路靶向治疗精神疾病 更笼统地说是疾病。

Project summary Transcranial magnetic stimulation (TMS) is an FDA-approved therapy for treatment-resistant depression, but clinical outcomes vary. We recently showed that TMS outcomes may be optimized by targeting different circuits to treat different symptoms (Siddiqi et al, Am J Psychiatry 2020). Among patients who received clinical TMS to the left dorsal lateral prefrontal cortex for depression, improvement in “dysphoric” symptoms was associated with TMS to one brain circuit, while improvement in “anxiosomatic” symptoms was associated with TMS to a different brain circuit. However, this study was unable to investigate biomarkers and mechanisms of targeting various brain circuits. Using resting-state fMRI data in a subset of this cohort, we have now generated preliminary data showing that treatment-induced connectivity change within each circuit can be used as a biomarker of which circuit was stimulated and which symptom clusters improved. Further, individualized connectivity between the patient’s TMS site and each of these circuits covaried with TMS-induced connectivity changes, suggesting a potential mechanism. However, these preliminary results are limited by small sample size with a retrospective design that relies on incidental variance in the TMS site rather than targeted stimulation of these two brain circuits. In the current project, we will prospectively target TMS in order to clearly assess its target-specific effects on functional connectivity. In Aim 1, we will test whether our prospective targeting of our two circuits will induce selective connectivity changes within those circuits. In Aim 2, we will test whether the magnitude of these connectivity changes can be predicted by the strength of the TMS site’s individualized connectivity to the underlying circuit. Together, this work will establish whether resting-state fMRI can act as a reliable biomarker of target engagement when seeking to modulate specific brain circuits in patients. Further, it will lend insight into potential mechanisms of previously observed symptom-specific neuromodulation effects. This work is a critical step towards mechanistically-driven clinical trials focused on symptom-specific and circuit-specific neuromodulation in depression, with the long-term goal of personalized and transdiagnostic circuit-targeted therapy for mental illness more generally.