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

项目摘要 经颅磁刺激（TMS）是FDA批准的治疗难治性抑郁症的疗法，但 临床结果不同。我们最近表明，TMS的结果可能会优化针对不同的， 治疗不同症状的回路（Siddiqi等人，Am J Psychiatry 2020）。在接受临床 经颅磁刺激左侧背外侧前额叶皮层抑郁症，改善“烦躁”症状， 与TMS的一个脑回路相关，而“焦虑症”症状的改善与 经颅磁刺激到不同的脑回路。然而，这项研究无法调查生物标志物和机制， 针对不同的脑回路 使用该队列的一个子集的静息状态fMRI数据，我们现在已经生成了初步数据，显示 每个回路内治疗诱导的连通性变化可用作哪个回路被治疗的生物标志物。 哪些症状群得到改善。此外，患者的设备之间的个体化连接性可以被实现。 TMS位点和这些回路中的每一个都与TMS诱导的连接性变化共变，这表明可能存在一个潜在的 机制然而，这些初步结果受到回顾性设计样本量小的限制 这依赖于TMS部位的偶然变化，而不是对这两个大脑回路的靶向刺激。在 在目前的项目中，我们将前瞻性地以TMS为目标，以明确评估其对特定目标的影响， 功能性连接。 在目标1中，我们将测试我们的两个回路的预期目标是否会诱导选择性连接 这些电路中的变化。在目标2中，我们将测试这些连接变化的幅度是否可以 可以通过TMS站点与底层电路的个性化连接的强度来预测。在一起， 这项工作将确定静息状态功能磁共振成像是否可以作为一个可靠的生物标志物的目标接合时， 试图调节患者的特定脑回路。此外，它将有助于深入了解 先前观察到的神经元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，重点是神经元特异性和回路特异性神经调节， 抑郁症，长期目标是个性化和跨诊断回路靶向治疗精神疾病， 疾病更普遍。

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.