Reliability of Repetitive TMS-induced Modulation of Cortical Excitability

摘要 重复经颅磁刺激（rTMS）是一种非侵入性脑刺激技术，能够 调节目标脑区域及其连接的脑回路中的活动， 刺激本身。rTMS用于神经科学研究，以研究人类认知过程中的大脑功能 和行为，并了解神经精神疾病的大脑病理生理学。临床上，rTMS方案 在广泛的疾病状态下具有诊断和治疗实用性， 美国食品和药物管理局（FDA）批准用于治疗耐药抑郁症。 然而，rTMS的神经调节作用的可变性及其来源是不明确的。这些知识 间隙代表了对rTMS结果的解释和研究设计的根本限制。 例如，计算或评估研究的样本量具有挑战性，并且无法优化 在不知道rTMS反应的个体差异是否 可复制的此外，不能假设在运动皮层中测试的rTMS协议将产生类似的结果。 神经调节作用时，给药到其他大脑区域。 在本提案中，我们将使用MRI引导的rTMS结合EMG、EEG和行为测量， 描述初级运动皮层（M1）和背外侧前额叶皮层中rTMS效应的变异性 （DLPFC）。在60名受试者的队列中，我们将评估受试者间和受试者内的重测信度， 应用于M1的最广泛使用的rTMS协议的调节作用。我们将比较 不同的rTMS方案对皮质脊髓兴奋性（通过运动诱发电位测量），皮质 兴奋性（通过同步TMS-EEG测量）和运动表现（使用顺序手指敲击 任务）。每名受试者将接受总共10次TMS-EMG-EEG行为会话，评估重复的 兴奋性和抑制性协议的会话。在60名受试者的单独队列中，我们将评估转移 通过将10 Hz rTMS和iTBS应用于M1和DLPFC，研究rTMS在大脑区域中的作用。每例受试者 将接受总共10次TMS-EEG行为会话，对比不同区域（M1）的刺激方案 相对于DLPFC）。所有受试者将接受广泛的基线评估，包括详细的检查， 神经心理学测量，结构和静息状态功能连接MRI，计算 建模、实验室和基因检测以及EEG，以确定受试者间反应变异性的预测因子 到rTMS。所有数据都将存放在一个安全的存储库中，并向其他调查人员公开。 本研究将确定rTMS神经调节作用的可重复性，量化内在的 方法在个体内和个体间、跨分析水平（神经生理学和 行为）和大脑区域（M1与DLPFC）。这些结果将作为指导 规划、开发和解释所有未来利用rTMS调节大脑功能的研究。

ABSTRACT Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive brain stimulation technique capable of modulating activity in the targeted brain region and its connected brain circuits beyond the duration of the stimulation itself. rTMS is utilized in neuroscience research to investigate brain function during human cognition and behavior, and to understand brain pathophysiology in neuropsychiatric diseases. Clinically, rTMS protocols have diagnostic and therapeutic utility across a wide spectrum of disease states, and four rTMS devices are cleared by the Food and Drug Administration (FDA) for treatment of medication-resistant depression. However, the variability of the neuromodulatory effects of rTMS and its sources are ill-defined. This knowledge gap represents a fundamental limitation for both, the interpretation of rTMS results and the design of studies. For example, it is challenging to calculate or assess the sample size for a study, and one cannot optimize rTMS parameters for an individual without knowing whether individual differences in rTMS response are reproducible. In addition, one cannot assume that rTMS protocols tested in motor cortex will produce similar neuromodulatory effects when administered to other brain regions. In this proposal we will use MRI-guided rTMS in combination with EMG, EEG and behavioral measures to characterize the variability of rTMS effects in primary motor cortex (M1) and in dorsolateral prefrontal cortex (DLPFC). In a cohort of 60 subjects, we will evaluate the inter-subject and intra-subject test-retest reliability of the modulatory effects of the most widely used rTMS protocols applied to M1. We will compare the impact of different rTMS protocols on corticospinal excitability (measured via motor-evoked potentials), cortical excitability (measured via simultaneous TMS-EEG), and motor performance (using a sequential finger tapping task). Each subject will undergo a total of 10 TMS-EMG-EEG-behavior sessions, evaluating repeated sessions of excitatory and inhibitory protocols. In a separate cohort of 60 subjects, we will evaluate the transfer of rTMS effects across brain regions by applying 10 Hz rTMS and iTBS to both M1 and DLPFC. Each subject will undergo a total of 10 TMS-EEG-behavior sessions contrasting stimulation protocols across regions (M1 versus DLPFC). All subjects will undergo extensive baseline assessment, including detailed exam, neuropsychological measures, structural and resting-state functional-connectivity MRI, computational modeling, laboratory and genetic testing, and EEG to identify predictors of inter-subject variability in response to rTMS. All data will be placed in a secure repository and made publicly accessible to other investigators. This study will define the reproducibility of the neuromodulatory effects of rTMS, quantifying the intrinsic variability of the method within and across individuals, across levels of analysis (neurophysiologic and behavioral) and brain regions (M1 versus DLPFC). These results will serve as a foundation to guide the planning, development and interpretation of all future studies utilizing rTMS to modulate brain function.