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 调节靶脑区及其连接的脑回路的活动超过持续时间 刺激本身。RTMS被用于神经科学研究，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。临床上，rTMS方案 在广泛的疾病状态下具有诊断和治疗作用，四种rTMS设备是 被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的神经调节作用及其来源的变异性还不清楚。这一知识 GAP是对rTMS结果的解释和研究设计的基本限制。 例如，计算或评估一项研究的样本量是具有挑战性的，而且无法优化 用于个人的rTMS参数，而不知道rTMS响应中的个体差异是否 可重现的。此外，人们不能假设在运动皮质中测试的rTMS方案会产生类似的结果。 当给药到其他大脑区域时，会产生神经调节效应。 在这项建议中，我们将使用MRI引导的rTMS结合EMG、EEG和行为测量来 表征初级运动皮质(M1)和背外侧前额叶皮质rTMS效应的变异性 (DLPFC)。在60名受试者中，我们将评估受试者间和受试者内的重测信度 适用于M1的最广泛使用的rTMS协议的调制效应。我们将比较 不同rTMS方案对皮质脊髓兴奋性(通过运动诱发电位测量)的影响 兴奋性(通过同时的TMS-EEG测量)和运动性能(使用连续的手指敲击 任务)。每个受试者将接受总共10次TMS-EMG-EEG-行为测试，重复评估 兴奋和抑制方案的会议。在一个由60名受试者组成的单独队列中，我们将评估转移 通过将10赫兹rTMS和ITBS应用于M1和DLPFC，研究rTMS对大脑各区域的影响。每个科目 将接受总共10次TMS-EEG行为会话，以对比不同区域(M1)的刺激方案 对DLPFC)。所有科目都将接受广泛的基线评估，包括详细的考试， 神经心理测量，结构和静息状态功能连通性磁共振成像，计算 建模、实验室和基因测试，以及EEG，以确定受试者之间反应差异的预测因素 转到rTMS。所有数据将被放置在一个安全的储存库中，并向其他调查人员公开访问。 这项研究将定义rTMS的神经调节作用的重复性，量化内在的 该方法在个体内和跨个体、不同分析水平(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 利用rTMS调节大脑功能的所有未来研究的规划、开发和解释。

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.