Impact of Timing, Targeting, and Brain State on rTMS of Human and Non-Human Primates

刺激人脑的非侵入性方法为安全、有效的治疗带来了巨大希望 精神和运动障碍，并广泛用于人类行为和疾病的基础研究 认知。其中一种方法是经颅磁刺激（TMS），它是应用时变 头皮上方的磁场会在大脑中感应出瞬态电场。 TMS 明显刺激 大脑并影响行为，但我们不知道它为什么起作用；它对大脑区域内神经活动的影响 网络在生物学层面上还没有被理解。该项目旨在确定影响的神经基础 由应用于脉冲序列的 TMS 引起，称为重复 TMS (rTMS)，这是一种由 FDA 治疗抑郁症。利用我们在并发单项期间应用 TMS 方法的专业知识 非人类灵长类动物的神经元记录技术以及人类的成像和头皮电位技术 （fMRI 和 EEG），我们的目标是解决 rTMS 设计和应用中的三个相互关联的问题：计时、 空间目标以及与大脑状态的相互作用。在所有研究中，神经元对 rTMS 的反应将是 在人类和非人类灵长类动物执行视觉运动任务时进行量化，该任务允许系统地 操纵大脑活动和认知状态。在这两个物种中，我们将重点关注特定的运动选择性 大脑区域、MT 以及与其连接的电路。首先，我们将确定定时对脉冲的影响 rTMS 期间传递的序列。我们将系统地权衡频率与传递的脉冲数量 当人类和非人类灵长类动物执行任务时，大脑活动和行为表现 被监控。 rTMS 时间参数的明确剂量反应关系将为两者建立 种。其次，我们将评估简单但原则性的分布式网络空间定位方法。 基于白质连接成像和 rTMS 诱导神经激活的计算模型， 我们将研究 TMS 线圈的位置和方向如何差异性地招募两条主要通路， 视觉系统的背侧和腹侧流从它发出。第三，我们要解决根本问题 rTMS 如何与大脑内源性活动相互作用的问题。通过操纵任务需求，我们将 系统地控制大脑状态并量化这如何改变 rTMS 对神经活动的影响， 认知表现。总而言之，该项目将产生一个多尺度数据集，将非 通过实验从人类灵长类动物到人类，这些实验应该很好地推广到其他大脑的研究 皮质回路。结果将有助于将依赖于试错测试的方法推进 rTMS 朝着建立在明确的生物学原理基础上的方向发展。

Non-invasive methods for stimulating the human brain show great promise for safe, effective treatments of psychiatric and motor disorders, and are in widespread use for basic research on human behavior and cognition. One such method, transcranial magnetic stimulation (TMS), is the application of time-varying magnetic fields above the scalp that induce transient electrical fields in the brain. TMS clearly stimulates the brain and affects behavior, but we do not know why it works; its effects on neural activity within brain regions and networks are not understood at a biological level. This project seeks to determine the neural basis of effects caused by TMS as applied in sequences of pulses, known as repetitive TMS (rTMS), a technique approved by the FDA for depression. Leveraging our expertise in application of TMS methodology during concurrent single neuron recording techniques in non-human primates and imaging and scalp potential techniques in humans (fMRI and EEG), we aim to resolve three interlocking problems in the design and application of rTMS: timing, spatial targeting, and interactions with brain state. In all studies, neuronal responses to rTMS will be quantified in human and non-human primates as they perform a visual motion task that allows systematic manipulation of brain activity and cognitive state. In both species, we will focus on a specific motion-selective brain area, MT, and the circuits that connect with it. First, we will determine the effects of timing on the pulse sequences delivered during rTMS. We will systematically trade off frequency with number of pulses delivered as human and non-human primates perform the task and brain activity and behavioral performance are monitored. Definitive dose-response relationships for rTMS temporal parameters will be established for both species. Second, we will assess simple but principled methods for spatial targeting of distributed networks. Based on imaging of white-matter connectivity and computational models of rTMS-induced neural activation, we will examine how location and orientation of the TMS coil differentially recruits two major pathways that emanate from it, the dorsal and ventral streams of the visual system. Third, we will tackle the fundamental question of how rTMS interacts with endogenous activity in the brain. By manipulating task demands, we will systematically control brain state and quantify how this alters the influence of rTMS on neural activity and cognitive performance. Taken together, this project will yield a multi-scale data set that links results from non- human primates to humans through experiments that should generalize well to the study of other cerebral cortical circuits. The results will help to advance rTMS from a method that relies on trial-and-error testing toward one that is founded on clear biological principles.