Investigating the molecular, cellular and circuit effects of transcranial magnetic stimulation

摘要 经颅磁刺激（TMS）是一种无创性脑刺激方法， 以安全的方式在人体内活动。由于其易于应用和针对特定大脑区域的能力， 经颅磁刺激（rTMS）的重复应用具有增强甚至取代经典药理学的潜力。 治疗策略然而，由于涉及其应用的巨大参数空间（振幅， 线圈位置和取向），最佳的，即，rTMS的个性化刺激参数非常难以 决定。最重要的是，优化TMS刺激参数的原则性努力受到严重限制 对分子和细胞机制的理解不足。体外记录和功能光学 切片制备中的成像允许直接评估TMS电场与神经元的相互作用， 高度受控的环境，并允许快速扫描人体无法实现的刺激参数 问题研究非人灵长类动物（NHP）模型由于其相似性而非常适合研究TMS的回路效应 以及进行侵入性记录以测量对TMS的电生理反应的能力。 计算模型可以预测TMS在神经组织中的电场分布，从而允许将神经组织中的电场耦合到TMS。 TMS的生物物理学及其生理效应。 在这里，我们建议使用体外切片制备详细研究改变TMS参数的影响， NHP记录和计算建模。我们计划研究的分子，细胞和电路的影响， 经颅磁刺激有三个具体目的：1.）TMS刺激参数的系统研究 （刺激强度，线圈取向）。2)我们将测量 在NHP模型中改变TMS参数的电路效应。3)TMS电场的计算模拟 跨越尺度。 我们的研究结果将形成一个机械的理解之间的基础TMS电生物物理学 场及其生理效应。这可以成为未来努力改善非侵入性的基础。 刺激技术。

Abstract Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method which can alter brain activity in humans in a safe manner. Due its ease of application and ability to target specific brain regions, the repetitive application of TMS (rTMS) has the potential of augmenting or even replacing classic pharmacologic treatment-strategies. However, due to the enormous parameter space concerning its application (amplitude, coil position and orientation), optimal, i.e., personalized stimulation parameters for rTMS are very difficult to determine. Most importantly, principled efforts for optimizing TMS stimulation parameters are seriously limited by a poor understanding of molecular and cellular mechanisms. In-vitro recordings and functional optical imaging in slice preparations allow a direct assessment of the interaction of TMS electric fields with neurons in a highly controlled environment and allow for a rapid scan of stimulation parameters not achievable in human studies. Non-human primate (NHP) models are ideally suited to study circuit effects of TMS due their similarity to humans and the ability to perform invasive recordings to measure the electrophysiological response to TMS. Computational models can predict the electric field distribution of TMS in neural tissue, allowing to couple the biophysics of TMS with its physiological effects. Here, we propose to study the effects of changing TMS parameters in detail using in-vitro slice preparation, NHP recordings and computational modelling. We plan to study the molecular, cellular and circuit effects of transcranial magnetic stimulation in three specific aims: 1.) Systematic study of TMS stimulation parameters (stimulation intensity, coil orientation) in-vitro using mouse vs. rat hippocampal slices. 2) We will measure the circuit effects of varying TMS parameters in a NHP model. 3) Computational modelling of TMS electric fields across scales. Our findings will form the foundation for a mechanistic understanding between the biophysics of TMS electric fields and their physiological effects. This can form the basis for future efforts to improve noninvasive stimulation technologies.