Biology and Biophysics of the Cortical Response to Transcranial Magnetic Stimulation

使用经颅磁刺激(TMS)作为治疗干预手段已获FDA批准用于治疗 抑郁症、强迫症和偏头痛，并显示出对许多其他大脑疾病的希望。 TMS的吸引力在于它的安全性、非侵入性和成熟的调节活动的能力 大脑区域。在人类受试者中，这种调节只在行为，认知， 或综合生理效应(如肌电、脑电、功能磁共振)。TMS的细微尺度反应和机制， 在生物物理和生物学对神经元和电路的影响方面，人们仍然知之甚少。这 知识差距阻碍TMS方案的合理设计，并使研究人员和临床医生依赖于 从宏观数据中试错方法和推论，以改进方法。缺乏 当瞄准非运动区时，简约主义的洞察力尤其有害，例如前额叶皮质 例如，由于EEG中的刺激伪影，无法获得即时神经反应的读数。我们的 总体目标是通过研究非人类TMS的神经回路机制来填补这一知识空白 灵长类动物的大脑。该方法结合了神经生理学实验的直接单元场和局部野。 初级运动皮质和大脑皮层神经回路的电位记录和多尺度计算模拟 前额叶皮质。目的1是建立对单个和成对TMS的急性反应的回路机制 脉搏。确定单个神经元件和经常性皮质回路的脉冲响应允许 在短时间尺度上详细检查神经招募的生物物理学和生物学。的一个主要目标 然而，TMS治疗是为了实现可控的、持久的神经调节，所以在目标2中，我们将扩展同样的治疗 神经生理学和建模方法研究重复TMS(RTMS)反应。这里的目标是 神经生理学的研究将是量化rTMS脉冲串对神经的长期变化的影响 因此，神经模拟将包含突触的可塑性。关键是，在这两个目标中，我们都将 在初级运动皮质进行实验和建模，在那里脊髓电位记录和 肌电图仪可以补充直接读出大脑皮质和前额叶皮质的神经效应，而只有 大脑皮层水平的记录适合描述神经调节效应。整个产品将是一个 实验和模型驱动的对TMS对皮质回路影响的机制理解，使 TMS效应解释中的变革性进展。总而言之，这些结果将促进 为神经调节设计TMS方案的更有生物学基础的、理性的方法。

The use of transcranial magnetic stimulation (TMS) as a therapeutic intervention is FDA-cleared for treating depression, obsessive-compulsive disorder, and migraine, and shows promise for a host of other brain disorders. The appeal of TMS is its safety, non-invasiveness, and well-established capacity for modulating the activity of brain regions. In human subjects, that modulation is assessed only at the gross scale of behavioral, cognitive, or aggregate physiological effects (e.g. EMG, EEG, fMRI). The fine-scale responses and mechanisms of TMS, at the level of biophysical and biological effects on neurons and circuits, remain poorly understood. This knowledge gap hinders rational design of TMS protocols and leaves researchers and clinicians dependent on trial-and-error approaches and inferences from macroscopic data to improve the methodology. The lack of reductionistic insight is particularly detrimental when targeting non-motor areas such as prefrontal cortex where a readout of the immediate neural response is unavailable, for example due to the stimulus artifact in EEG. Our overall goal is to fill in this knowledge gap by studying the neural circuit mechanisms of TMS in the non-human primate brain. The approach integrates neurophysiological experiments featuring direct single-unit and local field potential recordings and multiscale computational simulations of neural circuits in both primary motor cortex and prefrontal cortex. Aim 1 is to establish the circuit mechanisms of acute responses to single and paired TMS pulses. Determining the pulse response of single neural elements and recurrent cortical circuits permits a detailed examination of the biophysics and biology of neural recruitment at a short time scale. A main goal of TMS therapy is to achieve controlled, lasting neuromodulation, however, so in Aim 2 we will extend the same neurophysiological and modeling approaches to the study of responses to repetitive TMS (rTMS). Here the goal of the neurophysiology will be to quantify the effects of rTMS pulse trains on long-lasting changes in neural activity and, accordingly, the neural simulations will incorporate synaptic plasticity. Critically, in both Aims we will conduct the experiments and modeling both in primary motor cortex, where spinal potential recordings and electromyography can supplement direct readout of neural effects in cortex, and prefrontal cortex, where only cortical-level recordings are suited to characterize neuromodulatory effects. The overall product will be an experiment- and model-driven mechanistic understanding of the effect of TMS on cortical circuits, enabling a transformational advance in the interpretation of the effects of TMS. Taken together, the results will promote a more biologically-grounded, rational approach to designing TMS protocols for neuromodulation.