Biology and Biophysics of the Cortical Response to Transcranial Magnetic Stimulation

使用经颅磁刺激（TMS）作为治疗干预是FDA批准的治疗 抑郁症，强迫症和偏头痛，并显示出对其他大脑疾病的承诺。 TMS的吸引力在于它的安全性、非侵入性和良好的调节肿瘤细胞活性的能力。 大脑区域。在人类受试者中，仅在行为、认知、 或聚合生理效应（例如EMG、EEG、fMRI）。TMS的精细尺度反应和机制， 在对神经元和电路的生物物理和生物效应方面，仍然知之甚少。这 知识差距阻碍了TMS方案的合理设计，使研究人员和临床医生依赖于 试错法和从宏观数据中推断，以改进方法。缺乏 还原论的洞察力在针对非运动区域时特别有害，例如前额叶皮层， 例如由于EEG中的刺激伪像，即时神经响应的读出是不可用的。我们 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。 灵长类大脑该方法将神经生理学实验的直接单单位和局部场相结合 电位记录和多尺度计算模拟的神经回路在这两个初级运动皮层和 前额皮质目的1：建立单次和成对经颅磁刺激急性反应的环路机制 脉搏确定单个神经元和递归皮层回路的脉冲响应允许 详细检查生物物理学和生物学的神经募集在短时间尺度。的一个主要目标 然而，TMS治疗是为了实现受控的、持久的神经调节，因此在目标2中，我们将扩展相同的 神经生理学和建模方法来研究对重复TMS（rTMS）的反应。这里的目标 将量化rTMS脉冲串对神经系统长期变化的影响。 活动，因此，神经模拟将结合突触可塑性。关键是，在这两个目标中，我们将 在初级运动皮层进行实验和建模，其中脊髓电位记录和 肌电图可以补充皮层和前额叶皮层中的神经效应的直接读出，在前额叶皮层中， 皮质水平记录适合于表征神经调节作用。整个产品将是一个 实验和模型驱动的机制的理解TMS对皮层电路的影响，使一个 在解释经颅磁刺激效应方面取得了变革性进展。总的来说，这些结果将促进 这是一种更基于生物学的、合理的方法来设计用于神经调节的TMS协议。

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.