Rational Design of TMS for Neuromodulation

描述（由申请人提供）：经颅磁刺激（TMS）是一种探测和调节人脑功能的非侵入性方法。它被批准用于治疗抑郁症和术前皮质测绘；它在其他神经和精神疾病方面也显示出前景。然而，经颅磁刺激对神经元活动的确切影响尚不清楚。这种知识上的差距使我们无法以生物学为基础，合理地设计经颅磁刺激方案。为了填补这一空白，我们需要对经颅磁刺激对大脑神经元的影响有一个更好的机制理解，并需要一个“剂量-反应”曲线数据库，该数据库描述了经颅磁刺激参数（“剂量”）的选择与神经元活动（“反应”）的变化之间的关系。我们的项目旨在提供这样的机制洞察力和经验数据。我们的跨学科团队开发了一套新的工具和技术，使我们能够操纵经颅磁刺激参数，模拟产生的电磁场和神经元反应，并在应用经颅磁刺激时记录大脑神经元。在我们的第一组实验（目标1）中，我们将改变经颅磁刺激的时间参数。使用定制的TMS脉冲发生器，我们将系统地改变单个脉冲的外观（脉冲波形）以及它们如何依次应用（脉冲序列）。刺激区的同时记录将确定各种参数如何调节轴突、兴奋性神经元和抑制性神经元的放电速率。其次（目标2），我们将使用不同的线圈位置和类型的刺激线圈来改变TMS的空间参数，包括猕猴尺度的近似传统的数字8线圈以及最近批准用于抑郁症治疗的较少焦点线圈（H线圈）。同时在大脑中有针对性的记录，我们将绘制不同皮层区域的神经反应图。在这些实证研究的同时，我们将构建个体的、真实的、基于mri的头部模型，并结合神经反应模型，分别模拟各种神经元类型的电场空间分布和由此产生的反应。模拟将指导和借鉴经验神经记录，增强我们对经颅磁刺激机制的理解，并提供一种新的模拟工具，可以为经颅磁刺激剂量提供信息。这个项目的最终结果将是发现经颅磁刺激如何在单个神经元和简单电路的水平上影响大脑。结果应该是革命性的，可以帮助研究人员和临床医生驾驭经颅磁刺激的巨大参数空间，以便它可以更有效地用作神经科学的探针和临床治疗。

DESCRIPTION (provided by applicant): Transcranial magnetic stimulation (TMS) is a non-invasive method for probing and modulating human brain function. It is approved for the treatment of depression and pre-surgical cortical mapping; it also shows promise in other neurological and psychiatric disorders. Exactly what TMS does to neuronal activity, however, remains unknown. This gap in our knowledge precludes us from biologically-based, rational design of TMS protocols. To fill this gap, we need a better mechanistic understanding of the effect of TMS on cerebral neurons and a database of "dose-response" curves that describe how the selection of TMS parameters (the "dose") relates to changes of neuronal activity (the "response"). Our project aims to contribute such mechanistic insight and empirical data. Our interdisciplinary team has developed a novel repertoire of tools and techniques that permit us to manipulate the TMS stimulus parameters, model the resulting electromagnetic fields and neuronal responses, and record from cerebral neurons while TMS is applied. In our first set of experiments (Aim 1), we will vary the temporal parameters of TMS. Using a custom TMS pulse generator, we will systematically change what the individual pulses look like (the pulse waveform) and how they are applied sequentially (the pulse train). Concomitant recordings in the zone of stimulation will determine how the various parameters modulate the firing rates of axons, excitatory neurons, and inhibitory neurons. Second (Aim 2), we will vary the spatial parameters of TMS using various coil locations and types of stimulation coils, including macaque-scaled approximations to conventional figure-8 coils as well as less focal coils recently approved for depression treatment (H coils). With simultaneous targeted recordings in the brain we will map the neural response in various cortical regions. In parallel to these empirical studies, we will construct individual, realistic, MRI-based head models coupled with neural response models to simulate, respectively, the electric field spatial distribution and the resultin response of various neuron types. The simulations will both guide and be informed by the empirical neural recordings, enhancing our understating of the mechanisms of TMS and providing a novel simulation tool that could inform TMS dosage. The end result of this project will be to discover how TMS influences the brain at the level of single neurons and simple circuits. The outcome should be transformative in helping researchers and clinicians to navigate the vast parametric space of TMS so that it may be used more effectively as a probe in neuroscience, and as a clinical treatment.