Rational Design of TMS for Neuromodulation

描述(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手术前皮质标测；它在其他神经和精神疾病方面也显示出希望。然而，TMS对神经元活动的确切作用仍不清楚。我们知识上的这种差距使我们无法进行基于生物学的、合理的TMS方案设计。为了填补这一空白，我们需要更好地从机制上理解TMS对大脑神经元的影响，并建立一个“剂量-反应”曲线数据库，描述TMS参数(“剂量”)的选择如何与神经元活动(“反应”)的变化有关。我们的项目旨在提供这种机械性的见解和经验数据。我们的跨学科团队开发了一系列新颖的工具和技术，使我们能够操纵TMS刺激参数，模拟产生的电磁场和神经元反应，并在应用TMS时记录大脑神经元的数据。在我们的第一组实验(目标1)中，我们将改变TMS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)以及它们的顺序施加方式(脉冲序列)。刺激区的伴随记录将决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，包括猕猴比例的近似传统的8字形线圈以及最近被批准用于抑郁症治疗的较少焦点的线圈(H线圈)。有了大脑中的同步定向记录，我们将绘制出不同皮质区域的神经反应图。在这些经验研究的同时，我们将构建基于MRI的个体头部模型和神经反应模型，以分别模拟不同类型神经元的电场空间分布和结果响应。模拟将指导和信息的经验神经记录，加强我们对TMS的机制的低估，并提供了一种新的模拟工具，可以告知TMS剂量。这个项目的最终结果将是发现TMS如何在单个神经元和简单电路的水平上影响大脑。结果应该是变革性的，帮助研究人员和临床医生在TMS的巨大参数空间中导航，以便它可以更有效地用作神经科学的探针，并作为临床治疗。

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.