Cellular Mechanisms of Transcranial Magnetic Stimulation in Cerebellar Cortex

翻译后摘要：我们的目标是开发一个细胞水平的理解如何经颅磁刺激（TMS） 可以使用（i）体外电生理测量激活人小脑（Cb）中的神经元 海龟Cb，（ii）组织中的感应电场（E）的计算建模，以及（iii）MEG-EEG-TMS 人类扫视研究。由于Cb的局部显微解剖学和电生理学在进化上 从爬行动物到人类，基本的神经动力学很可能会普遍化。在目标1a中，我们 将使用我们的新的高分辨率电场计算方法（BEM-FMM）开发一个彻底的 了解体外组织（完整、切片）内的感应电场。我们的模拟将展示 体外制备中的电导率边界可以扭曲、削弱甚至逆转TMS诱导的电场 组织内部。计算的电场值将通过双极电极进行实验验证。在Aim中 图1b中，我们将研究最佳浴槽、组织和TMS线圈几何形状，以在 组织和设计一个通量集中器，以提供一个统一的强电场切片研究。在目标2a中，我们将 记录体外海龟Cb（完整，切片）对TMS的细胞外和细胞内反应。由于神经元 Cb中的元素（平行纤维（PF）、浦肯野细胞（PC）和PC轴突）以相互正交的方式排列 方向，我们将使电场沿着每个轴定向，以便选择性地刺激不同的细胞群， 确定相应的电场阈值。在目标2b中，我们将通过选择性的电 刺激攀爬纤维（CF）（通过下橄榄）和PF（通过脑桥，颗粒细胞和 MF）。我们还将在Cb悬垂的传入束上应用TMS，并测量内部的反应。 和细胞外。在目标3a中，我们将使用我们中的一个人开发的扫视任务来可靠地激活两个焦点。 区域在人类Cb和本地化和表征这些来源使用MEG-EEG。在目标3b中，我们将 使用我们新的电场计算方法计算人体Cb中的电场，并指定TMS 用于产生电场匹配的参数，在目标1-2中找到了PC和PF。在目标3c中，我们将使用 通过激活来自Aim 3a的焦点Cb区域对扫视进行TMS调制。TMS将应用于 不同的电流、线圈方向和电场极性。将监测经颅磁刺激对扫视的影响 眼动仪和同步脑电图EEG将与TMS诱导的反应进行比较， 目标2中的乌龟。我们希望这种方法将提供边界元模拟（目标1）， 海龟研究（目标2）和人类Cb研究（目标3），并导致更好地了解细胞 这为TMS在研究Cb在人脑功能中的作用开辟了新的应用领域。

Abstract: Our goal is to develop a cellular level understanding of how transcranial magnetic stimulation (TMS) may activate neurons in the human cerebellum (Cb) using (i) electrophysiological measurements in an in vitro turtle Cb, (ii) computational modeling of the induced electric (E) fields in the tissue and (iii) an MEG-EEG-TMS human saccade study. Since the local microanatomy and electrophysiology of the Cb are evolutionarily conserved from reptiles to man, it is likely that the fundamental neural dynamics will generalize. In Aim 1a, we will use our novel high-resolution E-field computation method (BEM-FMM) to develop a thorough understanding of the induced E-field inside the in vitro tissue (intact, slice). Our simulations will show how the conductivity boundaries in in vitro preparations can distort, weaken or even reverse the TMS-induced E-field inside the tissue. The computed E-field values will be verified experimentally with a bipolar electrode. In Aim 1b, we will investigate the optimal bath, tissue and TMS coil geometry for producing the required E-field in the tissue and design a flux concentrator to provide a uniform strong E-field for slice studies. In Aim 2a, we will record extracellular and intracellular responses to TMS in the turtle Cb in vitro (intact, slice). Since the neuronal elements in the Cb (parallel fibers (PF), Purkinje cells (PC) and PC axons) are arranged in mutually orthogonal directions, we will orient the E-field along each axis so as to selectively stimulate different cell populations and determine the corresponding E-field threshold. In Aim 2b, we will activate the PC via selective electrical stimulation of the climbing fibers (CF) (via the inferior olive) and the PF (via the pons, granule cells and the MF). We will also apply TMS on the afferent bundles in the Cb penduncle and measure the responses intra- and extracellularly. In Aim 3a, we will use a saccade task developed by one of us to reliably activate two focal regions in the human Cb and localize and characterize these sources using MEG-EEG. In Aim 3b, we will compute the E-field in the human Cb using our novel E-field computation method and specify the TMS parameters for producing an E-field matching that found in Aims 1-2 for PC and PF. In Aim 3c, we will use TMS-modulation of the saccade by activating the focal Cb regions from Aim 3a. The TMS will be applied at different latencies, coil orientations and E-field polarities. The effect of TMS on the saccade will be monitored using EOG, eye tracker and concurrent EEG. The EEG will be compared to TMS-induced responses from turtle in Aim 2. We expect that this approach will provide a direct link between the BEM simulations (Aim 1), the turtle studies (Aim 2) and the human Cb study (Aim 3) and result in a greater understanding of the cellular basis of TMS thus opening new applications of TMS for studying the role of the Cb in human brain function.