Cellular Mechanisms of Transcranial Magnetic Stimulation in Cerebellar Cortex

摘要：我们的目标是发展对经颅磁刺激(TMS)的细胞水平的理解。 可以激活人小脑(CB)中的神经元，使用(I)体外电生理测量 海龟CB，(Ii)组织中感应电场的计算模拟和(Iii)MEG-EEG-TMS 人类扫视研究。由于CB的局部显微解剖和电生理是进化的 从爬行动物到人类，基本的神经动力学很可能会得到推广。在目标1a中，我们 将使用我们新的高分辨率电场计算方法(BEM-FMM)来开发一种彻底的 对体外组织(完整切片)内诱导电场的理解。我们的模拟将展示 体外制剂中的电导边界可以扭曲、减弱甚至逆转TMS诱导的电场 在组织内部。计算的电场值将用双极电极进行实验验证。在AIM 1B，我们将研究产生所需电场的最佳浴池、组织和TMS线圈几何形状 组织，并设计了一个通量集中器，为切片研究提供一个均匀的强电场。在目标2a中，我们将 在体外(完整切片)记录甲鱼脐带血对TMS的细胞外和细胞内反应。因为神经元 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，我们将沿每个轴定向电场，以选择性地刺激不同的细胞群和 确定相应的电场阈值。在目标2b中，我们将通过选择性电子方式激活PC 刺激攀援纤维(CF)(通过下橄榄)和PF(通过桥脑、颗粒细胞和 Mf)。我们还将对CB悬臂中的传入束应用TMS，并测量内部的反应。 以及细胞外。在目标3a中，我们将使用我们其中一人开发的扫视任务来可靠地激活两个焦点 并使用脑磁图对这些来源进行定位和表征。在目标3b中，我们将 使用我们新的电场计算方法计算了人体脐带血中的电场，并指定了TMS 用于产生匹配于用于PC和PF的AIMS 1-2中的电场的参数。在Aim 3c中，我们将使用 TMS-通过激活来自AIM 3a的焦点CB区域来调制眼跳。TMS将在 不同的潜伏期、线圈方向和电场极性。TMS对眼跳的影响将被监测 使用EOG、眼球跟踪器和并发EEG。脑电波将与TMS诱发的反应进行比较 我们期望这种方法将在边界元模拟(目标1)、 海龟研究(目标2)和人类CB研究(目标3)，并导致对细胞 从而为研究CB在人脑功能中的作用开辟了TMS的新应用。

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.