Determining whether TMS changes the brain through brain synaptic plasticity

经颅磁刺激(TMS)改变了神经精神疾病的治疗方法 尽管仍然存在许多限制。如果没有对TMS如何产生持久的机械理解 大脑的治疗变化，进展将是偶然的，TMS只会达到它的一小部分 潜力。在TMS中有可能的参数的无限组合，包括刺激强度， 频率、脉宽、开关时间、模式和解剖位置。此外，其中每一个都是通过 影响大脑的参数将根据大脑位置、区域细胞类型、电路和活动而变化 每种疾病的特定模式和大脑状态都将决定结果。因此，至关重要的是 建立TMS作用的基本机制，使TMS的爆发具有临床导向， 假说驱动的研究将有一个机械论的理论基础。 在突触可塑性的广泛动物工作的基础上，我将在基础神经生物学方面架起桥梁 在我的论文中所学到的学习和认知机制与TMS的翻译工作 在实习期间学习以解决TMS研究中的主要差距：它如何产生持久的 大脑的治疗变化？解决这个问题的机械论方法基本上还没有得到检验。我 假设兴奋性TM(包括高频重复TM和间歇性Theta-Burst 刺激(TBS)诱导长时程增强(LTP)，抑制TMS(包括低频 RTMS和持续TBS)可诱发长期抑郁(LTD)。这两个过程都依赖于 神经元和NMDA受体活性，两者都受到抑制性γ-氨基丁酸的影响 酸(GABA)神经支配。 我建议在健康的人体受试者中进行一系列实验，结合药物治疗 LTP和LTD通过TMS治疗方案级联到运动皮质。电生理学 用肌电(EMG)评估运动诱发电位(MEP)的方法将允许进一步 阐明谷氨酸能对GABA能输入的贡献，并将直接影响 刺激策略。对TMS引起的大脑变化的机械性理解可能会释放 它的全部治疗潜力，从而改变了大脑疾病的治疗。

Transcranial Magnetic Stimulation (TMS) has transformed the approach to neuropsychiatric illness although many limitations remain. Without a mechanistic understanding of how TMS produces lasting therapeutic changes in the brain, advances will be serendipitous and TMS will only reach a fraction of its potential. There are unlimited combinations of parameters possible in TMS including stimulation intensity, frequency, pulse width, time on and off, patterns, and anatomic location. Moreover, the way each of these parameters affect the brain will change based on brain location, regional cell types, circuits and activity patterns specific to each disorder, and brain state will all determine outcome. It is therefore essential to establish the basic mechanism of TMS effects, so that the explosion of clinically-orientated, hypothesis-driven research will have a mechanistic rationale. Building on the extensive animal work in synaptic plasticity, I will bridge the basic neurobiological mechanisms of learning and cognition learned in my dissertation with the translational work of TMS I have learned during residency to address the major gap in TMS research: how does it produce lasting therapeutic changes in the brain? A mechanistic approach to this question remains essentially untested. I hypothesize that excitatory TMS (including high-frequency repetitive (r)TMS and intermittent theta-burst stimulation (TBS)) induces long-term potentiation (LTP), and inhibitory TMS (including low-frequency rTMS and continuous TBS) induces long-term depression (LTD). Both of these processes depend on neuronal and NMDA receptor activity, and both are under the influence of inhibitory gamma-aminobutryric acid (GABA) innervation. I propose a series of experiments in healthy human subjects combining pharmacologic manipulation of the LTP and LTD cascades with TMS treatment protocols to the motor cortex. Electrophysiologic approaches assessing motor evoked potentials (MEPs) with electromyography (EMG) will allow further elucidation of the contribution of glutamatergic versus GABAergic inputs, and will directly impact stimulation strategies. A mechanistic understanding of TMS-induced changes to the brain could unleash its full therapeutic potential, and thereby, transform the treatment of brain disorders.