Enhancement of Hippocampal Plasticity Using Repetitive Transcranial Magnetic Stimulation

新出现的证据表明，海马突触可塑性的功能障碍， 阿尔茨海默病（AD）进展过程中的神经元变性，是阿尔茨海默病（AD）的标志之一， 认知障碍虽然目前没有有效的疾病修饰治疗， AD，最近在AD动物模型中的临床前研究表明，重复经颅 磁刺激（rTMS）促进海马突触可塑性，并最终改善 学习和记忆能力。在这个应用中，我们将利用基于MRI的神经元连接 图作为指导，以精确传播由浅表rTMS引起的神经元兴奋 脉搏传到海马体这种图像引导方法的前提得到了以下两方面的支持： 先前发表的健康成人研究和我们在轻度遗忘症患者中的初步数据 认知障碍（aMCI）。我们的初步研究结果表明， 在结构上与海马体相连的大脑表层区域进行rTMS， 瞬时调节海马活动并增强联想记忆功能。具体 本研究的目的是：1）确定海马rTMS对记忆的行为效应 功能，2）验证MRI引导的rTMS对海马功能连接的影响;以及3） 制定一个个性化的图像引导海马rTMS方案60名aMCI患者 将入组双盲、随机、假对照、交叉研究， rTMS条件：兴奋刺激、抑制刺激和假刺激。每个 受试者将在每种情况下完成10次刺激，间隔4周， 条件，以避免潜在的遗留效应。在初步数据的基础上， 严格检验我们的假设，即主动rTMS协议对 记忆功能和海马功能连接，与假rTMS相比， 患有aMCI的人此外，从目标1和2获得的数据将用于制定 统计模型来预测对rTMS干预的反应。拟议的研究使用 以精准医学为基础的干预措施，提供一个创新平台， （包括功能性MRI和弥散张量成像）和rTMS，以改善记忆功能， 患有aMCI的人该项目代表了开发非侵入性 海马刺激方案，这将大大有利于阿尔茨海默病患者。

Emerging evidence indicates that dysfunction of hippocampal synaptic plasticity, which precedes neuronal degeneration during the progression of Alzheimer's disease (AD), underlies the hallmark cognitive impairment. Although there are currently no effective disease modifying treatments for AD, recent preclinical studies in animal models of AD have suggested that repetitive transcranial magnetic stimulation (rTMS) promotes hippocampal synaptic plasticity and, ultimately, improves learning and memory abilities. In this application, we will utilize MRI-based neuronal connectivity maps as a guide to precisely propagate the neuronal excitation elicited by the superficial rTMS pulse to the hippocampus. The premise of this image-guided approach is supported by both previously published research in healthy adults and our pilot data in individuals with amnestic mild cognitive impairment (aMCI). Our preliminary findings demonstrate that applying a single dose of rTMS over a superficial brain region that is structurally connected to the hippocampus can transiently modulate hippocampal activity and enhance associative memory function. The specific aims of this project are to 1) determine the behavioral effect of hippocampal rTMS on memory function, 2) verify MRI-guided rTMS effects on hippocampal functional connectivity; and 3) develop a personalized, image-guided hippocampal rTMS protocol. Sixty individuals with aMCI will be enrolled in the double-blind, randomized, sham-controlled, crossover study with three rTMS conditions: excitatory stimulation, inhibitory stimulation, and sham stimulation. Each participant will complete 10 stimulation sessions for each condition with a 4-week interval between conditions to avoid potential carry-over effects. Building on preliminary data, here we will rigorously test our hypothesis that active rTMS protocols have a stronger modulation effect on both memory function and hippocampal functional connectivity, compared with sham rTMS in individuals with aMCI. Furthermore, data acquired from aims 1 and 2 will be used to develop statistical models to predict responses to rTMS intervention. The proposed research uses interventions grounded in precision medicine to provide an innovative platform that integrates MRI (including functional MRI and diffusion-tensor imaging) and rTMS to improve memory function in individuals with aMCI. This project represents a critical step in developing a non-invasive hippocampal stimulation protocol that should greatly benefit patients with Alzheimer's disease.