Investigating the neural mechanisms of repetitive brain stimulation with invasive and noninvasive electrophysiology in humans

项目总结 抑郁症是全球残疾的主要原因，也是美国疾病负担的主要原因 到三分之一的抑郁症患者经历了难治性抑郁症，其定义为未能达到 在两次或两次以上的药物试验后有足够的改善。在过去的几年里，精神病学领域的重大进步 20年来，一种治疗难治性抑郁症的非药物选择的发展 重复经颅磁刺激(RTMS)。RTMS已被证明是一种有效的治疗方法。 患有耐药性抑郁症。虽然这是一个重大的进步，但大约一半的患者并没有 从rTMS中受益于抑郁症，原因尚不清楚。优化rtms的主要障碍之一 提高从rTMS中受益的患者的百分比是对以下方面的缺乏理解 RTMS如何工作以及为什么工作的基本机制。这一领域以前的工作由于严重依赖于 无创性测量大脑活动(功能磁共振、脑电)和行为，以评估潜在的 RTMS的机制。这些方法在时空分辨率方面有固有的局限性，尽管 几十年的研究还没有发现对其作用机制的令人满意的理解 人类的rTMS。目前的提案旨在应用一种新的方法，将侵入性和 评估rTMS效果的非侵入性方法，其时空分辨率远高于 到目前为止都是可能的。由于癫痫患者的临床原因，外科手术植入了颅内电极， 这项提议利用了这种独特的能力，可以直接从人脑中记录 用于治疗抑郁症的刺激方案的实施。我们的目标是确定关键的特征 大脑对重复剂量rTMS的反应特征与无与伦比的 使用颅内记录的空间和时间分辨率。我们通过评估颅内的 聚焦电刺激的效果，以最大限度地集中注意力和最大限度地减少感官影响(目标1)，翻译 通过测量rTMS的颅内效应无创刺激(目标2)，并平移颅内 使用同时测量的头皮脑电进行非侵入性记录(目标3)。我们的中心假设是 RTMS可预测地改变局部和下游地区的诱发反应和振荡功率，以及 这些变化在与抑郁相关的大脑区域的rTMS会话中累积。如果成功，这将是 该项目将通知非侵入性脑电特征，rTMS反应可追溯到颅内 生理学。通过将头皮脑电信号与可靠的神经来源联系起来，这些标记可以被利用来 优化现有治疗方法，开发新疗法，治疗效果总体明显提高。

PROJECT SUMMARY Depression is the leading cause of disability worldwide and the leading cause of disease burden in the U.S. Up to a third of depressed individuals experience treatment-resistant depression, defined as the failure to achieve adequate improvement after two or more medication trials. A major advance in the field of psychiatry in the last 20 years is the development of a non-pharmacological option for treatment resistant depression using repetitive transcranial magnetic stimulation (rTMS). rTMS has proven an effective treatment modality for those with medication-resistant depression. While this represents a major advance, about half of patients do not benefit from rTMS for depression, and it is not clear why. One of the major impediments to optimizing rTMS and improving the percentage of patients who benefit from rTMS is a lack of understanding with regards to the basic mechanisms of how and why rTMS works. Prior work in this field has been limited by relying heavily on non-invasive measures of brain activity (functional MRI, EEG) and behavior to assess the underlying mechanisms of rTMS. These methods have inherent limitations in spatiotemporal resolution and despite several decades of research have not uncovered a satisfactory understanding of the mechanisms of action of rTMS in humans. The current proposal aims to apply a novel approach that combines invasive and noninvasive methods to evaluate the effects of rTMS with much higher spatiotemporal resolution than has been possible to date. Intracranial electrodes are surgically implanted for clinical reasons in epilepsy patients, and this proposal takes advantage of that unique ability to record directly from the human brain during the administration of stimulation protocols used to treat depression. The goal is to characterize the key signatures of the brain’s response to repeated doses of rTMS with an unparalleled combination of spatial and temporal resolution using intracranial recordings. We do this by evaluating the intracranial effects of focused electrical stimulation to maximize focality and minimize sensory effects (Aim 1), translate stimulation noninvasively by measuring the intracranial effects of rTMS (Aim 2), and translate intracranial recordings noninvasively using simultaneously measured scalp EEG (Aim 3). Our central hypothesis is that rTMS predictably changes evoked responses and oscillatory power locally and in downstream regions, and these changes accumulate across rTMS sessions in brain regions relevant to depression. If successful, this project will inform noninvasive EEG signatures of rTMS response that can be traced back to intracranial physiology. By relating scalp EEG signatures to reliable neural sources, these markers can be leveraged to optimize current treatments, develop new treatments, and overall markedly improve treatment efficacy.