Investigating Network Plasticity Effects of Repetitive Brain Stimulation Following Invasive and Noninvasive Methods in Humans

项目摘要 这项以患者为导向的研究职业发展奖(K23)申请的目标是 支持开发新方法所需的额外培训、指导和经验 重复性脑刺激的颅内脑电分析 人类。重复脑刺激的一种形式是经颅磁刺激(TMS)。TMS有 彻底改变了神经精神疾病的治疗领域--这是一种新的、非侵入性的治疗方法 最常用于药物治疗的选项--难治性重度抑郁症。尽管如此，缓解率 从它的使用来看，是次优的，理想的刺激参数是未知的。 不理想的结果在很大程度上是由于我们对TMS神经生理学和 抗抑郁作用。TMS被认为是通过改变靶向大脑网络中的大脑兴奋性来发挥作用的 结构；对于抑郁症，这个目标是一个情绪网络，包括背外侧前额叶皮质。这个 大脑对重复刺激做出反应而改变兴奋性的能力被称为可塑性。非侵入性 测量可塑性的方法，如头皮脑电和磁共振成像(MRI)，通常是 不准确和不可靠的。该项目提出了一种侵入性表征大脑可塑性的新方法。 由颅内刺激(目标1)或TMS(目标2)诱导，具有精细的时空分辨率。这个 方法包括使用iEEG单脉冲诱发电位探测和量化兴奋性变化(a 癫痫患者重复刺激后的可塑性相关性)。网络连接配置文件将为 使用iEEG和静息状态MRI(AIM 3)进行分析，为侵入性和非侵入性之间提供独特的桥梁 非侵入性生理测量。这个项目测试了重复脑刺激的假设 (通过TMS和颅内刺激)将改变参数依赖的大脑兴奋性 这些影响将在受刺激的大脑网络的节点内最为明显。 更好地了解重复刺激如何通过大脑网络传播并改变大脑 兴奋性将重振迄今毫无结果的对目标参与和目标参与的可重现生物标志物的搜索 对这些新技术的治疗反应。这项研究的新方面包括TMS在人类中的应用 IEEG受试者，以及侵入性和非侵入性连接测量(IEEG)的独特组合 和核磁共振)，以深入表征刺激的网络效应。未来的发展方向是：1)使用这种方法 评估和改进新的脑刺激方案，以优化可塑性和治疗效果，以及2) 应用关于重复刺激网络效应的已学原理指导临床试验设计和 用于治疗其他脑部疾病，如抑郁症。爱荷华大学和这个导师团队 为落实这一建议提供丰富的研究环境和世界一流的设施。这些K23 这些活动符合我的长期职业目标，即优化治疗脑刺激，以改善患者护理。

Project Summary The goal of this Mentored Patient-Oriented Research Career Development Award (K23) application is to support the additional training, mentorship and experience needed to develop a new methodology for analyzing the effects of repetitive brain stimulation using intracranial electroencephalography (iEEG) in humans. One form of repetitive brain stimulation is transcranial magnetic stimulation (TMS). TMS has revolutionized the field of therapeutics for neuropsychiatric disorders – it is a novel, noninvasive treatment option used most commonly for medication-refractory major depressive disorder. Despite this, remission rates from its use are suboptimal and ideal stimulation parameters are unknown. Suboptimal outcomes are due in large part to our poor understanding of TMS neurophysiology and antidepressant effects. TMS is thought to work by altering brain excitability within a network of targeted brain structures; for depression, this target is an emotional network including the dorsolateral prefrontal cortex. The ability of the brain to change excitability in response to repeated stimuli is referred to as plasticity. Noninvasive methods of measuring plasticity, such as scalp EEG and magnetic resonance imaging (MRI), are often imprecise and unreliable. This project proposes a novel method to invasively characterize brain plasticity induced by intracranial stimulation (Aim 1) or TMS (Aim 2) with exquisite spatiotemporal resolution. The method involves using iEEG single-pulse evoked potentials to probe and quantify excitability change (a correlate of plasticity) after repetitive stimulation in epilepsy patients. Network connectivity profiles will be analyzed with both iEEG and resting state MRI (Aim 3) to provide a unique bridge between invasive and noninvasive physiology measures. This project tests the hypothesis that repetitive brain stimulation (delivered via TMS and intracranial stimulation) will alter brain excitability in a parameter-dependent manner, and these effects will be most pronounced within the nodes of the stimulated brain network. A better understanding of how repetitive stimulation propagates through brain networks and alters brain excitability will revitalize the to-date fruitless search for reproducible biomarkers of target engagement and treatment response with these new technologies. Novel aspects of this study include the use of TMS in human subjects with iEEG, and the unique combination of both invasive and noninvasive connectivity measures (iEEG and MRI) to deeply characterize network effects of stimulation. Future directions will be 1) using this method to evaluate and refine novel brain stimulation protocols to optimize plasticity and therapeutic efficacy, and 2) applying learned principles about network effects of repetitive stimulation to inform clinical trial design and therapeutic use in other brain disorders, such as depression. The University of Iowa and this mentor team provide a rich research environment and world-class facilities for implementing this proposal. These K23 activities align with my long-term career goal of optimizing therapeutic brain stimulation to improve patient care.