Closing the loop: development of real-time, personalized brain stimulation

项目摘要 我们迫切需要有针对性的个性化治疗精神健康障碍， 近50%的美国人在我们的有生之年。脑刺激治疗，包括重复经颅 磁刺激（rTMS）代表了纠正大脑功能障碍的创新方法的前沿 为精神病患者建立的网络。rTMS是FDA批准的抑郁症和强迫症- 强迫症（OCD）与临床试验正在进行的创伤后应激障碍（PTSD）和物质 使用，除其他外。然而，正如目前管理的，rTMS缺乏生物标志物来单独优化 治疗，因此具有较差的临床反应率（<50%）。如果没有个性化的rTMS， 一种适用于所有精神疾病的通用治疗方法，与抗抑郁药的使用方式没有什么不同。 使用同时TMS和脑电图（TMS-EEG），我确定了抑郁症的严重程度， 来自一项双盲随机临床试验的生物标志物，该试验治疗抑郁症患者， 安慰剂rTMS。该生物标志物的变化程度显著预测了rTMS后的临床改善 治疗直接的大脑记录进一步表明，一个单一的刺激会话是足以调节这一点， 生物标志物，表明这种基于大脑的生物标志物可以每天监测，以支持经验性治疗 优化. 考虑到这一点，我建议开发第一个广泛通用的实时生物标志物平台。 监测（目标1）和个性化rTMS治疗（目标2和3）。我将招募54名抑郁症患者 参与一项交叉、安慰剂对照研究，直接比较个性化、自适应rTMS与标准rTMS rTMS。主要结局将是抑郁症严重程度生物标志物的靶向参与和剂量反应。 这项工作的成功实施包括治疗反应者的早期分层和个性化 以及对无反应者更有效的治疗方法。这种方法广泛适用于其他抑郁症 生物标志物，所有接受rTMS治疗的精神病人群和其他脑刺激方式。更一般地说， 我的目标是建立人类大脑可塑性的基本原则，并构建快速发展的平台。 生物标志物开发、参与和整合到个性化脑刺激治疗中。

Project Summary We are in critical need of targeted and individualized treatments for mental health disorders, which affect nearly 50% of Americans during our lifetimes. Brain stimulation treatments, including repetitive transcranial magnetic stimulation (rTMS), represent the front-line of innovative approaches to correct dysfunctional brain networks for patients suffering from mental illness. rTMS is FDA-approved for depression and obsessive- compulsive disorder (OCD) with clinical trials underway for post-traumatic stress disorder (PTSD) and substance use, among others. However, as currently administered, rTMS lacks a biomarker to individually optimize treatment and thus suffers from a poor clinical response rate (<50%). Without personalization of rTMS, we risk a one-size-fits-all treatment for all psychiatric disorders, not dissimilar to how antidepressants are administered. Using simultaneous TMS and electroencephalography (TMS-EEG), I identified a depression severity biomarker from a double-blind randomized clinical trial treating depressed patients with one month of active or placebo rTMS. The degree of this biomarker change significantly predicted clinical improvement after rTMS treatment. Direct brain recordings further suggest that a single stimulation session is sufficient to modulate this biomarker, indicating that this brain-based biomarker can be monitored daily to support empiric treatment optimization. With this in mind, I propose to develop the first broadly generalizable platform for real-time biomarker monitoring (Aim #1) and personalized rTMS treatment (Aims #2 & 3). I will enroll 54 depressed patients to participate in a cross-over, placebo-controlled study directly comparing personalized, adaptive rTMS to standard rTMS. Primary outcome will be target engagement and dose-response of the depression severity biomarker. Successful implementation of this work includes the early stratification of treatment responders and personalized and more effective treatments for non-responders. This approach is broadly applicable to other depression biomarkers, all psychiatric populations treated with rTMS, and other brain stimulation modalities. More generally, my goals are to establish the fundamental principles of human brain plasticity and to construct platforms for rapid biomarker development, engagement, and integration into personalized brain stimulation treatments.