Personalized Closed-loop Theta Burst Stimulation for Treatment of Depression

项目总结 抑郁症在现代社会中越来越普遍。临床忧郁症是导致 世界各地的残疾和美国三分之二的自杀企图都是一种潜在疾病。精密度 神经调节，特别是经颅磁刺激(TMS)承诺了一种独特的技术 抑郁症的治疗探讨。TMS产生了一个受控良好的磁场，可以感应出焦点电场 大脑中的电场，并能在神经元中诱发动作电位。节奏型TMS已经被FDA批准用于主要 抑郁障碍、强迫症和尼古丁成瘾。新的TMS协议，例如 间歇性电刺激(TBS)可迅速诱导神经回路的持久增强。2019年，TBS 在证明三分钟的TBS治疗同样有效后，FDA是否批准用于抑郁症 作为40分钟的传统节奏性TMS。尽管TMS和TBS最初取得了成功，但它们面临的主要挑战 结果始终存在个体间和个体内的差异。这很可能是由于目前有限的 时空精准性差，缺乏个性化。 在这里，我建议开发和验证时空精确的个性化TBS，专为治疗 抑郁症。为此，我将创建一个闭环系统TBS-EEG，它通过利用 用于神经导航和实时时间精度的个体化结构磁共振成像 脑电(EEG)。使用神经导航，我将补偿已知的个体间差异 前额叶解剖和DLPFC的单个中心先前被发现是TMS的最佳靶点 在抑郁中。正在进行的脑电波将通知系统关于前额叶皮质的兴奋/抑制状态， 正如大脑振荡所反映的那样，在最兴奋的时候触发刺激脉冲。更进一步，我会提高的 通过标记与抑郁行为有关的个体前额叶脑振荡的功能精确度 在经过验证的认知测试中使用脑电。特别是，theta和Gamma振荡是已知的生物标志物 前额叶活动和抑郁障碍。从单个的θ和伽马频率，我将推导出 TBS的个性化参数。最后，我将进行一项双盲、安慰剂对照的健康研究 在临床人群中进行可行性研究，以评估个性化TBS的长期影响。 脑电对前额叶电生理和抑郁行为的影响。 所有这些共同努力将加强我们对前额叶环路机制的基本理解。 在精准医学的基础上实现抑郁症的新的个性化治疗 框架。

PROJECT SUMMARY Depressive disorders are increasingly prevalent in modern societies. Clinical depression is the leading cause of disability worldwide and an underlying condition for two-thirds of suicidal attempts in the United States. Precision neuromodulation and particularly transcranial magnetic stimulation (TMS) promise a unique technological approach to the therapy of depression. TMS creates a well-controlled magnetic field that induces a focal electric field in the brain and can elicit action potentials in neurons. Rhythmic TMS is already FDA-approved for major depressive disorder, obsessive-compulsive disorder, and nicotine addiction. Novel TMS protocols such as intermittent theta-burst stimulation (TBS) can rapidly induce lasting potentiation of neural circuits. In 2019, TBS was FDA-approved for depression after it was demonstrated that a three-minute TBS session was as effective as 40 minutes of conventional rhythmic TMS. Despite their initial success, a major challenge for TMS and TBS remains a persistent inter- and intra-individual variability of outcomes. This is likely due to currently limited spatiotemporal precision and lack of personalization. Here, I propose to develop and validate spatiotemporally precise personalized TBS tailored for the therapy of depression. For that, I will create a closed-loop TBS-EEG system that integrates spatial precision by leveraging individual structural magnetic resonance imaging for neuronavigation and temporal precision due to real-time electroencephalography (EEG). Using neuronavigation, I will compensate for known inter-individual variability in the prefrontal anatomy and focus the individual center of DLPFC previously found to be an optimal TMS target in depression. Ongoing EEG will inform the system about the excitatory/inhibitory states of the prefrontal cortex, as reflected in the brain oscillations, to trigger stimulation pulses at the most excitable time. Further, I will improve the functional precision by tagging the individual prefrontal brain oscillations implicated in depressive behavior using EEG during a validated cognitive test. In particular, theta and gamma oscillations are known biomarkers of prefrontal activity and depressive disorders. From the individual theta and gamma frequencies, I will derive the personalized parameters of TBS. Finally, I will conduct a double-blinded, placebo-controlled study in healthy humans and a feasibility study in a clinical population to assess the long-lasting effects of the personalized TBS- EEG on prefrontal electrophysiology and depressive behavior. All these combined efforts will enhance our fundamental understanding of the prefrontal circuitry mechanisms underlying depression and enable novel personalized therapy of depression within the precision-medicine framework.