Personalized Closed-loop Theta Burst Stimulation for Treatment of Depression

项目摘要 抑郁症在现代社会越来越普遍。临床抑郁症是导致 在美国，三分之二的自杀企图是一种潜在的疾病。精度 神经调节和特别是经颅磁刺激（TMS）承诺一种独特的技术， 抑郁症的治疗方法TMS产生一个控制良好的磁场， 脑中的电场，并可引发神经元的动作电位。节律性经颅磁刺激已经被FDA批准用于 抑郁症、强迫症和尼古丁成瘾。新型TMS协议，例如 间歇性θ-爆发刺激（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， 40分钟的常规节奏经颅磁刺激尽管取得了初步成功，但TMS和TBS面临的一个主要挑战是， 仍然是一个持久的个体间和个体内的变异性的结果。这可能是由于目前有限的 时空精确性和缺乏个性化。 在这里，我建议开发和验证时空精确的个性化TBS，为治疗 萧条为此，我将创建一个闭环TBS-EEG系统，通过利用 用于神经导航的个体结构磁共振成像和由于实时性而导致的时间精度 脑电图（EEG）。使用神经导航，我将补偿已知的个体间差异， 前额叶解剖结构和DLPFC的个体中心先前被发现是最佳TMS靶点 抑郁症持续的EEG将告知系统关于前额叶皮层的兴奋/抑制状态， 如在脑振荡中所反映的，以在最易兴奋的时间触发刺激脉冲。此外，我将改进 通过标记与抑郁行为有关的个体前额叶脑振荡， 在一个有效的认知测试中使用脑电图。特别是，θ和γ振荡是已知的生物标志物， 前额叶活动和抑郁症。从单独的θ和γ频率，我将推导出 TBS的个性化参数。最后，我将进行一项双盲、安慰剂对照的研究， 和临床人群中的可行性研究，以评估个性化TBS的长期效果， 脑电图对前额叶电生理和抑郁行为的影响。 所有这些结合起来的努力将加强我们对前额叶回路机制的基本理解 潜在的抑郁症，并使新的个性化治疗的抑郁症内的精确医学 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.