Utilizing changes in human brain connectivity to establish a dose-response relationship involved in the therapeutic actions of prefrontal brain stimulation on depression symptoms

摘要 重性抑郁症（MDD）是一种普遍存在且使人衰弱的疾病，并且改善治疗的发展受到限制 部分原因是对疾病缓解机制的认识不足。反过来，努力阐明 由于疾病的异质性和治疗的有限有效性， 需要数周到数月的时间来诱导缓解。在本申请中，我们建议专注于应用一种新颖的 神经刺激策略。我们最近开发了一种重复的经颅 磁刺激可诱导90%的1-5岁重度、难治性MDD患者缓解 我们称之为斯坦福大学加速智能神经调节疗法（SAINT）。这种方法 为开始探索MDD缓解的网络水平机制提供了一个新的工具。在圣徒之后，fc 显著降低默认模式网络（DMN）-膝下扣带皮层（sgACC）， 随着临床规模的变化。在本申请中，我们提出用活性药物靶向L-DLPFC-sgACC靶标。 （n=50）与假手术（n=50）SAINT，并确定活性SAINT（Aim 1）是否减弱sgACC-DMN连接 （2）明显减轻抑郁症状。fc的降低可能是 抑郁症;因此，我们将与这些潜在的调节剂的减少，以确定最佳的症状目标。 该提案的完成将进一步建立一种安全、有效和非侵入性的基于器械的治疗方法， TRD沿着迭代神经回路在每天刺激剂量下的变化， 临床效果。

ABSTRACT Major depressive disorder (MDD) is prevalent and debilitating, and development of improved treatments is limited in part by insufficient understanding of the mechanism of disease remission. In turn, efforts to elucidate mechanisms have been challenging due to disease heterogeneity and limited effectiveness of treatments, which require weeks-to-months to induce remission. In this application, we propose to focus on applying a novel neurostimulation strategy to participants with TRD. We recently developed a form of repetitive transcranial magnetic stimulation that induces remission in 90% of individuals with severe, treatment resistant MDD in 1-5 days which we called Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). This methodology provides a new tool to begin exploring the network-level mechanisms of MDD remission. Following SAINT, fc significantly decreases default mode network (DMN)-subgenual cingulate cortex (sgACC) which is correlated with change in clinical scales. In this application, we propose to target the L-DLPFC-sgACC target with active (n=50) versus sham (n=50) SAINT and determine if active SAINT (Aim 1) attenuates sgACC-DMN connectivity and (Aim 2) significantly reduces symptoms of depression. Decreases in fc may underlie reductions in depression; thus, we will relate reductions in these potential moderators to identify the best symptom targets. Completion of this proposal will further establish a safe, effective, and non-invasive device-based treatment for TRD along with the iterative neural circuitry changes at each daily dose of stimulation that summate to produce the clinical effect.