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 严重抑郁障碍(MDD)很普遍，并且使人虚弱，改进的治疗方法的发展有限 部分原因是对疾病缓解机制的认识不足。反过来，澄清的努力 由于疾病的异质性和治疗的有效性有限，机制一直具有挑战性， 需要几周到几个月的时间才能诱导缓解。在本申请中，我们建议重点应用一种新的 TRD患者的神经刺激策略。我们最近开发了一种重复的经颅 磁刺激可使90%的重症耐药MDD患者在1-5个月内缓解 我们称之为斯坦福加速智能神经调节疗法(SANT)的日子。这种方法论 为开始探索MDD缓解的网络级机制提供了新的工具。继圣徒之后，FC 显著降低默认模式网络(DMN)-亚膝扣带回皮质(SgACC)的相关 随着临床规模的变化而变化。在本应用中，我们提出了以主动目标L-DLPFC-SGACC为目标 (n=50)与假(n=50)SAINT，并确定活动SAINT(目标1)是否衰减sgACC-DMN连接 和(目标2)显著减少抑郁的症状。FC的减少可能是减少的基础 因此，我们将把这些潜在调节因子的减少联系起来，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设备的治疗方法 TRD和迭代神经回路在每天相加产生的每一剂量刺激下都会发生变化 临床疗效观察。

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.