Mechanistic circuit markers of transcranial magnetic stimulation outcomes in pharmacoresistant depression

! 项目总结/摘要 尽管重复经颅磁刺激（rTMS，以下简称TMS）被广泛采用， 我们仍然缺乏机械驱动的生物标志物，用于确定谁最有可能做出反应，以及为什么。 rTMS适用于耐药性抑郁症。我们必须找到更精确的解决方案， 考虑到抗药性抑郁症可能危及生命：自杀企图是自杀率的两倍， 非抵抗性抑郁症我们的目的是使用前瞻性设计来评估认知控制网络 连接性作为重复经颅磁刺激临床效果的预测生物标志物， TMS变化的响应生物标志物。我们有一个新的机会来实现这一目标， 对参加退伍军人管理局多项研究的100名患者的脑网络生物标志物进行了系统评价， 研究中心临床TMS程序。通过利用伞式临床rTMS计划，我们可以标准化交付 参数，以确保一致性。我们的主要生物标志物是认知控制的功能连接 人类大脑的一个网络，是控制思想和情感的中心。我们亦会评估 相应的行为表现。临床结局包括症状严重程度、自杀倾向和生活质量。 将在基线时，在5次rTMS（“低剂量”）治疗后评估生物标志物，以探索早期 反应，并在30个疗程后完成治疗（“较高剂量”）。为研究供电， 预计保守效应量至少为0.25，我们将招募100名患者参加VA临床试验， TMS程序。使用标准化的刺激参数和协调的神经成像程序，我们的目标是 1）探索rTMS促进认知控制的假定机制效应，并评估是否 认知控制网络的连接性以剂量依赖性方式变化，2）评估是否程度 认知控制网络连通性的变化预测了行为表现的相应变化 以及，3）识别基线功能连接和行为，沿着连接的早期变化， 行为，预测症状严重程度，自杀意念和生活质量的后续结果。创新 我们的设计包括1）足够的功率来询问成像标记，2）标准化以最小化 可变性，3）实施纵向设计以量化成像标记物中的rTMS相关变化，4） 任务诱发和静息状态成像标记物的整合，以及5）建立以下基础 将经验教训扩大到其他诊断和参数。 !

! PROJECT SUMMARY/ABSTRACT Despite the wide scale adoption of repetitive transcranial magnetic stimulation (rTMS, hereafter simply TMS), we still lack mechanistically-driven biomarkers designed to identify who is most likely to respond, and why. rTMS is indicated for pharmacoresistant depression. It is imperative that we find more precise solutions for these patients given that pharmacoresistant depression can be life threatening: suicide attempts are twice the rate of non-resistant depression. Our objective is to use a prospective design to evaluate cognitive control network connectivity as a predictive biomarker of the clinical effect of repetitive transcranial magnetic stimulation, and as a response biomarker of change with TMS. We have a novel opportunity to address this objective through a systematic evaluation of brain network biomarkers in 100 patients taking part in a Veterans Administration multi- site clinical TMS program. By utilizing the umbrella Clinical rTMS Program, we can standardize delivered parameters to ensure uniformity. Our primary biomarker is functional connectivity of the cognitive control network of the human brain that is central to the regulation of thought and emotion. We will also assess corresponding behavioral performance. Clinical outcomes are symptom severity, suicidality, and quality of life. Biomarkers will be assessed at baseline, after 5 sessions of rTMS (“low dose”) to explore mechanisms of early response, and upon completion of treatment after 30 sessions (“higher dose”). To power the study for an anticipated conservative effect size of at least .25, we will recruit 100 patients participating in the VA Clinical TMS Program. Using standardized stimulation parameters and harmonized neuroimaging procedures, our aims are to 1) probe the putative mechanistic effect of rTMS on promoting cognitive control and to assess whether connectivity of the cognitive control network changes in a dose-dependent manner, 2) to assess whether extent of change in cognitive control network connectivity predicts corresponding change in behavioral performance and, 3) to identify if baseline functional connectivity and behavior, along with early change in connectivity and behavior, predict subsequent outcomes in symptom severity, suicidal ideation, and quality of life. Innovations of our design include 1) adequate power to interrogate imaging markers, 2) standardization to minimize variability, 3) implementation of a longitudinal design to quantify rTMS-related changes in imaging markers, 4) integration of task-evoked and resting state imaging markers and, and 5) establishing the foundations for expanding lessons learned to additional diagnoses and parameters. !