Imaging Biomarkers for TMS treatment of Depression

描述（由申请人提供）：最近，美国食品和药物管理局批准了一种称为重复经颅磁刺激（rTMS）的技术，这是一种刺激大脑的非侵入性方法，用于治疗重度抑郁症（MDD）。虽然rTMS是不能耐受药物或对标准药物治疗无效的患者的重要替代方案，但与任何单一抗抑郁药治疗一样，rTMS无法完全缓解50- 65%患者的症状。提高rTMS疗效的主要障碍之一是我们对rTMS如何作用于大脑以缓解抑郁症的理解有限。rTMS改变神经兴奋性，典型的治疗过程包括25次rTMS疗程（每天1次）。在症状变化变得明显之前，通常需要15个或更多疗程，并且关于诱导变化的性质和程度的信息非常少（即，神经可塑性）。目前的建议将使用功能性磁共振成像（fMRI），以调查神经激活的MDD患者多次rTMS治疗后的左背外侧前额叶皮层（dlPFC），针对dlPFC的功能网络的变化。40例MDD患者将在执行工作记忆任务时接受扫描，因为MDD患者的工作记忆（WM）受损，工作记忆表现可靠地激活左侧dlPFC。患者将随机接受20次主动或20次假rTMS治疗，然后进行fMRI扫描。使用动脉自旋标记（ASL）功能磁共振成像，我们将定量脑血流（CBF）在WM性能和休息期间。由于MDD患者相对于健康对照受试者经常过度激活左侧dlPFC，因此预测左侧dlPFC激活 与假手术组相比，活性rTMS组的皮质效率降低，反映了作为rTMS治疗的特定结果的皮质效率改善。与假线圈刺激的比较应确定观察到的变化不是由于安慰剂或时间效应。还将评估功能性连接至左侧dlPFC的网络是否因主动rTMS而发生变化。将探索治疗前神经活动和随治疗的变化，作为可能调节和介导治疗反应的生物标志物。这项研究将通过提供与rTMS治疗相关的神经变化的信息来填补一个重要的空白，提高我们对rTMS机制的理解。 MDD是美国最常见的精神障碍之一，目前的药物治疗使至少1/3的患者出现持续的抑郁症状，这突出了开发和完善治疗的必要性。对MDD中rTMS改变的区域和网络的更好理解将开始开发治疗反应的生物标志物，并可能确定新的靶点，这两个关键步骤都是完善rTMS方法和提高治疗疗效所必需的。

DESCRIPTION (provided by applicant): Recently, the Food and Drug Administration has approved a technique called repetitive transcranial magnetic stimulation (rTMS), a noninvasive method for stimulating the brain, for the treatment of Major depressive disorder (MDD). While rTMS is an important alternative for patients who cannot tolerate medications or fail to respond to standard pharmacotherapy, like any single antidepressant treatment, rTMS fails to fully alleviate symptoms in 50- 65% of patients. One of the major stumbling blocks in improving the efficacy of rTMS efficacy is our limited understanding of how rTMS works on the brain to alleviate depression. rTMS changes neural excitability, and a typical treatment course consists of 25 rTMS sessions (1 session per day). Fifteen or more sessions are generally required before symptom changes become evident, and very little information exists about the nature and extent of induced changes (i.e., neural plasticity). The current proposal will use functional magnetic resonance imaging (fMRI) to investigate changes in neural activation in MDD patients after multiple rTMS treatments to left dorsolateral prefrontal cortex (dlPFC), targeting functional networks of the dlPFC. Forty patients with MDD will be scanned while performing a working memory task, as working memory (WM) is impaired in MDD and working memory performance reliably activates left dlPFC. Patients will be randomized to receive 20 active or 20 sham rTMS sessions, followed by fMRI scans. Using arterial spin labeling (ASL) fMRI, we will quantitate cerebral blood flow (CBF) during WM performance and during rest. As patients with MDD often overactivate left dlPFC relative to healthy control subjects, left dlPFC activation is predicted to decrease in the active rTMS group compared to the sham group, reflecting improved cortical efficiency as a specific result of the rTMS treatments. Comparison to stimulation with a sham coil should establish that observed changes are not due to placebo or time effects. Networks functionally connected to left dlPFC will also be assessed for changes as a result of active rTMS. Neural activity pre-treatment and changing with treatment will be explored as biomarkers which may moderate and mediate treatment response. The study will fill an important gap by providing information about neural changes associated with rTMS therapy, improving our understanding of the mechanism of rTMS. Impact of the proposed research: MDD is one of the most common mental disorders in the United States, and current pharmacologic treatments leave at least 1/3 of patients with persistent symptoms of depression, highlighting the need to develop and refine therapy. Improved understanding of regions and networks altered by rTMS in MDD will begin the development of a biomarker for treatment response and may identify new targets, both critical steps necessary to refine rTMS methods and improve treatment efficacy.