Imaging Biomarkers for TMS treatment of Depression

描述（由申请人提供）：最近，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）。虽然对于不能耐受药物或对标准药物治疗无反应的患者（如任何单一抗抑郁药物治疗），rTMS是一种重要的替代方案，但rTMS不能完全缓解50- 65%的患者的症状。提高rTMS疗效的主要障碍之一是我们对rTMS如何作用于大脑以减轻抑郁症的理解有限。rTMS改变神经兴奋性，一个典型的治疗过程包括25次rTMS疗程（每天1次）。在症状改变变得明显之前，通常需要15个或更多的疗程，而关于诱发变化的性质和程度（即神经可塑性）的信息很少。目前的提案将使用功能磁共振成像（fMRI）来研究MDD患者在多次rTMS治疗左背外侧前额叶皮层（dlPFC）后神经激活的变化，目标是dlPFC的功能网络。40名MDD患者在执行工作记忆任务时进行扫描，因为MDD患者的工作记忆（WM）受损，而工作记忆表现可靠地激活了左侧dlPFC。患者将随机接受20个活动或20个假rTMS疗程，然后进行fMRI扫描。使用动脉自旋标记（ASL）功能磁共振成像，我们将量化脑血流（CBF）在WM表现和休息时。与健康对照者相比，重度抑郁症患者经常过度激活左侧dlPFC，因此左侧dlPFC的激活被预测为

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.