Imaging Biomarkers for TMS treatment of Depression

描述(申请人提供)：最近，美国食品和药物管理局批准了一种名为重复经颅磁刺激(RTMS)的技术，这是一种非侵入性刺激大脑的方法，用于治疗严重抑郁障碍(MDD)。虽然rTMS对于不能耐受药物或对标准药物治疗无效的患者来说是一个重要的替代方案，就像任何单一的抗抑郁药物治疗一样，但rTMS未能在50%-65%的患者中完全缓解症状。提高rTMS疗效的主要绊脚石之一是我们对rTMS如何在大脑中缓解抑郁的有限理解。RTMS改变神经兴奋性，一个典型的疗程包括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次或更多的疗程，关于诱导变化的性质和程度(即神经可塑性)的信息很少。目前的建议将使用功能磁共振成像(FMRI)来研究MDD患者在多次rTMS治疗左侧背外侧前额叶皮质(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将接受扫描，因为MDD患者的工作记忆(WM)受损，工作记忆性能可靠地激活左侧dlPFC。患者将被随机分为20次活动rTMS会话或20次假rTMS会话，随后进行fMRI扫描。使用动脉自旋标记(ASL)功能磁共振成像，我们将量化脑血流量(CBF)在西医表演和休息时。由于与健康对照组相比，MDD患者经常过度激活左侧dlPFC，因此预计左侧dlPFC激活 与假手术组相比，活跃rTMS组的皮质效率降低，反映rTMS治疗的特定结果提高了皮质效率。与假线圈刺激相比，应该确定观察到的变化不是由于安慰剂或时间效应。功能上连接到左侧dlPFC的网络也将被评估作为活动rTMS的结果的变化。治疗前的神经活动和随着治疗而改变的神经活动将被探索为可能调节和调节治疗反应的生物标志物。这项研究将填补一个重要的空白，通过提供与rTMS治疗相关的神经变化的信息，提高我们对rTMS机制的理解。拟议研究的影响：MDD是美国最常见的精神障碍之一，目前的药物治疗至少会让三分之一的患者出现持续的抑郁症症状，这突显了开发和完善治疗方法的必要性。更好地了解rTMS在MDD中改变的区域和网络将开始开发治疗反应的生物标记物，并可能识别新的靶点，这两个关键步骤都是完善rTMS方法和提高治疗效果所必需的。

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.