Transcranial Magnetic Stimulation for Treatment of Obsessive Compulsive Disorder

描述（由申请人提供）：这项为期2年的R21申请研究了一种新型无创干预治疗严重强迫症（OCD）的可行性、有效性和安全性，通过神经回路和功能神经成像进行个性化治疗。难治性强迫症代表了一个未被满足的临床需求。局灶性脑刺激，在目前对强迫症潜在神经回路的理解的指导下，导致了重大的治疗进展，FDA人道主义批准了深部脑刺激（DBS）。这一令人兴奋的发展激发了人们对非侵入性替代疗法的兴趣。重复经颅磁刺激（rTMS）是一个有吸引力的选择，因为它的无创性和最近FDA批准抑郁症。最初针对前额外侧区域的rTMS研究在治疗严重强迫症患者方面取得了有限的成功。这也许并不奇怪，因为强迫症的经典DBS靶点太深，传统线圈无法到达。然而，我们的试验数据表明，低频（1hz）刺激rtms可达的目标（如前辅助运动区（SMA））可能能够改善强迫症的症状。最近的影像学和生理学研究表明，强迫症患者的运动回路（特别是sma前）中存在过度活跃的作用，而据报道，低频rTMS对运动回路具有抑制作用。我们的试点工作表明，1hz rTMS对sma前的运动皮层兴奋性测量有抑制作用，这些变化与结果相关，与基线高兴奋性的正常化一致。在这里，我们试图复制和扩展这些发现，使用严格的随机假对照试验设计。我们将在本方案中实施fmri引导下的rTMS，以针对sma前期，这与最近的研究一致，表明rTMS的疗效可能通过神经导航到个体解剖来提高。32名严重耐药强迫症患者将被随机分配接受主动或假rTMS，每天（5次/周）应用于sma前，持续4周。耶鲁-布朗强迫症量表（Y-BOCS）将被用作主要结果测量。应答者将被随访6个月以确定获益的持续性。我们还将收集强迫症中显示异常的神经生理生物标志物的数据，并通过rTMS进行改变。我们提出了3个目的：1)确定fmri引导下的rTMS对耐药强迫症预sma的可行性和治疗效果；2)评估fmri引导下的rTMS对强迫症的安全性；3)探索rTMS对预sma对强迫症运动皮层兴奋性TMS测量的影响。结果将扩展我们对强迫症神经回路的认识，阐明前sma的作用，并评估潜在的生物标志物的机制作用。他们还将提供关于rTMS的非侵入性神经调节是否可能成为治疗严重的耐药强迫症患者的有用途径的信息。如果我们的初步发现得到支持，这可能为这些严重受损的患者提供一种新的治疗途径。

DESCRIPTION (provided by applicant): This 2-year R21 application examines the feasibility, efficacy and safety of a novel noninvasive intervention for severe obsessive-compulsive disorder (OCD), informed by neurocircuitry and individualized through functional neuroimaging. Treatment-resistant OCD represents an unmet clinical need. Focal brain stimulation, guided by present understanding of the neurocircuitry underlying OCD, has led to major therapeutic advances as evidenced by the FDA humanitarian approval of deep brain stimulation (DBS). This exciting development has spurred interest in noninvasive alternatives. Repetitive Transcranial Magnetic Stimulation (rTMS) is an attractive option given its noninvasiveness and recent FDA approval for depression. Initial rTMS studies targeting lateral prefrontal regions have had limited success in treating individuals with severe OCD. This is perhaps not surprising since classical DBS targets for OCD are too deep to be accessed by conventional coils. However, our pilot data suggest that low frequency (1 Hz) stimulation of rTMS-accessible targets (e.g. pre-supplementary motor area (SMA)) may be able to improve symptoms of OCD. Recent imaging and physiology studies have suggested a role of hyperactivity in motor circuits (specifically pre-SMA) in OCD, and low frequency rTMS has been reported to have inhibitory effects on motor circuitry. Our pilot work suggests that 1 Hz rTMS delivered to the pre-SMA inhibits motor cortex excitability measures, and that these changes correlate with outcome, consistent with a normalization of baseline hyperexcitability. Here we seek to replicate and extend those findings, using a rigorous randomized sham-controlled trial design. We will implement fMRI-guided rTMS in this protocol to target pre-SMA, in line with recent work suggesting the efficacy of rTMS may be improved through neuronavigation to individual anatomy. Thirty- two patients with severe medication resistant OCD will be randomly assigned to receive active or sham rTMS applied to the pre-SMA daily (5 times/week) for up to four weeks. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) will be used as primary outcome measure. Responders will be followed for 6 months to determine persistence of benefit. We will also collect data on neurophysiological biomarkers shown to be abnormal in OCD and subject to change by rTMS. We propose 3 aims: 1) to determine the feasibility and therapeutic efficacy of fMRI-guided rTMS to pre-SMA in medication-resistant OCD, 2) to evaluate the safety of fMRI-guided rTMS in OCD, and 3) to explore the impact of rTMS to the pre-SMA on TMS measures of motor cortex excitability in OCD. Results will extend our knowledge of the neurocircuitry underlying OCD, clarifying the role of pre-SMA, and evaluating a potential biomarker of mechanistic action. They will also be informative about whether noninvasive neuromodulation with rTMS may be a useful avenue to pursue in the treatment of persons with severe, medication-resistant OCD. If our preliminary findings are supported, this may represent a novel therapeutic avenue for these severely impaired patients. PUBLIC HEALTH RELEVANCE: Severe Obsessive-Compulsive Disorder (OCD) is a disabling illness that causes significant suffering for individuals and their families. This project applies the latest advances in noninvasive modulation of brain function to translate new discoveries in the neurocircuitry of OCD into targeted treatments. The results of this study will contribute to a better understanding of the neural circuits underlying OCD, and will tell us whether imaging-guided repetitive Transcranial Magnetic Stimulation (rTMS) can be of clinical benefit in those patients that do not respond to the conventional treatments.