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申请检验了一种新的非侵入性干预严重强迫症(OCD)的可行性、有效性和安全性，通过神经回路获得信息，并通过功能神经成像进行个性化。难以治疗的强迫症代表着一种未得到满足的临床需求。在目前对强迫症潜在神经回路的了解指导下，局灶性脑刺激已导致重大治疗进展，FDA对深部脑刺激(DBS)的人道主义批准证明了这一点。这一令人兴奋的发展激发了人们对非侵入性替代技术的兴趣。重复性经颅磁刺激(RTMS)是一个有吸引力的选择，因为它是无创的，而且最近FDA批准了它用于抑郁症。最初针对外侧前额叶区域的rTMS研究在治疗严重强迫症患者方面取得的成功有限。这或许并不令人惊讶，因为传统的DBS针对强迫症的目标太深，无法通过常规线圈访问。然而，我们的试验数据表明，低频(1赫兹)刺激rTMS可触及的目标(例如，补充运动区前(SMA))可能能够改善强迫症的症状。最近的影像和生理学研究表明，强迫症患者的运动神经回路(特别是SMA前)存在过度活动，而低频rTMS对运动神经回路有抑制作用。我们的试点工作表明，1赫兹rTMS传递到SMA前抑制运动皮质兴奋性测量，并且这些变化与结果相关，与基线超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。我们将在此方案中实施fMRI引导的rTMS，以靶向SMA前，这与最近的工作一致，表明rTMS的疗效可能会通过神经导航到个体解剖而得到改善。32名严重耐药的强迫症患者将被随机分配到接受活动的或假的rTMS，接受SMA前每日(5次/周)最多四周的rTMS。耶鲁-布朗强迫量表(Y-BOCS)将被用作主要结果衡量标准。应答者将被跟踪6个月，以确定受益的持久性。我们还将收集在强迫症中显示异常的神经生理生物标记物的数据，并通过rTMS进行改变。我们提出3个目标：1)确定fMRI引导下rTMS治疗药物耐药的强迫症的可行性和疗效；2)评价fMRI引导下的rTMS治疗药物抵抗型强迫症的安全性；3)探讨rTMS对治疗前SMA对强迫症运动皮质兴奋性的影响。结果将扩展我们对强迫症背后的神经回路的知识，澄清SMA前的作用，并评估机械作用的潜在生物标记物。他们还将提供有关rTMS的非侵入性神经调节是否可能是治疗严重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。 公共卫生相关性：严重强迫症(OCD)是一种致残性疾病，给个人及其家人带来巨大痛苦。该项目应用大脑功能非侵入性调节的最新进展，将强迫症神经回路的新发现转化为有针对性的治疗。这项研究的结果将有助于更好地了解强迫症背后的神经回路，并将告诉我们，影像引导的重复经颅磁刺激(RTMS)是否对那些对传统治疗无效的患者具有临床益处。

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.