Magnetic Resonance-guided Focused Ultrasound Ablation of the Anterior Thalamus as a Novel Treatment Paradigm for Anxiety

项目摘要/摘要 磁共振成像引导的高强度聚焦超声消融(MRgFUSA)是一种变革性的治疗方法 神经外科手术入路，可产生精确且可见的损伤，使目标接触清晰，以及 提供了一种创新和机械的策略，以纠正潜在的神经病理生理学。与当前不同 神经调节技术(DBS，TMS，TDC)，MRgFUSA的热效应可以非侵入性地利用 并使用ExAblate 4000(InSightec)精确定位大脑深层结构和电路。MRgFUSA拥有最多 最近被应用于丘脑前核(ATN)，这是一种有希望的干预措施 药物治疗-难治性部分性或局灶性癫痫，尤其是起源于边缘颞叶(例如， 杏仁核)。这里关键的相关性是，ATN具有广泛的功能和结构连接到 杏仁核和部分性癫痫通常与增强的恐惧行为和临床焦虑有关，这 经常被夸大的杏仁核对威胁的反应所调节。此外，MPI Phan和其他人已经表明 杏仁核对威胁的反应，在焦虑症(ADS)的基线/治疗前被夸大，可以修改 并通过常规治疗“正常化”。顺理成章的是，ATN的MRgFUSA可能会减弱 焦虑症状，并通过减少杏仁核对威胁的反应来做到这一点。独一无二的是，MPI神经外科医生克里希纳 获得FDA批准的研究设备豁免(IDE)以消融ATN以治疗医学上的难治性 癫痫，为检验这一概念提供了前所未有的机会。这一发现将会异常地 影响很大，因为现有的ADS治疗方法效果不佳，而且治疗后的复发率 臭名昭著的高和长期缓解严重依赖于自愿继续治疗， 尤其是药物疗法。目前迫切需要为ADS开发新的治疗方法， 快速和永久地针对潜在的病理机制。为未来做好准备并降低风险 临床试验，并根据U01 RFA使用小型(n&lt；10)研究的要求，我们提出了第一个- 对已经在接受MRgFUSA的现有参与者进行了人体内概念验证实验- 用于癫痫的ATN(使用FDA批准的现有IDE)，在本提案中仅包括 具有高度焦虑(根据汉密尔顿焦虑量表，Ham-A；Hama Score&Gt；17衡量)来跟踪 MRgFUSA-ANT对杏仁核反应性及近远期功能恢复的即刻(术中)影响 在12个月的过程中出现焦虑症状。本项目试图回答3个问题：1)是MRgFUSA- 2)MRgFUSA-ATN能降低杏仁核对威胁的反应性； 3)MRgFUSA-ATN能否在术后第1天减少焦虑/恐惧症状，以及抗焦虑/恐惧的持久性。 焦虑的影响？如果成功，这项提议将提供一种指导性和变革性的方法，以 为焦虑症患者开发快速、永久但非侵入性的神经外科治疗 以及其他精神疾病，并告知、优化和降低未来临床MRgFUSA研究的风险。

PROJECT SUMMARY/ABSTRACT Magnetic resonance imaging-guided high intensity focused ultrasound ablation (MRgFUSA) is a transformative neurosurgical approach that produces a precise and visible lesion, such that ‘target’ engagement is clear, and offers an innovative and mechanistic strategy to correct an underlying neuropathophysiology. Unlike current neuromodulation techniques (DBS, TMS, TDCS), MRgFUSA’s thermal effects can be harnessed to non-invasively and precisely target deep brain structures and circuits using the Exablate 4000 (Insightec). MRgFUSA has most recently been applied to the anterior thalamic nuclei (ATN) which has emerged as promising intervention for medication-refractory partial or focal-onset epilepsy, particularly originating from the limbic temporal lobe (e.g., amygdala). Of key relevance here is that the ATN has extensive functional and structural connectivity to the amygdala and that partial epilepsy is often associated with enhanced fear behaviors and clinical anxiety, which is often mediated by exaggerated amygdala reactivity to threat. Moreover, MPI Phan and others have shown that amygdala reactivity to threat, exaggerated at baseline/pre-treatment in anxiety disorders (ADs), can be modified and “normalized” by conventional treatments. It stands to reason that MRgFUSA to the ATN could attenuate anxiety symptoms and do so by reducing amygdala reactivity to threat. Uniquely, MPI neurosurgeon Krishna has obtained a FDA-approved Investigational Device Exemption (IDE) to ablate the ATN for medically refractory epilepsy, providing an unprecedented opportunity to test this notion. This discovery would have exceptionally high impact because existing treatments for ADs are modestly effective, and relapse rates post-treatment are notoriously high and long-term remission is heavily dependent on voluntary continuation of treatment, particularly pharmacotherapy. There is an ongoing urgent need to develop new treatments for ADs that precisely targets an underlying pathological mechanism quickly and permanently. To set the stage for and de-risk future clinical trials and in accordance with the U01 RFA requirements using small (n<10) studies, we propose a first- in-human, proof-of-concept experiment to an existing participant pool who are already undergoing MRgFUSA- ATN for epilepsy (using the existing FDA-approved IDE) and for the purpose of this proposal include only those with high anxiety (as measured by the Hamilton Anxiety Rating Scale, HAM-A; HAMA score > 17) to track the immediate (intraoperative) effect of MRgFUSA-ANT on amygdala reactivity and short- and long-term reduction in anxiety symptoms over the course of 12 months. This project seeks to answer 3 questions: 1) Is MRgFUSA- ATN safe and tolerable, in a high anxiety cohort; 2) Can MRgFUSA-ATN reduce amygdala reactivity to threat; and 3) Can MRgFUSA-ATN reduce anxiety/fear symptoms by post-operative day 1, and how durable are the anti- anxiety effects? If successful, this proposal will provide a guiding and transformative approach towards developing fast-acting, permanent but non-invasive neurosurgical treatments for patients suffering from anxiety and other mental illnesses and inform, optimize and de-risk future clinical MRgFUSA studies.