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

项目概要/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 神经外科手术入路，产生精确可见的病变，使得“靶”接合清晰，以及 提供了一种创新的和机械的策略，以纠正潜在的神经病理生理学。不同于当前 神经调节技术（DBS，TMS，TDCS），MRgFUSA的热效应可以利用非侵入性 使用Exablate 4000（Insightec）精确定位大脑深层结构和回路。MRgFUSA拥有最多的 最近被应用于丘脑前核（ATN），这已成为有希望的干预， 药物难治性部分或局灶性发作癫痫，特别是起源于边缘颞叶（例如， 杏仁核）。这里的关键相关性是ATN与细胞具有广泛的功能和结构连接性。 杏仁核和部分癫痫通常与增强的恐惧行为和临床焦虑有关， 通常由杏仁核对威胁的过度反应所介导。此外，MPI Phan和其他人已经表明， 杏仁核对威胁的反应性，在焦虑症（AD）的基线/治疗前被夸大， 并通过常规治疗“正常化”。有理由认为，MRgFUSA到ATN可以减弱 焦虑症状，并通过减少杏仁核对威胁的反应来实现。独特的是，MPI神经外科医生Krishna 获得FDA批准的试验用器械豁免（IDE），以消融ATN治疗医学难治性 癫痫，提供了一个前所未有的机会来测试这一概念。这一发现将是一个例外， 高影响，因为现有的AD治疗方法是适度有效的，治疗后的复发率是 众所周知的高和长期缓解严重依赖于自愿继续治疗， 特别是药物治疗。目前迫切需要开发新的AD治疗方法， 快速而持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U 01 RFA要求使用小型（n<10）研究，我们提出了第一个- 对已经接受MRgFUSA的现有参与者进行人体概念验证实验- ATN治疗癫痫（使用现有FDA批准的IDE），出于本提案的目的，仅包括 高度焦虑（通过汉密尔顿焦虑评定量表（HAM-A）测量; HAMA评分> 17），以跟踪 MRgFUSA-ANT对杏仁核反应性的即刻（术中）影响以及短期和长期降低 焦虑症状的变化。本项目旨在回答3个问题：1）MRgFUSA- ATN在高焦虑队列中安全且可耐受; 2）MRgFUSA-ATN能否降低杏仁核对威胁的反应性; 和3）MRgFUSA-ATN是否可以在术后第1天减少焦虑/恐惧症状，以及抗焦虑/恐惧症状的持久性如何。 焦虑的影响？如果成功，这一建议将提供一个指导性和变革性的方法， 为患有焦虑症的患者开发快速，永久但非侵入性的神经外科治疗方法 和其他精神疾病，并为未来的临床MRgFUSA研究提供信息，优化和降低风险。

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.