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

磁共振引导下丘脑前部聚焦超声消融作为焦虑症的新型治疗范例

基本信息

批准号：
10565891
负责人：
TIMOTHY H LUCAS
金额：
$ 51.53万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565891
关键词：
Ablation Acute Adherence Aftercare Amygdaloid structure Anatomy Anterior Anterior Nuclear Group Anxiety Anxiety Disorders Attenuated Behavior Biological Assay Brain Clinical Clinical Trials Cognitive Therapy Collaborations Data Deep Brain Stimulation Devices Disease remission Dose Epilepsy Essential Tremor FDA approved Focused Ultrasound Focused Ultrasound Therapy Fright Functional Magnetic Resonance Imaging Future Human Human Anti-Mouse Antibody Intervention Intractable Epilepsy Laboratories Lesion Localized Lesion Location Magnetic Resonance Magnetic Resonance Imaging Major Depressive Disorder Measures Medial Mediating Medical Mental disorders Meta-Analysis Neurologic Neuropsychology Neurosurgeon Obsessive-Compulsive Disorder Partial Epilepsies Participant Pathologic Patient Self-Report Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Physical environment Postoperative Period Prefrontal Cortex Psychotherapy Refractory Relapse Reporting Resistance Rest Risk Risk Reduction Sampling Selective Serotonin Reuptake Inhibitor Site Sonication Structure Substance Addiction Suicide Symptoms Techniques Temporal Lobe Testing Thalamic structure Therapeutic Effect Thermal Ablation Therapy Time Transcranial magnetic stimulation United States Food and Drug Administration Ventral Nuclear Group Work anxiety reduction anxiety symptoms brain based clinical anxiety cohort conventional therapy experience experimental study first-in-human image guided innovation insight neural neuroregulation neurosurgery novel phase I trial psychiatric comorbidity response safety assessment treatment of anxiety disorders ultrasound ablation

项目摘要

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.

项目概要/摘要磁共振成像引导的高强度聚焦超声消融（MRgFUSA）是一种变革性的技术神经外科方法可产生精确且可见的病变，从而使“目标”接合清晰，并且提供了一种创新和机械的策略来纠正潜在的神经病理生理学，与当前的不同。神经调节技术（DBS、TMS、TDCS），MRgFUSA 的热效应可用于非侵入性治疗并使用 Exablate 4000 (Insightec) 精确定位深层大脑结构和回路。最近被应用于丘脑前核（ATN），这已成为有前途的干预措施药物难治性部分性或局灶性癫痫，特别是起源于边缘颞叶的癫痫（例如，此处的关键相关性是 ATN 与大脑具有广泛的功能和结构连接。杏仁核，部分癫痫通常与恐惧行为和临床焦虑的增强有关，这往往是由杏仁核对威胁的过度反应介导的。此外，MPI Phan 等人已经表明，杏仁核对威胁的反应，在焦虑症（AD）的基线/治疗前被夸大，可以被修改并通过常规治疗“正常化”，按理说，MRgFUSA 对 ATN 的作用可能会减弱。 MPI 神经外科医生 Krishna 独特地通过降低杏仁核对威胁的反应来缓解焦虑症状。获得 FDA 批准的研究设备豁免 (IDE)，用于消融治疗难治性 ATN 癫痫，为检验这一概念提供了前所未有的机会。影响很大，因为现有的 AD 治疗方法效果不大，而且治疗后的复发率很低众所周知，高且长期的缓解在很大程度上取决于自愿继续治疗，尤其是药物疗法，目前迫切需要开发针对 AD 的新疗法。快速、永久地针对潜在的病理机制，为未来奠定基础并消除风险。临床试验并根据使用小型（n<10）研究的 U01 RFA 要求，我们建议首先- 对已经接受 MRgFUSA 的现有参与者进行人体概念验证实验用于癫痫的 ATN（使用 FDA 批准的现有 IDE）并且就本提案而言仅包括那些高度焦虑（通过汉密尔顿焦虑评定量表 HAM-A 测量；HAMA 分数 > 17）来跟踪 MRgFUSA-ANT 对杏仁核反应性以及短期和长期减少的即时（术中）影响该项目旨在回答 3 个问题：1) MRgFUSA- 是否存在焦虑症状？ ATN 在高度焦虑人群中安全且可耐受；2) MRgFUSA-ATN 能否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/恐惧症状的持久性如何？如果成功，该提案将为解决焦虑问题提供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。