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）是一种变革性神经外科方法会产生精确且可见的病变，使得“目标”参与很明显，并且提供了一种创新的机械策略来纠正潜在的神经病理生理学。与电流不同神经调节技术（DBS，TMS，TDC），MRGFUSA的热效应可用于非侵入性并精确地使用Exablate 4000（Insightec）靶向深脑结构和电路。 Mrgfusa拥有最多最近被应用于丘脑前核里（ATN），该核里已成为承诺的干预措施药物难治性部分或焦点发作癫痫，尤其是源自边缘临时叶（例如，杏仁核）。这里的关键相关性是ATN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动画有关通常是由夸张的杏仁核对威胁的反应性介导的。而且，MPI Phan和其他人表明杏仁核对威胁的反应性，在焦虑症（AD）中夸大/夸大，可以修改并通过常规治疗“标准化”。有理由认为Mrgfusa到ATN可以减弱焦虑符号，并通过降低杏仁核对威胁的反应性来做到这一点。独特的是，MPI神经外科医生Krishna具有获得了FDA批准的研究装置豁免（IDE），以消除ATN的药物难治性癫痫病为检验这一概念提供了前所未有的机会。这个发现将具有异常高影响很大，因为现有的广告治疗方法适度有效，并且处理后的救济率是众所周知，高和长期缓解在很大程度上取决于自愿延续治疗，特别是药物治疗。迫切需要为广告开发新的治疗方法快速，永久地靶向一种潜在的病理机制。为未来的舞台设定舞台临床试验并根据U01 RFA的要求，使用小（n <10）研究，我们提出了先验在人类中，对现有参与池的概念验证实验，他们已经在进行MRGFUSA- 癫痫的ATN（使用现有FDA批准的IDE），目的仅包括这些高焦虑（按汉密尔顿焦虑评级量表来衡量，HAM-A； HAMA得分> 17）以跟踪 MRGFUSA-ANT对杏仁核反应性以及短期和长期降低的立即（术中）作用在12个月的动画症状中。该项目旨在回答3个问题：1）是mrgfusa- 在高焦虑群中，ATN安全可容忍； 2）MRGFUSA-ATN可以降低杏仁核对威胁的反应性； 3）MRGFUSA-ATN可以在术后第1天减轻焦虑/恐惧症状，抗抗药性耐用性焦虑效果？如果成功，该提议将为指导和变革性的方法提供为患有焦虑的患者开发快速作用，永久但无创神经外科治疗以及其他精神疾病，并为未来的临床MRGFUSA研究提供信息，优化和脱离风险。