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

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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.