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

Award Number: U01MH128677
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $403,556 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	4	12/31/2024	NON-COMPETING CONTINUATION	$403,556
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	001	4	1/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $403,556

Issue Date FY: 2024 ( Subtotal = $529,485 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	002	3	8/15/2024	NON-COMPETING CONTINUATION	$52,949
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	001	3	12/13/2023	NON-COMPETING CONTINUATION	$476,536
2024	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	2	11/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $529,485

Issue Date FY: 2023 ( Subtotal = $515,328 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	001	2	1/19/2023	NON-COMPETING CONTINUATION	$51,532
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	2	12/19/2022	NON-COMPETING CONTINUATION	$463,796
														Subtotal = $515,328

Issue Date FY: 2022 ( Subtotal = $532,134 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	1	2/7/2022	NEW	$532,134
														Subtotal = $532,134

Grand Total All Awards = $1,980,503

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

Award Number: U01MH128677

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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