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Deep Brain Stimulation of the Cerebellar Dentate Nucleus to Enhance Chronic, Post-Traumatic Brain Injury Rehabilitation

Award Number: R01NS116384
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Deep Brain Stimulation of the Cerebellar Dentate Nucleus to Enhance Chronic, Post-Traumatic Brain Injury Rehabilitation - ABSTRACT The overall goal of this research is to develop and translate effective neurostimulation-based therapies to facilitate neurologic recovery for patients with chronic, persistent deficits secondary to acquired brain injury. Despite progress in acute intervention strategies, traumatic brain injury (TBI) remains a leading cause of long- term disability in the United States and there is an on-going need for novel approaches to facilitate recovery and rehabilitation for survivors. Our group has shown previously that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN), the origin of the ascending dentatothalamocortical (DTC) pathway with widespread influence (via thalamus) across frontal and parietal cortical regions as well as to the basal ganglia, enhances motor rehabilitation in a chronic rodent model of middle cerebral artery ischemia. Therapeutic gains were associated with changes in perilesional cerebral cortical excitability, enhanced cerebral cortical reorganization, and evidence of increased synaptogenesis in perilesional cortex. Here, we will evaluate whether therapeutic benefit can be similarly realized for persistent motor and cognitive deficits following TBI, using a controlled cortical impact (CCI) model in rodents. Moreover, we will further characterize the LCN DBS-induced physiological and cellular changes that occur across perilesional cortical regions. In addition to the supporting evidence afforded by our prior work in rodent models of middle cerebral artery ischemia and our early results from human translation of that work, we provide preliminary evidence of behavioral efficacy and underlying physiological mechanisms in two treatment models: rats with induced motor deficits following fluid percussion injury (FPI) TBI over sensorimotor cortex as well as animals that showed cognitive deficits following bi-frontal CCI targeting medial prefrontal cortical regions. In the current proposal, our specific aims are 1) to confirm and extend our preliminary findings regarding LCN DBS' effects on post-TBI motor recovery, 2) to evaluate the potential LCN DBS to improve post-TBI cognitive function, 3) to characterize the nature of LCN DBS-mediated perilesional and DTC pathway reorganization post-CCI injury; and 4) to examine the cellular and molecular changes in perilesional cortical regions associated with LCN DBS. This study will provide preclinical evidence and support for future translational efforts of this novel therapeutic approach to enhancing chronic, post-TBI deficits.


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: 2024 ( Subtotal = $487,636 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/3/2024	NON-COMPETING CONTINUATION	$487,636
														Subtotal = $487,636

Issue Date FY: 2023 ( Subtotal = $505,487 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/23/2023	NON-COMPETING CONTINUATION	$505,487
														Subtotal = $505,487

Issue Date FY: 2022 ( Subtotal = $517,520 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/21/2022	NON-COMPETING CONTINUATION	$517,520
														Subtotal = $517,520

Issue Date FY: 2021 ( Subtotal = $508,515 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/8/2021	NON-COMPETING CONTINUATION	$508,515
														Subtotal = $508,515

Issue Date FY: 2020 ( Subtotal = $509,695 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/26/2020	NEW	$509,695
														Subtotal = $509,695

Grand Total All Awards = $2,528,853

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Deep Brain Stimulation of the Cerebellar Dentate Nucleus to Enhance Chronic, Post-Traumatic Brain Injury Rehabilitation

Award Number: R01NS116384

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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