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Brain stimulation for prevention of epileptogenesis

Award Number: R21NS117112
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 09/30/2023

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Brain stimulation for prevention of epileptogenesis - PROJECT SUMMARY The overall goal of this project is to establish the time course for developing abnormalities in hippocampal neural circuit action potential firing dynamics after pilocarpine induced hippocampal injury, determine whether maintenance of normal neuronal firing dynamics prevents epileptogenesis and establish the genetic mechanisms of those effects. Temporal lobe epilepsy (TLE) associated with mesial temporal sclerosis (MTS) is a common form of focal epilepsy in which seizures are difficult to treat and memory impairments are common. These factors enormously diminish the quality of life of people with TLE. MTS/TLE develops after brain injury via pathophysiological processes that take at least weeks to reach the endpoint of seizures and memory impairments. This suggests that there is a window of therapeutic opportunity to minimize adverse outcomes. Epileptogenesis is associated with an enormous number of pathological changes at the levels of gene expression, inflammation, synaptic plasticity, neuronal loss and neuronal reorganization amongst many others. Targeting individual pathogenic mechanisms has had limited success in preventing adverse outcomes in animal models of TLE. Thus, new approaches to preventing epileptogenesis are required. We suggest that the above pathophysiological processes converge to disrupt neural dynamics (the patterns of action potential firing over time). The consequent abnormal activity dependent sculpting of synaptic weights and gene expression iteratively alters the self-organization rules governing the formation of dynamic hippocampal circuits, with the emergence of a maladapted circuit. Brain stimulation to maintain normal dynamics from forming thus represents a novel approach to modifying epileptogenesis. The observation that brain stimulation can minimize seizures and improve cognition outside of stimulation periods in animal models with structural brain abnormalities, including MTS, supports the view that patterns of neural activity can be modified to improve network function. It remains unknown whether stimulation during the process of epileptogenesis reduces the development of maladaptive circuits. We will use optimized stimulation paradigms to perturb hippocampal firing patterns during the post-injury period to maintain normal interictal dynamics and establish whether this improves outcomes and whether gene expression changes provide mechanistic insight that could also be harnessed for therapeutic gain.


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 = -$72,786 )
2024	2020	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/4/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$72,786
														Subtotal = -$72,786

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	THE NEMOURS FOUNDATION	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	10/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$24,293
2023	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	10/25/2022	NEW	-$24,293
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/28/2022	NEW	-$201,334
2022	2020	NEMOURS FOUNDATION, THE	1600 ROCKLAND RD	WILMINGTON	DE	19803	NEW CASTLE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/28/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$201,334
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $429,000 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/27/2020	NEW	$429,000
														Subtotal = $429,000

Grand Total All Awards = $356,214

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Brain stimulation for prevention of epileptogenesis

Award Number: R21NS117112

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 09/30/2023

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