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Targeting Pathologic Spike-Ripples to Isolate and Disrupt Epileptic Dynamics

Award Number: R01NS119483
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: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Targeting Pathologic Spike-Ripples to Isolate and Disrupt Epileptic Dynamics - Project Summary Epilepsy is the world’s most common, serious brain disorder, affecting nearly 50 million people worldwide. For one-third of patients, seizures remain poorly controlled despite maximal medical management. In these patients, seizures often arise from a localized brain region, and neurosurgical interventions are the most effective treatment option. When successful, surgical interventions provide cure from seizures, and also prevent or reverse the disabling consequences of uncontrolled seizures. Critical to successful intervention is accurate identification of the core tissue responsible for generating seizures (i.e., the epileptogenic zone). Traditionally, this tissue would be surgically resected, but modern approaches aim to focally disrupt this tissue with targeted electrical stimulation (i.e. neuromodulation). Improvements in epilepsy care are now limited by (i) the inability to accurately identify the epileptogenic zone; (ii) a limited understanding of the mechanisms underlying epileptiform activity; (iii) a lack of understanding of how to target these mechanisms with neurostimulation. The most common approach to identify the epileptogenic zone is through continuous recording of a patient’s cortical electrical activity to capture seizures. However, because seizures are infrequent, this approach is expensive, time consuming, and unpleasant for patients. Moreover, this approach often fails to identify the epileptogenic zone, resulting in unsuccessful neurosurgical intervention in 20-70% of cases. To address this, interictal biomarkers of the epileptogenic zone that manifest between seizures are required. Two such biomarkers have been proposed: (a) interictal discharges or spikes, and (b) high frequency oscillations or ripples. While both signals have been extensively studied, neither accurately delimits the epileptogenic zone. Spikes are specific for epilepsy, but too spatially diffuse to identify the epileptogenic zone. Ripples are spatially focal, but represent both pathologic and physiologic processes. We address these limitations by focusing on the simultaneous occurrence of a spike and ripple, “spike-ripple” discharges, as an improved biomarker for the epileptogenic zone. Spike-ripples commonly occur in patients with epilepsy, improve the spatial specificity of spikes for the epileptogenic zone, and disentangle physiologic from pathologic ripples. Our interdisciplinary team will apply expertise in epilepsy, neurophysiology, neurosurgery, animal experiments, modeling, and statistics to: (i) develop a fully automated spike-ripple detector and compare its clinical utility to predict surgical outcome to spikes and ripples alone, (ii) identify the biological mechanisms that generate spike-ripple discharges using novel voltage imaging techniques in animal models combined with computational models; and (iii) develop principled neurostimulation protocols to disrupt the mechanisms that generate spike-ripples. Completion of these Aims will represent significant progress towards resolving fundamental questions in modern epilepsy research, an understanding of mechanisms in the core epileptogenic network that generate spike-ripples, and a principled approach to neurostimulation to focally disrupt these pathologic dynamics.


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: 2026 ( Subtotal = -$269,112 )
2026	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/25/2026	NON-COMPETING CONTINUATION	$0
2026	2025	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	6/15/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$269,112
														Subtotal = -$269,112

Issue Date FY: 2025 ( Subtotal = $674,011 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	7/18/2025	NON-COMPETING CONTINUATION	$68,070
2025	2025	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	9/11/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$361,709
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	9/11/2025	NON-COMPETING CONTINUATION	-$368,406
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/22/2024	NON-COMPETING CONTINUATION	$612,638
														Subtotal = $674,011

Issue Date FY: 2024 ( Subtotal = $662,002 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/11/2024	NON-COMPETING CONTINUATION	$47,772
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/14/2023	NON-COMPETING CONTINUATION	$614,230
														Subtotal = $662,002

Issue Date FY: 2023 ( Subtotal = $684,243 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/30/2023	NON-COMPETING CONTINUATION	$68,424
2023	2023	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/21/2022	NON-COMPETING CONTINUATION	$615,819
														Subtotal = $684,243

Issue Date FY: 2022 ( Subtotal = $683,061 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/28/2022	NON-COMPETING CONTINUATION	$68,305
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/15/2021	NON-COMPETING CONTINUATION	$614,756
														Subtotal = $683,061

Issue Date FY: 2021 ( Subtotal = $698,329 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/28/2020	NEW	$698,329
														Subtotal = $698,329

Grand Total All Awards = $3,132,534

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Targeting Pathologic Spike-Ripples to Isolate and Disrupt Epileptic Dynamics

Award Number: R01NS119483

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: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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