R01NS119483

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.

Hugo W. Moser Research Institute At Kennedy Krieger

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Baltimore, Maryland 212051531 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-24-254)

Amendment Since initial award the total obligations have increased 387% from $698,329 to $3,401,646.