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Principal Investigator: Catherine J Chu
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $662,002
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <Abscission><Action Potentials><Address><Affect><Animal Experiments><Animal Model><Animal Models and Related Studies><Automobile Driving><Biological><Biological Markers><Body Tissues><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Brain region><Caring><Cell Communication and Signaling><Cell Signaling><Clinical><Clinical Data><Computer Models><Computer Simulation><Computer based Simulation><Computerized Models><Consumption><Diffuse><Disabling><Drugs><E-stim><Electric Stimulation><Encephalon><Encephalon Diseases><Epilepsy><Epileptic Seizures><Epileptics><Event><Excision><Extirpation><Failure><Generations><High Frequency Oscillation><Human><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Individual><Institution><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Intractable Epilepsy><Machine Learning><Medical><Medication><Methods><Modeling><Modern Man><Modernization><Monitor><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Operative Procedures><Operative Surgical Procedures><Optics><Organism-Level Process><Organismal Process><Pathologic><Pathologic Processes><Pathological Processes><Patient Care><Patient Care Delivery><Patients><Pattern><Persons><Pharmaceutical Preparations><Physiologic><Physiologic Processes><Physiological><Physiological Processes><Protocol><Protocols documentation><Recurrence><Recurrent><Refractory><Refractory epilepsy><Removal><Reproducibility><Research><Resected><Seizure Disorder><Seizures><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Testing><Time><Tissues><Treatment Efficacy><animal experiment><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><candidate identification><care for patients><care of patients><caring for patients><clinical practice><computational modeling><computational models><computational simulation><computer based models><computerized modeling><computerized simulation><detector><driving><drug-resistant epilepsy><drug/agent><effective therapy><effective treatment><electrostimulation><epilepsia><epileptiform><epileptogenic><excitatory neuron><experiment><experimental animal><experimental animals><experimental research><experimental study><experiments><human data><imaging><imaging approach><imaging based approach><improved><in silico><in vivo><inhibitory neuron><intervention efficacy><interventional strategy><large data sets><large datasets><machine based learning><model of animal><model-based simulation><models and simulation><mouse model><murine model><neural control><neural regulation><neuromodulation><neuromodulatory><neuronal><neurophysiological><neurophysiology><neuroregulation><neurosurgery><novel><optical><prevent><preventing><resection><statistics><successful intervention><surgery><surgery outcome><surgical outcome><therapeutic efficacy><therapy efficacy><voltage>