Slow-Wave Sleep Enhancement to Treat Epilepsy and Its Comorbidities

SUMMARY Epilepsy affects about three million people in the U.S. Despite a century of work on pharmacotherapy, the rate of patients who are resistant to anti-seizure medications has barely shifted, and most patients have side effects. Surgical referral averages twenty years, but only about 35-65% of patients are cured. Epilepsy is not a single disease but has many causes. Epilepsy is nearly always accompanied by life-shortening and negatively impactful medical and neuropsychiatric comorbidities. A new approach is needed that can target a broad range of epilepsies and treat comorbidities. One approach that has been hiding in plain sight is related to the centuries- old observation that most people with epilepsy report sleep difficulties, which also correlate, independently of seizures, with a low quality of life. Clinical studies show a high rate of objective sleep abnormalities, including low sleep amounts, low sleep efficiency, and sleep fragmentation. There is a wealth of evidence that sleep disruption contributes to the exacerbation of epilepsy; insomnia causes cognitive difficulties and can even predict psychiatric disorders. Our overall hypothesis is that sleep disruption in epilepsy reciprocally worsens seizure control and contributes to or causes neuropsychiatric comorbidities. Barriers to progress have included a lack of means to boost sleep, a good model of sleep disruption in epilepsy, and the methods for analyzing vast datasets to answer these questions. We have overcome these barriers: We found that the intra-amygdala kainic acid model of murine epilepsy, a model of medial temporal lobe epilepsy, has all typical sleep abnormalities found in human focal epilepsy. We developed a method for chronic chemogenetic dosing that does not have carry-over effects and a means of accurately scoring seizures and sleep from long recordings. The central hypothesis of this project, consistent with our preliminary data, is that boosting slow-wave activity in sleep will (1) de-fragment and improve both sleep and wakefulness, (2) reduce seizures, and (3) improve memory and anxiety- and depression-related behaviors. Aim I will test the hypothesis that once daily chemogenetic boosting of sleep and slow-wave power will consolidate both sleep and wakefulness and outperform a proposed pharmacotherapy and a typical anti-seizure therapy that is effective in this model. Aim II will compare the chemogenetic consolidation of sleep alone versus boosting slow activity. This will test the hypothesis that slow-wave activity is necessary to have an anti-epileptic effect. Aim III will test the hypothesis that chemogenetic sleep enhancement will ameliorate memory dysfunction in temporal lobe epilepsy by examining spatial memory and its neurophysiological biomarkers of sharp-wave ripples and long-term potentiation. The second part of this aim will test the hypothesis that sleep enhancement will normalize anxiety/hyperactivity-related behaviors and anhedonia - a marker of depression. This study will be the first to examine chronic sleep enhancement as a therapeutic intervention for epilepsy and its comorbidities. This work will elucidate and facilitate mechanistic studies of sleep-epilepsy interactions and inform treatments for sleep problems that can impact epilepsy and its comorbidities. Project Number: 1R01NS147124-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Nigel Pedersen | Institution: UNIVERSITY OF CALIFORNIA AT DAVIS, DAVIS, CA | Award Amount: $548,368 | Activity Code: R01 | Study Section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT] View on NIH RePORTER: https://reporter.nih.gov/project-details/11279777