Sleep-driven adaptive neuromodulation in lennox-gastaut syndrome

The National Institute of Neurological Disorders and Stroke awarded the Regents of the University of Minnesota a cooperative agreement totaling $1,687,906 on June 15, 2026, under the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative (CFDA 93.372).

The research develops and validates a sleep-adaptive deep brain stimulation (DBS) strategy, branded ADAPT-LGS, targeting Lennox-Gastaut syndrome, a catastrophic childhood-onset epilepsy characterized by drug-resistant seizures and severe cognitive impairment. The strategy leverages the naturally antiepileptogenic desynchronization effects of REM sleep via the Percept DBS system. Using local field potential biosignals from the centromedian-parafascicular thalamus, the system detects epileptiform-rich non-REM sleep and dynamically adjusts stimulation amplitudes to desynchronize pathological thalamocortical activity through direct or indirect modulation of centromedian-parafascicular-to-pedunculopontine tegmental pathways. Work includes identifying optimal stimulation sites that activate the pedunculopontine tegmental region and desynchronize the thalamocortical network during non-REM sleep, validating spectral biomarkers for epileptiform-rich non-REM and motor seizures using ambulatory wearable sensors, and assessing the adaptive DBS's impact on seizure burden.

The University of Minnesota performs work at its Minneapolis, Minnesota campus through May 31, 2028. The BRAIN Initiative aims to accelerate development and application of innovative neurotechnologies to produce new understanding of how individual cells and neural circuits interact, ultimately enabling new treatments and prevention strategies for brain disorders.

Abstract

Lennox-gastaut syndrome (LGS) is a catastrophic childhood-onset epilepsy characterized by drug-resistant seizures, severe cognitive impairments, and profound behavioral challenges. A hallmark of LGS is the heightened seizure burden during non-REM (nrem) sleep, where epileptiform discharges amplify, disrupting sleep architecture, blocking REM transitions, and worsening neurodevelopmental decline. These disruptions perpetuate seizure activity, cognitive deficits, and behavioral challenges, highlighting the urgent need for therapies targeting state-dependent epileptiform activity. During nrem sleep, synchronized thalamocortical firing pattern amplifies epileptiform discharges, while asynchronous REM activity naturally limits their propagation. The pedunculopontine tegmental region (PPT), a regulator of nrem-to-REM transitions, plays a key role in thalamocortical desynchronization and offers a promising target for modulating the synchronous state that facilitates the epileptiform activity. Building on this mechanism, adapt-LGS (adaptive deep brain stimulation for advanced precision therapy in lennox-gastaut syndrome) introduces a novel sleep-adaptive DBS strategy leveraging REM sleep's intrinsic antiepileptogenic desynchronization effects via the percept DBS system. Using local field potential (LFP) biosignals from the centromedian-parafascicular (CM-PF) thalamus, the system detects epileptiform-rich nrem as a control signal and dynamically adjusts stimulation amplitudes to desynchronize pathological thalamocortical activity directly or indirectly via CM-PF-PPT pathways. Specific aims include 1) identifying optimal CM-PF stimulation sites that activate PPT and desynchronize the thalamocortical network during nrem sleep, 2) validating spectral biomarkers for epileptiform-rich nrem and motor seizures using ambulatory wearable sensors, and 3) assessing adaptive DBS's impact on seizure burden, sleep, and patient-centric outcomes in a double-blind crossover trial comparing adaptive DBS with continuous cycling DBS. Primary and secondary outcomes will be objectively measured with seizure-detection wristwatches and wearable sleep headbands, ensuring precise efficacy evaluation. By mimicking REM's natural desynchronization during epileptiform-rich nrem, adapt-LGS offers a transformative solution to reduce seizures, improve sleep quality, and establish a paradigm shift in epilepsy management, paving the way for personalized neuromodulation therapies in catastrophic epilepsies.