Impact of sleep-wake cycle on seizure generation in Juvenile Myoclonic Epilepsy

Impact of sleep-wake cycle on seizure generation in Juvenile Myoclonic Epilepsy Objective: The project aims to investigate the hypothesis that abnormal sleep-wake transitions are crucial in the generation of seizures in Juvenile Myoclonic Epilepsy (JME). The study explores spontaneous epileptic discharges, seizures, cortical excitability, and connectivity during different phases of the sleep-wake cycle. Background: Epilepsy is marked by unpredictable seizures and interictal epileptic discharges (IEDs) due to abnormal neural network activity. Sleep-wake rhythms significantly influence seizure occurrence. JME, a common generalized epilepsy syndrome, shows seizures primarily in the morning. Main Hypothesis: The central hypothesis posits that cortical excitability and IED occurrence increase during NREM sleep, but reduced cortico-cortical connectivity prevents abnormal activity from evolving into a seizure. At sleep-wake boundaries in JME, a co-occurrence of high cortical excitability (typical of sleep) and high cortico-cortical connectivity (typical of awakening) may facilitate seizure generation. Project Plan: Six experiments were conducted on JME individuals on antiseizure medications: 1. Analysis of EEG recordings for seizure predictors. 2. Investigation of circadian patterns of epileptic discharges. 3. Systematic review of cortical excitability measures in epilepsy. 4. Examination of circadian variations in cortical excitability and corticothalamic dynamics. 5. Assessment of occipito-central connectivity in photosensitive epilepsy using visual evoked potentials. 6. Study of steady-state visually evoked potentials during sleep, exploring connectivity changes. Key Findings: 1. Analysis of EEG recordings identified the duration of epileptic discharges as a predictor of seizure recurrence. 2. Prolonged discharges that were associated with increased seizure risk, occured mainly during wake, despite the fact that the overall incidence of interictal epileptic discharges (IEDs) was significantly higher during sleep. 3. A comprehensive review underscored the significance of standardizing measures of excitability and techniques for stimulation in epilepsy research. In the specific context of the technique employed herein, pioneering efforts in Transcranial Magnetic Stimulation with Electroencephalography (TMS-EEG) lacked consensus on which measurement accurately reflects cortical excitability in epilepsy. Meanwhile, investigations involving visual evoked potentials revealed that individuals with generalized epilepsies, particularly those with photosensitive traits, exhibited heightened amplitude and synchronization of visual evoked responses cortical excitability and corticothalamic dynamics in JME exhibited abnormal circadian patterns. 4. Cortical excitability and corticothalamic dynamics in JME exhibited no clear circadian patterns. TMS-EEG responses are slower when compared to healthy control, especially when seizures occur in a 8 months follow up period. 5. Evaluation of occipito-central connectivity in photosensitive idiopathic generalized epilepsy suggested increased connectivity in patients compared to controls. 6. Initial observations from two patients in steady-state visually evoked potentials during sleep suggested a decrease in effective connectivity among individuals with Juvenile Myoclonic Epilepsy (JME), even though there was an increased synchronization in the local response, preventing the onset of photic stimulation induced myoclonic seizures. Conclusion: The initial data supports the project's hypothesis, suggesting that higher excitability with reduction in effective connectivity during sleep in JME prevent seizure onset. Further investigations, including source modeling analysis, are warranted to deepen our understanding of connectivity patterns and their role in seizure generation in JME. These findings could inform future research on improving seizure prediction and therapeutic strategies for JME.