Objectives: This research explores the interaction between circadian rhythms and the cellular mechanisms responsible for epileptic seizures, by integrating circadian modulation into the Epileptor-2 model. The aim is to improve understanding of the underlying dynamics and identify optimized therapeutic strategies in phase with biological circadian cycles. Methods: A circadian factor was integrated into the Epileptor-2 model to simulate daily fluctuations in neuronal excitability and seizure onset. These variations interact with pharmacological treatments, and we modeled their effects to evaluate dose adjustments and schedules aligned with circadian rhythms. The pharmacokinetics of anti-epileptic drugs were parameterized to analyze their interaction with periods of peak seizure risk. Results: Integrating circadian fluctuations in ionic dynamics into the model has provided deeper mechanistic insights into their effects on neuronal excitability and seizure onset. Our simulations indicate that adjusting drug doses and administration schedules according to patients’ biological rhythms enhances treatment efficacy and lowers seizure risk. These findings highlight the significance of personalized chronotherapy, tailored to periods of highest seizure susceptibility, for optimizing epilepsy management. Significance: This study demonstrates how circadian modulation of ion dynamics influences neuronal excitability, seizure onset, and interactions with pharmacological treatment, providing insight into the mechanisms underlying ictal discharges. By incorporating these fluctuations into the Epileptor-2 model, we offer a mechanistic understanding of circadian rhythms in epilepsy. Our approach, combining cellular with chronotherapy modeling, represents a first step toward developing a valuable tool for optimizing antiepileptic treatments based on patient’s biological rhythms, ultimately enhancing the precision and effectiveness of epilepsy management.
