Low-Frequency Electrical Stimulation and Interseizure Delay: A Biophysical and Mathematical Representation

Abstrakt

The biological mechanisms underlying the spontaneous and recurrent transition to seizures in the epileptic brain are still poorly understood. As a result, seizures remain uncontrolled in a substantial proportion of patients with drug-refractory epilepsy. Brain stimulation is an emerging and promising method to treat various brain disorders, including drug-refractory epilepsy. Selected stimulation protocols demonstrated therapeutic efficacy in successfully reducing the seizure rate. The stimulation efficacy critically depends on chosen stimulation parameters, such as the time point, amplitude, and frequency of stimulation. This study aims to explore the neurobiological impact of 1 Hz stimulation and provide the mechanistic explanation behind its seizure-delaying and seizure-suppressing effects. We study this effect using a computational model, a modified version of the Epileptor-2 model, in close comparison with spontaneous seizures recorded in vitro in a high-potassium model of ictogenesis in rat hippocampal slices. In particular, we investigate: 1) the mechanisms and dynamics of spontaneous seizure emergence, 2) the seizure-delaying effect of the stimulation, and 3) the optimal stimulation parameters to achieve the maximal anti-seizure effect. We find that the modified Epileptor-2 model replicates key experimental observations and captures seizure dynamics and the anti-seizure effects of low-frequency electrical stimulation (LFES) observed in hippocampal slices. The model identifies critical thresholds for seizure onset and demonstrates that effective LFES requires optimal stimulation parameters—timing, amplitude, and duration—that exceed specific thresholds to delay seizures without triggering premature seizures. Our study highlights the central role of sodium-potassium pump dynamics in terminating seizures and mediating the LFES effect. The obtained results provide a mechanistic framework to optimize stimulation protocols and deepen our understanding of brain stimulation to design new and effective brain stimulation strategies to treat epilepsy.