Dysfunction-specific Mechanisms Critically Influence Seizure Onset and Termination in Epilepsy

Epileptic seizures arise from an abnormal synchronous firing of neurons, driven by an imbalance between excitatory and inhibitory neurotransmission. Understanding how various dysfunctions influence brain dynamics is essential for uncovering seizure mechanisms and developing effective treatments. Here, we present a neural mass model that combines an intuitive mathematical formulation with a clear biophysical interpretation to examine the role of excitatory and inhibitory dysfunctions in seizure onset and termination. We model the propagation of action potentials in the brain like the spread of an epidemic and establish a framework examining the interaction between one excitatory and one inhibitory population. Our model captures equilibria that correspond to different levels of neuronal activity: the equilibrium with maximal excitatory activity represents a seizure, and the equilibrium with minimal, non-zero neuronal activity represents normal brain activity. We then introduce various dysfunctions into the model such as an excessive drive to the excitatory population, depletion of inhibitory neurotransmitters, and depolarizing GABAergic neurotransmission and demonstrate that these dysfunctions can facilitate the transition from normal activity to seizure. Crucially, we show that interventions that only target the inhibitory neurotransmitter GABA fail to terminate a seizure when GABA is depolarising, whereas interventions targeting excitatory neurotransmission, such as levetiracetam, are more effective. Our findings highlight the importance of tailoring interventions to the specific underlying dysfunctions for effective seizure termination.