Transition dynamics and optogenetic controls of generalized periodic epileptiform discharges

This paper aims to analyze possible mechanisms underlying the generation of generalized periodic epileptiform discharges (GPEDs), especially to design targeted optogenetic regulation strategies. First and foremost, inspired by existing physiological experiments, we propose a new computational framework by introducing a second inhibitory neuronal population and related synaptic connections into the classic Liley mean field model. The improved model can simulate the basic normal and abnormal brain activities mentioned in previous studies, but much to our relief, it perfectly reproduces some types of GPEDs that match the clinical records. Specifically, results show that disinhibitory synaptic connections between inhibitory interneuronal populations are closely related to the occurrence, transition and termination of GPEDs, including delaying the occurrence of GPEDs caused by the excitatory AMPAergic autapses and regulating the transition process of GPEDs bidirectionally, which support the conjecture that selective changes of synaptic connections can trigger GPEDs. Additionally, we creatively offer six optogenetic strategies with dual targets. They can all control GPEDs well, just as experiments reveal that optogenetic stimulation of inhibitory interneurons can suppress abnormal activities in epilepsy or other brain diseases. More importantly, 1:1 coordinated reset stimulation with one period rest is concluded as the optimal strategy after taking into account the energy consumption and control effect. Hope these results provide feasible references for pathophysiological mechanisms of GPEDs.