Glial Modulation of Electrical Rhythms in a Neuroglial Network Model of Epilepsy

Objective: An important EEG-based biomarker for epilepsy is the phase-amplitude cross-frequency coupling (PAC) of electrical rhythms; however, the underlying pathways of these pathologic markers are not always clear. Since glial cells have been shown to play an active role in neuroglial networks, it is likely that some of these PAC markers are modulated via glial effects. Methods: We developed a 4-unit hybrid model of a neuroglial network, consisting of 16 sub-units, that combines a mechanistic representation of neurons with an oscillator-based Cognitive Rhythm Generator (CRG) representation of glial cells-astrocytes and microglia. The model output was compared with recorded generalized tonic-clonic patient data, both in terms of PAC features, and state classification using an unsupervised hidden Markov model (HMM). Results: The neuroglial model output showed PAC features similar to those observed in epileptic seizures. These generated PAC features were able to accurately identify spontaneous epileptiform discharges (SEDs) as seizure-like states, as well as a postictal-like state following the long-duration SED, when applied to the HMM machine learning algorithm trained on patient data. The evolution profile of the maximal PAC during the SED compared well with patient data, showing similar association with the duration of the postictal state. Conclusion: The hybrid neuroglial network model was able to generate PAC features similar to those observed in ictal and postictal epileptic states, which has been used for state classification and postictal state duration prediction. Significance: Since PAC biomarkers are important for epilepsy research and postictal state duration has been linked with risk of sudden unexplained death in epilepsy, this model suggests glial synaptic effects as potential targets for further analysis and treatment.