Spike-and-wave discharges of absence seizures in a sleep waves-constrained corticothalamic model

ABSTRACT Aims Recurrent network activity in corticothalamic circuits generates physiological and pathological EEG waves. Many computer models have simulated spike-and-wave discharges (SWDs), the EEG hallmark of absence seizures (ASs). However, these models either provided detailed simulated activity only in a selected territory (i.e. cortical or thalamic) or did not test whether their corticothalamic networks could reproduce the physiological activities that are generated by these circuits. Methods Using a biophysical large-scale corticothalamic model that reproduces the full extent of EEG sleep waves, including sleep spindles, delta and slow (<0.1 Hz) waves, here we investigated how single abnormalities in voltage- or transmitter-gated channels in the neocortex or thalamus lead to SWDs. Results We found that a selective increase in the tonic γ-aminobutyric acid type A receptor (GABA-A) inhibition of first order thalamocortical (TC) neurons or a selective decrease in cortical phasic GABA-A inhibition are sufficient to generate ∼4 Hz SWDs (as in humans) that invariably start in neocortical territories. Decreasing the leak conductance of higher order TC neurons leads to ∼7 Hz SWDs (as in rodent models) while maintaining sleep spindles at 7-14 Hz. Conclusion By challenging key features of current mechanistic views, this simulated ictal corticothalamic activity provides novel understanding of ASs and makes key testable predictions.