Seizure Transitions in Primary Generalized Epilepsy

14 Transitions into primary generalized epileptic seizures occur abruptly and synchronously across the brain. 15 Their potential triggers remain unknown. We used optogenetics to causally test the hypothesis that 16 rhythmic population bursting of excitatory neurons in a local neocortical region can rapidly trigger 17 absence seizures. Most previous studies have been purely correlational, and it remains unclear whether 18 epileptiform events induced by rhythmic stimulation (e.g. sensory/electrical) mimic actual spontaneous 19 seizures, especially regarding their spatiotemporal dynamics. Here, we used a novel combination of 20 intracortical optogenetic stimulation and microelectrode array recordings in freely moving WAG/Rij rats, 21 a model of absence epilepsy with a cortical focus in the somatosensory cortex (SI). We report three main 22 findings: (1) Brief rhythmic bursting, evoked by optical stimulation of neocortical excitatory neurons at 23 frequencies around 10 Hz, induced seizures consisting of self-sustained spike-wave discharges (SWDs) 24 for about 10% of stimulation trials. The probability of inducing seizures was frequency-dependent, 25 reaching a maximum at 10 Hz. (2) Local field potential power before stimulation and response amplitudes 26 during stimulation both predicted seizure induction, demonstrating a modulatory effect of brain states and 27 neural excitation levels. (3) Evoked responses during stimulation propagated as cortical waves, likely 28 reaching the cortical focus, which in turn generated self-sustained SWDs after stimulation was 29 terminated. Importantly, SWDs during induced and spontaneous seizures propagated with the same 30 spatiotemporal dynamics. Our findings demonstrate that local rhythmic bursting of excitatory neurons in 31 neocortex at particular frequencies, under susceptible ongoing brain states, is sufficient to trigger primary 32 generalized seizures with stereotypical spatiotemporal dynamics.