Cortical Layer and Spectrotemporal Architecture of Epileptiform Activity in vivo in a Mouse Model of Focal Cortical Malformation

Our objective is to examine the layer and spectrotemporal architecture and laminar distribution of high-frequency oscillations (HFOs) in a neonatal freeze lesion model of focal cortical dysplasia (FCD) associated with a high prevalence of spontaneous spike-wave discharges (SWDs). Electrophysiological recording of local field potentials (LFPs) in control and freeze lesion animals were obtained with linear micro-electrode arrays to detect presence of HFOs as compared to changes in spectral power, signal coherence, and single-unit distributions during hyper-excitable epochs of anesthesia-induced burst-suppression (B-S). Result were compared to HFOs observed during spontaneous SWDs in animals during sleep. Micro-electrode array recordings from the malformed cortex indicated significant increases in the presence of HFOs above 100 Hz and associated increases in spectral power and altered LFP coherence of recorded signals across cortical lamina of freeze-lesioned animals with spontaneous bursts of high-frequency activity, confined predominately to granular and supragranular layers. Spike sorting of well-isolated single-units recorded from freeze-lesioned cortex indicated an increase in putative excitatory cell activity in the outer cortical layers that showed only a weak association with HFOs while deeper inhibitory units were strongly phase-locked to high-frequency ripple (HER) oscillations (300-800 Hz). Both SWDs and B-S show increases in HFR activity that were phase-locked to the high-frequency spike pattern occurring at the trough of low frequency oscillations. The spontaneous cyclic spiking of cortical inhibitory cells appears to be the driving substrate behind the HFO patterns associated with SWDs and a hyperexcitable supragranular layer near the malformed cortex may play a key role in epileptogenesis in our model. These data, derived from a mouse model with a distinct focal cortical malformation, support recent clinical data that HFOs, particularly fast ripples, is a biomarker to help define the cortical seizure zone, and provide limited insights toward understanding cellular level changes underlying the HFOs.