High-frequency oscillations reveal progressive recruitment of remote cortex into the epileptic network in a mouse model of focal cortical dysplasia type II

Interictal epileptiform discharges (IEDs) and pathological high-frequency oscillations (HFOs) are established biomarkers of epileptogenic tissue, but how their spatiotemporal evolution reflects epileptic network reorganization in neocortical epilepsy remains unclear. We investigated longitudinal IED and HFO dynamics throughout epileptogenesis and chronic epilepsy in a mouse model of focal cortical dysplasia type II (FCD II). Long-term bilateral cortical recordings were obtained before and after spontaneous seizure onset. IEDs and HFOs (gamma, ripples, and fast ripples) were quantified in the dysplastic lesion and contralateral cortex during pre-epileptic, early, and late epileptic stages. The dysplastic lesion remained the principal seizure onset zone throughout disease progression and showed stable HFO activity after epilepsy onset. In contrast, the contralateral cortex exhibited progressive increases in IEDs and HFOs, demonstrating continuous recruitment into the epileptic network. Fast ripples were the earliest marker of this process, emerging within the first week after the first seizure and preceding increases in ripples, gamma, and IEDs. Propagation analysis showed that this contralateral increase was driven by independently generated HFOs rather than propagation from the lesion, indicating emergence of autonomous epileptogenic activity outside the primary focus. Spatiotemporal HFO analysis thus captures dynamic epileptic network remodeling beyond epileptogenic lesion. Fast ripples may serve as an early signature of network expansion and epileptogenicity emerging outside the primary lesion. Widespread structural and connectivity abnormalities extending beyond the lesion, combined with intense recurrent epileptic activity, may underlie the high endogenous epileptogenicity of FCD II, enabling small dysplastic lesions to recruit extensive neuronal networks across both hemispheres.