Abstracts

Rationale: The epileptic brain is often associated with the presence of high frequency oscillations (HFOs, >25 Hz) that have recently gained attention as potential biomarkers to help define the cortical seizure zone, however, animal model data linking HFOs with focal seizures is not available.  Methods: Using silicon depth electrode array and EEG arrays, we evaluate the aberrant spectral architecture and spatial distribution of HFOs associated with spontaneous spike-wave discharge (SWD) patterns in an experimental model of focal cortical dysplasia (FCD) induced by neonatal freeze lesions (FLs) to the right S1 cortex. Results: Chronic bipolar recordings from awake, behaving animals indicated a high prevalence of spontaneous SWDs in 83% (10/12) of animals exposed to the FL injury as evaluated at 5-11 months of age. SWDs were associated with a strong increase in HFOs locked to the spike/wave seizure pattern and largely confined to the ipsilateral cortex near the site of the FL injury. Additional acute recordings with linear micro-electrode arrays were obtained to evaluate laminar differences in HFOs during spontaneous periods of hyper-excitable burst-suppression activity under general anesthesia. FL animals exhibited significant increases in spontaneous HFOs that were confined to granular and supragranular layers with a concomitant increase in unit activity while control animals exhibited minimal changes in ‘ultra-high’ frequency responses above 100 Hz (i.e. ripple waves). Spike sorting of well-isolated single-units from FL cortex indicated a differential expression pattern of putative excitatory (EXC) versus inhibitory (INH) cells. EXC cells were predominately observed in the outer cortical layers and showed only weak association with HFOs while the deeper INH units were strongly phase-locked to ripple oscillations (100-800 Hz). The spontaneous cyclic spiking of cortical inhibitory cells appears to be the driving substrate behind HFOs and may prove useful in identifying regions of hyperexcitable tissue in the epileptic brain. Using the topographical maping methods enabled by the Neuronexus mouse EEG arrays recording from FLs mice, we demonstrated site specific HFOs  associated with the cortical malformations. Conclusions: In summary, the current studies indicate a strong prevalence of HFO activity in a model of FCD that are 1) mainly confined to the injured cortex, 2) originate in the upper cortical layers, 3) are most prominent during high-amplitude ‘spike’ deflections of the local field potential, and 4) indicate strong phase-locking to putative INH cells predominately within the supragranular layers of the malformed cortex. As demonstrated in the current study, the utilization of commercially available electrode arrays offers a powerful high-resolution tool for mapping the cortical circuitry of seizurogenic tissue and identification of key cellular markers underlying brain hyperexcitability and may help guide clinical diagnosis and treatment of the epileptic brain. Funding: NIH grants 5R01 NS094550