Abstracts

One of the most common cause of intractable epilepsy is partial seizures. It is believed that the seizures in these individuals arise from a focal hyperexcitable areas spreading to involve other areas of the brain. In addition to seizures, these areas also generate interictal spikes between seizures. While the underlying causes of symptomatic, focal epilepsy are quite varied, these electrophysiological properties remain more or less constant across patients. We have recently identified a highly-predictive core of activity-dependent genes expressed at human neocortical epileptic foci and here hypothesize that the expression of these genes that have potential roles in synaptic plasticity and epileptogenesis are driven by the degree of interictal epileptiform activity. The patients with pharmaco-resistent neocortical partial epilepsy undergoing two-stage epilepsy surgery were included in the study. Equal samples of neocortex underlying each recording electrode were used to prepare total RNA for quantitative real-time RT-PCR analysis. Both seizures and electrophysiological parameters of interictal spiking that included frequency, amplitude and shape were obtained from intracranial ECoG recordings over preceding days from the same electrodes. Gene expression of previously identified, activity-dependent genes at each electrode site were correlated to both seizure frequency and the above listed electrical parameters of the interictal spikes. Neocortical areas with higher frequency and amplitude of interictal spiking corresponded to regions of seizure onset compared to nearby cortical regions with minimal or no interictal spiking. However, we found no relationship between seizure frequency and gene expression for these genes that consist of immediate early genes, signaling genes, and genes that may promote synaptic strength. On the contrary, highly significant correlations were seen between the expression of these genes and both frequency and amplitude of interictal spiking. Interictal spiking is closely associated with expression of transcription factors and other genes that could play important roles in synaptic strengthening and organization. Since there was little correlation between gene expression and seizure frequency, we suggest that interictal spiking is a stronger driving force behind these gene changes and may be responsible for development and maintenance of hyper-connected cortical networks in epileptic neocortex. Quantitative EEG analysis of interictal human neocortical ECoG can be accomplished and it can also be fruitfully utilized to understand molecular mechanisms of epileptic neocrtex. (Supported by NINDS grant RO1 NS045207-01.)