Abstracts

Rationale: An estimated 2.9 million people in the U.S. alone have been diagnosed with epilepsy, and approximately 30% are refractory to medical therapies. Along with spontaneous recurring seizures (SRS), altered cognitive function is a common sequela of temporal lobe epilepsy (TLE). To date, there are no proven therapies for cognitive dysfunction in TLE, and the pathophysiology of these deficits is poorly understood. In this study, we compared the effects of theta frequency stimulation early in the disease progression of the medial septal nucleus (MSN) on septohippocampal oscillations, seizure threshold, and cognitive outcome. Methods: Male Sprague-Dawley rats underwent stereotaxic implantation of tungsten recording electrodes bilaterally into the MSN, dorsal and ventral hippocampi, and prelimbic cortex (PFC), as well as bipolar stimulating electrodes into the MSN. Baseline EEG was recorded on days 7-9 after electrode implantation. Animals then underwent saline or pilocarpine injection 10 days post-implantation (1 mg/kg scopolamine methyl nitrate followed 30 minutes later by 350 mg/kg pilocarpine). Convulsive seizures were terminated with 8 mg/kg of diazepam after 240 minutes. Rats were counterbalanced based on cycles of status into the following groups: no-stimulation, fixed theta (7.7 Hz, 80 A, with a 1 msec pulse-width; square or sine-wave), or theta burst (50 ms trains of 200 Hz, 7.7 trains per second, 50 A, 100 s pulse-width). Starting on post-injection day 4, animals were stimulated and recorded daily for 14 days: 5-minute baseline, followed by 30 minutes of stimulation, and 10 minutes of post-stimulation recording. Time-matched EEG was also recorded from non-stimulated and control animals. EEG was analyzed using power spectral analyses as well as P_episode, a measure of the percentage of time oscillating at a defined frequency range. Seizure threshold was evaluated with flurothyl and cognitive function on the Barnes maze. Results: Depressed theta oscillations were observed across all recorded regions in the weeks following pilocarpine treatment. All stimulation paradigms drove oscillations during active stimulation, but none resulted in persistent increases in power or percentage of time in the theta range. Square-wave stimulation during the latent period resulted in persistent increases in seizure threshold and improved cognitive function weeks following the last stimulation. Conclusions: These preliminary data suggest that pilocarpine injection results in altered theta oscillations within the MSN, dorsal and ventral hippocampi, and the PFC for several weeks after injection. Although stimulation during the latent period did not result in lasting changes in EEG, our data demonstrate persistent beneficial effects of stimulation on seizure threshold and cognitive performance. These data demonstrate that seizures lead to lasting changes in network activity as is evident by chronically depressed oscillations. Moreover, entraining oscillations has a long-term benefit to behavioral outcome in rats with TLE. Funding: The Bronte Endowment