Abstracts

Rationale: Temporal lobe epilepsy (TLE) represents more than 20% of all epilepsy cases, and as many as 40% of patients are refractory to pharmacological treatment. FDA approved electrical stimulation paradigms reduce seizures in refractory patients who are ineligible for surgical resection, but they do not treat common comorbidities such as cognitive decline. There is evidence that pathology detected in the EEG, such as the presence of epileptic discharges (interictal spikes), or diminished slow-wave theta oscillations, correlate both with ictal activity and poor cognitive outcome. We hypothesized that theta frequency stimulation of the medial septal nucleus (MSN) during early epileptogenesis would drive oscillatory activity, reduce epileptic discharges and improve cognitive performance in the novel object recognition (NOR) task. Methods: Recording electrodes were implanted in the prefrontal cortex, dorsal and ventral hippocampus, and MSN of adult male Sprague Dawley rats. Bipolar stimulating electrodes were also implanted in the MSN. Animals were injected with scopolamine (1 mg/kg) followed by pilocarpine (350 mg/kg) after 30 min, and diazepam (8 mg/kg) 4 hours later. Rats were counterbalanced into stimulation groups: sham, pilo, pilo-fixed theta (7.7 Hz, 80 µA), and pilo-theta burst (50 ms trains of 200 Hz, 7.7 trains/sec, 50 µA). On post-pilocarpine day 4 (PPD 4), rats received 30 minutes of daily stimulation for 13 days. After 4 weeks, rats received 2 days of habituation to the NOR environment and cognition was evaluated on PPD 45. Rats were exposed to 2 objects for 5 min (acquisition), then spent 3 hrs in a neutral cage, and subsequently were exposed to one familiar and one novel object for 5 min (test). Oscillations were evaluated in specific 3 sec epochs during acquisition based on behaviors (i.e. general movement, object interaction). Spikes were counted across 5 min for both acquisition and test. For the NOR test, recognition index was calculated (percentage of time animals interacted with the novel object relative to overall object interaction). Results: Preliminary data during NOR acquisition indicated a trend towards a reduction in power and the percentage of time theta oscillations were observed in the ventral hippocampus of pilocarpine-treated rats as compared to sham. There was also an increase in interictal spikes in the pilocarpine group that was detected across both trials. Theta oscillations and spike counts in stimulated animals were not different from sham. In the NOR, sham animals significantly preferred the novel object during the test whereas pilocarpine rats performed at chance. Stimulation restored performance to sham levels. Conclusions: These data suggest that acute stimulation of the MSN following pilocarpine injection results in lasting cognitive improvement. These persistent benefits may be a result of early stimulation driving activity, inducing circuit plasticity, and ultimately altering the progression of epilepsy as measured by fewer epileptic spikes and elevated theta oscillations. Funding: NS 084026 and the Bronte Epilepsy Foundation