Abstracts

Rationale: Among partial epilepsies, temporal lobe epilepsy (TLE) is most prevalent and approximately 40% of patients are resistant to antiepileptic drugs (AEDs). Importantly, in some cases AEDs lead to exacerbation of cognitive comorbidities. At present, there are no treatments aimed to address cognitive deficits associated with TLE. In the current study, we hypothesized that early intervention with low frequency stimulation (7.7 Hz, or theta burst) of the medial septal nucleus (MSN) would alter the course of epileptogenesis leading to a reduction in interictal spikes (IIS), and an increase in seizure threshold, while concurrently alleviating cognitive impairments in epileptic rats.  Methods: Adult male Sprague-Dawley rats were implanted with bipolar stimulating electrodes (tungsten) in the MSN in addition to recording electrodes in dorsal and ventral hippocampi, prefrontal cortex (PFC), and also MSN. Baseline EEG was recorded one week after surgery. Two weeks following implantation animals were selected randomly for sham or pilocarpine groups. Animals were injected with 1mg/kg scopolamine methyl nitrate followed by 350 mg/kg pilocarpine (or saline control) 30 minutes later. Convulsions were terminated with 8 mg/kg diazepam four hours post pilocarpine. Pilocarpine rats were counter-balanced into stimulation groups: no-stimulation, fixed theta (7.7 Hz, 80 μA, 1 msec pulse-width), or theta burst (50 ms trains of 200 Hz, 7.7 trains per second, 50 μA, 100 μs pulse-width). Starting on post pilocarpine day 4 (PPD 4), rats received 30 minutes of daily stimulation for 14 days. Time-matched EEG was recorded in all rats. EEG was again recorded on PPD 31, and animals underwent behavioral testing on PPD 43-54 (Barnes maze, novel object). Seizure threshold was evaluated on PPD 32 and 56.  Results: On PPD 4, Pilocarpine treated animals demonstrated significantly reduced theta peak frequency (6-10 Hz) across all brain regions with exception to PFC, and by PPD 31, IIS were observed in hippocampal recordings of all pilocarpine treated rats. Non-stimulated animals had a significant reduction in seizure threshold, increased escape latency on the Barnes maze, and no preference for the novel object. Animals receiving 7.7 Hz stimulation had both a significant reduction in IIS and increased seizure threshold. Cognitive performance was significantly improved on both the Barnes and novel object tasks. Burst stimulation did not reduce IIS but did increase seizure threshold. Similarly, latency was unaffected in the Barnes maze, but burst stimulation improved novel object exploration.  Conclusions: Our data demonstrates that early intervention via MSN theta stimulation results in a reduction of IIS, a persistent increase in seizure threshold, and also improved cognition. Above all, a singular treatment that can reduce potential epileptic biomarkers and associated comorbidities via network modulation represents a critical advancement in TLE treatment. Funding: Bronte Epilepsy Research Foundation, andNINDS NS084026