Abstracts

Rationale: An estimated 5.1 million people in the United States are diagnosed with epilepsy and, despite the introduction of newer antiepileptic drugs, ~40% have poor seizure control with medication alone.Over 50% of patients with medically refractory epilepsy exhibit chronic learning and memory deficits with no current therapy addressing this significant comorbidity.  In this study, we investigated the effects of low frequency stimulation (7.7 Hz) of the vagal nerve (VNS) on seizure threshold and cognitive performance in the pilocarpine model of temporal lobe epilepsy (TLE).  Methods: Adult male Sprague-Dawley rats were implanted with a VNS cuff around the left vagal nerve and individual tungsten recording electrodes were stereotaxically implanted bilaterally in the dorsal hippocampus. Two weeks post-implantation status epilepticus was induced with a combination of scopolamine methyl nitrate (1mg/kg, IP) and, 30 minutes later, pilocarpine (350 mg/kg, IP). Convulsive seizures were terminated with diazepam (8mg/kg, IP) after 240 minutes. Cycles of status were used to counterbalance animals: pilocarpine rats receiving stimulation (7.7 Hz, 80 μA, with a 1 msec pulse-width; n=4), and pilocarpine rats receiving no stimulation (n=4).  Sham animals (n=4) received similar treatment except that an equal volume of saline was injected as a control for pilocarpine. Four weeks post-pilocarpine, a baseline EEG was taken prior to initiating behavioral studies.  Cognitive performance was evaluated using the Barnes maze and novel object recognition task, and subsequently seizure threshold was measured with fluorothyl six weeks post-pilocarpine injection. Stimulation occurred during the entirety of each of the behavioral tasks and also during fluorthyl exposure. EEG was also recorded during behavioral and flurothyl testing. Results: There was evidence of interictal spikes in each of the pilocarpine-treated rats.  No seizures were observed during cognitive assessments. Pilocarpine rats had a longer latency to find the escape box on the Barnes maze and spent less time exploring a novel object as compared to sham controls.  In addition, pilocarpine-treated rats had a lower seizure threshold.  Pilocarpine rats receiving 7.7 Hz VNS had an improved latency to find the escape box on the Barnes maze and also explored the novel object more as compared to untreated pilocarpine rats.  Critically, 7.7 Hz VNS stimulation led to an increase in seizure threshold in pilocarpine rats.   Conclusions: Clinical VNS has been successful in reducing seizures in many patients, however there is no evidence that the standard 30 Hz stimulation paradigm has a positive effect on cognitive outcome.  With a small sample size, these preliminary data suggest that low frequency 7.7 Hz VNS can improve cognitive outcome and increase seizure threshold in rats with pilocarpine-induced epilepsy.  These findings are particularly exciting as there is currently no treatment that both reduces seizures and directly improves cognitive outcome in patients with temporal lobe epilepsy. Funding: UC Davis Clinical and Translational Science Center TL1, Bronte Endowment