Abstracts

Rationale: Along with spontaneous recurring seizures (SRSs), epilepsy is associated with persistent deficits in cognition. Hippocampal network dysfunction and a reduction in theta oscillations are correlated with diminished spatial learning. Pilocarpine-induced epilepsy reduces theta oscillatory activity and impairs cognition. Therefore we hypothesized that medial septal nucleus (MSN) stimulation to drive hippocampal theta would improve cognitive function and increase seizure threshold in rats exhibiting SRSs. Methods: Rats were injected with 1 mg/kg scopolamine methyl nitrate followed 30 minutes later by 350 mg/kg pilocarpine. Convulsive seizures were terminated with 8mg/kg of diazepam after 240 minutes. Sham rats received equivalent volumes of saline for each injection. On post injection day (PID) 32, animals underwent fluorothyl seizure threshold testing. On PID 33, twisted bipolar electrodes were stereotactically implanted in the MSN, right prefrontal cortex (PFC) and right hippocampus. Animals were then counterbalanced based on seizure threshold into one of three groups: no, pre-, or continuous stimulation. For each of the behavioral tasks EEG was collected from PFC and hippocampus, and stimulation of the MSN (7.7 Hz, 80 µA) was given either one-minute prior (pre) or continuously through each of the subsequent tasks. On PID 44, animals were tested for five days on the Barnes maze and then in the metric spatial recognition task. After completion of behavioral testing, animals were re-tested for fluorothyl seizure threshold under the same stimulation paradigm as in the behavioral tests. Results: Stimulation significantly improved performance on the Barnes maze in pilocarpine rats. Pilocarpine rats consistently used a random strategy to find the goal, while both pre- and continuously stimulated rats utilized peripheral and spatial search strategies similar to shams (p<0.05). Continuous stimulation of sham rats impaired normal function. In the metric task, pilocarpine rats failed to recognize a change in environment. However, similar to shams, those receiving theta stimulation re-explored objects in the novel configuration (p<0.05). As in the Barnes maze, continuous stimulation of shams led to impaired function. There was a significant decrease in seizure threshold in pilocarpine rats on PID 32 (p<0.05). Four weeks later, seizure threshold was further reduced in non-stimulated pilocarpine animals. Seizure threshold was significantly elevated in pilocarpine rats when they were stimulated either immediately before or continuously during fluorothyl exposure (p<0.05). Conclusions: The current findings demonstrate that both pre- and continuous MSN theta stimulation improve cognition while also significantly increasing seizure threshold in chronically epileptic rats. Conversely, continuous stimulation impairs performance in sham controls. These results suggest that MSN stimulation represents an exciting new application for electrical neuromodulation to reduce seizures and restore cognitive function in epilepsy.