Introduction: Epilepsy often leads to persistent cognitive deficits. Spatial memory deficits have been correlated with hippocampal dysfunction and reduced hippocampal theta oscillations. Previously, we demonstrated that hippocampal theta is reduced following status epilepticus. Furthermore, we showed that continuous medial septal nucleus (MSN) theta stimulation improves spatial memory in pilocarpine treated rats during the epileptogenic period. In the following study we assessed the effects of MSN theta stimulation on cognition and seizure threshold in chronic pilocarpine-induced epileptic rats.
Methods: Status epilepticus was induced in 11 adult male Sprague-Dawley rats (300-350 grams) using pilocarpine. Baseline flurothyl testing was performed at 5 weeks, and rats were then equally distributed into two groups based on seizure thresholds. A MSN stimulating/recording electrode as well as hippocampal and pre-frontal cortex recording electrodes were implanted the subsequent day. At week 6, rats received MSN theta (7.7Hz; 80µA) stimulation (n=6) or no stimulation (n=5) during the Barnes Maze task. Flurothyl testing was assessed again at 9 weeks after SE with or without MSN theta stimulation.
Results: Stimulation improved spatial working memory on the Barnes maze. Stimulated rats were more likely to utilize spatial search strategies (p<0.05) resulting in significantly fewer errors (p<0.05). Stimulation also increased both Racine stage 3 and stage 5 seizure thresholds. Between weeks 5 and 9, non-stimulated rats had a significant decrease in seizure threshold (p<0.05). Rats stimulated during the flurothyl test, however, had significantly higher seizure thresholds as compared to their baseline (p<0.05).
Conclusions: Deep brain MSN theta stimulation improves spatial learning, and increases seizure threshold in pilocarpine-induced epileptic rats. This suggests that MSN theta stimulation may be an effective neuromodulatory technique for treatment of cognitive deficits and seizures in epilepsy patients.
Patient Care: This pre-clinical study may be the basis for using neuromodulation to treat both the cognitive effects of epilepsy as well as reduce seizure frequency.
Learning Objectives: 1. Status epilepticus results in spatial and working memory deficits.
2. Medial septal nucleus theta stimulation improves spatial working memory in status epilepticus rats.
3. Following status epilepticus, medial septal nucleus theta stimulation increases seizure threshold.