Abstracts

Rationale: EEG recordings of patients with epilepsy during periods between seizures (interictal periods) often show brief high-amplitude spike waveforms, which stem from groups of aberrant neurons discharging in bursts. These interictal spikes (IS) are clinically useful in the diagnosis of many epileptic conditions, including temporal lobe epilepsy (TLE). However, they have been implicated in brief disruptions of region-dependent cortical processing in patients (transient cognitive impairment). Patients with TLE often have large numbers of IS in the hippocampus, an area important for learning and memory. We are investigating the transient cognitive effects of hippocampal IS with a modified rat model of temporal lobe epilepsy. Methods: 8 Sprague-Dawley rats were trained to perform an operant behavior task called delayed-match-to-sample (DMTS), which employs hippocampal-dependent short-term memory. Intact hippocampal function is crucial for accurate performance during extended time delays in this task. Rats were then implanted with custom depth electrodes in the ventral hippocampus bilaterally, and the right prelimbic prefrontal cortex. An infusion cannula was placed into the right ventral hippocampus. Following surgical recovery, rats were unilaterally infused with pilocarpine (0.6mg/mL, 1.5-2uL). The infusion was ceased upon EEG evidence of seizures, regardless of behavioral signs. This procedure produced chronic IS in the majority of animals using around 1mg of pilocarpine per rat. One week later, rats were briefly retrained on DMTS and subsequently tested on 60 trials per day for several weeks. Real-time EEG recordings were made simultaneously from all three brain and synchronized with the DMTS task data to determine the timing of IS within each trial. Results: 8-15 days after SE induction, IS developed in the infusion site. Interestingly, independent spike-generating foci were observed after several weeks in the contralateral hippocampus, as well as in the prefrontal cortex. Using within-subject measures, we compared the performance on trials with and without IS, and found an increased susceptibility to errors associated with IS. Ongoing work will analyze the relative impact of IS in specific epochs of the task (e.g. memory encoding, storage, retrieval), and whether there is a synergistic involvement of IS in the hippocampus and prefrontal cortex. Conclusions: This study confirms that transitory cognitive impairment is not limited to cortical neural processing, rather it extends to limbic areas involved in learning and memory. The hippocampus is critically important for these functions, yet is highly prone to IS in TLE and other conditions. Our results may have significant implications for individuals with epilepsy, particularly whether clinicians should strive to treat not only seizures, but interictal epileptiform abnormalities as well. This work was supported by NIH Grant 1R01NS056170.