Abstracts

Rationale: It is now widely accepted that interictal epileptic discharges (IEDs) can cause transient cognitive impairments in patients with epilepsy. Recent work from our laboratory shows that hippocampal IEDs disrupt performance in a rat model of epilepsy by affecting hippocampal processing in a memory task. Despite this detrimental effect, there is no treatment specifically targeting IEDs. Interestingly, several authors reported that IEDs were less frequent during periods where theta rhythm, a 4-12Hz rhythmical oscillation, was present and that IEDs can be suppressed by carbachol induction of theta rhythm. Theta rhythm can also be induced by electrical stimulation of specific reticular, septal and hypothalamic nuclei. This method has the advantage of being particularly efficient, instantaneous and rapidly reversible. We hypothesize that theta rhythm induction by deep brain stimulation (DBS) of these nuclei reversibly suppresses IEDs in epileptic rats. Methods: DBS electrodes were implanted stereotaxically in 10 adult sprague dawley rats in the following structures (2 rats each): Red nucleus, nucleus reticularis pontis oralis (RPO), supra-mammillary nucleus (SUP), posterior hypothalamus (PH) and medial septum (MS). Each animal was also implanted with an injection cannula aimed at the ventral hippocampus and a recording electrode in the dorsal hippocampal CA1-lacunosum moleculare region. Two weeks after surgery, status epilepticus was induced by intra hippocampal infusion of pilocarpine (0.6mg/mL, 1.5-2uL0.6mg/mL, 1.5-2uL) under intracranial EEG monitoring. Infusions were stopped when stage 4 seizures and sustained epileptic discharges (>1minute) were observed. Approximately two weeks later, rats developed spontaneous seizures and IEDs. Animals were monitored daily for IEDs. When a rat displayed a frequency of 3IEDs per minute, it was placed in an open field and DBS was performed. Stimulation parameters, such as frequency (1-200Hz), amplitude (0.1-2 mA) and stimulation patterns (bipolar, continuous square pulses vs. 7Hz bursts of 100Hz pulses) were systematically varied to induce the best theta suppression of IEDs. Results: DBS of all structures significantly induced theta rhythm. In most cases, except the MS, the best stimulation patterns to drive theta rhythm consisted of 80Hz bipolar squared pulses (1ms duration). Stimulus amplitude was adjusted for each animal and structure. MS stimulation however had to be performed at a 7Hz burst patterns to induce theta. In all cases, DBS induced theta strongly suppressed IEDs. Conclusions: These results show that DBS induction of theta rhythm strongly suppresses IEDs. Understanding the mechanisms responsible for this phenomenon will provide insights concerning the anti-epileptic effects of specific EEG and attention states. Further more, DBS suppression of IEDs during periods of high cognitive demand could improve the cognitive performance of epileptic patients suffering from cognitive impairments. Supported by NIH grants NS044295, NS056170