Suppression of hippocampal epileptic seizures in the kainate rat by Poisson distributed stimulation *Tine Wyckhuys, *Paul Boon, *Robrecht Raedt, *Bregt Van Nieuwenhuyse, *Kristl Vonck, and *yWytse Wadman *Laboratory for Clinical and Experimental Neurophysiology, Department of Neurology, Ghent University, Ghent, Belgium; and ySILS-Centre for NeuroScience, University of Amsterdam, Amsterdam, The Netherlands SUMMARY Purpose: Hippocampal deep brain stimulation (DBS) is an experimental therapy for patients with pharmacoresis- tant temporal lobe epilepsy (TLE). Despite the successful clinical application of DBS, the optimal stimulation parameters are undetermined. We evaluate the efficacy of a new form of DBS, using continuous stimuli with Pois- son distributed intervals (Poisson distributed stimulation, PDS) in the kainate (KA) rat model, a validated model for human TLE. Methods: Status epilepticus was elicited by injection of KA (i.p.). After development of spontaneous seizures, rats were implanted with hippocampal DBS- and depth elec- troencephalography (EEG) electrodes. After baseline EEG monitoring, one group of rats (n = 13) was treated with PDS and a second (n = 11) received regular high fre- quency stimulation (HFS) at 130 Hz. Stimulation inten- sity was 100 lA below the threshold for induction of epileptiform EEG activity. Results: Stimulation intensity was significantly lower for PDS (156 ± 20 lA) than HFS (207 ± 23 lA; p < 0.02). Seven (54%) of 13 rats treated with PDS and 5 (45%) of 11 rats treated with HFS experienced a significant reduc- tion in seizure frequency. In PDS-improved rats, seizure frequency was reduced to 33% (p < 0.01) of baseline value and in HFS-improved rats to 50% (p < 0.01). After termination of PDS, seizure rate returned to baseline value. Discussion: Continuous hippocampal PDS significantly reduces the number of spontaneous seizures. Compared to regular HFS, there is a slightly larger number of improved rats and a larger efficacy at a considerably lower stimulus intensity. The first two observations leave room for optimization, whereas a lower intensity is beneficial for battery life. KEY WORDS: Temporal lobe epilepsy, Deep brain stimu- lation, Hippocampus. More than 30% of patients with epilepsy remain inade- quately controlled despite antiepileptic medications (Kwan & Brodie, 2000). An experimental treatment option for patients ineligible for resective surgery is electrical stimula- tion of deep brain structures (deep brain stimulation, DBS) (Gwinn & Spencer, 2004). Because the basic mechanisms of action of DBS are unknown, several brain structures have been targeted, and optimal stimulation parameters are yet to be determined. Nevertheless, success of hippocampal DBS has been reported in human clinical trials (Velasco et al., 2000a,b, 2001a; Vonck et al., 2002; Osorio et al., 2005; Tellez-Zenteno et al., 2006; Boon et al., 2007) as well as in animal experiments (Bragin et al., 2002; Lopez-Meraz et al., 2004; Goodman et al., 2005; Cuellar-Herrera et al., 2006; Wyckhuys et al., 2007). Systemic or intracerebral injection of kainic acid (KA) triggers a cascade of molecular and cellular events leading to status epilepticus (SE) (Cavalheiro et al., 1982; Hellier et al., 1998), followed by a period of gradual increase in seizure frequency, which eventually stabilizes. Finally, rats display the spontaneous, generalized tonic–clonic convul- sions that resemble those seen in patients with temporal lobe epilepsy (TLE). Next we hypothesized that DBS, in the case of epilepsy, affects intrinsic excitability of the stimulated region by interfering with intrinsic homeostatic regulation of excit- ability or interferes with the generation and propagation of synchronous activity, the main characteristic of epileptic activity. We reasoned that such interference is more effec- tive for a nonsynchronized stimulation protocol than for a single frequency stimulation. For that reason we stimulated the target region with a Poisson distributed stimulation (PDS); however, in order to stay compatible with the most Accepted August 20, 2010; Early View publication October 22, 2010. Address correspondence to Tine Wyckhuys, MSc, PhD, Laboratory for Clinical and Experimental Neurophysiology (LCEN), Ghent University Hospital, Building B, 2nd floor, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: Tine.Wyckhuys@UGent.be Wiley Periodicals, Inc. ª 2010 International League Against Epilepsy Epilepsia, 51(11):2297–2304, 2010 doi: 10.1111/j.1528-1167.2010.02750.x FULL-LENGTH ORIGINAL RESEARCH 2297