Abstracts

Rationale: Electrical brain stimulation has been proposed as a promising treatment option for patients with medically resistant epilepsy disorder; however, the design of rational clinical trials has been hampered by our limited knowledge of the effects of electrical stimulation on the excitability and neurochemistry in epilepsy patients. Glutamate is elevated both interictally and with seizures in the epileptic human hippocampus, and may contribute to the neuronal damage and epileptogenicity. Fifty Hz stimulation, is a candidate therapeutic stimulation that is also used for clinical cortical mapping. Our objective was to determine the effects of 50 Hz stimulation on glutamate efflux in the human epileptic hippocampus and its relationship to basal interictal glutamate levels. Methods: Subjects were patients (n = 10) with intractable epilepsy admitted for intracranial EEG (icEEG) monitoring. Depth electrodes containing microdialysis probes were implanted in the suspected epileptic hippocampus. The stimulations were done after icEEG monitoring was completed and patients were restarted on their anti-epileptics. Depth electrodes (n=11) were stimulated at 50 Hz for a 720 ms train, every 5 sec X 5 times at a stimulus strength that did not induce after-discharges (2-10 mA). Microdialysis samples were collected every 2 min (2 µl/min flow rate) and were analyzed with HPLC for changes in glutamate levels. Basal interictal glutamate levels were obtained at a flow rate of 0.2 µl/min, at least 6 hrs away from any seizures. Results: Following stimulation, 4 patients experienced seizures and 2 patients experienced auras. A within-subjects analysis using a multivariate ANOVA with a Dunnett’s post-hoc test revealed that glutamate efflux at the time of stimulation (time zero) was significantly increased from baseline (F (22,180) = 2.97, p < .0001). A linear regression model on logarithmically transformed data showed that the peak glutamate efflux in response to stimulation was significantly related to basal interictal levels (R^2 = .809, p = .0010). Conclusions: Fifty Hz stimulation of the epileptic hippocampus results in increased excitability in our patients, as evidenced by stimulus-induced seizures and auras in 6 out of 10 patients. This stimulation also caused significant glutamate efflux, which was proportional to the elevation in basal interictal glutamate levels. We conclude that 50 Hz stimulation would not be optimal for seizure control in epilepsy. (Sources of funding - (1). NINDS (National Institute of Neurological Disorders and Stroke): P01NS39092, JDRF 4-2000-422, BIRWCH 1K12DA14038-01 (2). NIAAA (National Institute on Alcohol Abuse and Alcoholism): AA014906-01)