Effects of high-frequency stimulation on epileptiform activity in vitro: ON/OFF control paradigm

Purpose: To determine the effects of high-frequency electrical stimulation on electrographic seizure activity during and after stimulation (ON-effect and OFF-effect). Methods: The modulation and suppression of epileptiform activity during (ON-effect) and after (OFF-effect) high-frequency electrical stimulation was investigated using the high-K+ and picrotoxin hippocampal slice epilepsy models. Uniform sinusoidal fields (50 Hz) were applied with various intensity levels for 1 min across brain slices. Extracellular and intracellular activity were monitored during and after stimulation. Results: The ON-effects of high-frequency stimulation were highly variable across individual slices and models; ON-effects included modulation of activity, pacing, partial suppression, or activity resembling spreading-depression. On average, epileptic activity, measured as power in the extracellular fields, increased significantly during stimulation. Following the termination of electrical stimulation, a robust poststimulation suppression period was observed. This OFF suppression was observed even at relatively moderate stimulation intensities. The duration of OFF suppression increased with stimulation intensity, independent of ON-effects. Antagonism of GABA(A) function did not directly effect OFF suppression duration. Conclusions: The present results suggest that "rational" seizure control protocols using intermittent high-frequency electrical stimulation should control for both ON and OFF effects.