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

Summary 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.