Effects of acute hippocampal stimulation in the nonhuman primate penicillin model of temporal lobe seizures

Abstract

Asynchronous distributed multielectrode stimulation (ADMES) is a novel approach to deep brain stimulation for medication resistant temporal lobe epilepsy that has shown promise in rodent and in vitro seizure models. To further evaluate its effects on a pre-clinical model, we characterized the effect of unilateral ADMES in an NHP model of temporal lobe seizures induced by intra-hippocampal injection of penicillin (PCN). Four non-human primates were used for this study in two contemporaneous cohorts. One cohort (n=3 hemispheres) was implanted with the Medtronic RC+S stimulation (GIN cohort) and recording system connected to two 4-contact ring electrodes to evaluate three unilateral stimulation patterns: 7 Hz Ring ADMES, 20 Hz Dual Ring, and 125 Hz Dual Ring (analog of clinical stimulation). In an additional cohort (EPC cohort, n=2), two 12-contact segmented electrodes were implanted in the right hippocampus and connected to an externalized recording and stimulation system to allow more flexibility in the stimulation pattern. In this second cohort, 4 variations of stimulation were evaluated (7 Hz Full ADMES, 7 Hz Ring ADMES, 31 Hz Wide Ring, and 31 Hz Dual Ring). In the GIN cohort, we found an increase in seizure frequency and time spent in seizure during the 7 Hz Ring ADMES stimulation compared to the respective post-stimulation. A similar post-stimulation effect was found in the EPC cohort. We also found an increase in seizure frequency during the 7Hz full ADMES compared to the respective post-stimulation. However, we did not find a difference between pre-stimulation and stimulation conditions suggesting a possible post stimulation effect of the 7Hz hippocampal stimulation. In conclusion, in the NHP PCN model of temporal lobe seizures, acute asynchronous hippocampal stimulation was not therapeutic, however, our findings related to the post-stimulation effect can support future studies using hippocampal stimulation for the treatment of temporal lobe epilepsy.