Abstracts

Rationale: High frequency stimulation (HFS) used in deep brain stimulation (DBS) has been shown to reduce seizure frequency in clinical trials (Brain Res Bull 2014;109:13-21). HFS can modulate neuronal activities, but the precise underlying mechanisms are not completely understood yet. In the present work, we tested HFS on the chemically induced seizures in hippocampal slice from the temporal lobe epilepsy animal model. Especially, medial entorhinal cortex (MEC) as part of the entorhinal-hippocampal networks, which is known as an important neural pathway connecting the hippocampus to the neocortex (Nat Rev Neurosci 2010;11:339-350, Curr Opin Neurobiol 2018;52:107-114), and an important region for the initiation of seizure-like events (SLEs) (Prog Neurobiol. 2002;68:167-207). The goal of this study is to investigate the effects of HFS on the hippocampal seizures, as well as to elucidate how HFS alters neuronal dynamics involving seizure generation and propagation in entorhinal-hippocampal systems. Methods: We measured the spatiotemporal dynamic change of epileptic electroencephalogram (EEG) data using 6x10 channels of a planar microelectrode array (MEA) system in the entire hippocampal formations including CA3, CA1, dentate gyrus, subiculum, medial, and lateral entorhinal cortex from 14-day-old male Sprague-Dawley rats’ brain tissue slice. When a spontaneous SLEs occurred using 4-aminopyridine (4-AP) and was clearly identified (after 3–4s from the onset), we applied HFS (130Hz) on the layer Ⅲ of MEC through an external electrode-connected stimulator. Based on the concept of granger causality (GC), the effective connectivity was analyzed in 7 different frequency ranges; delta (1–4Hz), theta (4–8Hz), alpha (8–13Hz), beta (13–25Hz), gamma (25–55Hz), ripple (65–200Hz), and fast ripple (250–500Hz), respectively. Results: After applied HFS on the MEC when a spontaneous SLE occurred, SLE duration in stimulation groups (mean duration 35.87±8.90s) was reduced compared to non-stimulation groups (mean duration 148.07±89.76s). In addition, changes of GC rapidly decreased after HFS among the hippocampal subnetworks. Furthermore, Patterns of GC rapidly increased even before the ictal EEG onset time in the onset region, which was more remarkable in the most of frequency bands. Also, the directional changes especially increased in the seizure onset electrodes that was evolved sharply into the other channels involving epileptic networks. Conclusions: The present study showed that HFS on the ictal onset region reduced seizure duration. Also, HFS disrupted epileptic effective connectivity from ictal onset to other hippocampal subregions. Effective connectivity analysis methods of epileptic network applied to ictal EEGs could provide a deeper understanding of the spatiotemporal mechanism involving epileptic network dynamics. Funding: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (2017R1A2A2A05069647, 2019M3C1B8090803 and 2019M3C1B8090802 to H.W.L.).