Speaker: Nrupen Pakalapati
Advisor: Prof. D. Durand
Title: Low-Frequency Stimulation of Corpus Callosum Suppresses Epilepsy in the Cortex through γ-aminobutyric acid-B Receptor and Slow After-Hyperpolarization Mediated Reduction in Tissue Excitability
Abstract:
Objective: Deep brain stimulation (DBS), particularly low-frequency stimulation (LFS) targeting fiber tracts, has emerged as a potential therapy for drug-resistant epilepsy and for generalized epilepsy, both posing significant treatment challenges. LFS diffusely suppresses epilepsy in the cortex when applied to fiber tracts like the corpus callosum (CC). However, the mechanisms underlying LFS-induced suppression of epileptic activity in the cortex remain unknown. This study investigates how LFS of the CC provides an antiepileptic effect in the cortex in coronal rodent brain slices.
Methods: A 4-AP seizure model was created, and LFS stimulation parameters were optimized to provide the largest antiepileptic effect in the cortex when applied to the CC. Changes to tissue excitability and percent time spent seizing were measured due to LFS in ACSF, 4-AP, and under the presence of various specific and non-specific GABAB and sAHP antagonists.
Results: 5 Hz LFS maximally suppressed epileptic activity in the cortex (>80%). Tissue excitability measurements during LFS show a reduction across a wide range of interspike intervals (ISI) (50-1000 ms) with a maximum reduction at 200 ms, and notably, tissue excitability remained depressed at 1000 ms. When GABAB antagonists are independently administered, reduction in tissue excitability ceased in the 50-400 ms range, and the antiepileptic effect was greatly diminished (<15%), but the reduction in the 600-1000 ms range persisted—suggesting the presence of a different antiepileptic mechanism. Given the long-time frame of the antiepileptic effect, slow after-hyperpolarization (sAHP) antagonists were administered, and the antiepileptic effect was once again observed to be diminished (<15%). When both sAHP and GABAB antagonists were administered, LFS failed to provide any meaningful antiepileptic effect.
Significance: Stimulation of the CC provides an antiepileptic effect in a large portion of the cortex, and the resulting reduction in tissue excitability is mediated by GABAB receptors and sAHP mechanisms.