Spatiotemporally organized electrical stimulation to alleviate epileptic seizures

Abstract

Epilepsy is a prevalent neurological disorder affecting approximately 70 million individuals globally. Epileptic seizures are believed to be caused by abnormal and excessive electrical activity in the brain. Most of patients can be seizure-free with anti-seizure medications, however, around 30% of patients have known to be drug-refractory. Deep brain stimulation (DBS) has emerged as an alternative, offering spatial and temporal control over epileptic circuits. Various brain regions, including the hippocampus, anterior nuclei of the thalamus (ANT), centromedian thalamic nucleus (CM), and motor cortex, have been considered as potential targets for stimulation. The hippocampus is a promising stimulation target for treatment of epilepsy due to the intrinsic anatomical connectivity related to the generation and propagation of epileptic seizures in temporal lobe epilepsy (TLE), which is the most common type of epilepsy. However, direct control of the hippocampus with conventional electrical stimulation modality is considered to be not practicable due to its large size and elongated shape. In this context, we propose a sequential narrow-field (SNF) stimulation method for terminating epileptic seizures, while focusing stimulus energy at the spatially extensive hippocampal structure. Our hypothesis proposes that sequentially induced localized fields for each section could modulate the extensive structure as if a single high-frequency electric field is applied due to relatively slow axonal conduction (Figure 1) [1, 2]. To demonstrate the therapeutic efficacy of the proposed SNF stimulation modality, we immunohistochemically examined animal brains after acute seizure-suppressing experiments (Figure 2). As a potent analog of glutamate, KA has been used to induce intensive depolarization and subsequent cell death, which is a central phenomenon of TLE. The strong c-Fos expression in the CA1, CA3, dentate gyrus (DG), and cortex regions was observed 3 h after KA injection (Fig. 2a, top), which corresponded to hyperactivity in neurons during status epilepticus (SE) as previously reported [3]. However, c-Fos positive neurons in the SNF stimulation group were expressed in significantly lower amounts than in the non-stimulation group throughout the entire brain, except in the DG. The significant decrease in c-Fos expression in rodent brains treated with SNF stimulation signaled a strong inhibitory effect to neural hyperactivation by excitotoxicity during SE, and this phenomenon may ultimately result in substantial decreases in neuronal damage in the brain.