Brain Stimulation · Published 2026-05-25 · DOI 10.1016/j.brs.2026.103133
Taichi Sayanagi, Kenzo Kosugi, Luisa Cassini Ascencao, Kaito Makino, Yuya Takabatake, Mariateresa Merante, Takahiro Suzuki, Yoshifumi Abe, Toshiaki Teratani, Masahiro Toda, Kenji F. Tanaka
Background: Vagus nerve stimulation (VNS) is an established therapy for refractory epilepsy, indicating that enhanced vagal activity can suppress excessive brain excitability. However, whether endogenous vagal tone itself serves as an intrinsic antiepileptic mechanism remains unclear. We aimed to determine if endogenous vagal activity restrains epileptic dynamics and to elucidate the neural pathways involved. Methods: We employed an intrahippocampal kainate-induced mouse model of temporal lobe epilepsy and an optogenetic model of hippocampal excitability. We performed gain-of-function studies using cervical VNS (30 Hz) and loss-of-function studies using bilateral subdiaphragmatic vagotomy and selective ablation of VGluT2-positive vagal afferents. Results: Cervical VNS attenuated network hyperexcitability, significantly reducing delta power and root mean square (RMS) amplitude, consistent with its clinical efficacy. By contrast, bilateral subdiaphragmatic vagotomy increased delta power, RMS amplitude, and mortality, demonstrating that endogenous vagal activity restrains epileptic dynamics. In the optogenetic model, VNS suppressed, whereas vagotomy exacerbated, light-evoked after-discharges. Crucially, selective ablation of VGluT2-positive vagal afferents largely abolished the electrophysiological signatures of VNS, including power suppression and network desynchronization, establishing that the antiseizure action of VNS depends on intact afferent pathways. Conclusions: These findings identify endogenous vagal afferent signaling as a tonic brake on epileptic network activity and provide mechanistic evidence that cervical VNS suppresses seizures by amplifying this endogenous pathway. This work presents a conceptual and mechanistic framework for afferent-targeted neuromodulation strategies aimed at improving therapeutic precision in epilepsy.
Abstract from DOAJ. Public domain (CC0 1.0).
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Sayanagi, T., Kosugi, K., Ascencao, L., et al. (2026). Vagal afferents gate cortical excitability in a kainate-induced mouse model of temporal lobe epilepsy. Brain Stimulation. https://doi.org/10.1016/j.brs.2026.103133