Low-Frequency Stimulation at the Ventromedial Hypothalamus Exhibits Broad-Spectrum Efficacy Across Models of Epilepsy

The limited efficacy and very restricted antiseizure range of current deep brain stimulation (DBS) targets highlight the need to find an optimal target for managing various seizure types. Here, we aimed to investigate the efficacy of DBS on the ventromedial hypothalamus (VMH) in the different types of experimental epileptic seizures.

The efficacy of DBS was examined in various epileptic seizure models, and the potential mechanisms were investigated by using in vivo calcium signal recording and optogenetics.

The c-fos expression was significantly increased in the glutamatergic neurons of VMH (VMH^glu) following seizures. Then, 1-Hz low-frequency stimulation (LFS) at the VMH successfully attenuated the seizure severities across models of epilepsy, including the maximal electroshock, the pentylenetetrazol, the absence seizure, the cortical or hippocampal kainic acid-induced acute seizure, and the hippocampal-kindling models. The in vivo calcium imaging recordings revealed that LFS could inhibit the activities of the VMH^glu. Optogenetic inhibition of VMH^glu mirrored LFS's antiseizure impact. Further anterograde viral tracing confirmed the extensive distributed projections of VMH^glu, which may compose the circuitry basis of the broad-spectral efficacy of LFS.

These findings demonstrate that VMH-LFS is a broad-spectrum treatment approach for different seizure types by decreasing VMH^glu activity.