Breaking Bad Networks: Dorsal Striatal Stimulation for Seizure Control

Optogenetic Stimulation of the Dorsal Striatum Bidirectionally Controls Seizures Hyder SK, Lazarini-Lopes W, Toib J, Williams G, Sukharev A, Forcelli PA. Proc Natl Acad Sci U S A . 2025;122(14):e2419178122. doi:10.1073/pnas.2419178122. PMID: 40163720. Despite a century of development of antiseizure medications, up to a third of people with epilepsy do not achieve seizure freedom with drug therapy. Deep brain stimulation is of growing use, but just as with pharmacotherapy, is not universally effective. Identifying new targets for deep brain stimulation—and in particular sites that are effective against a range of seizure types—may close this gap. Engagement of the basal ganglia experimental seizures was first observed almost 75 y ago. However, the role of the basal ganglia's input nucleus, the striatum, in seizure control is relatively understudied. To address this gap, we used an optogenetic approach to activate and inactivate neurons in the dorsal striatum of rats submitted to the gamma-butyrolactone (GBL) model of absence epilepsy, amygdala kindling model of temporal lobe epilepsy, and pilocarpine-induced Status Epilepticus (SE). Open-loop (continuous light delivery) optogenetic activation of dorsal striatal neurons robustly suppressed seizures in all models. By contrast, open-loop optogenetic silencing increased absence seizure expression and facilitated SE onset but had no effect on kindled seizures. In the GBL model, we also tested the effects of closed-loop modulation (light delivery in response to seizure detection). Closed-loop activation reduced duration of spike-wave discharges (SWDs), while closed-loop inhibition increased SWD duration. These results demonstrated previously unrecognized antiabsence effects associated with striatal neuromodulation. These findings demonstrate a robust, bidirectional role of the dorsal striatum in the control of multiple seizure types, suggesting that the striatum is a site that can exert broad-spectrum control of seizures.