Unearthing the mechanisms of responsive neurostimulation for epilepsy

Responsive neurostimulation (RNS) is an effective therapy for people with drug-resistant focal epilepsy. In clinical trials, RNS therapy results in a meaningful reduction in median seizure frequency, but the response is highly variable across individuals, with many receiving minimal or no benefit. Understanding why this variability occurs will help improve use of RNS therapy. Here we advocate for a reexamination of the assumptions made about how RNS reduces seizures. This is now possible due to large patient cohorts having used this device, some long-term. Two foundational assumptions have been that the device's intracranial leads should target the seizure focus/foci directly, and that stimulation should be triggered only in response to detected epileptiform activity. Recent studies have called into question both hypotheses. Here, we discuss these exciting new studies and suggest future approaches to patient selection, lead placement, and device programming that could improve clinical outcomes. Rao and Rolston discuss recent challenges to foundational assumptions underlying responsive neurostimulation therapy for drug-resistant epilepsy. An emerging mechanistic model helps explain variability in clinical outcomes and suggests this therapy may have untapped potential for reducing seizures.