State-dependent effects of responsive neurostimulation depend on seizure localization

Brain-responsive neurostimulation (RNS) is firmly ensconced among treatment options for drug-resistant focal epilepsy, but over a quarter of patients treated with the RNS® System do not experience meaningful seizure reduction. Initial titration of RNS therapy is typically similar for all patients, raising the possibility that treatment response might be enhanced by consideration of patient-specific variables. Indeed, small, single-centre studies have yielded preliminary evidence that RNS System effectiveness depends on the brain state during which stimulation is applied. The generalizability of these findings remains unclear, however, and it is unknown whether state-dependent effects of responsive neurostimulation are also stratified by location of the seizure onset zone where stimulation is delivered. We aimed to determine whether state-dependent effects of the RNS System are evident in the large, diverse, multi-centre cohort of RNS System clinical trial participants and to test whether these effects differ between mesiotemporal and neocortical epilepsies. Eighty-one of 256 patients treated with the RNS System across 31 centres during clinical trials met the criteria for inclusion in this retrospective study. Risk states were defined in relation to phases of daily and multi-day cycles of interictal epileptiform activity that are thought to determine seizure likelihood. We found that the probabilities of risk state transitions depended on the stimulation parameter being changed, the starting seizure risk state and the stimulated brain region. Changes in two commonly adjusted stimulation parameters, charge density and stimulation frequency, produced opposite effects on risk state transitions depending on seizure localization. Greater variance in acute risk state transitions was explained by state-dependent responsive neurostimulation for bipolar stimulation in neocortical epilepsies and for monopolar stimulation in mesiotemporal epilepsies. Variability in the effectiveness of RNS System therapy across individuals may relate, at least partly, to the fact that current treatment paradigms do not account fully for fluctuations in brain states or locations of simulation sites. State-dependence of electrical brain stimulation may inform the development of next-generation closed-loop devices that can detect changes in brain state and deliver adaptive, localization-specific patterns of stimulation to maximize therapeutic effects.