Objective:       

Responsive neurostimulation (RNS) for epilepsy applies therapeutic stimulation in response to detected epileptic activity using intracranial electrodes. Prior studies have found that people with successful seizure reduction using RNS devices undergo functional network changes¹. We hypothesise that the timing of stimulation, specifically stimulation during non-epileptic brain states, is critical in driving long-term changes to restore healthy brain networks.

Methods:

Simulation episodes occurring in low-risk epochs was characterized in a cohort of 40 people with epilepsy treated with the RNS System at the University of Utah, USA. People were categorized into three groups based on their seizure reduction values: super responders (>90% reduction, n=10), intermediate responders (≥ 50% reduction and ≤ 90% reduction), n=19, and poor responders (<50% reduction, n=11). Low-risk periods were defined as days which had fewer long epileptic episode counts than the weekly average from the prior week.

Results:

Super-responders spent more time in and experienced more frequent stimulation during low-risk seizure periods (Pearson’s correlation: p=1.88e-3 and p=1.59e-3). Additionally, circadian rhythmicity was an indicator of improved seizure reduction (Pearson’s correlation: p=0.045 and 1.55e-3), and stimulation of super-responders was less phase- locked to long epileptic episodes (two-sample Kuiper test; p<0.01). Baseline seizure frequency, epilepsy duration, and age was not a statistical predictor of outcome.

Conclusions:

Individuals with greater seizure reduction experienced more stimulation episodes during low-risk periods and spent more time in low-risk periods from stimulation onset. Targeting low-risk brain states may improve seizure reduction though neuromodulation via network restructuring driven by neuromodulation-induced plasticity.