  An implanted device for brain-responsive neurostimulation (RNS System) is
approved as an effective treatment to reduce seizures in adults with
medically-refractory focal epilepsy. Clinical trials of the RNS System
demonstrate population-level reduction in average seizure frequency, but
therapeutic response is highly variable. Recent evidence links seizures to
cyclical fluctuations in underlying risk. We tested the hypothesis that
effectiveness of responsive neurostimulation varies based on current state
within cyclical risk fluctuations. We analyzed retrospective data from 25
adults with medically-refractory focal epilepsy implanted with the RNS System.
Chronic electrocorticography was used to record electrographic seizures, and
hidden Markov models decoded seizures into fluctuations in underlying risk.
State-dependent associations of RNS System stimulation parameters with changes
in risk were estimated. Higher charge density was associated with improved
outcomes, both for remaining in a low seizure risk state and for transitioning
from a high to a low seizure risk state. The effect of stimulation frequency
depended on initial seizure risk state: when starting in a low risk state,
higher stimulation frequencies were associated with remaining in a low risk
state, but when starting in a high risk state, lower stimulation frequencies
were associated with transition to a low risk state. Findings were consistent
across bipolar and monopolar stimulation configurations. The impact of RNS on
seizure frequency exhibits state-dependence, such that stimulation parameters
which are effective in one seizure risk state may not be effective in another.
These findings represent conceptual advances in understanding the therapeutic
mechanism of RNS, and directly inform current practices of RNS tuning and the
development of next-generation neurostimulation systems.
