A Method for Precisely Timed, On-Demand Intracranial Stimulation Using the RNS Device

Introduction: Deep brain stimulation (DBS) is a promising treatment for numerous brain diseases. However, randomized trials investigating continuous stimulation have proven ineffective. Instead, compelling evidence suggests that providing bursts of stimulation during physiologically relevant epochs may be necessary. Currently, however, technical limitations prevent this in humans: triggering devices via external controllers has unpredictable delays, while infection risk precludes externalized electrodes.

Here, we demonstrate precisely timed, on-demand stimulation by triggering the Neuropace RNS system using low-current exogenous stimulation, in both ex-vivo and anesthetized non-human primate (NHP) models.

Methods: We leveraged the RNS device’s capability to detect electrical waveforms and provide responsive stimulation. During ex-vivo testing, an RNS grid electrode and depth electrode connected to the RNS were placed in separate saline baths. Exogenous stimulation injected into the first bath via digital stimulator was detected by the grid electrode; the RNS was programmed to provide responsive stimulation, via the depth electrode. An anesthetized NHP model was used for in-vivo testing: the strip electrode was inserted sub-galealy, and EEG electrodes delivered exogenous stimulation through the scalp. In both models, additional electrodes sampled voltage data to study lag times. Lag times were analyzed automatedly in Matlab.

Results: Exogenous stimulation reliably triggered the RNS during ex-vivo testing, during more than 2000 stimulation events using various parameters. Median onset lag was 369 ms (IQR 339 – 404) in response to 115 Hz exogenous stimulation (200 ms, 2 mA). Testing in an anesthetized NHP model confirmed reliable triggering of the device in-vivo. Lag times were not statistically different from saline testing (p= 0.629, Kruskal-Wallis test). Importantly, the device was triggered using stimulation currents below humans’ perception threshold, highlighting the real-world applicability of this approach.

Conclusion : We have developed a method for delivering precisely timed, on-demand stimulation using the RNS device. This approach may enable delivering physiologically aligned DBS in humans.