Association of Closed-Loop Brain Stimulation Neurophysiological Features With Seizure Control Among Patients With Focal Epilepsy

Abstract

IMPORTANCE A bidirectional brain-computer interface that performs neurostimulation has been shown to improve seizure control in patients with refractory epilepsy, but the therapeutic mechanism is unknown. OBJECTIVE To investigate whether electrographic effects of responsive neurostimulation (RNS), identified in electrocorticographic (ECOG) recordings from the device, are associated with patient outcomes. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of ECOG recordings and accompanying clinical meta-data from 11 consecutive patients with focal epilepsy who were implanted with a neurostimulation system between January 28, 2015, and June 6, 2017, with 22 to 112 weeks of follow-up. Recorded ECOG data were obtained from the manufacturer; additional system-generated meta-data, including recording and detection settings, were collected directly from the manufacturer's management system using an in-house, custom-built platform. Electrographic seizure patterns were identified in RNS recordings and evaluated in the time-frequency domain, which was locked to the onset of the seizure pattern.MAIN OUTCOMES AND MEASURES Patterns of electrophysiological modulation were identified and then classified according to their latency of onset in relation to triggered stimulation events. Seizure control after RNS implantation was assessed by 3 main variables: mean frequency of seizure occurrence, estimated mean severity of seizures, and mean duration of seizures. Overall seizure outcomes were evaluated by the extended Personal Impact of Epilepsy Scale questionnaires, a patient-reported outcome measure of 3 domains (seizure characteristics, medication adverse effects, and quality of life), with a range of possible scores from 0 to 300 in which lower scores indicate worse status, and the Engel scale, which comprises 4 classes (I-IV) in which lower numbers indicate greater improvement. RESULTS Electrocorticographic data from 11 patients (8 female; mean [range] age, 35 [19-65] years; mean [range] duration of epilepsy, 19 [5-37] years) were analyzed. Two main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network were discovered: direct and indirect effects. Direct effects included ictal inhibition and early frequency modulation but were not associated with improved clinical outcomes (odds ratio [OR], 0.67; 95% CI, 0.06-7.35; P > .99). Only indirect effects-those occurring remote from triggered stimulation-were associated with improved clinical outcomes (OR, infinity; 95% CI, -infinity to infinity; P = .02). These indirect effects included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation. CONCLUSIONS AND RELEVANCE These findings suggest that RNS effectiveness may be explained by long-term, stimulation-induced modulation of seizure network activity rather than by direct effects on each detected seizure.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy

“…41 In addition, recent studies have shown that features in the ECoG data may provide objective biomarkers that can be used to assess the clinical response to stimulation. 42,43 In addition, it may be possible to use an individual patient's ECoG data to identify periods of heightened seizure risk. 44,45 In the future, these data may be used to supplement the patient's clinical report.…”

Real‐world experience with direct brain‐responsive neurostimulation for focal onset seizures

“…Stimulating into well‐developed electrographic seizures may not always disrupt electrographic seizure activity, perhaps because the seizure has already propagated beyond the region that can be impacted by spatially limited stimulation. It is possible that delivering acute disruptive stimulation into abnormal (interictal) electrographic activity (not only seizures) is effective because of providing longer‐term neuromodulation 19,28 . This hypothesis is supported by the observation that the total duration of stimulation received was a median of 4.5 min/d (IQR = 1.4‐9.3 min/d) in the real‐world patients, which is significantly greater than in the Pivotal trial population (median = 3.0 minutes of stimulation per day, IQR = 1.5‐5.1 min/d) at 2 years postoperatively ( P = .024), although substantially less than with open‐loop scheduled stimulation approaches.…”

Responsive neurostimulation for regional neocortical epilepsy

“…Indeed, the effects of brain stimulation on epileptogenic networks remain largely unknown, and the relative contributions of lead configuration and stimulation pathway (ie, anode/cathode electrode designations) to therapeutic efficacy are currently undefined . Modeling studies suggest that the volume of tissue activated by DBS electrodes is on the order of cubic millimeters .…”