Responsive neurostimulation with low‐frequency stimulation

Abstract

Deep brain stimulation and responsive neurostimulation (RNS) use highfrequency stimulation (HFS) per the pivotal trials and manufacturerrecommended therapy protocols. However, not all patients respond to HFS. In this retrospective case series, 10 patients implanted with the RNS System were programmed with low-frequency stimulation (LFS) to treat their seizures; nine of these patients were previously treated with HFS (100 Hz or greater). LFS was defined as frequency < 10 Hz. Burst duration was increased to at least 1000 ms. With HFS, patients had a median seizure reduction (MSR) of 13% (interquartile range[IQR] = −67 to 54) after a median of 19 months (IQR = 8-49). In contrast, LFS was associated with a 67% MSR (IQR = 13-95) when compared to HFS and 76% MSR (IQR = 43-91) when compared to baseline prior to implantation. Charge delivered per hour and pulses per day were not significantly different between HFS and LFS, although time stimulated per day was longer for LFS (228 min) than for HFS (7 min). There were no LFS-specific adverse effects reported by any of the patients. LFS could represent an alternative, effective method for delivering stimulation in focal drug-resistant epilepsy patients treated with the RNS System.

Emerging approaches in neurostimulation for epilepsy

“…Programming approaches are largely determined by parameters used in pivotal trials, in which high-frequency (>100 Hz) stimulation has typically been used for invasive modalities [42 ▪ ]. However, low-frequency stimulation (<10 Hz) has been used for continuous neocortical stimulation [4], DBS-CM [43] and RNS [44 ▪ ]. Stimulation frequency may affect limbic system deactivation [45] and seizure clustering [46 ▪ ].…”

Current state of the epilepsy drug and device pipeline

“…[46][47][48] Many unanswered questions surround candidate and stimulation parameter selection. For example, in a study among 10 patients with poor response to high-frequency stimulation, transition to low-frequency stimulation was associated with a 76% median seizure reduction compared to pre-implantation baseline, 49 raising questions about how to tailor parameters. Moreover, future investigation should not just focus on optimizing stimulation parameters, but also on how short-term biomarker changes might predict long-term clinical response, and how to tailor stimulation timing to an individual patient's high-risk periods per RNS electrocorticography.…”

Stimulation to probe, excite, and inhibit the epileptic brain

“…98 Despite these differences, interestingly, outcomes are generally similar across a wide range of stimulation approaches. 99 Certainly, stimulation parameters and details of brain state dynamics can affect outcomes, and yet sometimes even basic, standardized approaches are similarly effective.…”

“…In one example, stimulation of the medial septum in a rat hippocampal kindling model showed that responsive closed loop stimulation at the level of individual stimulation pulses (which is not the case with RNS) was effective, whereas open loop stimulation was not 98 . Despite these differences, interestingly, outcomes are generally similar across a wide range of stimulation approaches 99 . Certainly, stimulation parameters and details of brain state dynamics can affect outcomes, and yet sometimes even basic, standardized approaches are similarly effective.…”