Vagus Nerve Stimulation: Rapid versus Slow Cycling in a Laboratory Model

Abstract

Timing of neurostimulation has historically differed for epilepsy and movement disorders, with the former being intermittent and the latter being continuous. Reasons for this variation are uncertain. Studies by Agnew et al. [1] on peripheral nerves suggested that tissue was less stressed by intermittent electrical stimulation, although this may not be the case for clinical neurostimulation within safe parameters. The original neurocybernetic vagus nerve stimulation (VNS) system was designed to allow a range of on and off periods from 5 min to 3 h [2, 3], Bbelieved to be adequate for recovery of the nerve from the effects of the previous stimulation,^with reference to Agnew and McCreery [4]. In a study by Zabara [5] of canine strychnine-induced seizures, VNS for 4 min attenuated seizures for 16 min after stimulation. A Brough rule of thumbŵ as suggested that seizures are suppressed for a time period 4-fold the duration of the stimulation. If this rule extended to the clinical trials, then the suppression induced by 30 s of VNS would be expected to last for 2 min. The initial clinical trial employed a schedule of 30 s stimulation on, followed by 5 min off, on a regular clock cycle [6].When the therapeutic response to VNS is suboptimal after 3 months of therapy, increasing the duty cycle (ratio of time on to time off) has been recommended [7]. Benefits of such a change are individual and anecdotal. A review of response to different parameter settings observed a median reduction of seizure frequency of 21 % at 3 months of stimulation versus 39 % at 12 months when off time was reduced to < 1.1 min [8]. Other cycle times did not experience that degree of improvement from 3 to 12 months, but those other cycle times started at a higher level of improvement at 3 months. DeGiorgio et al. [9] randomized 61 subjects to 1 of 3 regimens (seconds on/seconds off): 7/18, 30/30, 30/180. Median seizure reductions were, respectively, 22 %, 26 %, and 29 % (nonsignificantly different). A VNS registry of 269 patients found no differences with standard or rapid cycling, or when changing from standard to rapid cycling [10]. Therefore, the evidence for benefit of rapid cycling of VNS is limited. The latest generation of stimulator can deliver stimulation in response to a preprogrammed degree of ictal tachycardia, thereby providing a type of responsive rapid cycling [11,12].When optimal stimulation parameters and the mechanisms underlying them are unknown, controlled experiments in a laboratory can be useful, and such an experiment is provided by the article by Larsen et al. [13] in this issue, entitled BVagus nerve stimulation applied with a rapid cycle has more profound influence on hippocampal electrophysiology than standard cycle.T he investigators implanted stimulating electrodes in rat perforant path (PP), which is afferent to dentate gyrus of hippocampus, and recording field [electroencephalography (EEG)] electrodes in dentate gyrus. Spontaneous dentate EEG and EEG evoked by PP stimulation were studied under different conditions of...

Vagus nerve stimulation for drug-resistant epilepsy

“…Despite there being no apparent advantage in initially treating with rapid cycling compared with using other modalities, it may be useful to change the VNS setting to shorter off times in people whose seizures do not respond. Recent experimental studies also show the benefit of rapid cycling, although with limited clinical evidence for this 22…”

Epilepsy patients with and without perceived benefit from vagus nerve stimulation: A long-term observational single center study

“…Most patients received standard treatment with stimulation for 30-60 s every five to three minutes with recommended duty cycles [9]. Only few patients received rapid cycling stimulation with shorter intervals and stimulation times, as the clinical evidence of an enhanced efficacy from these parameters is limited [26,27]. Subtle effects on mood, cognition and wakefulness could not be appropriately assessed in this real-world study, but changes were not obvious after cessation of treatment.…”