Modulation of the thalamus by microburst vagus nerve stimulation: a feasibility study protocol

Abstract

Vagus nerve stimulation (VNS) was the first device-based therapy for epilepsy, having launched in 1994 in Europe and 1997 in the United States. Since then, significant advances in the understanding of the mechanism of action of VNS and the central neurocircuitry that VNS modulates have impacted how the therapy is practically implemented. However, there has been little change to VNS stimulation parameters since the late 1990s. Short bursts of high frequency stimulation have been of increasing interest to other neuromodulation targets e.g., the spine, and these high frequency bursts elicit unique effects in the central nervous system, especially when applied to the vagus nerve. In the current study, we describe a protocol design that is aimed to assess the impact of high frequency bursts of stimulation, called "Microburst VNS", in subjects with refractory focal and generalized epilepsies treated with this novel stimulation pattern in addition to standard anti-seizure medications. This protocol also employed an investigational, fMRI-guided titration protocol that permits personalized dosing of Microburst VNS among the treated population depending on the thalamic blood-oxygen-level-dependent signal. The study was registered on clinicaltrials.gov (NCT03446664). The first subject was enrolled in 2018 and the final results are expected in 2023.

Keywords: drug-resistant epilepsy; feasibility study; focal epilepsy; generalized epilepsy; vagus nerve stimulation.

Figure 1

Microburst VNS consists of short bursts of pulses separated by brief off-times called interburst intervals (IBIs). The μVNS waveform incorporates 7 stimulation parameters with a range of available settings (Table 3). On compatible pulse generators, μVNS can be selected as a stimulation setting for the normal mode, the magnet mode, or the autostim mode, which can be set to different levels to deliver VNS (traditional or μVNS) at a regular cadence or based on a specific triggering event. In its current embodiment, μVNS can be delivered from standard VNS Therapy leads and implantable pulse generators with form factors similar to existing VNS devices.

Figure 2

Flow chart of overall study events. After screening and consent, enrolled patients underwent a 3-month prospective baseline period followed by implantation. All subjects were then followed for up to 12 months, with the first 6 months including an intensive, imaging-guided titration program and the last 6 months including telephone and in-office visits. Clinical outcome measures were collected at all boxes shown in white, though reports of adverse events could be collected at any time, including outside of study visits. During fMRI visits (Figure 3), study outcome measures were collected sporadically during rest periods between scans to minimize the impact of the duration of the visit on the subject's schedule.

Figure 3

Flow chart of activities during an fMRI titration visit. The device was initially deactivated, and then, a tolerability protocol was followed. The purpose of the tolerability protocol was to identify VNS and μVNS intensities that evoked intolerable side effects so that side effects that induced involuntary movement (e.g., cough) could be avoided in the scanner. Based on the tolerability assessments, a maximum intensity was determined for VNS (Sweep 1) and μVNS (Sweeps 2 and 3). A study representative then programmed the Sweep 1 parameters into the device's “Parameter Sweep Mode”, which is an investigational function that allows the pulse generator to sequentially modify programming settings at a future time (e.g., in the scanner). The subject was then positioned into the scanner, and multiple functional and anatomical scans were collected. When Sweep 1 concluded, the subject was removed from the scanner and study representatives programmed Sweep 2 based on the tolerability assessment and re-admitted the subject to the scanning environment. While Sweep 2 was underway, study representatives analyzed the Sweep 1 fMRI data to identify the settings associated with the peak BOLD response in the thalamic ROI. When Sweep 2 concluded and the subject was removed from the scanner, study representatives analyzed the Sweep 2 fMRI results similar to the procedure for the Sweep 1 results; however, when programming the subject for Sweep 3, the optimal μVNS intensity identified in the Sweep 2 results was used. When Sweep 3 concluded, a final analysis was completed by study representatives to identify the μVNS parameters that the subject would leave the clinic with.