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.

Optimized microburst VNS elicits fMRI responses beyond thalamic‐specific response from standard VNS

“…First, the trends toward significance may become significant with improvements in scanning parameters, larger number of participants, or more homogeneous group of participants. Second, relationships between BOLD signal and seizure responses may be modulated by time such that BOLD relationship with multiple scanning sessions may be more revealing than a single cross‐sectional pre‐VNS time point; clinical responses to VNS are known to improve over time 2 . Finally, the only modest correlation between thalamic microburst and seizure outcomes may also be surprising.…”

“…Drug‐resistant epilepsy status was established by review of medical records and confirmed by study epilepsy physician at each site. Participants had to be eligible for surgical implantation of a VNS device and able and willing to undergo 3T MRI after implantation 2 . All participants provided written informed consent prior to participation, and all study procedures were approved by the Institutional Review Boards of each site.…”

“…This therapy is also frequently used for the treatment of patients with generalized and other seizure types 1 . The stimulation parameters and adjustment methods have remained relatively unchanged over time 2 . The efficacy of VNS for the treatment of drug‐resistant seizures was proven in four randomized controlled trials with pooled mean percentage decrease in seizure frequency at the last follow‐up of 34% and pooled probability of being a responder (≥50% seizure reduction) of 42.7% 1,3 .…”

“…The goals of the present study were twofold—to firmly establish the typical brain response patterns to VNS using a large cohort of patients with focal‐ and generalized‐onset seizures and to determine if the peak BOLD signal responses to standard VNS parameters are different from the peak responses elicited by an optimized microburst stimulation paradigm (i.e., assess for potential differences in the MOA). Further, for the first time, we wanted to conduct this neuroimaging investigation in stimulation‐naïve epilepsy participants to determine if the pre‐VNS treatment fMRI activation patterns (rather than longitudinal patterns) are associated with treatment response 2,16 . Our hypotheses were that while both stimulation parameters (standard vs. microburst) would involve thalamic responses, there would be differences in extra‐thalamic VNS responses between the groups.…”

“… 1 The stimulation parameters and adjustment methods have remained relatively unchanged over time. 2 The efficacy of VNS for the treatment of drug‐resistant seizures was proven in four randomized controlled trials with pooled mean percentage decrease in seizure frequency at the last follow‐up of 34% and pooled probability of being a responder (≥50% seizure reduction) of 42.7%. 1 , 3 While these numbers indicate reasonable efficacy, one may ask if there is a possibility of adjusting or changing the stimulation parameters in order to provide better seizure control while also decreasing the potential for adverse events related to VNS.…”