Peripheral Nerve Stimulation
Noninvasive Transcutaneous Vagus Nerve Stimulation Decreases Whole Blood Culture-Derived Cytokines and Chemokines: A Randomized, Blinded, Healthy Control Pilot Trial

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Objectives

The purpose of this study was to test the transcutaneous noninvasive vagus nerve stimulator (nVNS) (gammaCore©) device to determine if it modulates the peripheral immune system, as has been previously published for implanted vagus nerve stimulators.

Materials and Methods

A total of 20 healthy males and females were randomized to receive either nVNS or sham stimulation (SST). All subjects underwent an initial blood draw at 8:00 am, followed by stimulation with nVNS or SST at 8:30 am. Stimulation was repeated at 12:00 pm and 6:00 pm. Additional blood samples were withdrawn 90 min and 24 hour after the first stimulation session. After samples were cultured using the Myriad RBM TruCulture (Austin, TX) system (WBCx), levels of cytokines and chemokines were measured by the Luminex assay and statistical analyses within and between groups were performed using the Wilcoxon Signed Ranks Test and Mann-Whitney U with the statistical program R.

Results

A significant percent decrease in the levels of the cytokine interleukin [IL]-1β, tumor necrosis factor [TNF] levels, and chemokine, interleukin [IL]-8 IL-8, macrophage inflammatory protein [MIP]-1α, and monocyte chemoattractant protein [MCP]-1 levels was observed in the nVNS group non-lipopolysaccharide (LPS)-stimulated whole blood culture (n-WBCx) at the 24-hour time point (p < 0.05). In SST group, there was a significant percent increase in IL-8 at 90 min post-stimulation (p < 0.05). At 90 min, the nVNS group had a greater percent decrease in IL-8 concentration (p < 0.05) compared to SST group. The nVNS group had a greater percent decrease in cytokines (TNF, IL-1β) and chemokines (MCP-1 and IL-8) at 24 hour (p < 0.05) in comparison to SST. LPS-stimulated whole blood cultures (L-WBCx) did not show a significant decrease in cytokine levels in either the nVNS or SST group across any time points. The nVNS group showed a significant percent increase in LPS-stimulated IL-10 levels at the 24-hour time point in comparison to SST.

Conclusions

nVNS downregulates inflammatory cytokine release suggesting that nVNS may be an effective anti-inflammatory treatment.

Section snippets

INTRODUCTION

The vagus nerve (cranial nerve X) is the primary neural component of the parasympathetic nervous system. It is a critical mediator of physiological homeostasis due to its control of heart rate, motility, and secretion of the gastrointestinal tract, pancreatic endocrine and exocrine secretion, hepatic glucose production, and other visceral functions. Importantly vagal activity suppresses innate immune and inflammatory responses to pathogen invasion and tissue injury (1., 2., 3.). Growing

Study Subjects

Twenty subjects were recruited through the Clinical and Translation Research Institute (CTRI) at the University of California, San Diego Health System and randomly assigned to receive either nVNS or SST. All subjects were between the ages of 18 and 61 years, were deemed healthy by medical and physical examination, and did not take any chronic medications. There were 10 active and 10 sham subjects, with an equal ratio of male to females 6:4. Subjects were instructed to refrain from taking any

Subjects

Subject groups were similar in age, sex, body mass index, heart rate, and blood pressure (Table 1). The average age of the cohort was 36 ± 14 years for the sham group and 35.8 ± 14.5 years for the treated group. The study population was composed of 65% Caucasian, 30% Asian, and 5% African American individuals. Adverse events were minor during stimulation and equal across both groups, with headache and pain during stimulation noted most commonly (Table 1). One male subject who reported muscle

DISCUSSION

In this pilot study, nVNS significantly decreased the release of pro-inflammatory cytokines in whole blood culture when compared to sham stimulation.

Data from Tracey (1) indicate that afferent vagal-mediated signals are relayed to the NTS and that the Dorsal Motor Nucleus (DMN) activates vagal efferents targeted to the celiac ganglion, thereby stimulating the CAP (deactivating monocytes) and resulting in decreased release of peripheral cytokines. Vagus nerve stimulation is believed to mediate

CONCLUSION

For the first time to our knowledge, we show transcutaneous nVNS modulates human inflammatory cytokines and chemokines, as measured by WBCx. The significant decrement in cytokines and chemokines seen in this study supports the concept that such stimulation activates cholinergic-mediated anti-inflammatory responses the vagal NTS-PVN-HPA and NTS-PVN-LC pathway. Other as yet undiscovered reflex pathways might also contribute. Future studies will focus on nVNS anti-inflammatory mechanisms in

Acknowledgements

Statistical support was provided by the Clinical and Translational Research Institute. The CTRI is partially supported by the National Institutes of Health, Grant UL1TR001442 of CTSA funding. The authors thank the nursing staff at the UCSD CTRI for their kindness and diligent work.

Authorship Statements

Dr. Lerman designed and wrote the study. Dr. Lerman and Katie Lam carried out the study. Drs. Lerman, Baker, Hauger, Davis, Huang, Sorkin and Simon prepared the manuscript. James Proudfoot carried out the statistical

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    Source(s) of financial support: Electrocore LLC (Investigator Initiated Grant).

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