title: Noninvasive Transcutaneous Vagus Nerve Stimulation Decreases Whole Blood Culture-Derived Cytokines and Chemokines: A Randomized, Blinded, Healthy Control Pilot Trial.
abstract: OBJECTIVE
  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.
  
  
  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 Additional blood samples were withdrawn 90 min and 24 hour after the first stimulation session.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.
authors.affiliation: Department of Psychiatry, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.|Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.|Department of Anesthesiology, University of California, San Diego, San Diego, CA, USA.|Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: Imanuel
authors.initials: I
authors.lastname: Lerman
authors.affiliation: Department of Psychiatry, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.|Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.|Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hauger
authors.affiliation: Department of Anesthesiology, University of California, San Diego, San Diego, CA, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Sorkin
authors.affiliation: Department of Anesthesiology, Clinical and Translational Research Institute, University of California, San Diego, San Diego, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Proudfoot
authors.affiliation: Department of Anesthesiology, University of California, San Diego, San Diego, CA, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Davis
authors.affiliation: Department of Anesthesiology, University of California, San Diego, San Diego, CA, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, University of California, San Diego, San Diego, CA, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Lam
authors.affiliation: Electrocore Research Unit, Basking Ridge, NJ, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Simon
authors.affiliation: Department of Psychiatry, Center of Excellence for Stress and Mental Health, San Diego, CA, USA.|Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA, USA.|Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: Dewleen G
authors.initials: DG
authors.lastname: Baker
mesh_terms: D000293:Adolescent; D000328:Adult; D001773:Blood Cells / Q000187:drug effects; D000071997:Blood Culture; D016207:Cytokines / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D012867:Skin / Q000294:innervation*; D018709:Statistics, Nonparametric; D013997:Time Factors; D055536:Vagus Nerve Stimulation / Q000379:methods*; D055815:Young Adult
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides
keywords: Cholinergic anti-inflammatory pathway; immunomodulation; neuromodulation; vagus nerve stimulation