Peripheral Nerve StimulationNoninvasive Transcutaneous Vagus Nerve Stimulation Decreases Whole Blood Culture-Derived Cytokines and Chemokines: A Randomized, Blinded, Healthy Control Pilot Trial
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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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2022, NeuronCitation Excerpt :Stimulation with 20 kHz for 30 min daily for 12 weeks resulted in improved disease scores compared with baseline values and anti-inflammatory effects in these RA patients (Marsal et al., 2021; Tracey, 2021). Noninvasive transcutaneous stimulation of the cervical vagus nerve has also been studied in healthy volunteers (Lerman et al., 2016), patients with Sjogren’s syndrome (Tarn et al., 2019), and RA patients—with specific benefit for those with high disease activity scores (Drewes et al., 2021). Noninvasive electrical transcutaneous stimulation is clinically approved for the adjunct treatment of acute opioid withdrawal symptoms (Qureshi et al., 2020).
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2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In an RCT of sVNS, N = 10 healthy adults received transvenous sVNS, with N = 10 controls receiving sham placebo stimulation, LPS stimulated cytokine production did not differ between VNS and control conditions (Kox et al., 2015). In another study, N = 10 subjects were exposed to cervical tVNS while N = 10 control participants were exposed to a sham stimulation (Lerman et al., 2016). Levels of IL-1β, IL-6, IL-10, and TNFα were measured as circulating levels in serum and production in response to LPS stimulation.
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Source(s) of financial support: Electrocore LLC (Investigator Initiated Grant).