Auricular Vagus Neuromodulation-A Systematic Review on Quality of Evidence and Clinical Effects

Nishant Verma, Jonah D Mudge, Maïsha Kasole, Rex C Chen, Stephan L Blanz, James K Trevathan, Eric G Lovett, Justin C Williams, Kip A Ludwig, Nishant Verma, Jonah D Mudge, Maïsha Kasole, Rex C Chen, Stephan L Blanz, James K Trevathan, Eric G Lovett, Justin C Williams, Kip A Ludwig

Abstract

Background: The auricular branch of the vagus nerve runs superficially, which makes it a favorable target for non-invasive stimulation techniques to modulate vagal activity. For this reason, there have been many early-stage clinical trials on a diverse range of conditions. These trials often report conflicting results for the same indication. Methods: Using the Cochrane Risk of Bias tool we conducted a systematic review of auricular vagus nerve stimulation (aVNS) randomized controlled trials (RCTs) to identify the factors that led to these conflicting results. The majority of aVNS studies were assessed as having "some" or "high" risk of bias, which makes it difficult to interpret their results in a broader context. Results: There is evidence of a modest decrease in heart rate during higher stimulation dosages, sometimes at above the level of sensory discomfort. Findings on heart rate variability conflict between studies and are hindered by trial design, including inappropriate washout periods, and multiple methods used to quantify heart rate variability. There is early-stage evidence to suggest aVNS may reduce circulating levels and endotoxin-induced levels of inflammatory markers. Studies on epilepsy reached primary endpoints similar to previous RCTs testing implantable vagus nerve stimulation therapy. Preliminary evidence shows that aVNS ameliorated pathological pain but not evoked pain. Discussion: Based on results of the Cochrane analysis we list common improvements for the reporting of results, which can be implemented immediately to improve the quality of evidence. In the long term, existing data from aVNS studies and salient lessons from drug development highlight the need for direct measures of local neural target engagement. Direct measures of neural activity around the electrode will provide data for the optimization of electrode design, placement, and stimulation waveform parameters to improve on-target engagement and minimize off-target activation. Furthermore, direct measures of target engagement, along with consistent evaluation of blinding success, must be used to improve the design of controls-a major source of concern identified in the Cochrane analysis. The need for direct measures of neural target engagement and consistent evaluation of blinding success is applicable to the development of other paresthesia-inducing neuromodulation therapies and their control designs.

Keywords: auricular stimulation; auricular vagus nerve stimulation; blinding (masking); microneurography; systematic review; target engagement; transcutaneous vagus nerve stimulation; vagus nerve stimulation or VNS.

Conflict of interest statement

EL is an employee of LivaNova PLC. JW and KL are scientific board members and have stock interests in NeuroOne Medical Inc., a company developing next generation epilepsy monitoring devices. JW also has an equity interest in NeuroNexus technology Inc., a company that supplies electrophysiology equipment and multichannel probes to the neuroscience research community. KL is also a paid member of the scientific advisory board of Cala Health, Blackfynn, Abbott and Battelle. KL also is a paid consultant for Galvani and Boston Scientific. KL is a consultant to and co-founder of Neuronoff Inc. None of these associations are directly relevant to the work presented in this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Verma, Mudge, Kasole, Chen, Blanz, Trevathan, Lovett, Williams and Ludwig.

Figures

Figure 1
Figure 1
(A) Innervation of the auricle by five nerves (Watanabe et al., 2016): auricular branch of the vagus nerve (ABVN), chorda tympani (CT) from the facial nerve, auriculotemporal nerve originating from the mandibular branch of the trigeminal nerve, great auricular nerve, and lesser occipital nerve. (B) Artist impression of auricular innervation (He et al., 2012). Refer to Peuker and Filler (2002) dissection study mapping the innervation of the human auricle performed in 7 cadavers for original photographs. Note, microdissection cannot trace the finest of nerve branches. (C) Overlapping regions of innervation reported between the auricular branch of the vagus nerve (ABVN), great auricular nerve (GAN), and lesser occipital nerve (Peuker and Filler, 2002). Here the ABVN and GAN overlap for 37% of the area on the medial dorsal middle third of the ear—setting the precedent for large overlaps in regions innervated by different nerves. Commonly used electrodes: (D) Clips transcutaneously targeting the tragus and earlobe simultaneously in the intervention group (Stavrakis et al., 2015). (E) NEMOS electrodes by Cerbomed (Erlangen, Germany) transcutaneously targeting cymba concha in the intervention group and ear lobe in the sham group (Frangos et al., 2015). (F) Parasym (London, UK) transcutaneously targeting tragus in the intervention group and ear lobe in the sham group (Stavrakis et al., 2020). (G) Percutaneously targeting intrinsic auricular muscles zones in the intervention group (Cakmak et al., 2017). (H) Innovative Health Solutions (Versailles, IN, USA) percutaneously targeting several cranial nerves in the auricular and periauricular region in the intervention group (Kovacic et al., 2017).
Figure 2
Figure 2
Adapted PRISMA flow chart.
Figure 3
Figure 3
Visualization of stimulation waveform parameters in 41 reviewed aVNS RCTs. Illustrated here are the interquartile ranges, maximums, minimums, and medians of the stimulation waveform parameters, including extreme cases. Median stimulation amplitude is 1.0 mA, pulse width is 250 us, and frequency is 22.5 Hz. Studies that report ranges for parameters are included as a single value representing the average of the boundaries of that range.
Figure 4
Figure 4
Summary of Cochrane Risk of Bias overall and section scores for 38 publications reviewed.
Figure 5
Figure 5
Types of controls used in aVNS clinical trials. The ideal control is indistinguishable from active intervention, to both subject and investigator, yet therapeutically inert.

References

    1. Translating Neuromodulation (2019). Translating Neuromodulation. Nat. Biotechnol. 37, 967–967. 10.1038/s41587-019-0263-3
    1. Addorisio M. E., Imperato G. H., de Vos A. F., Forti S., Goldstein R. S., Pavlov V. A., et al. . (2019). Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear. Bioelectron. Med. 5:4. 10.1186/s42234-019-0020-4
    1. Afanasiev S. A., Pavliukova E. N., Kuzmichkina M. A., Rebrova T., Anfinogenova Y., Likhomanov K. S., et al. . (2016). Nonpharmacological correction of hypersympatheticotonia in patients with chronic coronary insufficiency and severe left ventricular dysfunction: nonpharmacological correction of hypersympatheticotonia. Ann. Noninvasive Electrocardiol. 21, 548–556. 10.1111/anec.12349
    1. Aihua L., Lu S., Liping L., Xiuru W., Hua L., Yuping W. (2014). A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy. Epilepsy Behav. 39, 105–110. 10.1016/j.yebeh.2014.08.005
    1. American Association of Neurological Surgeons (2021). Vagus Nerve Stimulation. Available online at: (accessed January 12, 2021).
    1. Anderson D. N., Duffley G., Vorwerk J., Dorval A. D., Butson C. R. (2019). Anodic stimulation misunderstood: preferential activation of fiber orientations with anodic waveforms in deep brain stimulation. J. Neural. Eng. 16:016026. 10.1088/1741-2552/aae590
    1. Andreas M., Arzl P., Mitterbauer A., Ballarini N. M., Kainz F.-M., Kocher A., et al. . (2019). Electrical stimulation of the greater auricular nerve to reduce postoperative atrial fibrillation. Circ. Arrhythm. Electrophysiol. 12:e007711. 10.1161/CIRCEP.119.008067
    1. Antonino D., Teixeira A. L., Maia-Lopes P. M., Souza M. C., Sabino-Carvalho J. L., Murray A. R., et al. . (2017). Non-invasive vagus nerve stimulation acutely improves spontaneous cardiac baroreflex sensitivity in healthy young men: a randomized placebo-controlled trial. Brain Stimul. 10, 875–881. 10.1016/j.brs.2017.05.006
    1. Badran B. W., Mithoefer O. J., Summer C. E., LaBate N. T., Glusman C. E., Badran A. W., et al. . (2018). Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate. Brain Stimul. 11, 699–708. 10.1016/j.brs.2018.04.004
    1. Badran B. W., Yu A. B., Adair D., Mappin G., DeVries W. H., Jenkins D. D., et al. . (2019). Laboratory administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): technique, targeting, and considerations. J. Vis. Exp. 143:e58984. 10.3791/58984
    1. Bas H., Kleinert J. M. (1999). Anatomic variations in sensory innervation of the hand and digits. J. Hand Surg. Am. 24, 1171–1184. 10.1053/jhsu.1999.1171
    1. Bauer S., Baier H., Baumgartner C., Bohlmann K., Fauser S., Graf W., et al. . (2016). Transcutaneous Vagus Nerve Stimulation (tVNS) for treatment of drug-resistant epilepsy: a randomized, double-blind clinical trial (cMPsE02). Brain Stimul. 9, 356–363. 10.1016/j.brs.2015.11.003
    1. Becq G. J.-P. C., Barbier E. L., Achard S. (2020). Brain networks of rats under anesthesia using resting-state fMRI: comparison with dead rats, random noise and generative models of networks. J. Neural Eng. 17:045012. 10.1088/1741-2552/ab9fec
    1. Ben-Menachem E., Manon-Espaillat R., Ristanovic R., Wilder B. J., Stefan H., Mirza W., et al. . (1994). Vagus nerve stimulation for treatment of partial seizures: 1. a controlled study of effect on seizures. Epilepsia 35, 616–626. 10.1111/j.1528-1157.1994.tb02482.x
    1. Bermejo P., López M., Larraya I., Chamorro J., Cobo J. L., Ordóñez S., et al. . (2017). Innervation of the human cavum conchae and auditory canal: anatomical basis for transcutaneous auricular nerve stimulation. Biomed. Res. Int. 2017, 1–10. 10.1155/2017/7830919
    1. Billman G. E. (2013). The LF/HF ratio does not accurately measure cardiac sympatho-vagal balance. Front. Physio. 4:26. 10.3389/fphys.2013.00026
    1. Bootsma M., Swenne C. A., Janssen M. J. A., Cats V. M., Schalij M. J. (2003). Heart rate variability and sympathovagal balance: pharmacological validation. Neth. Heart J. 11, 250–259.
    1. Borges U., Laborde S., Raab M. (2019). Influence of transcutaneous vagus nerve stimulation on cardiac vagal activity: not different from sham stimulation and no effect of stimulation intensity. PLoS ONE 14:e0223848. 10.1371/journal.pone.0223848
    1. Botvinik-Nezer R., Holzmeister F., Camerer C. F., Dreber A., Huber J., Johannesson M., et al. . (2020). Variability in the analysis of a single neuroimaging dataset by many teams. Nature 582, 84–88. 10.1038/s41586-020-2314-9
    1. Bretherton B., Atkinson L., Murray A., Clancy J., Deuchars S., Deuchars J. (2019). Effects of transcutaneous vagus nerve stimulation in individuals aged 55 years or above: potential benefits of daily stimulation. Aging 11, 4836–4857. 10.18632/aging.102074
    1. Broekman M. M. T. J., Roelofs H. M. J., Hoentjen F., Wiegertjes R., Stoel N., Joosten L. A., et al. . (2015). LPS-stimulated whole blood cytokine production is not related to disease behavior in patients with quiescent Crohn's disease. PLoS ONE 10:e0133932. 10.1371/journal.pone.0133932
    1. Burger A. M., D'Agostini M., Verkuil B., Van Diest I. (2020). Moving beyond belief: a narrative review of potential biomarkers for transcutaneous vagus nerve stimulation. Psychophysiology 57:e13571. 10.1111/psyp.13571
    1. Burger A. M., Van der Does W., Thayer J. F., Brosschot J. F., Verkuil B. (2019). Transcutaneous vagus nerve stimulation reduces spontaneous but not induced negative thought intrusions in high worriers. Biol. Psychol. 142, 80–89. 10.1016/j.biopsycho.2019.01.014
    1. Busch V., Zeman F., Heckel A., Menne F., Ellrich J., Eichhammer P. (2013). The effect of transcutaneous vagus nerve stimulation on pain perception – an experimental study. Brain Stimul. 6, 202–209. 10.1016/j.brs.2012.04.006
    1. Cakmak Y. O. (2019). Concerning auricular vagal nerve stimulation: occult neural networks. Front. Hum. Neurosci. 13:421. 10.3389/fnhum.2019.00421
    1. Cakmak Y. O., Apaydin H., Kiziltan G., Gündüz A., Ozsoy B., Olcer S., et al. . (2017). Rapid alleviation of Parkinson's disease symptoms via electrostimulation of intrinsic auricular muscle zones. Front. Hum. Neurosci. 11:338. 10.3389/fnhum.2017.00338
    1. Centre for Evidence-Based Medicine (2009). Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009). Available online at: (accessed November 26, 2020).
    1. Chang Y.-C., Cracchiolo M., Ahmed U., Mughrabi I., Gabalski A., Daytz A., et al. . (2020). Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers. Brain Stimul. 13, 1617–1630. 10.1016/j.brs.2020.09.002
    1. Chiluwal A., Narayan R. K., Chaung W., Mehan N., Wang P., Bouton C. E., et al. . (2017). Neuroprotective effects of trigeminal nerve stimulation in severe traumatic brain injury. Sci. Rep. 7:6792. 10.1038/s41598-017-07219-3
    1. Clancy J. A., Mary D. A., Witte K. K., Greenwood J. P., Deuchars S. A., Deuchars J. (2014). Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 7, 871–877. 10.1016/j.brs.2014.07.031
    1. De Couck M., Cserjesi R., Caers R., Zijlstra W. P., Widjaja D., Wolf N., et al. . (2017). Effects of short and prolonged transcutaneous vagus nerve stimulation on heart rate variability in healthy subjects. Autonomic Neurosci. 203, 88–96. 10.1016/j.autneu.2016.11.003
    1. De Ferrari G. M., Stolen C., Tuinenburg A. E., Wright D. J., Brugada J., Butter C., et al. . (2017). Long-term vagal stimulation for heart failure: eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial. Int. J. Cardiol. 244, 229–234. 10.1016/j.ijcard.2017.06.036
    1. Deer T. R., Hunter C. W., Mehta P., Sayed D., Grider J. S., Lamer T. J., et al. . (2020). A systematic literature review of dorsal root ganglion neurostimulation for the treatment of pain. Pain Med. 21, 1581–1589. 10.1093/pm/pnaa005
    1. Del Giudice M., Gangestad S. W. (2018). Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain Behav. Immun. 70, 61–75. 10.1016/j.bbi.2018.02.013
    1. DiMasi J. A., Grabowski H. G., Hansen R. W. (2016). Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 47, 20–33. 10.1016/j.jhealeco.2016.01.012
    1. Doherty M., Dieppe P. (2009). The “placebo” response in osteoarthritis and its implications for clinical practice. Osteoarthritis Cartilage 17, 1255–1262. 10.1016/j.joca.2009.03.023
    1. Duarte R. V., McNicol E., Colloca L., Taylor R. S., North R. B., Eldabe S. (2020a). Randomized placebo-/sham-controlled trials of spinal cord stimulation: a systematic review and methodological appraisal. Neuromodulation 23, 10–18. 10.1111/ner.13018
    1. Duarte R. V., Nevitt S., McNicol E., Taylor R. S., Buchser E., North R. B., et al. . (2020b). Systematic review and meta-analysis of placebo/sham controlled randomised trials of spinal cord stimulation for neuropathic pain: Pain 161, 24–35. 10.1097/j.pain.0000000000001689
    1. Elgendi M., Fletcher R., Liang Y., Howard N., Lovell N. H., Abbott D., et al. . (2019). The use of photoplethysmography for assessing hypertension. npj Digit. Med. 2:60. 10.1038/s41746-019-0136-7
    1. Farmer D. F., Strzelczyk A., Finisguerra A., Gourine A. V., Gharabaghi A., Hasan A., et al. . (2020). International consensus based review and recommendations for minimum reporting standards in research on transcutaneous vagus nerve stimulation (Version 2020). Front. Hum. Neurosci. 14:568051. 10.3389/fnhum.2020.568051
    1. Fisher H., Stowell J., Garcia R., Sclocco R., Goldstein J., Napadow V., et al. . (2018). “Acute effects of respiratory-gated auricular vagal afferent nerve stimulation in the modulation of blood pressure in hypertensive patients,” in 2018 Computing in Cardiology Conference (CinC) (Maastricht: ), 1–4. 10.22489/CinC.2018.346
    1. Frangos E., Ellrich J., Komisaruk B. R. (2015). Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans. Brain Stimul. 8, 624–636. 10.1016/j.brs.2014.11.018
    1. Frøkjaer J. B., Bergmann S., Brock C., Madzak A., Farmer A. D., Ellrich J., et al. . (2016). Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. Neurogastroenterol. Motil. 28, 592–598. 10.1111/nmo.12760
    1. Gallo J. M. (2010). Pharmacokinetic/ pharmacodynamic-driven drug development: pharmacokinetic/pharmacodynamic-driven drug development. Mt. Sinai J. Med. 77, 381–388. 10.1002/msj.20193
    1. Goetz C. G., Tilley B. C., Shaftman S. R., Stebbins G. T., Fahn S., Martinez-Martin P., et al. . (2008). Movement disorder society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results: MDS-UPDRS: clinimetric assessment. Mov. Disord. 23, 2129–2170. 10.1002/mds.22340
    1. Goldberger J. J. (1999). Sympathovagal balance: how should we measure it? Am. J. Physiol. Heart Circulat. Physiol. 276, H1273–H1280. 10.1152/ajpheart.1999.276.4.H1273
    1. Grill W. M. (1999). Modeling the effects of electric fields on nerve fibers: influence of tissue electrical properties. IEEE Trans. Biomed. Eng. 46, 918–928. 10.1109/10.775401
    1. Gruber B., Froeling M., Leiner T., Klomp D. W. J. (2018). RF coils: a practical guide for nonphysicists: RF Coils. J. Magn. Reson. Imaging 48, 590–604. 10.1002/jmri.26187
    1. Gupta U., Bhatia S., Garg A., Sharma A., Choudhary V. (2011). Phase 0 clinical trials in oncology new drug development. Perspect. Clin. Res. 2:13. 10.4103/2229-3485.76285
    1. Guru A., Kumar N., Ravindra Shanthakumar S., Patil J., Nayak Badagabettu S., Aithal Padur A., et al. . (2015). Anatomical study of the ulnar nerve variations at high humeral level and their possible clinical and diagnostic implications. Anat. Res. Int. 2015, 1–4. 10.1155/2015/378063
    1. Handforth A., DeGiorgio C. M., Schachter S. C., Uthman B. M., Naritoku D. K., Tecoma E. S., et al. . (1998). Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 51, 48–55. 10.1212/WNL.51.1.48
    1. Hasan A., Wolff-Menzler C., Pfeiffer S., Falkai P., Weidinger E., Jobst A., et al. . (2015). Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study. Eur. Arch. Psychiatry Clin. Neurosci. 265, 589–600. 10.1007/s00406-015-0618-9
    1. Hayano J., Yuda E. (2019). Pitfalls of assessment of autonomic function by heart rate variability. J. Physiol. Anthropol. 38:3. 10.1186/s40101-019-0193-2
    1. He W., Wang X., Shi H., Shang H., Li L., Jing X., et al. . (2012). Auricular acupuncture and vagal regulation. Evid. Based Complement. Alternat. Med. 2012:786839. 10.1155/2012/786839
    1. Hein E., Nowak M., Kiess O., Biermann T., Bayerlein K., Kornhuber J., et al. . (2013). Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. J. Neural. Transm. 120, 821–827. 10.1007/s00702-012-0908-6
    1. Hewitt J. A., Brown L. L., Murphy S. J., Grieder F., Silberberg S. D. (2017). Accelerating biomedical discoveries through rigor and transparency. ILAR J. 58, 115–128. 10.1093/ilar/ilx011
    1. Higgins P. J., Savović J., Page J. M., Elbers G. R., Sterne A. J. (2019). Cochrane Training Chapter 8: Assessing Risk of Bias in a Randomized Trial. Available online at: (accessed November 26, 2020).
    1. Howick J., Friedemann C., Tsakok M., Watson R., Tsakok T., Thomas J., et al. . (2013). Are treatments more effective than placebos? A systematic review and meta-analysis. PLoS ONE 8:e62599. 10.1371/journal.pone.0062599
    1. Huang F., Dong J., Kong J., Wang H., Meng H., Spaeth R. B., et al. . (2014). Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study. BMC Complement. Altern. Med. 14:203. 10.1186/1472-6882-14-203
    1. Institute of Medicine . (2014). Improving and Accelerating Therapeutic Development for Nervous System Disorders: Workshop Summary. Washington, DC: The National Academies Press.
    1. Janner H., Klausenitz C., Gürtler N., Hahnenkamp K., Usichenko T. I. (2018). Effects of electrical transcutaneous vagus nerve stimulation on the perceived intensity of repetitive painful heat stimuli: a blinded placebo- and sham-controlled randomized crossover investigation. Anesthesia Analgesia 126, 2085–2092. 10.1213/ANE.0000000000002820
    1. Jiang Y., Po S. S., Amil F., Dasari T. W. (2020). Non-invasive low-level tragus stimulation in cardiovascular diseases. Arrhythm. Electrophysiol. Rev. 9, 40–46. 10.15420/aer.2020.01
    1. Johnson J. I., Decker S., Zaharevitz D., Rubinstein L. V., Venditti J. M., Schepartz S., et al. . (2001). Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. Cancer 84, 1424–1431. 10.1054/bjoc.2001.1796
    1. Johnson M. I., Hajela V. K., Ashton C. H., Thompson J. W. (1991). The effects of auricular transcutaneous electrical nerve stimulation (TENS) on experimental pain threshold and autonomic function in healthy subjects: Pain 46, 337–342. 10.1016/0304-3959(91)90116-F
    1. Juel J., Brock C., Olesen S., Madzak A., Farmer A., Aziz Q., et al. . (2017). Acute physiological and electrical accentuation of vagal tone has no effect on pain or gastrointestinal motility in chronic pancreatitis. JPR Volume 10, 1347–1355. 10.2147/JPR.S133438
    1. Kahn L., Mathkour M., Lee S. X., Gouveia E. E., Hanna J. A., Garces J., et al. . (2019). Long-term outcomes of deep brain stimulation in severe Parkinson's disease utilizing UPDRS III and modified Hoehn and Yahr as a severity scale. Clin. Neurol. Neurosurg. 179, 67–73. 10.1016/j.clineuro.2019.02.018
    1. Kang M., Ragan B. G., Park J.-H. (2008). Issues in outcomes research: an overview of randomization techniques for clinical trials. J. Athl. Train. 43, 215–221. 10.4085/1062-6050-43.2.215
    1. Kaniusas E., Kampusch S., Tittgemeyer M., Panetsos F., Gines R. F., Papa M., et al. . (2019). Current directions in the auricular vagus nerve stimulation I – a physiological perspective. Front. Neurosci. 13:854. 10.3389/fnins.2019.00854
    1. Keute M., Machetanz K., Berelidze L., Guggenberger R., Gharabaghi A. (2021). Neuro-cardiac coupling predicts transcutaneous auricular Vagus Nerve Stimulation effects. Brain Stimul. 14, 209–216. 10.1016/j.brs.2021.01.001
    1. Kovacic K., Hainsworth K., Sood M., Chelimsky G., Unteutsch R., Nugent M., et al. . (2017). Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol. Hepatol. 2, 727–737. 10.1016/S2468-1253(17)30253-4
    1. Kutlu N., Özden A. V., Alptekin H. K., Alptekin J. Ö. (2020). The impact of auricular vagus nerve stimulation on pain and life quality in patients with fibromyalgia syndrome. Biomed Res. Int. 2020, 1–10. 10.1155/2020/8656218
    1. Laqua R., Leutzow B., Wendt M., Usichenko T. (2014). Transcutaneous vagal nerve stimulation may elicit anti- and pro-nociceptive effects under experimentally-induced pain — a crossover placebo-controlled investigation. Autonomic Neurosci. 185, 120–122. 10.1016/j.autneu.2014.07.008
    1. Li M., Yao X., Sun L., Zhao L., Xu W., Zhao H., et al. . (2020). Effects of electroconvulsive therapy on depression and its potential mechanism. Front. Psychol. 11:80. 10.3389/fpsyg.2020.00080
    1. LivaNova (2017). VNS Therapy Dosing Guideline SenTiva. Available online at: (accessed November 26, 2020).
    1. Maharjan A., Wang E., Peng M., Cakmak Y. O. (2018). Improvement of olfactory function with high frequency non-invasive auricular electrostimulation in healthy humans. Front. Neurosci. 12:225. 10.3389/fnins.2018.00225
    1. Marmerstein J. T., McCallum G. A., Durand D. M. (2021). Direct measurement of vagal tone in rats does not show correlation to HRV. Sci. Rep. 11:1210. 10.1038/s41598-020-79808-8
    1. McNeal D. R. (1976). Analysis of a model for excitation of myelinated nerve. IEEE Trans. Biomed. Eng. BME-23, 329–337. 10.1109/TBME.1976.324593
    1. Moher D., Hopewell S., Schulz K. F., Montori V., Gotzsche P. C., Devereaux P. J., et al. . (2010). CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 340, c869–c869. 10.1136/bmj.c869
    1. Moher D., Liberati A., Tetzlaff J., Altman D. G., The PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: the prisma statement. PLoS Med. 6:e1000097. 10.1371/journal.pmed.1000097
    1. Morimoto R. (1993). Cells in stress: transcriptional activation of heat shock genes. Science 259, 1409–1410. 10.1126/science.8451637
    1. Murray A. R., Atkinson L., Mahadi M. K., Deuchars S. A., Deuchars J. (2016). The strange case of the ear and the heart: The auricular vagus nerve and its influence on cardiac control. Autonomic Neurosci. 199, 48–53. 10.1016/j.autneu.2016.06.004
    1. Nair B. (2019). Clinical trial designs. Indian Dermatol. Online J. 10, 193–201. 10.4103/idoj.IDOJ_475_18
    1. Napadow V., Edwards R. R., Cahalan C. M., Mensing G., Greenbaum S., Valovska A., et al. . (2012). Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Med. 13, 777–789. 10.1111/j.1526-4637.2012.01385.x
    1. Napadow V., Sclocco R., Henderson L. A. (2019). Brainstem neuroimaging of nociception and pain circuitries: PAIN Rep. 4:E745. 10.1097/PR9.0000000000000745
    1. Nicolai E. N., Settell M. L., Knudsen B. E., McConico A. L., Gosink B. A., Trevathan J. K., et al. . (2020). Sources of off-target effects of vagus nerve stimulation using the helical clinical lead in domestic pigs. J. Neural. Eng. 17:046017. 10.1088/1741-2552/ab9db8
    1. Ottaviani M. M., Wright L., Dawood T., Macefield V. G. (2020). In vivo recordings from the human vagus nerve using ultrasound-guided microneurography. J. Physiol. 598, 3569–3576. 10.1113/JP280077
    1. Pagnin D., de Queiroz V., Pini S., Cassano G. B. (2004). Efficacy of ECT in depression: a meta-analytic review. J. ECT 20:8. 10.1097/00124509-200403000-00004
    1. Parameswaran N., Patial S. (2010). Tumor necrosis factor-α signaling in macrophages. Crit. Rev. Eukar. Gene Expr. 20, 87–103. 10.1615/CritRevEukarGeneExpr.v20.i2.10
    1. Paul S. M., Mytelka D. S., Dunwiddie C. T., Persinger C. C., Munos B. H., Lindborg S. R., et al. . (2010). How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat. Rev. Drug Discov. 9, 203–214. 10.1038/nrd3078
    1. Payne N. A., Prudic J. (2009). Electroconvulsive therapy: Part I. a perspective on the evolution and current practice of ECT. J. Psychiatr. Pract. 15, 346–368. 10.1097/01.pra.0000361277.65468.ef
    1. Peuker E. T., Filler T. J. (2002). The nerve supply of the human auricle. Clin. Anat. 15, 35–37. 10.1002/ca.1089
    1. Poulsen A. H., Tigerholm J., Meijs S., Andersen O. K., Mørch C. D. (2020). Comparison of existing electrode designs for preferential activation of cutaneous nociceptors. J. Neural. Eng. 17:036026. 10.1088/1741-2552/ab85b1
    1. Provitera V., Nolano M., Pagano A., Caporaso G., Stancanelli A., Santoro L. (2007). Myelinated nerve endings in human skin. Muscle Nerve. 35, 767–775. 10.1002/mus.20771
    1. Rattay F. (1999). The basic mechanism for the electrical stimulation of the nervous system. Neuroscience 89, 335–346. 10.1016/S0306-4522(98)00330-3
    1. Reynolds P. J., Fan W., Andresen M. C. (2006). Capsaicin- resistant arterial baroreceptors. J. Negat. Results Biomed. 5:6. 10.1186/1477-5751-5-6
    1. Ritchie M. K., Wilson C. A., Grose B. W., Ranganathan P., Howell S. M., Ellison M. B. (2016). Ultrasound-guided greater auricular nerve block as sole anesthetic for ear surgery. Clin. Pract. 6:856. 10.4081/cp.2016.856
    1. Robbins M. S., Lipton R. B. (2017). Transcutaneous and percutaneous neurostimulation for headache disorders. Headache 57, 4–13. 10.1111/head.12829
    1. Rong P., Liu A., Zhang J., Wang Y., He W., Yang A., et al. . (2014). Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial. Clin. Sci. 10.1042/CS20130518. [Epub ahead of print].
    1. Sabbah H. N., Ilsar I., Zaretsky A., Rastogi S., Wang M., Gupta R. C. (2011). Vagus nerve stimulation in experimental heart failure. Heart Fail. Rev. 16, 171–178. 10.1007/s10741-010-9209-z
    1. Salama M., Akan A., Mueller M. R. (2020). Transcutaneous stimulation of auricular branch of the vagus nerve attenuates the acute inflammatory response after lung lobectomy. World J. Surg. 44, 3167–3174. 10.1007/s00268-020-05543-w
    1. Seagard J. L., van Brederode J. F., Dean C., Hopp F. A., Gallenberg L. A., Kampine J. P. (1990). Firing characteristics of single-fiber carotid sinus baroreceptors. Circ. Res. 66, 1499–1509. 10.1161/01.RES.66.6.1499
    1. Shen D., Lu Z. (2006). Estimate Carryover Effect in Clinical Trial Crossover Designs, 7. Available online at:
    1. Stavrakis S., Humphrey M. B., Scherlag B. J., Hu Y., Jackman W. M., Nakagawa H., et al. . (2015). Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J. Am. Coll. Cardiol. 65, 867–875. 10.1016/j.jacc.2014.12.026
    1. Stavrakis S., Stoner J. A., Humphrey M. B., Morris L., Filiberti A., Reynolds J. C., et al. . (2020). TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation). JACC Clin. Electrophysiol. 6, 282–291. 10.1016/j.jacep.2019.11.008
    1. Sterne J. A. C., Savović J., Page M. J., Elbers R. G., Blencowe N. S., Boutron I., et al. . (2019). RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366:l4898. 10.1136/bmj.l4898
    1. Stoddard M. B., Pinto V., Keiser P. B., Zollinger W. (2010). Evaluation of a whole-blood cytokine release assay for use in measuring endotoxin activity of Group B neisseria meningitidis vaccines made from Lipid A acylation mutants. CVI 17, 98–107. 10.1128/CVI.00342-09
    1. Stowell J., Garcia R., Staley R., Sclocco R., Fisher H., Napadow V., et al. . (2019). “Dose-optimization of Respiratory-Gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) for blood pressure modulation in hypertensive patients,” in 2019 Computing in Cardiology (CinC) (Singapore: ), 1–4. 10.22489/CinC.2019.098
    1. Straube A., Ellrich J., Eren O., Blum B., Ruscheweyh R. (2015). Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial. J. Headache Pain 16:63. 10.1186/s10194-015-0543-3
    1. Thurm C. W., Halsey J. F. (2005). “Measurement of cytokine production using whole blood,” in Current Protocols in Immunology, eds. Coligan J. E., Bierer B. E., Margulies D. H., Shevach E. M., Strober W. (Hoboken, NJ: John Wiley & Sons, Inc.), im0718bs66.
    1. Tobaldini E., Toschi-Dias E., Appratto de Souza L., Rabello Casali K., Vicenzi M., Sandrone G., et al. . (2019). Cardiac and peripheral autonomic responses to orthostatic stress during transcutaneous vagus nerve stimulation in healthy subjects. JCM 8:496. 10.3390/jcm8040496
    1. Tran N., Asad Z., Elkholey K., Scherlag B. J., Po S. S., Stavrakis S. (2019). Autonomic neuromodulation acutely ameliorates left ventricular strain in humans. J. Cardiovasc. Trans. Res. 12, 221–230. 10.1007/s12265-018-9853-6
    1. Tsaava T., Datta-Chaudhuri T., Addorisio M. E., Masi E. B., Silverman H. A., Newman J. E., et al. . (2020). Specific vagus nerve stimulation parameters alter serum cytokine levels in the absence of inflammation. Bioelectron Med. 6:8. 10.1186/s42234-020-00042-8
    1. Turner H. M., III., Bernard R. M. (2006). Calculating and synthesizing effect sizes. CICSD 33, 42–55. 10.1044/cicsd_33_S_42
    1. Tutar B., Atar S., Berkiten G., Üstün O., Kumral T. L., Uyar Y. (2020). The effect of transcutaneous electrical nerve stimulation (TENS) on chronic subjective tinnitus. Am. J. Otolaryngol. 41:102326. 10.1016/j.amjoto.2019.102326
    1. Usami K., Kawai K., Sonoo M., Saito N. (2013). Scalp-recorded evoked potentials as a marker for afferent nerve impulse in clinical vagus nerve stimulation. Brain Stimul. 6, 615–623. 10.1016/j.brs.2012.09.007
    1. Wagatsuma A., Okuyama T., Sun C., Smith L. M., Abe K., Tonegawa S. (2018). Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context. Proc. Natl. Acad. Sci. U.S.A. 115, E310–E316. 10.1073/pnas.1714082115
    1. Watanabe K., Tubbs R. S., Satoh S., Zomorodi A. R., Liedtke W., Labidi M., et al. . (2016). Isolated deep ear canal pain: possible role of auricular branch of vagus nerve—case illustrations with cadaveric correlation. World Neurosurg. 96, 293–301. 10.1016/j.wneu.2016.08.102
    1. Wellmark (2018). Vagus Nerve Stimulation (VNS) and Vagal Blocking Therapy. Available online at: (accessed November 26, 2020).
    1. Wolf V., Kühnel A., Teckentrup V., Koenig J., Kroemer N. B. (2021). Does non-invasive vagus nerve stimulation affect heart rate variability? A living and interactive Bayesian meta-analysis. bioRxiv [preprint]. 10.1101/2021.01.18.426704
    1. Wright B. J., O'Brien S., Hazi A., Kent S. (2015). Increased systolic blood pressure reactivity to acute stress is related with better self-reported health. Sci. Rep. 4:6882. 10.1038/srep06882
    1. Yang B., Pham T., Goldbach-Mansky R., Gadina M. (2011). Accurate and simple measurement of the pro-inflammatory cytokine IL-1β using a whole blood stimulation assay. J. Vis. Exp. 49:e2662. 10.3791/2662
    1. Yap J. Y. Y., Keatch C., Lambert E., Woods W., Stoddart P. R., Kameneva T. (2020). Critical review of transcutaneous vagus nerve stimulation: challenges for translation to clinical practice. Front. Neurosci. 14:284. 10.3389/fnins.2020.00284
    1. Yoo P. B., Lubock N. B., Hincapie J. G., Ruble S. B., Hamann J. J., Grill W. M. (2013). High-resolution measurement of electrically-evoked vagus nerve activity in the anesthetized dog. J. Neural Eng. 10:026003. 10.1088/1741-2560/10/2/026003
    1. Yu L., Huang B., Po S. S., Tan T., Wang M., Zhou L., et al. . (2017). Low-level tragus stimulation for the treatment of ischemia and reperfusion injury in patients with ST-Segment elevation myocardial infarction. JACC Cardiovasc. Intervent. 10, 1511–1520. 10.1016/j.jcin.2017.04.036
    1. Zamotrinsky A. V., Kondratiev B., de Jong J. W. (2001). Vagal neurostimulation in patients with coronary artery disease. Autonomic Neurosci. 88, 109–116. 10.1016/S1566-0702(01)00227-2

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