Advertisement

Transcutaneous vagus nerve stimulation - A brief introduction and overview

  • Max J. Hilz
    Correspondence
    Corresponding author at: University of Erlangen-Nuremberg, Schlossplatz 4, D-91054 Erlangen, Germany.
    Affiliations
    Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany

    Icahn School of Medicine at Mount Sinai, New York, NY, USA
    Search for articles by this author
Published:September 27, 2022DOI:https://doi.org/10.1016/j.autneu.2022.103038

      Abstract

      Invasive cervical vagus nerve stimulation (VNS) is approved for the treatment of epilepsies, depression, obesity, and for stroke-rehabilitation. The procedure requires surgery, has side-effects, is expensive and not readily available. Consequently, transcutaneous VNS (tVNS) has been developed 20 years ago as non-invasive, less expensive, and easily applicable alternative. Since the vagus nerve reaches the skin at the outer acoustic canal and ear, and reflex-responses such as the ear-cough-reflex or the auriculo-cardiac reflex have been observed upon auricular stimulation, the ear seems well suited for tVNS. However, several sensory nerves with variable fiber-density and significant overlap innervate the outer ear: the auricular branch of the vagus nerve (ABVN), the auriculotemporal nerve, greater auricular nerve, and to some extent the lesser occipital nerve. VNS requires activation of Aβ-fibers which are far less present in the ABVN than the cervical vagus nerve. Thus, optimal stimulation sites and parameters, and tVNS-algorithms need to be further explored. Unravelling central pathways and structures that mediate tVNS-effects is another challenge. tVNS impulses reach the nucleus of the solitary tract and activate the locus-coeruleus-norepinephrine system. However, many more brain areas are activated or deactivated upon VNS, including structures of the central autonomic network and the limbic system. Still, the realm of therapeutic tVNS applications grows rapidly and includes medication-refractory epilepsies, depressive mood disorders, headaches including migraine, pain, heart failure, gastrointestinal inflammatory diseases and many more. tVNS might become a standard tool to enhance autonomic balance and function in various autonomic, neurological, psychiatric, rheumatologic, as well as other diseases.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Apovian C.M.
        • Shah S.N.
        • Wolfe B.M.
        • Ikramuddin S.
        • Miller C.J.
        • Tweden K.S.
        • Billington C.J.
        • Shikora S.A.
        Two-year outcomes of vagal nerve blocking (vBloc) for the treatment of obesity in the ReCharge trial.
        Obes. Surg. 2017; 27: 169-176
        • Austelle C.W.
        • O’Leary G.H.
        • Thompson S.
        • Gruber E.
        • Kahn A.
        • Manett A.J.
        • Short B.
        • Badran B.W.
        A comprehensive review of vagus nerve stimulation for depression.
        Neuromodulation. 2022; 25: 309-315https://doi.org/10.1111/ner.13528
        • Ay I.
        • Napadow V.
        • Ay H.
        Electrical stimulation of the vagus nerve dermatome in the external ear is protective in rat cerebral ischemia.
        Brain Stimul. 2015; 8: 7-12
        • Badran B.W.
        • Brown J.C.
        • Dowdle L.T.
        • Mithoefer O.J.
        • LaBate N.T.
        • Coatsworth J.
        • DeVries W.H.
        • Austelle C.W.
        • McTeague L.M.
        • Yu A.
        • Bikson M.
        • Jenkins D.D.
        • George M.S.
        Tragus or cymba conchae? Investigating the anatomical foundation of transcutaneous auricular vagus nerve stimulation (taVNS).
        Brain Stimul. 2018; 11: 947-948
        • Badran B.W.
        • Mithoefer O.J.
        • Summer C.E.
        • LaBate N.T.
        • Glusman C.E.
        • Badran A.W.
        • DeVries W.H.
        • Summers P.M.
        • Austelle C.W.
        • McTeague L.M.
        • Borckardt J.J.
        • George M.S.
        Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate.
        Brain Stimul. 2018; 11: 699-708
        • Badran B.W.
        • Yu A.B.
        • Adair D.
        • Mappin G.
        • DeVries W.H.
        • Jenkins D.D.
        • George M.S.
        • Bikson M.
        Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): technique, targeting, and considerations.
        J. Vis. Exp. 2019;
        • Bailey P.
        • Bremer F.
        A sensory cortical representation of the vagus nerve: with a note on the effects of low blood pressure on the cortical electrogram.
        J. Neurophysiol. 1938; 1: 405-412
        • Benarroch E.E.
        Central Autonomic Network: Functional Organization and Clinical Correlations.
        Futura Publishing Company, Inc, Armonk, NY1997
        • Ben-Menachem E.
        • Hamberger A.
        • Hedner T.
        • Hammond E.J.
        • Uthman B.M.
        • Slater J.
        • Treig T.
        • Stefan H.
        • Ramsay R.E.
        • Wernicke J.F.
        • et al.
        Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures.
        Epilepsy Res. 1995; 20: 221-227
        • Butt M.F.
        • Albusoda A.
        • Farmer A.D.
        • Aziz Q.
        The anatomical basis for transcutaneous auricular vagus nerve stimulation.
        J. Anat. 2020; 236: 588-611
        • Clancy J.A.
        • Mary D.A.
        • Witte K.K.
        • Greenwood J.P.
        • Deuchars S.A.
        • Deuchars J.
        Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity.
        Brain Stimul. 2014; 7: 871-877
        • Dell P.
        • Olson R.
        Thalamic, cortical and cerebellar projections of vagal visceral afferences.
        C. R. Seances Soc. Biol. Fil. 1951; 145: 1084-1088
        • Dodrill C.B.
        • Morris G.L.
        Effects of vagal nerve stimulation on cognition and quality of life in epilepsy.
        Epilepsy Behav. 2001; 2: 46-53
        • Elger G.
        • Hoppe C.
        • Falkai P.
        • Rush A.J.
        • Elger C.E.
        Vagus nerve stimulation is associated with mood improvements in epilepsy patients.
        Epilepsy Res. 2000; 42: 203-210
        • Ellrich J.
        Transcutaneous auricular vagus nerve stimulation.
        J. Clin. Neurophysiol. 2019; 36: 437-442
        • Engel D.
        The gastroauricular phenomenon and related vagus reflexes.
        Arch. Psychiatr. Nervenkr. (1970). 1979; 227: 271-277
        • Evensen K.
        • Jorgensen M.B.
        • Sabers A.
        • Martiny K.
        Transcutaneous vagal nerve stimulation in treatment-resistant depression: a feasibility study.
        Neuromodulation. 2022; 25: 443-449
        • Fornai F.
        • Ruffoli R.
        • Giorgi F.S.
        • Paparelli A.
        The role of locus coeruleus in the antiepileptic activity induced by vagus nerve stimulation.
        Eur. J. Neurosci. 2011; 33: 2169-2178
        • Garamendi-Ruiz I.
        • Gomez-Esteban J.C.
        Cardiovascular autonomic effects of vagus nerve stimulation.
        Clin. Auton. Res. 2019; 29: 183-194
        • Ginsberg L.E.
        • Eicher S.A.
        Great auricular nerve: anatomy and imaging in a case of perineural tumor spread.
        AJNR Am. J. Neuroradiol. 2000; 21: 568-571
        • Giordano F.
        • Zicca A.
        • Barba C.
        • Guerrini R.
        • Genitori L.
        Vagus nerve stimulation: surgical technique of implantation and revision and related morbidity.
        Epilepsia. 2017; 58: 85-90
        • Gonzalez H.F.J.
        • Yengo-Kahn A.
        • Englot D.J.
        Vagus nerve stimulation for the treatment of epilepsy.
        Neurosurg. Clin. N. Am. 2019; 30: 219-230
        • Gupta D.
        • Verma S.
        • Vishwakarma S.K.
        Anatomic basis of Arnold's ear-cough reflex.
        Surg. Radiol. Anat. 1986; 8: 217-220
        • Harden C.L.
        • Pulver M.C.
        • Ravdin L.D.
        • Nikolov B.
        • Halper J.P.
        • Labar D.R.
        A pilot study of mood in epilepsy patients treated with vagus nerve stimulation.
        Epilepsy Behav. 2000; 1: 93-99
        • He W.
        • Wang X.
        • Shi H.
        • Shang H.
        • Li L.
        • Jing X.
        • Zhu B.
        Auricular acupuncture and vagal regulation.
        Evid. Based Complement. Alternat. Med. 2012; 2012786839
        • Holle-Lee D.
        • Gaul C.
        Noninvasive vagus nerve stimulation in the management of cluster headache: clinical evidence and practical experience.
        Ther. Adv. Neurol. Disord. 2016; 9: 230-234
        • Hyvarinen P.
        • Yrttiaho S.
        • Lehtimaki J.
        • Ilmoniemi R.J.
        • Makitie A.
        • Ylikoski J.
        • Makela J.P.
        • Aarnisalo A.A.
        Transcutaneous vagus nerve stimulation modulates tinnitus-related beta- and gamma-band activity.
        Ear Hear. 2015; 36: e76-e85
        • Ikramuddin S.
        • Blackstone R.P.
        • Brancatisano A.
        • Toouli J.
        • Shah S.N.
        • Wolfe B.M.
        • Fujioka K.
        • Maher J.W.
        • Swain J.
        • Que F.G.
        • Morton J.M.
        • Leslie D.B.
        • Brancatisano R.
        • Kow L.
        • O'Rourke R.W.
        • Deveney C.
        • Takata M.
        • Miller C.J.
        • Knudson M.B.
        • Tweden K.S.
        • Shikora S.A.
        • Sarr M.G.
        • Billington C.J.
        Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial.
        JAMA. 2014; 312: 915-922
        • Klein H.U.
        • Ferrari G.M.
        Vagus nerve stimulation: a new approach to reduce heart failure.
        Cardiol. J. 2010; 17: 638-644
        • Komisaruk B.R.
        • Frangos E.
        Vagus nerve afferent stimulation: projection into the brain, reflexive physiological, perceptual, and behavioral responses, and clinical relevance.
        Auton. Neurosci. 2022; 237102908
        • Krahl S.E.
        • Senanayake S.S.
        • Handforth A.
        Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats.
        Epilepsia. 2001; 42: 586-589
        • Kraus T.
        • Hosl K.
        • Kiess O.
        • Schanze A.
        • Kornhuber J.
        • Forster C.
        BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation.
        J. Neural Transm. (Vienna). 2007; 114: 1485-1493
        • Li L.
        • Wang D.
        • Pan H.
        • Huang L.
        • Sun X.
        • He C.
        • Wei Q.
        Non-invasive vagus nerve stimulation in cerebral stroke: current status and future perspectives.
        Front. Neurosci. 2022; 16820665
        • Liu J.
        • Fang J.
        • Wang Z.
        • Rong P.
        • Hong Y.
        • Fan Y.
        • Wang X.
        • Park J.
        • Jin Y.
        • Liu C.
        • Zhu B.
        • Kong J.
        Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression.
        J. Affect. Disord. 2016; 205: 319-326
        • Marangell L.B.
        • Rush A.J.
        • George M.S.
        • Sackeim H.A.
        • Johnson C.R.
        • Husain M.M.
        • Nahas Z.
        • Lisanby S.H.
        Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes.
        Biol. Psychiatry. 2002; 51: 280-287
        • Mertens A.
        • Raedt R.
        • Gadeyne S.
        • Carrette E.
        • Boon P.
        • Vonck K.
        Recent advances in devices for vagus nerve stimulation.
        Expert Rev. Med. Devices. 2018; 15: 527-539
        • Murray A.R.
        • Atkinson L.
        • Mahadi M.K.
        • Deuchars S.A.
        • Deuchars J.
        The strange case of the ear and the heart: the auricular vagus nerve and its influence on cardiac control.
        Auton. Neurosci. 2016; 199: 48-53
        • Mwamburi M.
        • Liebler E.J.
        • Tenaglia A.T.
        Review of non-invasive vagus nerve stimulation (gammaCore): efficacy, safety, potential impact on comorbidities, and economic burden for episodic and chronic cluster headache.
        Am. J. Manag. Care. 2017; 23: S317-S325
        • Nahas Z.
        • Marangell L.B.
        • Husain M.M.
        • Rush A.J.
        • Sackeim H.A.
        • Lisanby S.H.
        • Martinez J.M.
        • George M.S.
        Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes.
        J. Clin. Psychiatry. 2005; 66: 1097-1104
        • Redgrave J.N.
        • Moore L.
        • Oyekunle T.
        • Ebrahim M.
        • Falidas K.
        • Snowdon N.
        • Ali A.
        • Majid A.
        Transcutaneous auricular vagus nerve stimulation with concurrent upper limb repetitive task practice for poststroke motor recovery: a pilot study.
        J. Stroke Cerebrovasc. Dis. 2018; 27: 1998-2005
        • Reid S.A.
        Surgical technique for implantation of the neurocybernetic prosthesis.
        Epilepsia. 1990; 31: S38-S39
        • Rong P.
        • Liu J.
        • Wang L.
        • Liu R.
        • Fang J.
        • Zhao J.
        • Zhao Y.
        • Wang H.
        • Vangel M.
        • Sun S.
        • Ben H.
        • Park J.
        • Li S.
        • Meng H.
        • Zhu B.
        • Kong J.
        Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study.
        J. Affect. Disord. 2016; 195: 172-179
        • Rush A.J.
        • Marangell L.B.
        • Sackeim H.A.
        • George M.S.
        • Brannan S.K.
        • Davis S.M.
        • Howland R.
        • Kling M.A.
        • Rittberg B.R.
        • Burke W.J.
        • Rapaport M.H.
        • Zajecka J.
        • Nierenberg A.A.
        • Husain M.M.
        • Ginsberg D.
        • Cooke R.G.
        Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.
        Biol. Psychiatry. 2005; 58: 347-354
        • Rush A.J.
        • Sackeim H.A.
        • Marangell L.B.
        • George M.S.
        • Brannan S.K.
        • Davis S.M.
        • Lavori P.
        • Howland R.
        • Kling M.A.
        • Rittberg B.
        • Carpenter L.
        • Ninan P.
        • Moreno F.
        • Schwartz T.
        • Conway C.
        • Burke M.
        • Barry J.J.
        Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study.
        Biol. Psychiatry. 2005; 58: 355-363
        • Ryvlin P.
        • Rheims S.
        • Hirsch L.J.
        • Sokolov A.
        • Jehi L.
        Neuromodulation in epilepsy: state-of-the-art approved therapies.
        Lancet Neurol. 2021; 20: 1038-1047
        • Sackeim H.A.
        • Rush A.J.
        • George M.S.
        • Marangell L.B.
        • Husain M.M.
        • Nahas Z.
        • Johnson C.R.
        • Seidman S.
        • Giller C.
        • Haines S.
        • Simpson Jr., R.K.
        • Goodman R.R.
        Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome.
        Neuropsychopharmacology. 2001; 25: 713-728
        • Stefan H.
        • Kreiselmeyer G.
        • Kerling F.
        • Kurzbuch K.
        • Rauch C.
        • Heers M.
        • Kasper B.S.
        • Hammen T.
        • Rzonsa M.
        • Pauli E.
        • Ellrich J.
        • Graf W.
        • Hopfengartner R.
        Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial.
        Epilepsia. 2012; 53: e115-e118
        • Straube A.
        • Ellrich J.
        • Eren O.
        • Blum B.
        • Ruscheweyh R.
        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. 2015; 16: 543
        • Toffa D.H.
        • Touma L.
        • El Meskine T.
        • Bouthillier A.
        • Nguyen D.K.
        Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: a critical review.
        Seizure. 2020; 83: 104-123
        • Trevizol A.P.
        • Shiozawa P.
        • Taiar I.
        • Soares A.
        • Gomes J.S.
        • Barros M.D.
        • Liquidato B.M.
        • Cordeiro Q.
        Transcutaneous vagus nerve stimulation (taVNS) for major depressive disorder: an open label proof-of-concept trial.
        Brain Stimul. 2016; 9: 453-454
        • Ventureyra E.C.
        Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept.
        Childs Nerv. Syst. 2000; 16: 101-102
        • Vonck K.
        • Boon P.
        • Van Roost D.
        Anatomical and physiological basis and mechanism of action of neurostimulation for epilepsy.
        Acta Neurochir. Suppl. 2007; 97: 321-328
        • Wang Z.
        • Yu L.
        • Wang S.
        • Huang B.
        • Liao K.
        • Saren G.
        • Tan T.
        • Jiang H.
        Chronic intermittent low-level transcutaneous electrical stimulation of auricular branch of vagus nerve improves left ventricular remodeling in conscious dogs with healed myocardial infarction.
        Circ. Heart Fail. 2014; 7: 1014-1021
        • Yakunina N.
        • Kim S.S.
        • Nam E.C.
        Optimization of transcutaneous vagus nerve stimulation using functional MRI.
        Neuromodulation. 2017; 20: 290-300
        • Zannad F.
        • De Ferrari G.M.
        • Tuinenburg A.E.
        • Wright D.
        • Brugada J.
        • Butter C.
        • Klein H.
        • Stolen C.
        • Meyer S.
        • Stein K.M.
        • Ramuzat A.
        • Schubert B.
        • Daum D.
        • Neuzil P.
        • Botman C.
        • Castel M.A.
        • D'Onofrio A.
        • Solomon S.D.
        • Wold N.
        • Ruble S.B.
        Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural cardiac TherApy foR heart failure (NECTAR-HF) randomized controlled trial.
        Eur. Heart J. 2015; 36: 425-433