Study of the Transcutaneous Auricular Vagus Nerve Stimulation May Advance Outcome in Chronic Pediatric Inflammatory Diseases
Main Article Content
Abstract
The recent insight that the immune system is innervated has initiated a search for neural reflex circuits suitable for therapeutic targeting in human inflammatory diseases. The inflammatory reflex, signaling along the vagus system to maintain immune system homeostasis, is the best characterized such circuit. Proinflammatory molecules, extracellularly released during infectious or sterile injury, are sensed by afferent vagal nerves that transmit this information to the nucleus of tractus solitarius in the brainstem. The afferent signals generate efferent action potentials that travel from the brainstem via efferent vagal nerves to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors on immunocompetent cells to inhibit proinflammatory cytokine release. These mobile anti-inflammatory T lymphocytes thus operate both inside and outside compartments innervated by the vagus system. Therapeutic proof-of-concept anti-inflammatory studies following surgical implantation of electrical vagus nerve stimulators were first conducted in rheumatoid arthritis and Crohn´s disease. Long term use of these devices was uneventful, while the initial surgical procedure caused adverse effects in some patients. The auricular branch of the vagus nerve reaches superficial parts in the concha and tragus in both ears, enabling transcutaneous electrical auricular vagus nerve stimulation (taVNS) as a safer therapeutic alternative. Invasive VNS and taVNS activate similar parts of the central nervous system indicated by functional imaging methods. Pilot taVNS studies in patients with inflammatory diseases have so far been conducted to treat rheumatoid arthritis, osteoarthritis, lupus, pediatric inflammatory bowel diseases, and pediatric nephrotic syndromes.
Keywords:
Inflammatory reflex, taVNS, Acetylcholine, Inflammation, Pain
Article Details
How to Cite
ANDERSSON, Ulf.
Study of the Transcutaneous Auricular Vagus Nerve Stimulation May Advance Outcome in Chronic Pediatric Inflammatory Diseases.
Medical Research Archives, [S.l.], v. 10, n. 5, june 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2783>. Date accessed: 23 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i5.2783.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6(12):1191-1197.
2. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex--linking immunity and metabolism. Nat Rev Endocrinol. 2012;8(12):743-754.
3. Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and Therapeutic Relevance of Neuro-immune Communication. Immunity. 2017;46(6):927-942.
4. Dinarello CA. Anti-inflammatory Agents: Present and Future. Cell. 2010;140(6):935-950.
5. Bluestone JA, Anderson M. Tolerance in the Age of Immunotherapy. N Engl J Med. 2020;383(12):1156-1166.
6. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. Jama. 2006;295(19):2275-2285.
7. Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol. 2012;30:313-335.
8. Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J Exp Med. 2012;209(6):1057-1068.
9. Pavlov VA, Chavan SS, Tracey KJ. Bioelectronic Medicine: From Preclinical Studies on the Inflammatory Reflex to New Approaches in Disease Diagnosis and Treatment. Cold Spring Harb Perspect Med. 2020;10(3).
10. Andersson U, Tracey KJ. A new approach to rheumatoid arthritis: treating inflammation with computerized nerve stimulation. Cerebrum. 2012;2012:3.
11. Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta AD, Levine YA, Faltys M, Zitnik R, Tracey KJ, Tak PP. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113(29):8284-8289.
12. Bonaz B, Sinniger V, Pellissier S. Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases. Front Neurosci. 2021;15:650971.
13. Yakunina N, Kim SS, Nam EC. Optimization of Transcutaneous Vagus Nerve Stimulation Using Functional MRI. Neuromodulation. 2017;20(3):290-300.
14. Ellrich J. Transcutaneous Auricular Vagus Nerve Stimulation. J Clin Neurophysiol. 2019;36(6):437-442.
15. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458-462.
16. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853-859.
17. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117(2):289-296.
18. Pavlov VA, Chavan SS, Tracey KJ. Molecular and Functional Neuroscience in Immunity. Annu Rev Immunol. 2018;36:783-812.
19. Maier SF, Goehler LE, Fleshner M, Watkins LR. The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci. 1998;840:289-300.
20. Kressel AM, Tsaava T, Levine YA, Chang EH, Addorisio ME, Chang Q, Burbach BJ, Carnevale D, Lembo G, Zador AM, Andersson U, Pavlov VA, Chavan SS, Tracey KJ. Identification of a brainstem locus that inhibits tumor necrosis factor. Proc Natl Acad Sci U S A. 2020;117(47):29803-29810.
21. Suarez AN, Hsu TM, Liu CM, Noble EE, Cortella AM, Nakamoto EM, Hahn JD, de Lartigue G, Kanoski SE. Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nat Commun. 2018;9(1):2181.
22. Broncel A, Bocian R, Kłos-Wojtczak P, Konopacki J. Medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation. PLoS One. 2018;13(11):e0206532.
23. Lehner KR, Silverman HA, Addorisio ME, Roy A, Al-Onaizi MA, Levine Y, Olofsson PS, Chavan SS, Gros R, Nathanson NM, Al-Abed Y, Metz CN, Prado VF, Prado MAM, Tracey KJ, Pavlov VA. Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation. Front Immunol. 2019;10:585.
24. Metz CN, Pavlov VA. Treating disorders across the lifespan by modulating cholinergic signaling with galantamine. J Neurochem. 2021;158(6):1359-1380.
25. Gallowitsch-Puerta M, Tracey KJ. Immunologic role of the cholinergic anti-inflammatory pathway and the nicotinic acetylcholine alpha 7 receptor. Ann N Y Acad Sci. 2005;1062:209-219.
26. Ren C, Tong YL, Li JC, Lu ZQ, Yao YM. The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism. Int J Biol Sci. 2017;13(1):46-56.
27. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al-Abed Y, Wang H, Metz C, Miller EJ, Tracey KJ, Ulloa L. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10(11):1216-1221.
28. Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K, Lin X, Levi J, Parrish WR, Rosas-Ballina M, Czura CJ, Larosa GJ, Miller EJ, Tracey KJ, Al-Abed Y. Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit Care Med. 2007;35(4):1139-1144.
29. Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334(6052):98-101.
30. Olofsson PS, Steinberg BE, Sobbi R, Cox MA, Ahmed MN, Oswald M, Szekeres F, Hanes WM, Introini A, Liu SF, Holodick NE, Rothstein TL, Lövdahl C, Chavan SS, Yang H, Pavlov VA, Broliden K, Andersson U, Diamond B, Miller EJ, Arner A, Gregersen PK, Backx PH, Mak TW, Tracey KJ. Blood pressure regulation by CD4(+) lymphocytes expressing choline acetyltransferase. Nat Biotechnol. 2016;34(10):1066-1071.
31. Abdulkhaleq LA, Assi MA, Abdullah R, Zamri-Saad M, Taufiq-Yap YH, Hezmee MNM. The crucial roles of inflammatory mediators in inflammation: A review. Vet World. 2018;11(5):627-635.
32. Yang H, Andersson U, Brines M. Neurons Are a Primary Driver of Inflammation via Release of HMGB1. Cells. 2021;10(10).
33. Yang H, Zeng Q, Silverman HA, Gunasekaran M, George SJ, Devarajan A, Addorisio ME, Li J, Tsaava T, Shah V, Billiar TR, Wang H, Brines M, Andersson U, Pavlov VA, Chang EH, Chavan SS, Tracey KJ. HMGB1 released from nociceptors mediates inflammation. Proc Natl Acad Sci U S A. 2021;118(33).
34. Einck L, Bustin M. The intracellular distribution and function of the high mobility group chromosomal proteins. Exp Cell Res. 1985;156(2):295-310.
35. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248-251.
36. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418(6894):191-195.
37. Yang H, Wang H, Andersson U. Targeting Inflammation Driven by HMGB1. Front Immunol. 2020;11:484.
38. Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev. 2007;220:35-46.
39. Schiraldi M, Raucci A, Muñoz LM, Livoti E, Celona B, Venereau E, Apuzzo T, De Marchis F, Pedotti M, Bachi A, Thelen M, Varani L, Mellado M, Proudfoot A, Bianchi ME, Uguccioni M. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med. 2012;209(3):551-563.
40. Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ, 3rd, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspects Med. 2014;40:1-116.
41. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139-162.
42. Andersson U, Yang H, Harris H. Extracellular HMGB1 as a therapeutic target in inflammatory diseases. Expert Opin Ther Targets. 2018;22(3):263-277.
43. Li F, Chen Z, Pan Q, Fu S, Lin F, Ren H, Han H, Billiar TR, Sun F, Li Q. The protective effect of PNU-282987, a selective α7 nicotinic acetylcholine receptor agonist, on the hepatic ischemia-reperfusion injury is associated with the inhibition of high-mobility group box 1 protein expression and nuclear factor κB activation in mice. Shock. 2013;39(2):197-203.
44. Li DJ, Huang F, Ni M, Fu H, Zhang LS, Shen FM. α7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II-Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide-Dependent SIRT1 Activity. Arterioscler Thromb Vasc Biol. 2016;36(8):1566-1576.
45. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. Embo j. 2003;22(20):5551-5560.
46. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-471.
47. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. Embo j. 2004;23(12):2369-2380.
48. Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A, Lundbäck P, Palmblad K, Andersson U, Harris H, Svensson CI. Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain. 2014;155(9):1802-1813.
49. Agalave NM, Svensson CI. Extracellular high-mobility group box 1 protein (HMGB1) as a mediator of persistent pain. Mol Med. 2015;20(1):569-578.
50. Zi SF, Li JH, Liu L, Deng C, Ao X, Chen DD, Wu SZ. Dexmedetomidine-mediated protection against septic liver injury depends on TLR4/MyD88/NF-κB signaling downregulation partly via cholinergic anti-inflammatory mechanisms. Int Immunopharmacol. 2019;76:105898.
51. Lu B, Kwan K, Levine YA, Olofsson PS, Yang H, Li J, Joshi S, Wang H, Andersson U, Chavan SS, Tracey KJ. α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release. Mol Med. 2014;20(1):350-358.
52. Lamkanfi M, Sarkar A, Vande Walle L, Vitari AC, Amer AO, Wewers MD, Tracey KJ, Kanneganti TD, Dixit VM. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J Immunol. 2010;185(7):4385-4392.
53. Larsson B, Elmqvist H, Rydén L, Schüller H. Lessons from the first patient with an implanted pacemaker: 1958-2001. Pacing Clin Electrophysiol. 2003;26(1 Pt 1):114-124.
54. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia. 1990;31 Suppl 2:S40-43.
55. Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, Nahas Z, Haines S, Simpson RK, Jr., Goodman R. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry. 2000;47(4):276-286.
56. Bonaz B, Sinniger V, Hoffmann D, Clarençon D, Mathieu N, Dantzer C, Vercueil L, Picq C, Trocmé C, Faure P, Cracowski JL, Pellissier S. Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28(6):948-953.
57. Bonaz B, Picq C, Sinniger V, Mayol JF, Clarençon D. Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterol Motil. 2013;25(3):208-221.
58. Toffa DH, Touma L, El Meskine T, Bouthillier A, Nguyen DK. 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.
59. Pavlov VA. The evolving obesity challenge: targeting the vagus nerve and the inflammatory reflex in the response. Pharmacol Ther. 2021;222:107794.
60. Genovese MC, Gaylis NB, Sikes D, Kivitz A, Lewis Horowitz D, Peterfy C, Glass EV, Levine YA, Chernoff D. Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study. The Lancet Rheumatology. 2020;2(9):e527-e538.
61. Sinniger V, Pellissier S, Fauvelle F, Trocmé C, Hoffmann D, Vercueil L, Cracowski JL, David O, Bonaz B. A 12-month pilot study outcomes of vagus nerve stimulation in Crohn's disease. Neurogastroenterol Motil. 2020;32(10):e13911.
62. Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat. 2002;15(1):35-37.
63. Bermejo P, López M, Larraya I, Chamorro J, Cobo JL, Ordóñez S, Vega JA. Innervation of the Human Cavum Conchae and Auditory Canal: Anatomical Basis for Transcutaneous Auricular Nerve Stimulation. Biomed Res Int. 2017;2017:7830919.
64. Magdaleno-Madrigal VM, Valdés-Cruz A, Martínez-Vargas D, Martínez A, Almazán S, Fernández-Mas R, Fernández-Guardiola A. Effect of electrical stimulation of the nucleus of the solitary tract on the development of electrical amygdaloid kindling in the cat. Epilepsia. 2002;43(9):964-969.
65. Lulic D, Ahmadian A, Baaj AA, Benbadis SR, Vale FL. Vagus nerve stimulation. Neurosurg Focus. 2009;27(3):E5.
66. Mercante B, Ginatempo F, Manca A, Melis F, Enrico P, Deriu F. Anatomo-Physiologic Basis for Auricular Stimulation. Med Acupunct. 2018;30(3):141-150.
67. Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2015;8(3):624-636.
68. Zhao YX, He W, Jing XH, Liu JL, Rong PJ, Ben H, Liu K, Zhu B. Transcutaneous auricular vagus nerve stimulation protects endotoxemic rat from lipopolysaccharide-induced inflammation. Evid Based Complement Alternat Med. 2012;2012:627023.
69. Go YY, Ju WM, Lee CM, Chae SW, Song JJ. Different Transcutaneous Auricular Vagus Nerve Stimulation Parameters Modulate the Anti-Inflammatory Effects on Lipopolysaccharide-Induced Acute Inflammation in Mice. Biomedicines. 2022;10(2).
70. Kohoutova M, Horak J, Jarkovska D, Martinkova V, Tegl V, Nalos L, Vistejnova L, Benes J, Sviglerova J, Kuncova J, Matejovic M, Stengl M. Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis. Crit Care Med. 2019;47(6):e461-e469.
71. Li S, Wang Y, Gao G, Guo X, Zhang Y, Zhang Z, Wang Y, Zhang J, Wang J, Li L, Yang Y, Rong P. Transcutaneous Auricular Vagus Nerve Stimulation at 20 Hz Improves Depression-Like Behaviors and Down-Regulates the Hyperactivity of HPA Axis in Chronic Unpredictable Mild Stress Model Rats. Front Neurosci. 2020;14:680.
72. Li S, Zhai X, Rong P, McCabe MF, Wang X, Zhao J, Ben H, Wang S. Therapeutic effect of vagus nerve stimulation on depressive-like behavior, hyperglycemia and insulin receptor expression in Zucker fatty rats. PLoS One. 2014;9(11):e112066.
73. Li S, Sun C, Rong P, Zhai X, Zhang J, Baker M, Wang S. Auricular vagus nerve stimulation enhances central serotonergic function and inhibits diabetic neuropathy development in Zucker fatty rats. Mol Pain. 2018;14:1744806918787368.
74. He W, Jing XH, Zhu B, Zhu XL, Li L, Bai WZ, Ben H. The auriculo-vagal afferent pathway and its role in seizure suppression in rats. BMC Neurosci. 2013;14:85.
75. Wang S, Zhai X, Li S, McCabe MF, Wang X, Rong P. Transcutaneous vagus nerve stimulation induces tidal melatonin secretion and has an antidiabetic effect in Zucker fatty rats. PLoS One. 2015;10(4):e0124195.
76. Ma J, Zhang L, He G, Tan X, Jin X, Li C. Transcutaneous auricular vagus nerve stimulation regulates expression of growth differentiation factor 11 and activin-like kinase 5 in cerebral ischemia/reperfusion rats. J Neurol Sci. 2016;369:27-35.
77. Tarnawski L, Reardon C, Caravaca AS, Rosas-Ballina M, Tusche MW, Drake AR, Hudson LK, Hanes WM, Li JH, Parrish WR, Ojamaa K, Al-Abed Y, Faltys M, Pavlov VA, Andersson U, Chavan SS, Levine YA, Mak TW, Tracey KJ, Olofsson PS. Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex. Front Immunol. 2018;9:2648.
78. Ollivier V, Parry GC, Cobb RR, de Prost D, Mackman N. Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells. J Biol Chem. 1996;271(34):20828-20835.
79. Rong P, Liu A, Zhang J, Wang Y, Yang A, Li L, Ben H, Li L, Liu R, He W, Liu H, Huang F, Li X, Wu P, Zhu B. An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation. Chin Med J (Engl). 2014;127(2):300-304.
80. Sabers A, Aumüller-Wagner S, Christensen LR, Henning O, Kostov K, Lossius M, Majoie M, Mertens A, Nielsen L, Vonck K, Wagner L. Feasibility of transcutaneous auricular vagus nerve stimulation in treatment of drug resistant epilepsy: A multicenter prospective study. Epilepsy Res. 2021;177:106776.
81. von Wrede R, Rings T, Schach S, Helmstaedter C, Lehnertz K. Transcutaneous auricular vagus nerve stimulation induces stabilizing modifications in large-scale functional brain networks: towards understanding the effects of taVNS in subjects with epilepsy. Sci Rep. 2021;11(1):7906.
82. Kong J, Fang J, Park J, Li S, Rong P. Treating Depression with Transcutaneous Auricular Vagus Nerve Stimulation: State of the Art and Future Perspectives. Front Psychiatry. 2018;9:20.
83. Liu CH, Yang MH, Zhang GZ, Wang XX, Li B, Li M, Woelfer M, Walter M, Wang L. Neural networks and the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation in depression. J Neuroinflammation. 2020;17(1):54.
84. Addorisio ME, Imperato GH, de Vos AF, Forti S, Goldstein RS, Pavlov VA, van der Poll T, Yang H, Diamond B, Tracey KJ, Chavan SS. Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear. Bioelectron Med. 2019;5:4.
85. Marsal S, Corominas H, de Agustín JJ, Pérez-García C, López-Lasanta M, Borrell H, Reina D, Sanmartí R, Narváez J, Franco-Jarava C, Peterfy C, Narváez JA, Sharma V, Alataris K, Genovese MC, Baker MC. Non-invasive vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study. The Lancet Rheumatology. 2021;3(4):e262-e269.
86. Marsal S, Corominas H, De Agustin JJ, Perez-Garcia C, Lopez Lasanta M, Borrell Paños H, Reina-Sanz D, Sanmartí R, Narváez J, Franco-Jarava C, Peterfy C, Narvaez JA, Sharma V, Alataris K, Genovese MC, Baker M. AB0264 1-YEAR RESULTS OF A NON-INVASIVE AURICULAR VAGUS NERVE STIMULATION DEVICE IN PATIENTS WITH RHEUMATOID ARTHRITIS. Annals of the Rheumatic Diseases. 2021;80(Suppl 1):1158-1159.
87. Courties A, Deprouw C, Maheu E, Gibert E, Gottenberg JE, Champey J, Banneville B, Chesnel C, Amarenco G, Rousseau A, Berenbaum F, Sellam J. Effect of Transcutaneous Vagus Nerve Stimulation in Erosive Hand Osteoarthritis: Results from a Pilot Trial. J Clin Med. 2022;11(4).
88. Aranow C, Atish-Fregoso Y, Lesser M, Mackay M, Anderson E, Chavan S, Zanos TP, Datta-Chaudhuri T, Bouton C, Tracey KJ, Diamond B. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann Rheum Dis. 2021;80(2):203-208.
89. Sahn B, Pascuma K, Tracey K, Markowitz J. P072 Non-invasive Vagal Nerve Stimulation to Treat Crohn Disease and Ulcerative Colitis in Children and Young Adults: A Proof-of-Concept Clinical Trial. Am J Gastroenterol. 2021;116(Suppl 1):S19.
90. Merchant K, Zanos S, Datta-Chaudhuri T, Deutschman CS, Sethna CB. Transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of pediatric nephrotic syndrome: a pilot study. Bioelectron Med. 2022;8(1):1.
91. Yap JYY, Keatch C, Lambert E, Woods W, Stoddart PR, Kameneva T. Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Front Neurosci. 2020;14:284.
2. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex--linking immunity and metabolism. Nat Rev Endocrinol. 2012;8(12):743-754.
3. Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and Therapeutic Relevance of Neuro-immune Communication. Immunity. 2017;46(6):927-942.
4. Dinarello CA. Anti-inflammatory Agents: Present and Future. Cell. 2010;140(6):935-950.
5. Bluestone JA, Anderson M. Tolerance in the Age of Immunotherapy. N Engl J Med. 2020;383(12):1156-1166.
6. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. Jama. 2006;295(19):2275-2285.
7. Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol. 2012;30:313-335.
8. Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J Exp Med. 2012;209(6):1057-1068.
9. Pavlov VA, Chavan SS, Tracey KJ. Bioelectronic Medicine: From Preclinical Studies on the Inflammatory Reflex to New Approaches in Disease Diagnosis and Treatment. Cold Spring Harb Perspect Med. 2020;10(3).
10. Andersson U, Tracey KJ. A new approach to rheumatoid arthritis: treating inflammation with computerized nerve stimulation. Cerebrum. 2012;2012:3.
11. Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta AD, Levine YA, Faltys M, Zitnik R, Tracey KJ, Tak PP. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113(29):8284-8289.
12. Bonaz B, Sinniger V, Pellissier S. Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases. Front Neurosci. 2021;15:650971.
13. Yakunina N, Kim SS, Nam EC. Optimization of Transcutaneous Vagus Nerve Stimulation Using Functional MRI. Neuromodulation. 2017;20(3):290-300.
14. Ellrich J. Transcutaneous Auricular Vagus Nerve Stimulation. J Clin Neurophysiol. 2019;36(6):437-442.
15. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458-462.
16. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853-859.
17. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117(2):289-296.
18. Pavlov VA, Chavan SS, Tracey KJ. Molecular and Functional Neuroscience in Immunity. Annu Rev Immunol. 2018;36:783-812.
19. Maier SF, Goehler LE, Fleshner M, Watkins LR. The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci. 1998;840:289-300.
20. Kressel AM, Tsaava T, Levine YA, Chang EH, Addorisio ME, Chang Q, Burbach BJ, Carnevale D, Lembo G, Zador AM, Andersson U, Pavlov VA, Chavan SS, Tracey KJ. Identification of a brainstem locus that inhibits tumor necrosis factor. Proc Natl Acad Sci U S A. 2020;117(47):29803-29810.
21. Suarez AN, Hsu TM, Liu CM, Noble EE, Cortella AM, Nakamoto EM, Hahn JD, de Lartigue G, Kanoski SE. Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nat Commun. 2018;9(1):2181.
22. Broncel A, Bocian R, Kłos-Wojtczak P, Konopacki J. Medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation. PLoS One. 2018;13(11):e0206532.
23. Lehner KR, Silverman HA, Addorisio ME, Roy A, Al-Onaizi MA, Levine Y, Olofsson PS, Chavan SS, Gros R, Nathanson NM, Al-Abed Y, Metz CN, Prado VF, Prado MAM, Tracey KJ, Pavlov VA. Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation. Front Immunol. 2019;10:585.
24. Metz CN, Pavlov VA. Treating disorders across the lifespan by modulating cholinergic signaling with galantamine. J Neurochem. 2021;158(6):1359-1380.
25. Gallowitsch-Puerta M, Tracey KJ. Immunologic role of the cholinergic anti-inflammatory pathway and the nicotinic acetylcholine alpha 7 receptor. Ann N Y Acad Sci. 2005;1062:209-219.
26. Ren C, Tong YL, Li JC, Lu ZQ, Yao YM. The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism. Int J Biol Sci. 2017;13(1):46-56.
27. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al-Abed Y, Wang H, Metz C, Miller EJ, Tracey KJ, Ulloa L. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10(11):1216-1221.
28. Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K, Lin X, Levi J, Parrish WR, Rosas-Ballina M, Czura CJ, Larosa GJ, Miller EJ, Tracey KJ, Al-Abed Y. Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit Care Med. 2007;35(4):1139-1144.
29. Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334(6052):98-101.
30. Olofsson PS, Steinberg BE, Sobbi R, Cox MA, Ahmed MN, Oswald M, Szekeres F, Hanes WM, Introini A, Liu SF, Holodick NE, Rothstein TL, Lövdahl C, Chavan SS, Yang H, Pavlov VA, Broliden K, Andersson U, Diamond B, Miller EJ, Arner A, Gregersen PK, Backx PH, Mak TW, Tracey KJ. Blood pressure regulation by CD4(+) lymphocytes expressing choline acetyltransferase. Nat Biotechnol. 2016;34(10):1066-1071.
31. Abdulkhaleq LA, Assi MA, Abdullah R, Zamri-Saad M, Taufiq-Yap YH, Hezmee MNM. The crucial roles of inflammatory mediators in inflammation: A review. Vet World. 2018;11(5):627-635.
32. Yang H, Andersson U, Brines M. Neurons Are a Primary Driver of Inflammation via Release of HMGB1. Cells. 2021;10(10).
33. Yang H, Zeng Q, Silverman HA, Gunasekaran M, George SJ, Devarajan A, Addorisio ME, Li J, Tsaava T, Shah V, Billiar TR, Wang H, Brines M, Andersson U, Pavlov VA, Chang EH, Chavan SS, Tracey KJ. HMGB1 released from nociceptors mediates inflammation. Proc Natl Acad Sci U S A. 2021;118(33).
34. Einck L, Bustin M. The intracellular distribution and function of the high mobility group chromosomal proteins. Exp Cell Res. 1985;156(2):295-310.
35. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248-251.
36. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418(6894):191-195.
37. Yang H, Wang H, Andersson U. Targeting Inflammation Driven by HMGB1. Front Immunol. 2020;11:484.
38. Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev. 2007;220:35-46.
39. Schiraldi M, Raucci A, Muñoz LM, Livoti E, Celona B, Venereau E, Apuzzo T, De Marchis F, Pedotti M, Bachi A, Thelen M, Varani L, Mellado M, Proudfoot A, Bianchi ME, Uguccioni M. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med. 2012;209(3):551-563.
40. Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ, 3rd, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspects Med. 2014;40:1-116.
41. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139-162.
42. Andersson U, Yang H, Harris H. Extracellular HMGB1 as a therapeutic target in inflammatory diseases. Expert Opin Ther Targets. 2018;22(3):263-277.
43. Li F, Chen Z, Pan Q, Fu S, Lin F, Ren H, Han H, Billiar TR, Sun F, Li Q. The protective effect of PNU-282987, a selective α7 nicotinic acetylcholine receptor agonist, on the hepatic ischemia-reperfusion injury is associated with the inhibition of high-mobility group box 1 protein expression and nuclear factor κB activation in mice. Shock. 2013;39(2):197-203.
44. Li DJ, Huang F, Ni M, Fu H, Zhang LS, Shen FM. α7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II-Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide-Dependent SIRT1 Activity. Arterioscler Thromb Vasc Biol. 2016;36(8):1566-1576.
45. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. Embo j. 2003;22(20):5551-5560.
46. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-471.
47. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. Embo j. 2004;23(12):2369-2380.
48. Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A, Lundbäck P, Palmblad K, Andersson U, Harris H, Svensson CI. Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain. 2014;155(9):1802-1813.
49. Agalave NM, Svensson CI. Extracellular high-mobility group box 1 protein (HMGB1) as a mediator of persistent pain. Mol Med. 2015;20(1):569-578.
50. Zi SF, Li JH, Liu L, Deng C, Ao X, Chen DD, Wu SZ. Dexmedetomidine-mediated protection against septic liver injury depends on TLR4/MyD88/NF-κB signaling downregulation partly via cholinergic anti-inflammatory mechanisms. Int Immunopharmacol. 2019;76:105898.
51. Lu B, Kwan K, Levine YA, Olofsson PS, Yang H, Li J, Joshi S, Wang H, Andersson U, Chavan SS, Tracey KJ. α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release. Mol Med. 2014;20(1):350-358.
52. Lamkanfi M, Sarkar A, Vande Walle L, Vitari AC, Amer AO, Wewers MD, Tracey KJ, Kanneganti TD, Dixit VM. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J Immunol. 2010;185(7):4385-4392.
53. Larsson B, Elmqvist H, Rydén L, Schüller H. Lessons from the first patient with an implanted pacemaker: 1958-2001. Pacing Clin Electrophysiol. 2003;26(1 Pt 1):114-124.
54. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia. 1990;31 Suppl 2:S40-43.
55. Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, Nahas Z, Haines S, Simpson RK, Jr., Goodman R. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry. 2000;47(4):276-286.
56. Bonaz B, Sinniger V, Hoffmann D, Clarençon D, Mathieu N, Dantzer C, Vercueil L, Picq C, Trocmé C, Faure P, Cracowski JL, Pellissier S. Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28(6):948-953.
57. Bonaz B, Picq C, Sinniger V, Mayol JF, Clarençon D. Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterol Motil. 2013;25(3):208-221.
58. Toffa DH, Touma L, El Meskine T, Bouthillier A, Nguyen DK. 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.
59. Pavlov VA. The evolving obesity challenge: targeting the vagus nerve and the inflammatory reflex in the response. Pharmacol Ther. 2021;222:107794.
60. Genovese MC, Gaylis NB, Sikes D, Kivitz A, Lewis Horowitz D, Peterfy C, Glass EV, Levine YA, Chernoff D. Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study. The Lancet Rheumatology. 2020;2(9):e527-e538.
61. Sinniger V, Pellissier S, Fauvelle F, Trocmé C, Hoffmann D, Vercueil L, Cracowski JL, David O, Bonaz B. A 12-month pilot study outcomes of vagus nerve stimulation in Crohn's disease. Neurogastroenterol Motil. 2020;32(10):e13911.
62. Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat. 2002;15(1):35-37.
63. Bermejo P, López M, Larraya I, Chamorro J, Cobo JL, Ordóñez S, Vega JA. Innervation of the Human Cavum Conchae and Auditory Canal: Anatomical Basis for Transcutaneous Auricular Nerve Stimulation. Biomed Res Int. 2017;2017:7830919.
64. Magdaleno-Madrigal VM, Valdés-Cruz A, Martínez-Vargas D, Martínez A, Almazán S, Fernández-Mas R, Fernández-Guardiola A. Effect of electrical stimulation of the nucleus of the solitary tract on the development of electrical amygdaloid kindling in the cat. Epilepsia. 2002;43(9):964-969.
65. Lulic D, Ahmadian A, Baaj AA, Benbadis SR, Vale FL. Vagus nerve stimulation. Neurosurg Focus. 2009;27(3):E5.
66. Mercante B, Ginatempo F, Manca A, Melis F, Enrico P, Deriu F. Anatomo-Physiologic Basis for Auricular Stimulation. Med Acupunct. 2018;30(3):141-150.
67. Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2015;8(3):624-636.
68. Zhao YX, He W, Jing XH, Liu JL, Rong PJ, Ben H, Liu K, Zhu B. Transcutaneous auricular vagus nerve stimulation protects endotoxemic rat from lipopolysaccharide-induced inflammation. Evid Based Complement Alternat Med. 2012;2012:627023.
69. Go YY, Ju WM, Lee CM, Chae SW, Song JJ. Different Transcutaneous Auricular Vagus Nerve Stimulation Parameters Modulate the Anti-Inflammatory Effects on Lipopolysaccharide-Induced Acute Inflammation in Mice. Biomedicines. 2022;10(2).
70. Kohoutova M, Horak J, Jarkovska D, Martinkova V, Tegl V, Nalos L, Vistejnova L, Benes J, Sviglerova J, Kuncova J, Matejovic M, Stengl M. Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis. Crit Care Med. 2019;47(6):e461-e469.
71. Li S, Wang Y, Gao G, Guo X, Zhang Y, Zhang Z, Wang Y, Zhang J, Wang J, Li L, Yang Y, Rong P. Transcutaneous Auricular Vagus Nerve Stimulation at 20 Hz Improves Depression-Like Behaviors and Down-Regulates the Hyperactivity of HPA Axis in Chronic Unpredictable Mild Stress Model Rats. Front Neurosci. 2020;14:680.
72. Li S, Zhai X, Rong P, McCabe MF, Wang X, Zhao J, Ben H, Wang S. Therapeutic effect of vagus nerve stimulation on depressive-like behavior, hyperglycemia and insulin receptor expression in Zucker fatty rats. PLoS One. 2014;9(11):e112066.
73. Li S, Sun C, Rong P, Zhai X, Zhang J, Baker M, Wang S. Auricular vagus nerve stimulation enhances central serotonergic function and inhibits diabetic neuropathy development in Zucker fatty rats. Mol Pain. 2018;14:1744806918787368.
74. He W, Jing XH, Zhu B, Zhu XL, Li L, Bai WZ, Ben H. The auriculo-vagal afferent pathway and its role in seizure suppression in rats. BMC Neurosci. 2013;14:85.
75. Wang S, Zhai X, Li S, McCabe MF, Wang X, Rong P. Transcutaneous vagus nerve stimulation induces tidal melatonin secretion and has an antidiabetic effect in Zucker fatty rats. PLoS One. 2015;10(4):e0124195.
76. Ma J, Zhang L, He G, Tan X, Jin X, Li C. Transcutaneous auricular vagus nerve stimulation regulates expression of growth differentiation factor 11 and activin-like kinase 5 in cerebral ischemia/reperfusion rats. J Neurol Sci. 2016;369:27-35.
77. Tarnawski L, Reardon C, Caravaca AS, Rosas-Ballina M, Tusche MW, Drake AR, Hudson LK, Hanes WM, Li JH, Parrish WR, Ojamaa K, Al-Abed Y, Faltys M, Pavlov VA, Andersson U, Chavan SS, Levine YA, Mak TW, Tracey KJ, Olofsson PS. Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex. Front Immunol. 2018;9:2648.
78. Ollivier V, Parry GC, Cobb RR, de Prost D, Mackman N. Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells. J Biol Chem. 1996;271(34):20828-20835.
79. Rong P, Liu A, Zhang J, Wang Y, Yang A, Li L, Ben H, Li L, Liu R, He W, Liu H, Huang F, Li X, Wu P, Zhu B. An alternative therapy for drug-resistant epilepsy: transcutaneous auricular vagus nerve stimulation. Chin Med J (Engl). 2014;127(2):300-304.
80. Sabers A, Aumüller-Wagner S, Christensen LR, Henning O, Kostov K, Lossius M, Majoie M, Mertens A, Nielsen L, Vonck K, Wagner L. Feasibility of transcutaneous auricular vagus nerve stimulation in treatment of drug resistant epilepsy: A multicenter prospective study. Epilepsy Res. 2021;177:106776.
81. von Wrede R, Rings T, Schach S, Helmstaedter C, Lehnertz K. Transcutaneous auricular vagus nerve stimulation induces stabilizing modifications in large-scale functional brain networks: towards understanding the effects of taVNS in subjects with epilepsy. Sci Rep. 2021;11(1):7906.
82. Kong J, Fang J, Park J, Li S, Rong P. Treating Depression with Transcutaneous Auricular Vagus Nerve Stimulation: State of the Art and Future Perspectives. Front Psychiatry. 2018;9:20.
83. Liu CH, Yang MH, Zhang GZ, Wang XX, Li B, Li M, Woelfer M, Walter M, Wang L. Neural networks and the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation in depression. J Neuroinflammation. 2020;17(1):54.
84. Addorisio ME, Imperato GH, de Vos AF, Forti S, Goldstein RS, Pavlov VA, van der Poll T, Yang H, Diamond B, Tracey KJ, Chavan SS. Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear. Bioelectron Med. 2019;5:4.
85. Marsal S, Corominas H, de Agustín JJ, Pérez-García C, López-Lasanta M, Borrell H, Reina D, Sanmartí R, Narváez J, Franco-Jarava C, Peterfy C, Narváez JA, Sharma V, Alataris K, Genovese MC, Baker MC. Non-invasive vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study. The Lancet Rheumatology. 2021;3(4):e262-e269.
86. Marsal S, Corominas H, De Agustin JJ, Perez-Garcia C, Lopez Lasanta M, Borrell Paños H, Reina-Sanz D, Sanmartí R, Narváez J, Franco-Jarava C, Peterfy C, Narvaez JA, Sharma V, Alataris K, Genovese MC, Baker M. AB0264 1-YEAR RESULTS OF A NON-INVASIVE AURICULAR VAGUS NERVE STIMULATION DEVICE IN PATIENTS WITH RHEUMATOID ARTHRITIS. Annals of the Rheumatic Diseases. 2021;80(Suppl 1):1158-1159.
87. Courties A, Deprouw C, Maheu E, Gibert E, Gottenberg JE, Champey J, Banneville B, Chesnel C, Amarenco G, Rousseau A, Berenbaum F, Sellam J. Effect of Transcutaneous Vagus Nerve Stimulation in Erosive Hand Osteoarthritis: Results from a Pilot Trial. J Clin Med. 2022;11(4).
88. Aranow C, Atish-Fregoso Y, Lesser M, Mackay M, Anderson E, Chavan S, Zanos TP, Datta-Chaudhuri T, Bouton C, Tracey KJ, Diamond B. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann Rheum Dis. 2021;80(2):203-208.
89. Sahn B, Pascuma K, Tracey K, Markowitz J. P072 Non-invasive Vagal Nerve Stimulation to Treat Crohn Disease and Ulcerative Colitis in Children and Young Adults: A Proof-of-Concept Clinical Trial. Am J Gastroenterol. 2021;116(Suppl 1):S19.
90. Merchant K, Zanos S, Datta-Chaudhuri T, Deutschman CS, Sethna CB. Transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of pediatric nephrotic syndrome: a pilot study. Bioelectron Med. 2022;8(1):1.
91. Yap JYY, Keatch C, Lambert E, Woods W, Stoddart PR, Kameneva T. Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Front Neurosci. 2020;14:284.