Basic research studies of the inflammatory reflex

Physiology and immunology of the cholinergic antiinflammatory pathway.
Tracey KJ. J Clin Invest. 2007;117(2):289-96. doi: 10.1172/JCI30555.PMID: 17273548.
Reflex principles of immunological homeostasis.
Andersson U, Tracey KJ. Annu Rev Immunol. 2012;30:313-35. doi: 10.1146/annurev-immunol-020711-075015.
Vagus nerve SARS-CoV-2 infection and inflammatory reflex dysfunction: Is there a causal relationship?
Andersson U, Tracey KJ. J Intern Med. 2024;295(1):91-102. doi: 10.1111/joim.13746.
Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit.
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. Science. 2011;334(6052):98-101. doi: 10.1126/science.1209985.
Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Nature. 2000;405(6785):458-62. doi: 10.1038/35013070.PMID: 10839541.
The inflammatory reflex.
Tracey KJ. Nature. 2002;420(6917):853-9. doi: 10.1038/nature01321.PMID: 12490958.
Nociceptor α7nAChR activation blunts neuronal HMGB1 release and attenuates inflammation and nociceptive behavior.
Yang H, Morgan TS, Petruzzelli S, Hashimoto O, Hepler TD, Tynan A, Chaudhry S, Brines M, Andersson U, Chavan SS, Tracey KJ. Mol Med. 2025;31(1):324. doi: 10.1186/s10020-025-01387-z.
Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia.
Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, Chavan S, Tracey KJ. Proc Natl Acad Sci U S A. 2008;105(31):11008-13. doi: 10.1073/pnas.0803237105.
Neural reflexes in inflammation and immunity.
Andersson U, Tracey KJ. J Exp Med. 2012;209(6):1057-68. doi: 10.1084/jem.20120571.
A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen.
Matteoli G, Gomez-Pinilla PJ, Nemethova A, Di Giovangiulio M, Cailotto C, van Bree SH, Michel K, Tracey KJ, Schemann M, Boesmans W, Vanden Berghe P, Boeckxstaens GE. Gut. 2014;63(6):938-48. doi: 10.1136/gutjnl-2013-304676.
α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release.
Lu B, Kwan K, Levine YA, Olofsson PS, Yang H, Li J, Joshi S, Wang H, Andersson U, Chavan SS, Tracey KJ. Mol Med. 2014;20(1):350-8. doi: 0.2119/molmed.2013.00117.
Neural regulation of immunity: molecular mechanisms and clinical translation.
Pavlov VA, Tracey KJ.Nat Neurosci. 2017;20(2):156-166. doi: 10.1038/nn.4477.
Neurons Are the Inflammatory Problem.
Tracey KJ. Cell. 2018 May;173(5):1066-1068. doi: 10.1016/j.cell.2018.05.005.
Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation.
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. Front Immunol. 2019;10:585. doi: 10.3389/fimmu.2019.00585.
Identification of a brainstem locus that inhibits tumor necrosis factor.
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. Proc Natl Acad Sci U S A. 2020;117(47):29803-29810. doi: 10.1073/pnas.2008213117.
Neural representation of cytokines by vagal sensory neurons.
Huerta TS, Chen AC, Chaudhry S, Tynan A, Morgan T, Park K, Adamovich-Zeitlin R, Haider B, Li JH, Nagpal M, Zanos S, Pavlov VA, Brines M, Zanos TP, Chavan SS, Tracey KJ, Chang EH. Nat Commun. 2025;16(1):3840. doi: 10.1038/s41467-025-59248-6.

Clinical studies using invasive vagus nerve stimulation

Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial.
Tesser JRP, Crowley AR, Box EJ, June JP, Wickersham PB, Valenzuela GJ, Gaylis NB, Lam GKW, Pacheco LA, Ridley DJ, Pinto-Patarroyo GP, Novack SN, Churchill MA, Kohler M, Lee EC, Pando JA, Parris GR, Peterson JR, Shah T, Singhal AK, Vuong V, Levine YA, Evangelista ML, Derosier AA, Curtis JR, Richardson RM, Chernoff D. Nat Med. 2025. doi: 10.1038/s41591-025-04114-7.
Neuroimmune Modulation for Drug-Refractory Rheumatoid Arthritis: Long-Term Safety and Efficacy in 
Patients Enrolled in a Pilot Vagus Nerve Stimulation Study.
Gaylis NB, Sikes D, Kivitz A, Horowitz DL, Evangelista M, Levine YA, Chernoff D.Rheumatol Ther. 2025 Dec;12(6):1125-1136. doi: 10.1007/s40744-025-00798-y. 
Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis.
Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Mehta AD, Levine YA, Faltys M, Zitnik R, Tracey KJ, Tak PP. Proc Natl Acad Sci U S A. 2016;113(29):8284-9. doi: 10.1073/pnas.1605635113.
A new approach to rheumatoid arthritis: treating inflammation with computerized nerve stimulation.
Andersson U, Tracey KJ. Cerebrum. 2012; 2012:3. Epub 2012.PMID: 23447789
A 12-month pilot study outcomes of vagus nerve stimulation in Crohn's disease.
Sinniger V, Pellissier S, Fauvelle F, Trocmé C, Hoffmann D, Vercueil L, Cracowski JL, David O, Bonaz B.Neurogastroenterol Motil. 2020;32(10):e13911. doi: 10.1111/nmo.13911. 
Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn's Disease Patients: 
A Prospective Open-label Study.
D'Haens G, Eberhardson M, Cabrijan Z, Danese S, van den Berg R, Löwenberg M, Fiorino G, Schuurman PR, Lind G, Almqvist P, Olofsson PS, Tracey KJ, Hanauer SB, Zitnik R, Chernoff D, Levine YA.J Crohns Colitis. 2023;17(12):1897-1909. doi: 10.1093/ecco-jcc/jjad151.
Bioelectronic Medicine: From Preclinical Studies on the Inflammatory Reflex to New Approaches 
in Disease Diagnosis and Treatment.
Pavlov VA, Chavan SS, Tracey KJ. Cold Spring Harb Perspect Med. 2020;10(3):a034140. doi: 10.1101/cshperspect.a034140.

Clinical studies using cymba conchae vagus nerve stimulation

Transcutaneous Auricular Vagus Nerve Stimulation: From Concept to Application.
Wang Y, Li SY, Wang D, Wu MZ, He JK, Zhang JL, Zhao B, Hou LW, Wang JY, Wang L, Wang YF, Zhang Y, Zhang ZX, Rong PJ.Neurosci Bull. 2021;37(6):853-862. doi: 10.1007/s12264-020-00619-y. 
Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus 
erythematosus: a randomised, double-blind, sham-controlled pilot trial.
Aranow C, Atish-Fregoso Y, Lesser M, Mackay M, Anderson E, Chavan S, Zanos TP, Datta-Chaudhuri T, Bouton C, Tracey KJ, Diamond B. Ann Rheum Dis. 2021;80(2):203-208. doi: 10.1136/annrheumdis-2020-217872.
Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear.
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. Bioelectron Med. 2019;5:4. doi: 10.1186/s42234-019-0020-4.
Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: 
a proof-of-concept clinical trial.
Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: 
a proof-of-concept clinical trial.
Non-invasive vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study.
Marsal, S. et al. 2021. The Lancet Rheumatology 3, e262-e269, doi:10.1016/S2665-9913(20)30425-2.
Auricular vagus nerve stimulation for mitigation of inflammation and vasospasm in subarachnoid hemorrhage: 
a single-institution randomized controlled trial.
Huguenard AL, Tan G, Rivet DJ, Gao F, Johnson GW, Adamek M, Coxon AT, Kummer TT, Osbun JW, Vellimana AK, Limbrick DD, Zipfel GJ, Brunner P, Leuthardt EC.J Neurosurg. 2025;142(6):1720-1731. doi: 10.3171/2024.10.JNS241643
Clinical Efficacy of Auricular Vagus Nerve Stimulation in the Treatment of Chronic and Acute Pain: 
A Systematic Review and Meta-analysis.
Duff IT, Likar R, Perruchoud C, Kampusch S, Köstenberger M, Sator S, Stremnitzer C, Wolf A, Neuwersch-Sommeregger S, Abd-Elsayed A.Pain Ther. 2024;13(6):1407-1427. doi: 10.1007/s40122-024-00657-8.
Monitoring of cardiorespiratory vagal desynchrony using novel biomarkers derived from smartwatch electrocardiograms in a patient recovering from long COVID: case report.
Kranck G, Ståhlberg M, Andersson U, Lundin J, Fedorowski A.Eur Heart J Case Rep. 2025 Aug 29;9(10):ytaf425. doi: 10.1093/ehjcr/ytaf425.
Study of the transcutaneous auricular vagus nerve stimulation may advance outcome in chronic pediatric inflammatory diseases.
Andersson, U. Medical Research Archives.2022 10, doi:10.18103/mra.v10i5.2783.
Optimization of Transcutaneous Vagus Nerve Stimulation Using Functional MRI.
Yakunina N, Kim SS, Nam EC.Neuromodulation. 2017;20(3):290-300. doi: 10.1111/ner.12541.
The nerve supply of the human auricle.
Peuker ET, Filler TJ.Clin Anat. 2002; 15(1):35-7. doi: 10.1002/ca.1089. PMID:11835542