Collaborators GS. Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795–820. https://doi.org/10.1016/s1474-4422(21)00252-0.

Article  CAS  Google Scholar 

Chapman SN, Mehndiratta P, Johansen MC, McMurry TL, Johnston KC, Southerland AM. Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke. Vasc Health Risk Manag. 2014;10:75–87. https://doi.org/10.2147/vhrm.S39213.

Article  PubMed  PubMed Central  Google Scholar 

Kameda-Smith MM, Pai AM, Jung Y, Duda T, van Adel B. Advances in mechanical thrombectomy for acute ischemic stroke due to large vessel occlusion. Crit Rev Biomed Eng. 2021;49(5):13–70. https://doi.org/10.1615/CritRevBiomedEng.2022042563.

Article  PubMed  Google Scholar 

Boode B, Welzen V, Franke C, van Oostenbrugge R. Estimating the number of stroke patients eligible for thrombolytic treatment if delay could be avoided. Cerebrovasc Dis. 2007;23(4):294–8. https://doi.org/10.1159/000098330.

Article  PubMed  Google Scholar 

MacKenzie IER, Moeini-Naghani I, Sigounas D. Trends in endovascular mechanical thrombectomy in treatment of acute ischemic stroke in the United States. World Neurosurg. 2020;138:e839–46. https://doi.org/10.1016/j.wneu.2020.03.105.

Article  PubMed  Google Scholar 

Lanska DJJL. Corning and vagal nerve stimulation for seizures in the 1880s. Neurology. 2002;58(3):452–9. https://doi.org/10.1212/wnl.58.3.452.

Article  PubMed  Google Scholar 

• O’Reardon JP, Cristancho P, Peshek AD. Vagus nerve stimulation (VNS) and treatment of depression: to the brainstem and beyond. Psychiatry (Edgmont). 2006;3(5):54–63. This review explores VNS’s efficacy and safety, providing insights for clinicians considering it as a treatment option for severe depression.

• Afra P, Adamolekun B, Aydemir S, Watson GDR. Evolution of the vagus nerve stimulation (VNS) therapy system technology for drug-resistant epilepsy. Front Med Technol. 2021;3:696543. https://doi.org/10.3389/fmedt.2021.696543. This review discusses the system’s evolution, device approval milestones, and compares open-loop and closed-loop generator models. It also includes battery life projections and examines stimulation mode interactions to differentiate between generator models.

Liu CY, Russin J, Adelson DP, Jenkins A, Hilmi O, Brown B, et al. Vagus nerve stimulation paired with rehabilitation for stroke: implantation experience from the VNS-REHAB trial. J Clin Neurosci. 2022;105:122–8. https://doi.org/10.1016/j.jocn.2022.09.013.

Article  PubMed  Google Scholar 

Vargas-Caballero M, Warming H, Walker R, Holmes C, Cruickshank G, Patel B. Vagus nerve stimulation as a potential therapy in early Alzheimer’s disease: a review. Front Hum Neurosci. 2022;16:866434. https://doi.org/10.3389/fnhum.2022.866434.

Article  CAS  PubMed  PubMed Central  Google Scholar 

• Sigurdsson HP, Raw R, Hunter H, Baker MR, Taylor JP, Rochester L, et al. Noninvasive vagus nerve stimulation in Parkinson’s disease: current status and future prospects. Expert Rev Med Devices. 2021;18(10):971–84. https://doi.org/10.1080/17434440.2021.1969913. This review explores the potential of nVNS as a novel therapy for improving gait, cognitive control, and managing non-motor symptoms in PD. While early findings suggest promise in addressing gait issues in early PD, further research is needed to establish nVNS as an effective therapeutic approach in PD and related conditions.

Neren D, Johnson MD, Legon W, Bachour SP, Ling G, Divani AA. Vagus nerve stimulation and other neuromodulation methods for treatment of traumatic brain injury. Neurocrit Care. 2016;24(2):308–19. https://doi.org/10.1007/s12028-015-0203-0.

Article  CAS  PubMed  Google Scholar 

• Divani AA, Salazar P, Ikram HA, Taylor E, Wilson CM, Yang Y, et al. Non-invasive vagus nerve stimulation improves brain lesion volume and neurobehavioral outcomes in a rat model of traumatic brain injury. J Neurotrauma. 2023;40(13–14):1481–94. https://doi.org/10.1089/neu.2022.0153. A study assessed nVNS in a rat model of TBI. Rats were divided into control, low-dose nVNS, and high-dose nVNS groups. High-dose nVNS significantly reduced brain lesion volume, improved neurobehavioral performance, and reduced cortical volume loss compared to the control and low-dose groups. This suggests the potential of nVNS as an acute treatment for TBI with broad clinical implications.

• Yakunina N, Nam EC. Direct and transcutaneous vagus nerve stimulation for treatment of tinnitus: a scoping review. Front Neurosci. 2021;15:680590. https://doi.org/10.3389/fnins.2021.680590. This review discusses the current state of knowledge, safety, and effectiveness of both VNS and tVNS, either alone or with acoustic stimulation, in treating tinnitus in human subjects, highlighting existing limitations in the field.

Wu Y, Song L, Wang X, Li N, Zhan S, Rong P, et al. Transcutaneous vagus nerve stimulation could improve the effective rate on the quality of sleep in the treatment of primary insomnia: a randomized control trial. Brain Sci. 2022;12(10):1296. https://doi.org/10.3390/brainsci12101296.

Article  PubMed  PubMed Central  Google Scholar 

• Hasan MY, Siran R, Mahadi MK. The effects of vagus nerve stimulation on animal models of stroke-induced injury: a systematic review. Biology (Basel). 2023;12(4):555. https://doi.org/10.3390/biology12040555. VNS shows potential in improving neurological scores, reducing infarct volume, and influencing various cellular processes.

Mwamburi M, Liebler EJ, Tenaglia AT. 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(17 Suppl):S317–25.

PubMed  Google Scholar 

Arsava EM, Topcuoglu MA, Ay I, Ozdemir AO, Gungor IL, Togay Isikay C, et al. Assessment of safety and feasibility of non-invasive vagus nerve stimulation for treatment of acute stroke. Brain Stimul. 2022;15(6):1467–74. https://doi.org/10.1016/j.brs.2022.10.012.

Article  PubMed  Google Scholar 

van der Meij A, van Walderveen MAA, Kruyt ND, van Zwet EW, Liebler EJ, Ferrari MD, et al. NOn-invasive Vagus nerve stimulation in acute Ischemic Stroke (NOVIS): a study protocol for a randomized clinical trial. Trials. 2020;21(1):878. https://doi.org/10.1186/s13063-020-04794-1.

Article  PubMed  PubMed Central  Google Scholar 

Duris K, Lipkova J, Jurajda M. Cholinergic anti-inflammatory pathway and stroke. Curr Drug Deliv. 2017;14(4):449–57. https://doi.org/10.2174/1567201814666170201150015.

Article  CAS  PubMed  Google Scholar 

Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton Neurosc : Basic Clin. 2000;85(1–3):1–17. https://doi.org/10.1016/s1566-0702(00)00215-0.

Article  CAS  Google Scholar 

Fonseca MT, Moretti EH, Marques LMM, Machado BF, Brito CF, Guedes JT, et al. A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation. Sci Signal. 2021;14(679):eabb0969. https://doi.org/10.1126/scisignal.abb0969.

Article  CAS  PubMed  Google Scholar 

Jarczyk J, Yard BA, Hoeger S. The cholinergic anti-inflammatory pathway as a conceptual framework to treat inflammation-mediated renal injury. Kidney Blood Press Res. 2019;44(4):435–48. https://doi.org/10.1159/000500920.

Article  CAS  PubMed  Google Scholar 

Berthoud HR, Powley TL. Interaction between parasympathetic and sympathetic nerves in prevertebral ganglia: morphological evidence for vagal efferent innervation of ganglion cells in the rat. Microsc Res Tech. 1996;35(1):80–6. https://doi.org/10.1002/(sici)1097-0029(19960901)35:1%3c80::Aid-jemt7%3e3.0.Co;2-w.

Article  CAS  PubMed  Google Scholar 

Berthoud HR, Powley TL. Characterization of vagal innervation to the rat celiac, suprarenal and mesenteric ganglia. J Auton Nerv Syst. 1993;42(2):153–69. https://doi.org/10.1016/0165-1838(93)90046-w.

Article  CAS  PubMed  Google Scholar 

Janitzky K. Impaired phasic discharge of locus coeruleus neurons based on persistent high tonic discharge-a new hypothesis with potential implications for neurodegenerative diseases. Front Neurol. 2020;11:371. https://doi.org/10.3389/fneur.2020.00371.

Article  PubMed  PubMed Central  Google Scholar 

•• Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, et al. Safety, feasibility, and efficacy of vagus nerve stimulation paired with upper-limb rehabilitation after ischemic stroke. Stroke. 2016;47(1):143–50. https://doi.org/10.1161/strokeaha.115.010477. A clinical pilot study involving participants with moderate to severe upper-limb impairment after ischemic stroke explored the safety and feasibility of VNS paired with rehabilitation. The VNS group experienced minor side effects, and the study found that VNS paired with rehabilitation showed a significant improvement in upper-limb function compared to rehabilitation alone in the per-protocol analysis.

Safi S, Ellrich J, Neuhuber W. Myelinated axons in the auricular branch of the human vagus nerve. Anat Rec (Hoboken, NJ : 2007). 2016;299(9):1184–91. https://doi.org/10.1002/ar.23391.

Article  Google Scholar 

Redgrave J, Day D, Leung H, Laud PJ, Ali A, Lindert R, et al. Safety and tolerability of transcutaneous vagus nerve stimulation in humans; a systematic review. Brain Stimul. 2018;11(6):1225–38. https://doi.org/10.1016/j.brs.2018.08.010.

Article  CAS  PubMed  Google Scholar 

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. https://doi.org/10.3389/fnins.2020.00284.

Article  PubMed  PubMed Central  Google Scholar 

Hulsey DR, Hays SA, Khodaparast N, Ruiz A, Das P, Rennaker RL 2nd, et al. Reorganization of motor cortex by vagus nerve stimulation requires cholinergic innervation. Brain Stimul. 2016;9(2):174–81. https://doi.org/10.1016/j.brs.2015.12.007.

Article  PubMed  PubMed Central  Google Scholar 

Dorr AE, Debonnel G. Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. J Pharmacol Exp Ther. 2006;318(2):890–8. https://doi.org/10.1124/jpet.106.104166.

Article  CAS  PubMed  Google Scholar 

Engineer ND, Kimberley TJ, Prudente CN, Dawson J, Tarver WB, Hays SA. Targeted vagus nerve stimulation for rehabilitation after stroke. Front Neurosci. 2019;13:280. https://doi.org/10.3389/fnins.2019.00280.

Article  PubMed  PubMed Central  Google Scholar 

Li J, Zhang Q, Li S, Niu L, Ma J, Wen L, et al. α7nAchR mediates transcutaneous auricular vagus nerve stimulation-induced neuroprotection in a rat model of ischemic stroke by enhancing axonal plasticity. Neurosci Lett. 2020;730:135031. https://doi.org/10.1016/j.neulet.2020.135031.

Article  CAS  PubMed  Google Scholar 

Meyers EC, Solorzano BR, James J, Ganzer PD, Lai ES, Rennaker RL 2nd, et al. Vagus nerve stimulation enhances stable plasticity and generalization of stroke recovery. Stroke. 2018;49(3):710–7. https://doi.org/10.1161/strokeaha.117.019202.

Article  PubMed  PubMed Central  Google Scholar 

Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex–linking immunity and metabolism. Nat Rev Endocrinol. 2012;8(12):743–54. https://doi.org/10.1038/nrendo.2012.189.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117(2):289–96. https://doi.org/10.1172/jci30555.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Czura CJ, Rosas-Ballina M, Tracey KJ. CHAPTER 3 - cholinergic regulation of inflammation. In: Ader R, editor. Psychoneuroimmunology. 4th ed. Burlington: Academic Press; 2007. p. 85–96.