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European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Vagus Nerve Stimulation | Review

Exploring the potential of vagus nerve stimulation in treating brain diseases: a review of immunologic benefits and neuroprotective efficacy

Authors: Zeping Jin, Jing Dong, Yang Wang, Yunpeng Liu

Published in: European Journal of Medical Research | Issue 1/2023

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Abstract

The vagus nerve serves as a critical connection between the central nervous system and internal organs. Originally known for its effectiveness in treating refractory epilepsy, vagus nerve stimulation (VNS) has shown potential for managing other brain diseases, including ischaemic stroke, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. However, the precise mechanisms of VNS and its benefits for brain diseases are not yet fully understood. Recent studies have found that VNS can inhibit inflammation, promote neuroprotection, help maintain the integrity of the blood-brain barrier, have multisystemic modulatory effects, and even transmit signals from the gut flora to the brain. In this article, we will review several essential studies that summarize the current theories of VNS and its immunomodulatory effects, as well as the therapeutic value of VNS for brain disorders. By doing so, we aim to provide a better understanding of how the neuroimmune network operates and inspire future research in this field.
Literature
1.
Wafa HA, Wolfe CDA, Emmett E, Roth GA, Johnson CO, Wang Y. Burden of stroke in europe: thirty-year projections of incidence, prevalence, deaths, and disability-adjusted life years. Stroke. 2020;51:2418–27.PubMedPubMedCentral
2.
Karlawish J. How are we going to live with Alzheimer’s disease? Health Aff (Millwood). 2014;33:541–6.PubMed
3.
4.
Capizzi A, Woo J, Verduzco-Gutierrez M. Traumatic brain injury: an overview of epidemiology, pathophysiology, and medical management. Med Clin North Am. 2020;104:213–38.PubMed
5.
Yu ZJ, Weller RA, Sandidge K, Weller EB. Vagus nerve stimulation: can it be used in adolescents or children with treatment-resistant depression? Curr Psychiatry Rep. 2008;10:116–22.PubMed
6.
Batson S, Shankar R, Conry J, Boggs J, Radtke R, Mitchell S, et al. Efficacy and safety of VNS therapy or continued medication management for treatment of adults with drug-resistant epilepsy: systematic review and meta-analysis. J Neurol. 2022;269:2874–91.PubMedPubMedCentral
7.
Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry. 2005;58:355–63.PubMed
8.
Dawson J, Liu CY, Francisco GE, Cramer SC, Wolf SL, Dixit A, et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet. 2021;397:1545–53.PubMedPubMedCentral
9.
Merrill CA, Jonsson MA, Minthon L, Ejnell H, CsS H, Blennow K, et al. Vagus nerve stimulation in patients with Alzheimer’s disease: additional follow-up results of a pilot study through 1 year. J Clin Psychiatry. 2006;67:1171–8.PubMed
10.
Dawson J, Engineer ND, Prudente CN, Pierce D, Francisco G, Yozbatiran N, et al. Vagus nerve stimulation paired with upper-limb rehabilitation after stroke: one-year follow-up. Neurorehabil Neural Repair. 2020;34:609–15.PubMed
11.
Mondal B, Choudhury S, Simon B, Baker MR, Kumar H. Noninvasive vagus nerve stimulation improves gait and reduces freezing of gait in Parkinson’s disease. Mov Disord. 2019;34:917–8.PubMed
12.
Hays SA. Enhancing rehabilitative therapies with vagus nerve stimulation. Neurotherapeutics. 2016;13:382–94.PubMed
13.
Darrow MJ, Mian TM, Torres M, Haider Z, Danaphongse T, Rennaker RL Jr, et al. Restoration of somatosensory function by pairing vagus nerve stimulation with tactile rehabilitation. Ann Neurol. 2020;87:194–205.PubMedPubMedCentral
14.
Shi C, Flanagan SR, Samadani U. Vagus nerve stimulation to augment recovery from severe traumatic brain injury impeding consciousness: a prospective pilot clinical trial. Neurol Res. 2013;35:263–76.PubMedPubMedCentral
15.
Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006;147(Suppl 1):S232-240.PubMedPubMedCentral
16.
Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20:19–33.PubMedPubMedCentral
17.
Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol. 2016;594:5781–90.PubMedPubMedCentral
18.
19.
Meregnani J, Clarençon D, Vivier M, Peinnequin A, Mouret C, Sinniger V, et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci. 2011;160:82–9.PubMed
20.
Johnson RL, Wilson CG. A review of vagus nerve stimulation as a therapeutic intervention. J Inflamm Res. 2018;11:203–13.PubMedPubMedCentral
21.
Creutzberg KC, Sanson A, Viola TW, Marchisella F, Begni V, Grassi-Oliveira R, et al. Long-lasting effects of prenatal stress on HPA axis and inflammation: a systematic review and multilevel meta-analysis in rodent studies. Neurosci Biobehav Rev. 2021;127:270–83.PubMed
22.
O’Keane V, Dinan TG, Scott L, Corcoran C. Changes in hypothalamic-pituitary-adrenal axis measures after vagus nerve stimulation therapy in chronic depression. Biol Psychiatry. 2005;58:963–8.PubMed
23.
Perrin AJ, Pariante CM. Endocrine and immune effects of non-convulsive neurostimulation in depression: a systematic review. Brain Behav Immun. 2020;87:910–20.PubMed
24.
De Herdt V, Puimege L, De Waele J, Raedt R, Wyckhuys T, El Tahry R, et al. Increased rat serum corticosterone suggests immunomodulation by stimulation of the vagal nerve. J Neuroimmunol. 2009;212:102–5.PubMed
25.
de Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol. 2007;151:915–29.PubMedPubMedCentral
26.
Verbois SL, Scheff SW, Pauly JR. Time-dependent changes in rat brain cholinergic receptor expression after experimental brain injury. J Neurotrauma. 2002;19:1569–85.PubMed
27.
Verbois S, Sullivan P, Scheff S, Pauly J. Traumatic brain injury reduces hippocampal α7 nicotinic cholinergic receptor binding. J Neurotrauma. 2000;17:1001–11.PubMed
28.
Kelso ML, Wehner JM, Collins AC, Scheff SW, Pauly JR. The pathophysiology of traumatic brain injury in α7 nicotinic cholinergic receptor knockout mice. Brain Res. 2006;1083:204–10.PubMed
29.
Smith DC, Tan AA, Duke A, Neese SL, Clough RW, Browning RA, et al. Recovery of function after vagus nerve stimulation initiated 24 hours after fluid percussion brain injury. J Neurotrauma. 2006;23:1549–60.PubMed
30.
Zhou L, Lin J, Lin J, Kui G, Zhang J, Yu Y. Neuroprotective effects of vagus nerve stimulation on traumatic brain injury. Neural Regen Res. 2014;9:1585.PubMedPubMedCentral
31.
Lu X-x, Hong Z-q, Tan Z, Sui M-h, Zhuang Z-q, Liu H-h, et al. Nicotinic acetylcholine receptor alpha7 subunit mediates vagus nerve stimulation-induced neuroprotection in acute permanent cerebral ischemia by a7nAchR/JAK2 pathway. Med Sci Monitor Int Med J Experim Clin Res. 2017;23:6072.
32.
Jiang Y, Li L, Liu B, Zhang Y, Chen Q, Li C. Vagus nerve stimulation attenuates cerebral ischemia and reperfusion injury via endogenous cholinergic pathway in rat. PLoS ONE. 2014;9: e102342.PubMedPubMedCentral
33.
Jiang Y, Li L, Liu B, Zhang Y, Chen Q, Li C. PPARγ upregulation induced by vagus nerve stimulation exerts anti-inflammatory effect in cerebral ischemia/reperfusion rats. Med Sci Monit. 2015;21:268–75.PubMedPubMedCentral
34.
Huffman WJ, Subramaniyan S, Rodriguiz RM, Wetsel WC, Grill WM, Terrando N. Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice. Brain Stimul. 2019;12:19–29.PubMed
35.
Chen H, Feng Z, Min L, Deng W, Tan M, Hong J, et al. Vagus nerve stimulation reduces neuroinflammation through microglia polarization regulation to improve functional recovery after spinal cord injury. Front Neurosci. 2022;16: 813472.PubMedPubMedCentral
36.
Gautron L, Rutkowski JM, Burton MD, Wei W, Wan Y, Elmquist JK. Neuronal and nonneuronal cholinergic structures in the mouse gastrointestinal tract and spleen. J Comp Neurol. 2013;521:3741–67.PubMedPubMedCentral
37.
Vida G, Peña G, Kanashiro A, Thompson-Bonilla Mdel R, Palange D, Deitch EA, et al. β2-Adrenoreceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system. FASEB J. 2011;25:4476–85.PubMedPubMedCentral
38.
Li Z, Liu T, Feng Y, Tong Y, Jia Y, Wang C, et al. PPARγ alleviates sepsis-induced liver injury by inhibiting hepatocyte pyroptosis via inhibition of the ROS/TXNIP/NLRP3 signaling pathway. Oxid Med Cell Longev. 2022;2022:1269747.PubMedPubMedCentral
39.
Vetuschi A, Pompili S, Gaudio E, Latella G, Sferra R. PPAR-γ with its anti-inflammatory and anti-fibrotic action could be an effective therapeutic target in IBD. Eur Rev Med Pharmacol Sci. 2018;22:8839–48.PubMed
40.
Ji J, Xue TF, Guo XD, Yang J, Guo RB, Wang J, et al. Antagonizing peroxisome proliferator-activated receptor γ facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway. Aging Cell. 2018;17: e12774.PubMedPubMedCentral
41.
Lin TW, Harward SC, Huang YZ, McNamara JO. Targeting BDNF/TrkB pathways for preventing or suppressing epilepsy. Neuropharmacology. 2020;167: 107734.PubMed
42.
Shah AP, Carreno FR, Wu H, Chung YA, Frazer A. Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation: comparison with desipramine. Neuroscience. 2016;322:273–86.PubMed
43.
O’Leary OF, Ogbonnaya ES, Felice D, Levone BR, L CC, Fitzgerald P, et al. The vagus nerve modulates BDNF expression and neurogenesis in the hippocampus. Eur Neuropsychopharmacol. 2018;28:307–16.PubMed
44.
Lang UE, Bajbouj M, Gallinat J, Hellweg R. Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation. Psychopharmacology. 2006;187:56–9.PubMed
45.
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;49:710–7.PubMedPubMedCentral
46.
Tseng CT, Gaulding SJ, Dancel CLE, Thorn CA. Local activation of α2 adrenergic receptors is required for vagus nerve stimulation induced motor cortical plasticity. Sci Rep. 2021;11:21645.PubMedPubMedCentral
47.
Fang J, Rong P, Hong Y, Fan Y, Liu J, Wang H, et al. Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder. Biol Psychiatry. 2016;79:266–73.PubMed
48.
Gebhardt N, Bär KJ, Boettger MK, Grecksch G, Keilhoff G, Reichart R, et al. Vagus nerve stimulation ameliorated deficits in one-way active avoidance learning and stimulated hippocampal neurogenesis in bulbectomized rats. Brain Stimul. 2013;6:78–83.PubMed
49.
Ghacibeh GA, Shenker JI, Shenal B, Uthman BM, Heilman KM. The influence of vagus nerve stimulation on memory. Cogn Behav Neurol. 2006;19:119–22.PubMed
50.
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.PubMedPubMedCentral
51.
Jiang Y, Li L, Ma J, Zhang L, Niu F, Feng T, et al. Auricular vagus nerve stimulation promotes functional recovery and enhances the post-ischemic angiogenic response in an ischemia/reperfusion rat model. Neurochem Int. 2016;97:73–82.PubMed
52.
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.PubMed
53.
Li P, Liu H, Sun P, Wang X, Wang C, Wang L, et al. Chronic vagus nerve stimulation attenuates vascular endothelial impairments and reduces the inflammatory profile via inhibition of the NF-κB signaling pathway in ovariectomized rats. Exp Gerontol. 2016;74:43–55.PubMed
54.
55.
Marchi N, Guiso G, Caccia S, Rizzi M, Gagliardi B, Noé F, et al. Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development. Neurobiol Dis. 2006;24:429–42.PubMed
56.
Kaya M, Gurses C, Kalayci R, Ekizoglu O, Ahishali B, Orhan N, et al. Morphological and functional changes of blood-brain barrier in kindled rats with cortical dysplasia. Brain Res. 2008;1208:181–91.PubMed
57.
Kaya M, Becker AJ, Gürses C. Blood-brain barrier, epileptogenesis, and treatment strategies in cortical dysplasia. Epilepsia. 2012;53(Suppl 6):31–6.PubMed
58.
Kaya M, Orhan N, Karabacak E, Bahceci MB, Arican N, Ahishali B, et al. Vagus nerve stimulation inhibits seizure activity and protects blood-brain barrier integrity in kindled rats with cortical dysplasia. Life Sci. 2013;92:289–97.PubMed
59.
Lopez NE, Krzyzaniak MJ, Costantini TW, Putnam J, Hageny AM, Eliceiri B, et al. Vagal nerve stimulation decreases blood-brain barrier disruption after traumatic brain injury. J Trauma Acute Care Surg. 2012;72:1562–6.PubMed
60.
Chen X, He X, Luo S, Feng Y, Liang F, Shi T, et al. Vagus nerve stimulation attenuates cerebral microinfarct and colitis-induced cerebral microinfarct aggravation in mice. Front Neurol. 2018;9:798.PubMedPubMedCentral
61.
Yang Y, Yang LY, Orban L, Cuylear D, Thompson J, Simon B, et al. Non-invasive vagus nerve stimulation reduces blood-brain barrier disruption in a rat model of ischemic stroke. Brain Stimul. 2018;11:689–98.PubMedPubMedCentral
62.
Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915–20.PubMed
63.
Hosoi T, Okuma Y, Nomura Y. Electrical stimulation of afferent vagus nerve induces IL-1β expression in the brain and activates HPA axis. Am J Physiol-Regul Integr Comp Physiol. 2000;279:R141–7.PubMed
64.
Costantini TW, Bansal V, Krzyzaniak M, Putnam JG, Peterson CY, Loomis WH, et al. Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells. Am J Physiol Gastrointest Liver Physiol. 2010;299:G1308-1318.PubMedPubMedCentral
65.
Li S, Lv J, Li J, Zhao Z, Guo H, Zhang Y, et al. Intestinal microbiota impact sepsis associated encephalopathy via the vagus nerve. Neurosci Lett. 2018;662:98–104.PubMed
66.
Zhang Y, Xie B, Chen X, Zhang J, Yuan S. A key role of gut microbiota-vagus nerve/spleen axis in sleep deprivation-mediated aggravation of systemic inflammation after LPS administration. Life Sci. 2021;265: 118736.PubMed
67.
Haney MM, Ericsson AC, Lever TE. Effects of intraoperative vagal nerve stimulation on the gastrointestinal microbiome in a mouse model of amyotrophic lateral sclerosis. Comp Med. 2018;68:452–60.PubMedPubMedCentral
68.
Sj Ni, Yao ZY, Wei X, Heng X, Qu SY, Zhao X, et al. Vagus nerve stimulated by microbiota-derived hydrogen sulfide mediates the regulation of berberine on microglia in transient middle cerebral artery occlusion rats. Phytother Res. 2022;36:2964.
69.
Caruso A, Nicoletti F, Mango D, Saidi A, Orlando R, Scaccianoce S. Stress as risk factor for Alzheimer’s disease. Pharmacol Res. 2018;132:130–4.PubMed
70.
Gil K, Bugajski A, Kurnik M, Thor P. Electrical chronic vagus nerve stimulation activates the hypothalamic-pituitary-adrenal axis in rats fed high-fat diet. Neuro Endocrinol Lett. 2013;34:314–21.PubMed
71.
Banni S, Carta G, Murru E, Cordeddu L, Giordano E, Marrosu F, et al. Vagus nerve stimulation reduces body weight and fat mass in rats. PLoS ONE. 2012;7: e44813.PubMedPubMedCentral
72.
Migdady I, Russman A, Buletko AB. Atrial fibrillation and ischemic stroke: a clinical review. Semin Neurol. 2021;41:348–64.PubMed
73.
Yu L, Scherlag BJ, Sha Y, Li S, Sharma T, Nakagawa H, et al. Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle. Heart Rhythm. 2012;9:804–9.PubMed
74.
Yuan Y, Jiang Z, He Y, Ding FB, Ding SA, Yang Y, et al. Continuous vagal nerve stimulation affects atrial neural remodeling and reduces atrial fibrillation inducibility in rabbits. Cardiovasc Pathol. 2015;24:395–8.PubMed
75.
Zhang SJ, Huang CX, Zhao QY, Zhang SD, Dai ZX, Zhao HY, et al. The role of α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation. Int Heart J. 2021;62:607–15.PubMed
Metadata
Title
Exploring the potential of vagus nerve stimulation in treating brain diseases: a review of immunologic benefits and neuroprotective efficacy
Authors
Zeping Jin
Jing Dong
Yang Wang
Yunpeng Liu
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01439-2

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