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Auricular vagus nerve stimulation: a new option to treat inflammation in COVID-19?

INTRODUCTION

COVID-19 is an infectious disease caused by the new coronavirus (SARS-CoV-2), which invades alveolar epithelial cells through angiotensin-2 converting enzyme (ACE2) receptors11 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80.e8. https://doi.org/10.1016/j.cell.2020.02.052
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,22 Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259-60. https://doi.org/10.1038/s41569-020-0360-5
https://doi.org/10.1038/s41569-020-0360-...
. Infection is triggered by the binding of the spike protein (S) of SARS-CoV-1 or SARS-CoV-2 to ACE233 Costa IBSDS, Bittar CS, Rizk SI, Araújo Filho AE, Santos KAQ, Machado TIV, et al. The heart and COVID-19: what cardiologists need to know. Arq Bras Cardiol. 2020;114(5):805-16. https://doi.org/10.36660/abc.20200279
https://doi.org/10.36660/abc.20200279...
and, through this binding, the virus enters the host cell, where ACE2 is later inactivated. As this enzyme is abundantly found in alveolar epithelial cells and in the myocardium, potentially serious damage can occur in the lungs and heart22 Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259-60. https://doi.org/10.1038/s41569-020-0360-5
https://doi.org/10.1038/s41569-020-0360-...
,44 Vellingiri B, Jayaramayya K, Iyer M, Narayanasamy A, Govindasamy V, Giridharan B, et al. COVID-19: a promising cure for the global panic. Sci Total Environ. 2020;725:138277. https://doi.org/10.1016/j.scitotenv.2020.138277
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COVID-19 can cause acute respiratory distress syndrome (ARDS), leading to severe hypoxemia, and is associated with thromboembolic events. In ARDS, small-sized pulmonary blood vessels become more permeable, which leads to fluid leakage into the alveoli, impairing pulmonary gas exchange55 Stevens JP, Law A, Giannakoulis J. Acute respiratory distress syndrome. JAMA. 2018;319(7):732. https://doi.org/10.1001/jama.2018.0483
https://doi.org/10.1001/jama.2018.0483...
. ARDS is characterized by generalized inflammation in the lungs, inflammatory cytokine storms, and an imbalance in the sympathetic-parasympathetic activity of the autonomic nervous system (ANS)66 Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res. 2020;7(1):11. https://doi.org/10.1186/s40779-020-00240-0
https://doi.org/10.1186/s40779-020-00240...
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Several treatments have been tried for ARDS from COVID-19, based on its pathophysiology using ACE-2 receptors, and some of the most feared complications such as pulmonary thromboembolism. Unfortunately, the results were not promising. The BRACE CORONA trial77 Lopes RD, Macedo AVS, Barros E Silva PGM, Moll-Bernardes RJ, Dos Santos TM, Mazza L, et al. Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19: a randomized clinical trial. JAMA. 2021;325(3):254-64. https://doi.org/10.1001/jama.2020.25864
https://doi.org/10.1001/jama.2020.25864...
determined whether discontinuation compared with the continuation of ACE inhibitors (ACEIs) or angiotensin-2 receptor blockers (ARBs) changed the number of days alive and out of the hospital through 30 days in 659 patients hospitalized with mild or moderate COVID-19 who were taking ACEIs or ARBs, and there was no significant difference for those assigned to discontinue vs. continue these medications. The ACTION trial88 Lopes RD, Barros E Silva PGM, Furtado RHM, Macedo AVS, Bronhara B, Damiani LP, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397(10291):2253-63. https://doi.org/10.1016/S0140-6736(21)01203-4
https://doi.org/10.1016/S0140-6736(21)01...
investigated whether patients hospitalized with mild to moderate COVID-19 and elevated D-dimer concentration benefited from therapeutic vs. prophylactic anticoagulation, and results at day 30 have shown that therapeutic anticoagulation did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation.

All that said and based on its preclinical effects and some initial clinical studies, auricular vagus nerve stimulation (aVNS) emerges as a promising therapy for the treatment of inflammation in COVID-19, especially its pulmonary manifestations, due to its positive effect on autonomic balance, as discussed in the following sections.

VAGUS NERVE, INFLAMMATORY RESPONSE, AND AUTONOMIC BALANCE

The vagus nerve (10th cranial pair) is the largest and most important nerve in the parasympathetic nervous system and modulates the immune response to inflammatory processes that occur in our body99 Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003;9(5-8):125-34. PMID: 14571320,1010 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
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. It is composed of sensory (»80%) and motor fibers1111 Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. Auton Neurosci. 2000;85(1-3):1-17. https://doi.org/10.1016/S1566-0702(00)00215-0
https://doi.org/10.1016/S1566-0702(00)00...
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Inflammatory mediators released due to any aggression (e.g., pro-inflammatory cytokines) activate vagal afferent fibers that convey information to the nucleus of the solitary tract (NST)99 Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003;9(5-8):125-34. PMID: 14571320. Activation of NST neurons originates the anti-inflammatory response in the following two different ways11 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80.e8. https://doi.org/10.1016/j.cell.2020.02.052
https://doi.org/10.1016/j.cell.2020.02.0...
. In the first, known as the hypothalamic-pituitary adrenal axis (HPAA)1212 Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J Intern Med. 2017;282(1):46-63. https://doi.org/10.1111/joim.12611
https://doi.org/10.1111/joim.12611...
, NST efferents to the paraventricular nucleus of the hypothalamus stimulate the release of corticotropin-releasing hormone (CRH), which stimulates the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH reaches the adrenal gland, stimulating the production of glucocorticoids, which act on the spleen leading to reduction of cytokine release22 Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259-60. https://doi.org/10.1038/s41569-020-0360-5
https://doi.org/10.1038/s41569-020-0360-...
. In the second way, known as “cholinergic anti-inflammatory reflex,” NST efferents activate the dorsal motor nucleus of the vagus nerve (DMNV), and its cholinergic motoneurons project to the splenic nerve in the celiac ganglion, releasing acetylcholine (ACh) in the preganglionic terminals and provoking release of norepinephrine (NE) in the spleen, which ultimately inhibits macrophages’ cytokines release, decreasing inflammation. Both responses are illustrated in Figures 1 and 2.

Figure 1
Diagram of the vagus nerve-mediated anti-inflammatory responses. The vagus nerve plays a key role in the neuro-endocrine-immune axis, having a dual anti-inflammatory role through its afferent and efferent fibers. In an infection, such as that caused by COVID-19, a primary immune response leads to the release of pro-inflammatory cytokines, generating an inflammatory process at the site of infection, in this case, the lungs and heart. Released cytokines are recognized by afferent fibers of the vagus nerve (blue arrows; information about inflammation from the lung, heart, and blood) that transmit such information to the nucleus of the solitary tract. The activation of nucleus of the solitary tract neurons is the origin of the anti-inflammatory response, which is generated through two different pathways. The first, known as the “hypothalamic-pituitary-adrenal axis,” nucleus of the solitary tract efferents to the hypothalamus (orange arrows) stimulate the release of corticotrophin-releasing hormone, which stimulates the secretion of adrenocorticotropic hormone from the pituitary gland. adrenocorticotropic hormone reaches the adrenal glands (purple arrow), where it stimulates the production of glucocorticoids (cortisol in humans). Glucocorticoids act on the spleen (red arrow), which leads to reduced cytokine release by acting on cells of the immune system. The second, known as the “cholinergic anti-inflammatory reflex”, nucleus of the solitary tract efferents to dorsal motor nucleus of the vagus nerve, the dorsal motor nucleus of the vagus nerve (black arrow, green nucleus), and stimulates the cholinergic motoneurons that project to the splenic nerve in the celiac ganglion (yellow arrow). Acetylcholine, released from the preganglionic terminals, excites celiac neurons and provokes the release of norepinephrine in the spleen (NE, green arrow). Then, the splenic response inhibits macrophages’ cytokine release, decreasing inflammation. Reprinted with permission from Kaniusas et al.2424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
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Figure 2
Scheme of the anti-inflammatory activity of the vagal efferents. Vagal efferents arise from the dorsal motor nucleus of the vagus nerve and project to the celiac ganglion, where they synapse with the splenic nerve. dorsal motor nucleus of the vagus nerve efferents activity stimulates the splenic nerve, which releases norepinephrine over the spleen. Norepinephrine binds to β2 adrenergic receptors expressed on splenic macrophages and splenic lymphocytes. Norepinephrine binding on macrophages inhibits the release of pro-inflammatory cytokines by these cells. Norepinephrine binding on lymphocytes provokes the release of acetylcholine, which is recognized by α7-acetylcholine receptors on the membrane of the macrophages. α7-Acetylcholine receptors activation provokes a disruption of the cytokine release pathway. Reprinted with permission from Kaniusas et al.2424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
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A shift in the balance of the ANS toward sympathetic predominance can lead to (chronic) diseases associated with this system1313 Stojanovich L, Milovanovich B, Luka SR, Popovich-Kuzmanovich D, Bisenich V, Djukanovich B, et al. Cardiovascular autonomic dysfunction in systemic lupus, rheumatoid arthritis, primary Sjögren syndrome and other autoimmune diseases. Lupus. 2007;16(3):181-5. https://doi.org/10.1177/0961203306076223
https://doi.org/10.1177/0961203306076223...
. In COVID-19, hyperactivity of the sympathetic nervous system can cause excessive release of plasma epinephrine and norepinephrine, which leads to pulmonary vasoconstriction and increased capillary permeability1414 Liu Y, Tao T, Li W, Bo Y. Regulating autonomic nervous system homeostasis improves pulmonary function in rabbits with acute lung injury. BMC Pulm Med. 2017;17(1):98. https://doi.org/10.1186/s12890-017-0436-0
https://doi.org/10.1186/s12890-017-0436-...
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At this point, a positive feedback system is created in favor of the sympathetic system that causes an exponential worsening of symptoms. That is, acute lung injury causes an additional imbalance with increased sympathetic tone and significant elevation of plasma interleukins (IL)-6 and 10, accompanied by considerable hemorrhage, edema, consolidation, atelectasis, neutrophil infiltration, alveolar epithelial edema type I, and other deleterious effects1414 Liu Y, Tao T, Li W, Bo Y. Regulating autonomic nervous system homeostasis improves pulmonary function in rabbits with acute lung injury. BMC Pulm Med. 2017;17(1):98. https://doi.org/10.1186/s12890-017-0436-0
https://doi.org/10.1186/s12890-017-0436-...
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In addition, the loss of autonomic balance worsens the inflammation caused by COVID-19 through the renin-angiotensin-aldosterone system (RAAS), a cascade of vasoactive peptides1515 Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19. N Engl J Med. 2020;382(17):1653-9. https://doi.org/10.1056/NEJMsr2005760
https://doi.org/10.1056/NEJMsr2005760...
, which has recently been proposed as a mediator of lung injury caused by ARDS1616 Busse LW, Chow JH, McCurdy MT, Khanna AK. COVID-19 and the RAAS-a potential role for angiotensin II?. Crit Care. 2020;24(1):136. https://doi.org/10.1186/s13054-020-02862-1
https://doi.org/10.1186/s13054-020-02862...
. Indeed, activation of the sympathetic nervous system and RAAS seem to be intrinsically and reciprocally linked, at least in the case of patients with hypertension1717 Fisher JP, Paton JF. The sympathetic nervous system and blood pressure in humans: implications for hypertension. J Hum Hypertens. 2012;26(8):463-75. https://doi.org/10.1038/jhh.2011.66
https://doi.org/10.1038/jhh.2011.66...
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Finally, there is also a decreased vagal tone in some patients with COVID-19, which implies destabilized sympathetic-vagal balance, favoring the deleterious effects of the disease, as demonstrated in a recent publication1818 Rangon CM, Krantic S, Moyse E, Fougère B. The vagal autonomic pathway of COVID-19 at the crossroad of Alzheimer's disease and aging: a review of knowledge. J Alzheimers Dis Rep. 2020;4(1):537-51. https://doi.org/10.3233/ADR-200273
https://doi.org/10.3233/ADR-200273...
. To sum up, the dorsal vagal complex of the brainstem can be a target of SARS-CoV-2 because of its specifically high enrichment in ACE2 and could be reached readily by the virus through two distinct lung-to-brain routes, namely, the vagus nerve and the blood circulation.

INNERVATION OF THE EAR

To understand the effects of auricular vagus nerve stimulation, we need to know the innervation of the ear, which is rich and multiple1919 Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat. 2002;15(1):35-7. https://doi.org/10.1002/ca.1089
https://doi.org/10.1002/ca.1089...
. The main nerves involved are auriculotemporal nerve (the branch of trigeminal nerve, fifth cranial pair), auricular branch of the vagus nerve (ABVN), and great auricular nerve (GAN), formed by the roots of C1-C2-C3. The ABVN innervates the central region of the auricle: the concha (upper and lower), much of the antihelix, and the internal portion of the tragus (Figure 3).

Figure 3
Diagram of the outer ear and area of innervation by the vagus nerve. ABVN: auricular branch of the vagus nerve.

This innervation, particularly the trigeminal areas and the cervical nerves, is often mixed and its limits are variable2020 He W, Wang X, Shi H, Shang H, Li L, Jing X, et al. Auricular acupuncture and vagal regulation. Evid Based Complement Alternat Med. 2012;2012:786839. https://doi.org/10.1155/2012/786839
https://doi.org/10.1155/2012/786839...
. One study, which involved dissection of 14 ears from 7 cadavers1919 Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat. 2002;15(1):35-7. https://doi.org/10.1002/ca.1089
https://doi.org/10.1002/ca.1089...
, showed the complete course of ear innervation. Its results are displayed in Table 1.

Table 1
Innervation pattern of the lateral surface of the ear.

In a recently published review2121 Butt MF, Albusoda A, Farmer AD, Aziz Q. The anatomical basis for transcutaneous auricular vagus nerve stimulation. J Anat. 2020;236(4):588-611. https://doi.org/10.1111/joa.13122
https://doi.org/10.1111/joa.13122...
, the authors argue that the three main sites in the ear where the vagus nerve can be stimulated are the superior concha, the inferior concha, and the internal wall of the tragus, which covers the external auditory meatus. Evidence supporting the stimulation of these sites comes from both studies with ear dissection in cadavers1919 Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat. 2002;15(1):35-7. https://doi.org/10.1002/ca.1089
https://doi.org/10.1002/ca.1089...
and functional magnetic resonance imaging (fMRI)2222 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):624-36. https://doi.org/10.1016/j.brs.2014.11.018
https://doi.org/10.1016/j.brs.2014.11.01...
,2323 Yakunina N, Kim SS, Nam EC. Optimization of transcutaneous vagus nerve stimulation using functional MRI. Neuromodulation. 2017;20(3):290-300. https://doi.org/10.1111/ner.12541
https://doi.org/10.1111/ner.12541...
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It is important to remember that the ear is the only place in the body where the vagus is externalized and can be accessed in a simple and non-invasive way.

AURICULAR VAGUS NERVE STIMULATION

Auricular vagus nerve stimulation (aVNS) is produced by non-invasive auricular electrical stimulation of the vagus nerve2424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
, through electrodes or miniature needles placed in the concha and/or in the inferior part of the tragus, and both the left and right ear can be used since the afferent information from the vagus merges when reaching the brainstem2525 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation II - an engineering perspective. Front Neurosci. 2019;13:772. https://doi.org/10.3389/fnins.2019.00772
https://doi.org/10.3389/fnins.2019.00772...
,2626 Chen M, Yu L, Ouyang F, Liu Q, Wang Z, Wang S, et al. The right side or left side of noninvasive transcutaneous vagus nerve stimulation: based on conventional wisdom or scientific evidence?. Int J Cardiol. 2015;187:44-5. https://doi.org/10.1016/j.ijcard.2015.03.351
https://doi.org/10.1016/j.ijcard.2015.03...
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Invasive (surgically implanted) and non-invasive (transcutaneous or percutaneous) stimulation are the options available to stimulate the vagus nerve. Devices for non-invasive stimulation are based on the existence of a distribution of vagal afferents in the skin region, both in the external ear (the auricular branch of the vagus nerve) and in the neck (the cervical branch of the vagus nerve). aVNS has been proposed as a new analgesic and anti-inflammatory intervention.

Both cervical vagus nerve stimulation (VNS) and aVNS have comparable physiological effects2525 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation II - an engineering perspective. Front Neurosci. 2019;13:772. https://doi.org/10.3389/fnins.2019.00772
https://doi.org/10.3389/fnins.2019.00772...
,2727 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation I - a physiological perspective. Front Neurosci. 2019;13:854. https://doi.org/10.3389/fnins.2019.00854
https://doi.org/10.3389/fnins.2019.00854...
. Brain activity patterns induced by aVNS were similar to patterns induced by cervical VNS2828 Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol. 2010;27(2):130-8. https://doi.org/10.1097/WNP.0b013e3181d64d8a
https://doi.org/10.1097/WNP.0b013e3181d6...
, with equally favorable therapeutic results.

THERAPEUTIC EFFECTS OF VAGAL STIMULATION

The therapeutic effects of parasympathetic activity induced by aVNS are supported by a wide range of state-of-the-art clinical and experimental data: decrease in pro-inflammatory cytokines (TNF-α, IL-8, IL-1ß, and IL-6), modulation of pulmonary lesions by activating anti-inflammatory pathways, improvement of pulmonary and cardiac functions, adjusting the autonomic imbalance, and so on1414 Liu Y, Tao T, Li W, Bo Y. Regulating autonomic nervous system homeostasis improves pulmonary function in rabbits with acute lung injury. BMC Pulm Med. 2017;17(1):98. https://doi.org/10.1186/s12890-017-0436-0
https://doi.org/10.1186/s12890-017-0436-...
,2929 Huang Y, Zhao C, Su X. Neuroimmune regulation of lung infection and inflammation. QJM. 2019;112(7):483-87. https://doi.org/10.1093/qjmed/hcy154
https://doi.org/10.1093/qjmed/hcy154...
,3030 Stavrakis S, Stoner JA, Humphrey MB, Morris L, Filiberti A, Reynolds JC, et al. TREAT AF (transcutaneous electrical vagus nerve stimulation to suppress atrial fibrillation): a randomized clinical trial. JACC Clin Electrophysiol. 2020;6(3):282-91. https://doi.org/10.1016/j.jacep.2019.11.008
https://doi.org/10.1016/j.jacep.2019.11....
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Imbalances in ANS activity have been linked to many clinical disorders, including heart failure3131 Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2011;32(7):847-55. https://doi.org/10.1093/eurheartj/ehq391
https://doi.org/10.1093/eurheartj/ehq391...
, inflammatory bowel disease3232 Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology. 2006;131(4):1122-30. https://doi.org/10.1053/j.gastro.2006.08.016
https://doi.org/10.1053/j.gastro.2006.08...
, and chronic pain syndromes3333 Farmer AD, Aziz Q. Mechanisms of visceral pain in health and functional gastrointestinal disorders. Scand J Pain. 2014;5(2):51-60. https://doi.org/10.1016/j.sjpain.2014.01.002
https://doi.org/10.1016/j.sjpain.2014.01...
. In general, reported imbalances involve elevated sympathetic activity associated with a deficit in parasympathetic activity3434 Farmer AD, Albu-Soda A, Aziz Q. Vagus nerve stimulation in clinical practice. Br J Hosp Med (Lond). 2016;77(11):645-51. https://doi.org/10.12968/hmed.2016.77.11.645
https://doi.org/10.12968/hmed.2016.77.11...
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VNS corrects autonomic imbalance and increases parasympathetic activity1010 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
https://doi.org/10.1038/nrendo.2012.189...
,2424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
. A regularization of the autonomic balance will decrease sympathetic activity, which, in turn, will cause vasodilation and, consequently, improve oxygenation. In addition, VNS-mediated nitric oxide release3535 Sator-Katzenschlager SM, Scharbert G, Kozek-Langenecker SA, Szeles JC, Finster G, Schiesser AW, et al. The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture. Anesth Analg. 2004;98(5):1359-64, table of contents. https://doi.org/10.1213/01.ane.0000107941.16173.f7
https://doi.org/10.1213/01.ane.000010794...
, combined with its anti-inflammatory effects, mediates cardiovascular responses, potentially leading to further improvement in tissue oxygenation in terms of a positive feedback system2424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
,2727 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation I - a physiological perspective. Front Neurosci. 2019;13:854. https://doi.org/10.3389/fnins.2019.00854
https://doi.org/10.3389/fnins.2019.00854...
. Therefore, it is expected that the respiratory feedback provided by VNS favors the control of pulmonary inflammation.

Next, we will examine some scientific evidence for the use of taVNS.

Pre-clinical evidence

In animal models of inflammation, vagus nerve stimulation results in decreased inflammatory activity and increased anti-inflammatory activity, preventing tissue injury and increasing survival. For example, aVNS reduced the amount of pro-inflammatory cytokines3636 Bonaz B, Sinniger V, Pellissier S. Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-19? Bioelectron Med. 2020;6:15. https://doi.org/10.1186/s42234-020-00051-7
https://doi.org/10.1186/s42234-020-00051...
as well as the levels of norepinephrine2828 Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol. 2010;27(2):130-8. https://doi.org/10.1097/WNP.0b013e3181d64d8a
https://doi.org/10.1097/WNP.0b013e3181d6...
, reinforcing its anti-inflammatory effects and counterbalancing sympathetic hyperactivity. VNS provided favorable effects on rheumatoid arthritis in rats3737 Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA. 2016;113(29):8284-9. https://doi.org/10.1073/pnas.1605635113
https://doi.org/10.1073/pnas.1605635113...
, as well as reduced intestinal inflammation induced by surgery and improved intestinal transit3838 Matteoli G, Gomez-Pinilla PJ, Nemethova A, Di Giovangiulio M, Cailotto C, Bree SH, et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut. 2014;63(6):938-48. https://doi.org/10.1136/gutjnl-2013-304676
https://doi.org/10.1136/gutjnl-2013-3046...
. Furthermore, it prevented the development of shock in rats by inhibiting the synthesis of tumor necrosis factor3939 Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458-62. https://doi.org/10.1038/35013070
https://doi.org/10.1038/35013070...
and reduced inflammation in an experimentally induced model of colitis4040 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(1-2):82-9. https://doi.org/10.1016/j.autneu.2010.10.007
https://doi.org/10.1016/j.autneu.2010.10...
. aVNS demonstrated its efficiency in rats with lethal endotoxemia or polymicrobial infection, reducing the production of tumor necrosis factor through its anti-inflammatory effects4141 Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M, et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit Care Med. 2007;35(12):2762-8. https://doi.org/10.1097/01.CCM.0000288102.15975.BA
https://doi.org/10.1097/01.CCM.000028810...
. aVNS also suppressed lipopolysaccharide-induced inflammatory responses in toxemic rats by decreasing the levels of pro-inflammatory cytokines, indicating that it modulates immune functions through the cholinergic anti-inflammatory pathway4242 Zhao YX, He W, Jing XH, Liu JL, Rong PJ, Ben H, et al. Transcutaneous auricular vagus nerve stimulation protects endotoxemic rat from lipopolysaccharide-induced inflammation. Evid Based Complement Alternat Med. 2012;2012:627023. https://doi.org/10.1155/2012/627023
https://doi.org/10.1155/2012/627023...
.

Laboratory research demonstrates the protective effects of vagal stimulation on the lung4343 Krzyzaniak MJ, Peterson CY, Cheadle G, Loomis W, Wolf P, Kennedy V, et al. Efferent vagal nerve stimulation attenuates acute lung injury following burn: the importance of the gut-lung axis. Surgery. 2011;150(3):379-89. https://doi.org/10.1016/j.surg.2011.06.008
https://doi.org/10.1016/j.surg.2011.06.0...
. Vagal stimulation protected rats against respiratory distress syndrome induced by Mesobuthus tamulus venom, improving respiratory parameters, hypoxemia, pulmonary edema, and histopathological changes, although it did not show the same result in rats with oleic acid-induced ARDS, which seems to indicate different mechanisms of vagal action in these cases4444 Akella A, Deshpande SB. Vagal efferent stimulation protects against Mesobuthus tamulus venom-induced acute respiratory distress syndrome in rats. Toxicon. 2015;108:189-201. https://doi.org/10.1016/j.toxicon.2015.10.013
https://doi.org/10.1016/j.toxicon.2015.1...
. Johnson et al.4545 Johnson RL, Murray ST, Camacho DK, Wilson CG. Vagal nerve stimulation attenuates IL-6 and TNFα expression in respiratory regions of the developing rat brainstem. Respir Physiol Neurobiol. 2016;229:1-4. https://doi.org/10.1016/j.resp.2016.03.014
https://doi.org/10.1016/j.resp.2016.03.0...
showed that VNS diminishes the expression of proinflammatory cytokines TNF-α and IL-6 in the respiratory brain nuclei of developing rats, thereby reducing the inflammation caused by lipopolysaccharide instilled in the trachea, and may remain a viable alternative to antibiotics.

Clinical evidence

All the data mentioned below come from observational and interventional studies, small randomized clinical trials, and reviews. Most of the studies mentioned were observational studies, which somewhat limits the level of evidence derived from them.

VNS favorably modulates several cardiovascular parameters, resulting in a reduction in blood pressure4646 Annoni EM, Xie X, Lee SW, Libbus I, KenKnight BH, Osborn JW, et al. Intermittent electrical stimulation of the right cervical vagus nerve in salt-sensitive hypertensive rats: effects on blood pressure, arrhythmias, and ventricular electrophysiology. Physiol Rep. 2015;3(8):e12476. https://doi.org/10.14814/phy2.12476
https://doi.org/10.14814/phy2.12476...
,4747 Mahadi KM, Lall VK, Deuchars SA, Deuchars J. Cardiovascular autonomic effects of transcutaneous auricular nerve stimulation via the tragus in the rat involve spinal cervical sensory afferent pathways. Brain Stimul. 2019;12(5):1151-8. https://doi.org/10.1016/j.brs.2019.05.002
https://doi.org/10.1016/j.brs.2019.05.00...
, reduction in arrhythmias4646 Annoni EM, Xie X, Lee SW, Libbus I, KenKnight BH, Osborn JW, et al. Intermittent electrical stimulation of the right cervical vagus nerve in salt-sensitive hypertensive rats: effects on blood pressure, arrhythmias, and ventricular electrophysiology. Physiol Rep. 2015;3(8):e12476. https://doi.org/10.14814/phy2.12476
https://doi.org/10.14814/phy2.12476...
, and suppression of atrial fibrillation3030 Stavrakis S, Stoner JA, Humphrey MB, Morris L, Filiberti A, Reynolds JC, et al. TREAT AF (transcutaneous electrical vagus nerve stimulation to suppress atrial fibrillation): a randomized clinical trial. JACC Clin Electrophysiol. 2020;6(3):282-91. https://doi.org/10.1016/j.jacep.2019.11.008
https://doi.org/10.1016/j.jacep.2019.11....
, the last one shown by Stavrakis et al. in a small randomized clinical trial. VNS inhibits sympathetic hyperactivity in heart failure4848 Zhang Y, Popovic ZB, Bibevski S, Fakhry I, Sica DA, Wagoner DR, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail. 2009;2(6):692-9. https://doi.org/10.1161/CIRCHEARTFAILURE.109.873968
https://doi.org/10.1161/CIRCHEARTFAILURE...
and reverses cardiac remodeling after myocardial infarction4949 Buchholz B, Donato M, Perez V, Deutsch ACR, Höcht C, Del Mauro JS, et al. Changes in the loading conditions induced by vagal stimulation modify the myocardial infarct size through sympathetic-parasympathetic interactions. Pflugers Arch. 2015;467(7):1509-22. https://doi.org/10.1007/s00424-014-1591-2
https://doi.org/10.1007/s00424-014-1591-...
. Thus, VNS could favorably modulate cardiovascular complications in patients with COVID-19, especially in those with comorbidities, and could reduce the percentage of fatal outcomes2424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
.

VNS attenuated ventilation-induced lung injury, reducing pro-apoptosis and pro-inflammatory reactions3636 Bonaz B, Sinniger V, Pellissier S. Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-19? Bioelectron Med. 2020;6:15. https://doi.org/10.1186/s42234-020-00051-7
https://doi.org/10.1186/s42234-020-00051...
,5050 Johnson RL, Wilson CG. A review of vagus nerve stimulation as a therapeutic intervention. J Inflamm Res. 2018;11:203-13. https://doi.org/10.2147/JIR.S163248
https://doi.org/10.2147/JIR.S163248...
. In hemorrhagic shock, vagal stimulation has prevented intestinal barrier failure and lung injury5151 Reys LG, Ortiz-Pomales YT, Lopez N, Cheadle G, Oliveira PG, Eliceiri B, et al. Uncovering the neuroenteric-pulmonary axis: vagal nerve stimulation prevents acute lung injury following hemorrhagic shock. Life Sci. 2013;92(13):783-92. https://doi.org/10.1016/j.lfs.2013.02.009
https://doi.org/10.1016/j.lfs.2013.02.00...
, relieving the latter through a decrease in cell permeability5252 Levy G, Fishman JE, Xu DZ, Dong W, Palange D, Vida G, et al. Vagal nerve stimulation modulates gut injury and lung permeability in trauma-hemorrhagic shock. J Trauma Acute Care Surg. 2012;73(2):338-42; discussion 342. https://doi.org/10.1097/TA.0b013e31825debd3
https://doi.org/10.1097/TA.0b013e31825de...
,5353 Powell K, Shah K, Hao C, Wu YC, John A, Narayan RK, et al. Neuromodulation as a new avenue for resuscitation in hemorrhagic shock. Bioelectron Med. 2019;5:17. https://doi.org/10.1186/s42234-019-0033-z
https://doi.org/10.1186/s42234-019-0033-...
, mainly due to its anti-inflammatory properties.

Huang et al. showed, in a prospective observational trial, that VNS reduces inflammation by restoring balance to the sympathetic-parasympathetic binomial, reducing sympathetic activity, and slowing down the progression of sepsis5454 Huang LF, Yao YM, Dong N, Yu Y, He LX, Sheng ZY. Association between regulatory T cell activity and sepsis and outcome of severely burned patients: a prospective, observational study. Crit Care. 2010;14(1):R3. https://doi.org/10.1186/cc8232
https://doi.org/10.1186/cc8232...
.

In inflammation, respiratory dysfunction, and cardiovascular diseases, aVNS has the effect of reducing the production of pro-inflammatory cytokines5555 Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117(2):289-96. https://doi.org/10.1172/JCI30555
https://doi.org/10.1172/JCI30555...
,5656 Stavrakis S, Humphrey MB, Scherlag BJ, Hu Y, Jackman WM, Nakagawa H, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. 2015;65(9):867-75. https://doi.org/10.1016/j.jacc.2014.12.026
https://doi.org/10.1016/j.jacc.2014.12.0...
; decreasing inflammation in chronic processes such as rheumatoid arthritis, postoperative ileus, and inflammatory bowel disease1212 Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J Intern Med. 2017;282(1):46-63. https://doi.org/10.1111/joim.12611
https://doi.org/10.1111/joim.12611...
,5757 Bonaz B, Sinniger V, Hoffmann D, Clarençon D, Mathieu N, Dantzer C, et al. Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28(6):948-53. https://doi.org/10.1111/nmo.12792
https://doi.org/10.1111/nmo.12792...
; and systemic inflammation and attenuation of the postoperative acute inflammatory response of pulmonary lobectomy2424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
,3737 Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA. 2016;113(29):8284-9. https://doi.org/10.1073/pnas.1605635113
https://doi.org/10.1073/pnas.1605635113...
.

aVNS improves cardiac baroreflex sensitivity5858 Antonino D, Teixeira AL, Maia-Lopes PM, Souza MC, Sabino-Carvalho JL, Murray AR, et al. Non-invasive vagus nerve stimulation acutely improves spontaneous cardiac baroreflex sensitivity in healthy young men: a randomized placebo-controlled trial. Brain Stimul. 2017;10(5):875-81. https://doi.org/10.1016/j.brs.2017.05.006
https://doi.org/10.1016/j.brs.2017.05.00...
, increases venocapillary oxygenation in the deep tissues of diabetic patients2424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
, increases skin temperature in humans with peripheral artery dysfunctions and patients with chronic wounds caused by diabetes5959 Széles JC, Litscher G. Objectivation of cerebral effects with a new continuous electrical auricular stimulation technique for pain management. Neurol Res. 2004;26(7):797-800. https://doi.org/10.1179/016164104225016100
https://doi.org/10.1179/0161641042250161...
, and improves symptoms in peripheral obstructive arterial diseases6060 Payrits T, Ernst A, Ladits E, Pokorny H, Viragos I, Längle F. Vagal stimulation - a new possibility for conservative treatment of peripheral arterial occlusion disease. Zentralbl Chir. 2011;136(5):431-5. https://doi.org/10.1055/s-0031-1283739
https://doi.org/10.1055/s-0031-1283739...
. Systemic effects of aVNS also include improvement of metabolic processes6161 Huang F, Dong J, Kong J, Wang H, Meng H, Spaeth RB, et al. Erratum to: Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study. BMC Complement Altern Med. 2016;16(1):218. https://doi.org/10.1186/s12906-016-1190-1
https://doi.org/10.1186/s12906-016-1190-...
,6262 Ju Y, Zhang H, Chen M, Chi X, Lan W, Zhang H, et al. Effects of auricular stimulation in the cavum conchae on glucometabolism in patients with type 2 diabetes mellitus. Complement Ther Med. 2014;22(5):858-63. https://doi.org/10.1016/j.ctim.2014.09.002
https://doi.org/10.1016/j.ctim.2014.09.0...
(aVNS reduced 2-h glucose tolerance, systolic blood pressure, fasting plasma glucose and glycosylated hemoglobin compared to sham), attenuation of neurological disorders6363 Ylikoski J, Lehtimäki J, Pirvola U, Mäkitie A, Aarnisalo A, Hyvärinen P, et al. Non-invasive vagus nerve stimulation reduces sympathetic preponderance in patients with tinnitus. Acta Otolaryngol. 2017;137(4):426-31. https://doi.org/10.1080/00016489.2016.1269197
https://doi.org/10.1080/00016489.2016.12...
(aVNS increased heart rate variability inducing a shift in autonomic nervous system function from sympathetic preponderance to parasympathetic predominance, and can be used to treat tinnitus-triggered stress), improvement of cognitive performance6464 Rong PJ, Fang JL, Wang LP, Meng H, Liu J, Ma YG, et al. Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial. BMC Complement Altern Med. 2012;12:255. https://doi.org/10.1186/1472-6882-12-255
https://doi.org/10.1186/1472-6882-12-255...
(reducing depressive disorder symptoms without the burden of surgical intervention), and pain relief2727 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation I - a physiological perspective. Front Neurosci. 2019;13:854. https://doi.org/10.3389/fnins.2019.00854
https://doi.org/10.3389/fnins.2019.00854...
,3535 Sator-Katzenschlager SM, Scharbert G, Kozek-Langenecker SA, Szeles JC, Finster G, Schiesser AW, et al. The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture. Anesth Analg. 2004;98(5):1359-64, table of contents. https://doi.org/10.1213/01.ane.0000107941.16173.f7
https://doi.org/10.1213/01.ane.000010794...
(aVNS significantly improved low back pain, specially neuropathic pain, compared to manual acupuncture in a randomized clinical trial).

Recently, Seitz et al.6565 Seitz T, Szeles JC, Kitzberger R, Holbik J, Grieb A, Wolf H, et al. Percutaneous auricular vagus nerve stimulation reduces inflammation in critical Covid-19 patients. Front Physiol. 2022;13:897257. https://doi.org/10.3389/fphys.2022.897257
https://doi.org/10.3389/fphys.2022.89725...
published a small clinical trial about aVNS and COVID-19 lung inflammation in patients admitted to the intensive care unit (ICU) but not yet ventilated. The study involved 10 patients randomized either to aVNS plus standard of care (SOC) or SOC alone (dexamethasone for at least 10 days and prophylactic anticoagulation therapy). aVNS was performed with the AuriStim device (Multisana, GmbH, Austria), stimulation frequency 1 Hz continuous, 3 h ON/3 h OFF for 24 h, until the patient died or was discharged from the ICU. The results showed decreased pro-inflammatory parameters as follows: a reduction in the C-reactive protein levels by 80%, a reduction in the TNF-α levels by 58.1%, and a reduction in the DDIMER levels by 66%, all after 7 days of treatment. Moreover, there was an increase in anti-inflammatory biomarkers such as IL (interleukin)-10 levels by 66% after 7 days, over the aVNS duration, and without collateral effects.

It seems that both cervical VNS and aVNS are promising options in the treatment of different inflammatory diseases and can help patients with COVID-193636 Bonaz B, Sinniger V, Pellissier S. Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-19? Bioelectron Med. 2020;6:15. https://doi.org/10.1186/s42234-020-00051-7
https://doi.org/10.1186/s42234-020-00051...
,6666 Azabou E, Bao G, Bounab R, Heming N, Annane D. Vagus nerve stimulation: a potential adjunct therapy for COVID-19. Front Med (Lausanne). 2021;8:625836. https://doi.org/10.3389/fmed.2021.625836
https://doi.org/10.3389/fmed.2021.625836...
, especially those with significant sympathetic-parasympathetic imbalance. As biophysical principles and results are similar for both forms of vagal electrostimulation, aVNS is promising as it is not invasive. Czura et al.6767 Czura CJ, Bikson M, Charvet L, Chen JDZ, Franke M, Fudim M, et al. Neuromodulation strategies to reduce inflammation and improve lung complications in COVID-19 patients. Front Neurol. 2022;13:897124. https://doi.org/10.3389/fneur.2022.897124
https://doi.org/10.3389/fneur.2022.89712...
published in 2022 a very complete review of all available neuromodulation strategies to reduce inflammation and improve lung complications in COVID-19 patients.

SIDE EFFECTS AND CONTRAINDICATIONS

aVNS is safe, with minor side effects such as headache, dizziness, skin irritation, or pain6868 Badran BW, Mithoefer OJ, Summer CE, LaBate NT, Glusman CE, Badran AW, et al. Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate. Brain Stimul. 2018;11(4):699-708. https://doi.org/10.1016/j.brs.2018.04.004
https://doi.org/10.1016/j.brs.2018.04.00...
. Surface electrodes are used in transcutaneous aVNS (taVNS), making the stimulation not as selective and precise as when using miniature needles, which can contribute to a lower effectiveness of the technique and a higher incidence of side effects. Stimulation is usually done intermittently (around 1 h, 3–4 times a day), with a total duration of stimulation of approximately 3–4 h per day.

On the contrary, percutaneous aVNS (paVNS) employs microelectrodes with needles, which favors a more precise and specific stimulation of nerve endings2525 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation II - an engineering perspective. Front Neurosci. 2019;13:772. https://doi.org/10.3389/fnins.2019.00772
https://doi.org/10.3389/fnins.2019.00772...
,2727 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation I - a physiological perspective. Front Neurosci. 2019;13:854. https://doi.org/10.3389/fnins.2019.00854
https://doi.org/10.3389/fnins.2019.00854...
. The skin impedance is much lower, which allows for a more efficient and economical stimulus with minimal side effects such as bleeding (<1%) and skin irritation (<10%)3535 Sator-Katzenschlager SM, Scharbert G, Kozek-Langenecker SA, Szeles JC, Finster G, Schiesser AW, et al. The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture. Anesth Analg. 2004;98(5):1359-64, table of contents. https://doi.org/10.1213/01.ane.0000107941.16173.f7
https://doi.org/10.1213/01.ane.000010794...
,6969 Kampusch S, Kaniusas E, Thürk F, Felten D, Hofmann I, Széles JC. Device development guided by user satisfaction survey on auricular vagus nerve stimulation. Curr Dir Biomed Eng. 2016;2(1):593-7. https://doi.org/10.1515/cdbme-2016-0131
https://doi.org/10.1515/cdbme-2016-0131...
. The stimulus is also performed intermittently (3 h ON, 3 h OFF), but remains active day and night, with a much longer stimulation time than in taVNS (12 h vs. 4–5 h), for 2–4 days, offering chronic stimulation for chronic ailments.

Very mild adverse effects of aVNS have been reported7070 Tekdemir I, Aslan A, Elhan A. A clinico-anatomic study of the auricular branch of the vagus nerve and Arnold's ear-cough reflex. Surg Radiol Anat. 1998;20(4):253-7. PMID: 9787391,7171 Napadow V, Edwards RR, Cahalan CM, Mensing G, Greenbaum S, Valovska A, et al. Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Med. 2012;13(6):777-89. https://doi.org/10.1111/j.1526-4637.2012.01385.x
https://doi.org/10.1111/j.1526-4637.2012...
and observed in a few cases: Arnold's cough reflex, vasovagal reflex, tearing, and bradycardia, all of which are indirect effects of afferent-efferent vagal reflexes. Furthermore, it is known that stimulation of cholinergic nerves can cause bronchial spasm and increase mucus production in the airways7272 Velden VH, Hulsmann AR. Autonomic innervation of human airways: structure, function, and pathophysiology in asthma. Neuroimmunomodulation. 1999;6(3):145-59. https://doi.org/10.1159/000026376
https://doi.org/10.1159/000026376...
, which could attenuate the beneficial effects of aVNS in the anti-inflammatory process. Fortunately, these are all very rare side effects, occurring in less than 1% of the patients, and are widely overcome by the potential advantages of aVNS, in view of severity of comorbidities in COVID-19 patients.

aVNS is contraindicated in people with vagal hypersensitivity, hemophilia, psoriasis vulgaris at the application site, and patients with active implantable devices, such as pacemakers, because of their possible interference with the pacing device. There are no reports of special adverse events or contraindications for aVNS in viral infections such as COVID-192424 Kaniusas E, Szeles JC, Kampusch S, Alfageme-Lopez N, Yucuma-Conde D, Li X, et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front Physiol. 2020;11:890. https://doi.org/10.3389/fphys.2020.00890
https://doi.org/10.3389/fphys.2020.00890...
.

TYPES OF NERVOUS FIBERS AND STIMULATION PARAMETERS

Nerve fibers can be classified into three groups based on their diameter: groups A (Aα, Aβ, Aγ, and Aδ), B, and C. Different types of nerve fibers have different diameters and thicknesses of the myelin sheath (Table 2), which correspond to different conduction speeds, with thicker myelinated fibers typically linked to faster conduction speeds7373 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
https://doi.org/10.3389/fnins.2020.00284...
.

Table 2
Classification of the nerve fibers.

At the cervical level, the vagus nerve consists mainly of small-diameter unmyelinated C fibers (65–80%), a smaller portion of intermediate-diameter myelinated B fibers, and large-diameter myelinated A fibers7474 Vonck K, Herdt V, Boon P. Vagal nerve stimulation--a 15-year survey of an established treatment modality in epilepsy surgery. Adv Tech Stand Neurosurg. 2009;34:111-46. https://doi.org/10.1007/978-3-211-78741-0_5
https://doi.org/10.1007/978-3-211-78741-...
. Kraus et al.7575 Kraus T, Hösl 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(11):1485-93. https://doi.org/10.1007/s00702-007-0755-z
https://doi.org/10.1007/s00702-007-0755-...
showed that, in the treatment of epilepsy, the destruction of peripheral C fibers did not influence the VNS-suppression of induced seizures, and the therapeutic effects of VNS were attributed to the maximum recruitment of thickened A and B afferent nerve fibers7676 Evans MS, Verma-Ahuja S, Naritoku DK, Espinosa JA. Intraoperative human vagus nerve compound action potentials. Acta Neurol Scand. 2004;110(4):232-8. https://doi.org/10.1111/j.1600-0404.2004.00309.x
https://doi.org/10.1111/j.1600-0404.2004...
. Other authors7777 Stefan H, Kreiselmeyer G, Kerling F, Kurzbuch K, Rauch C, Heers M, et al. Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial. Epilepsia. 2012;53(7):e115-8. https://doi.org/10.1111/j.1528-1167.2012.03492.x
https://doi.org/10.1111/j.1528-1167.2012...
have shown that aVNS does not cause painful sensations in participants, which suggests that afferent C axons and thin myelinated Aδ axons are not activated.

As with the stimulation of the cervical branches of the vagus nerve with low-intensity electrical currents, the ideal would be that ABVN stimulation activates only thick myelinated fibers, without activating the reduced diameter unmyelinated C fibers with their higher stimulation thresholds. ABVN is a general sensory fiber and is one of the few branches of the vagus that does not contain motor fibers. As such, the myelinated fibers found in ABVN would be expected to be sensory axons from group A rather than autonomic fibers from group B. Only one study determined the number of myelinated axons that are present in ABVN7878 Safi S, Ellrich J, Neuhuber W. Myelinated axons in the auricular branch of the human vagus nerve. Anat Rec (Hoboken). 2016;299(9):1184-91. https://doi.org/10.1002/ar.23391
https://doi.org/10.1002/ar.23391...
. According to this study, about 50% of the measured myelinated axons had a diameter between 2.5 and 4.4 μm, suggesting that they belong to the Aδ group. Almost 20% of the axons showed a diameter >7 μm, suggesting that these fibers belong to the Aβ class. However, ABVN contains almost six times less class Aβ nerve fibers than those found in the cervical branch of the vagus nerve. This number also varied widely between individuals, which may explain why some individuals do not experience therapeutic effects after treatment with aVNS, as well as explain the anatomical basis behind the mechanism and efficacy of aVNS2121 Butt MF, Albusoda A, Farmer AD, Aziz Q. The anatomical basis for transcutaneous auricular vagus nerve stimulation. J Anat. 2020;236(4):588-611. https://doi.org/10.1111/joa.13122
https://doi.org/10.1111/joa.13122...
.

A tingling sensation should be targeted, as pointed out by some studies7979 Sclocco R, Garcia RG, Kettner NW, Isenburg K, Fisher HP, Hubbard CS, et al. The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: a multimodal ultrahigh-field (7T) fMRI study. Brain Stimul. 2019;12(4):911-21. https://doi.org/10.1016/j.brs.2019.02.003
https://doi.org/10.1016/j.brs.2019.02.00...
,8080 Garcia RG, Lin RL, Lee J, Kim J, Barbieri R, Sclocco R, et al. Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients. Pain. 2017;158(8):1461-72. https://doi.org/10.1097/j.pain.0000000000000930
https://doi.org/10.1097/j.pain.000000000...
. This is because the non-painful stimulus of ABVN would recruit more of the myelinated Aβ fibers in the ear, responsible for mechanoreception and touch sensation, and not the Aδ fibers, responsible for the sensation of pain and temperature. As already mentioned, thicker Aβ fibers are more easily recruitable than smaller Aδ fibers2525 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation II - an engineering perspective. Front Neurosci. 2019;13:772. https://doi.org/10.3389/fnins.2019.00772
https://doi.org/10.3389/fnins.2019.00772...
. For this effect to be obtained, the stimulus must be performed with lower current intensities, always below the painful threshold.

Another important parameter to optimize the recruitment of Aβ fibers is the stimulation frequency8181 Dietrich S, Smith J, Scherzinger C, Hofmann-Preiss K, Freitag T, Eisenkolb A, et al. A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI. Biomed Tech (Berl). 2008;53(3):104-11. https://doi.org/10.1515/BMT.2008.022
https://doi.org/10.1515/BMT.2008.022...
. Slightly higher frequencies, between 20 and 25 Hz, are better for peripheral electrical stimulation of the parasympathetic nervous system, while lower frequencies (between 0.5 and 10 Hz) are better for the sympathetic nervous system. This is because higher frequencies show a shorter duration of the depolarization period and, therefore, are only able to recruit larger and more easily excitable nerve fibers2727 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation I - a physiological perspective. Front Neurosci. 2019;13:854. https://doi.org/10.3389/fnins.2019.00854
https://doi.org/10.3389/fnins.2019.00854...
, such as Aβ fibers, which can indirectly modulate the parasympathetic nervous system. On the contrary, more recent studies8282 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. https://doi.org/10.1186/s10194-015-0543-3
https://doi.org/10.1186/s10194-015-0543-...
,8383 Zhang Y, Liu J, Li H, Yan Z, Liu X, Cao J, et al. Transcutaneous auricular vagus nerve stimulation at 1 Hz modulates locus coeruleus activity and resting state functional connectivity in patients with migraine: an fMRI study. Neuroimage Clin. 2019;24:101971. https://doi.org/10.1016/j.nicl.2019.101971
https://doi.org/10.1016/j.nicl.2019.1019...
have shown good results in inflammatory diseases with the use of low frequencies as well, and therefore the ideal frequency has not been established yet.

Many studies have shown that stimulus efficiency has been increased by burst stimulation for 3–4 h a day2525 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation II - an engineering perspective. Front Neurosci. 2019;13:772. https://doi.org/10.3389/fnins.2019.00772
https://doi.org/10.3389/fnins.2019.00772...
,8484 Szabó CÁ, Salinas FS, Papanastassiou AM, Begnaud J, Ravan M, Eggleston KS, et al. High-frequency burst vagal nerve simulation therapy in a natural primate model of genetic generalized epilepsy. Epilepsy Res. 2017;138:46-52. https://doi.org/10.1016/j.eplepsyres.2017.10.010
https://doi.org/10.1016/j.eplepsyres.201...
. A burst can be defined as the discharge of impulses for a short time, followed by an off interval. One or more nerve impulses triggered by vagal sensory afferences in response to single electrical stimuli are less likely to influence systemic regulation or brain activity (e.g., sympathetic-vagal balance) than a rhythmic sequence of these impulses2525 Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al. Current directions in the auricular vagus nerve stimulation II - an engineering perspective. Front Neurosci. 2019;13:772. https://doi.org/10.3389/fnins.2019.00772
https://doi.org/10.3389/fnins.2019.00772...
,8585 Kaniusas E, Samoudi AM, Kampusch S, Bald K, Tanghe E, Martens L, et al. Stimulation pattern efficiency in percutaneous auricular vagus nerve stimulation: experimental versus numerical data. IEEE Trans Biomed Eng. 2020;67(7):1921-35. https://doi.org/10.1109/TBME.2019.2950777
https://doi.org/10.1109/TBME.2019.295077...
.

Therefore, from a practical point of view, based on studies published in recent years, there is a potential role for aVNS to treat inflammation, as in COVID-19 and other conditions. However, there is still no convincing evidence from properly designed studies to endorse a formal recommendation. All we can say is that it is a very attractive experimental therapy that deserves further investigation.

Below, we propose three different types of aVNS for the treatment of COVID-19 and its inflammatory manifestations, which can be implemented using a cutaneous electrical stimulation device:

  1. Burst stimuli at frequency of 20–25 Hz, pulse width of 500 μs, intensity below pain threshold, 30 s ON/30 s OFF; this option is mostly used in taVNS;

  2. Continuous stimuli at a frequency of 1 Hz, pulse width of 500 μs to 1 ms, intensity below pain threshold (generally <1.5 mA);

  3. In this third option, we propose a new concept of vagal stimulation based on very recent studies8585 Kaniusas E, Samoudi AM, Kampusch S, Bald K, Tanghe E, Martens L, et al. Stimulation pattern efficiency in percutaneous auricular vagus nerve stimulation: experimental versus numerical data. IEEE Trans Biomed Eng. 2020;67(7):1921-35. https://doi.org/10.1109/TBME.2019.2950777
    https://doi.org/10.1109/TBME.2019.295077...
    ,8686 Shen LL, Sun JB, Yang XJ, Deng H, Qin W, Du MY, et al. Reassessment of the effect of transcutaneous auricular vagus nerve stimulation using a novel burst paradigm on cardiac autonomic function in healthy young adults. Neuromodulation. 2022;25(3):433-42. https://doi.org/10.1111/ner.13521
    https://doi.org/10.1111/ner.13521...
    . Stimulus frequency of 1 Hz, pulse width of 1 ms, maximum intensity of 1.5–2 mA (only required to feel a tingling sensation), train of 100 biphasic pulses every 200 ms (0.2 s), remaining without any stimulus for 0.8 s, and repeating the stimulus again in the same way in the subsequent seconds. This is a new concept of burst, in which a very fast pulse sequence is sent within a 1 Hz period, which proved to be more effective in tested in-silico models and pre-clinical settings to excite Aβ fibers and produce vagal neuromodulation8585 Kaniusas E, Samoudi AM, Kampusch S, Bald K, Tanghe E, Martens L, et al. Stimulation pattern efficiency in percutaneous auricular vagus nerve stimulation: experimental versus numerical data. IEEE Trans Biomed Eng. 2020;67(7):1921-35. https://doi.org/10.1109/TBME.2019.2950777
    https://doi.org/10.1109/TBME.2019.295077...
    ,8787 Kampusch S, Kaniusas E, Széles JC. Modulation of muscle tone and sympathovagal balance in cervical dystonia using percutaneous stimulation of the auricular vagus nerve. Artif Organs. 2015;39(10):E202-12. https://doi.org/10.1111/aor.12621
    https://doi.org/10.1111/aor.12621...
    .

Electrodes or needles should be placed on the superior concha, or on both the superior and inferior concha, and connected to the equipment (Figures 4 and 5). In paVNS, the microelectrodes with needles are connected via wires to a stimulation device fixed in the neck (Figure 5), and the points should be selected by transillumination8585 Kaniusas E, Samoudi AM, Kampusch S, Bald K, Tanghe E, Martens L, et al. Stimulation pattern efficiency in percutaneous auricular vagus nerve stimulation: experimental versus numerical data. IEEE Trans Biomed Eng. 2020;67(7):1921-35. https://doi.org/10.1109/TBME.2019.2950777
https://doi.org/10.1109/TBME.2019.295077...
of the outer ear (to visualize auricular vascularization) or by electrical point detection3535 Sator-Katzenschlager SM, Scharbert G, Kozek-Langenecker SA, Szeles JC, Finster G, Schiesser AW, et al. The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture. Anesth Analg. 2004;98(5):1359-64, table of contents. https://doi.org/10.1213/01.ane.0000107941.16173.f7
https://doi.org/10.1213/01.ane.000010794...
,6969 Kampusch S, Kaniusas E, Thürk F, Felten D, Hofmann I, Széles JC. Device development guided by user satisfaction survey on auricular vagus nerve stimulation. Curr Dir Biomed Eng. 2016;2(1):593-7. https://doi.org/10.1515/cdbme-2016-0131
https://doi.org/10.1515/cdbme-2016-0131...
.

Figure 4
MicroEstim device and electrodes positioned on the ear (upper and lower concha) for stimulation. (A) MicroEstim (NKL Produtos Eletrônicos, Brusque, SC) with ear electrodes. (B) Electrodes positioned on the ear, on the upper and lower concha.
Figure 5
AuriStim for percutaneous auricular vagus nerve stimulation.

The stimulus must be performed every day for as long as the patient remains hospitalized, with intervals of at least 3 h between sessions.

CONCLUSIONS

Vagus nerve stimulation modulates parasympathetic anti-inflammatory pathways and reestablishes sympathetic-vagal balance, which may help in the treatment of respiratory and cardiac diseases. As it is a simple and safe clinical procedure, it may have a promising role as a co-adjuvant treatment for inflammatory manifestations caused by COVID-19 and similar viruses, requiring larger clinical studies before a more solid recommendation can be made about its use.

One of the simplest ways to stimulate the vagus nerve and restore autonomic balance is through stimulation of its auricular branch (aVNS), which, in addition to producing effects like those achieved by cervical vagal stimulation, has the advantage of being non-invasive.

aVNS is a procedure with few side effects and contraindications, occurring in less than 1% of cases. Furthermore, different devices are available on the market with European CE certificates and American FDA approval for various pathologies.

There is still a vast field of research for this therapeutic method, involving different populations at risk (such as the elderly), other potentially serious inflammatory diseases, and different stimulation parameters.

  • Funding: none.
  • Acquired knowledge:
    In this review article, we discuss the mechanisms of action of transcutaneous atrial vagal stimulation (taVNS) and its therapeutic effects, providing experimental and clinical evidence that supports its use in inflammation, sympathetic-vagal balance, and respiratory and cardiovascular dysfunctions in COVID-19. Finally, we propose stimulation parameters based on recent studies for the treatment of the latter.

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Publication Dates

  • Publication in this collection
    02 June 2023
  • Date of issue
    2023

History

  • Received
    21 Mar 2023
  • Accepted
    19 Apr 2023
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