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. 2023 Jun 2;69(6):e20230345.
doi: 10.1590/1806-9282.20230345. eCollection 2023.

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

Fernando Mendes Sant'Anna  1   2 , Rodrigo César Lima Resende  3 , Lucas Bonacossa Sant'Anna  4 , Sérgio Lívio Menezes Couceiro  2 , Romero Bonacossa Soares Pinto  5 , Mariana Bonacossa Sant'Anna  4 , Liaw Wen Chao  6 , Jozsef Constantin Szeles  7 , Eugenijus Kaniusas  8
Affiliations

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

Fernando Mendes Sant'Anna et al. Rev Assoc Med Bras (1992). .
No abstract available

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Conflict of interest statement

Conflicts of interest: the authors declare there is no conflicts of interest.

Figures

Figure 1
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..
Figure 2
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..
Figure 3
Figure 3. Diagram of the outer ear and area of innervation by the vagus nerve. ABVN: auricular branch of the vagus nerve.
Figure 4
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
Figure 5. AuriStim for percutaneous auricular vagus nerve stimulation.
See this image and copyright information in PMC

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