Transcutaneous auricular vagus nerve stimulation as a novel therapy connecting the central and peripheral systems: a review

Abstract

Currently, clinical practice and scientific research mostly revolve around a single disease or system, but the single disease-oriented diagnostic and therapeutic paradigm needs to be revised. This review describes how transcutaneous auricular vagus nerve stimulation (taVNS), a novel non-invasive neuromodulation approach, connects the central and peripheral systems of the body. Through stimulation of the widely distributed vagus nerve from the head to the abdominal cavity, this therapy can improve and treat central system disorders, peripheral system disorders, and central-peripheral comorbidities caused by autonomic dysfunction. In the past, research on taVNS has focused on the treatment of central system disorders by modulating this brain nerve. As the vagus nerve innervates the heart, lungs, liver, pancreas, gastrointestinal tract, spleen and other peripheral organs, taVNS could have an overall modulatory effect on the region of the body where the vagus nerve is widespread. Based on this physiological basis, the authors summarize the existing evidence of the taVNS ability to regulate cardiac function, adiposity, glucose levels, gastrointestinal function, and immune function, among others, to treat peripheral system diseases, and complex diseases with central and peripheral comorbidities. This review shows the successful examples and research progress of taVNS using peripheral neuromodulation mechanisms from more perspectives, demonstrating the expanded scope and value of taVNS to provide new ideas and approaches for holistic therapy from both central and peripheral perspectives.

Figure 1

Peripheral organs innervated by the vagus nerve and related functions. Ach, acetylcholine; α7nAChR, nicotinic acetylcholine receptor α7 subunit; DMN, dorsal motor nucleus; IL, interleukin; NF-κB nuclear factor-kappa B; NTS, nucleus tractus solitaries; TNF-α, tumor necrosis factor-α.

Figure 2

Functional anatomy of taVNS in requlating cardiac activity. After activating the NTS and DMN, through efferent vagus nerve, taVNS reduces the expression of TGF-β1 by regulating the reninangiotensin-aldosterone system, thereby inhibiting the formation of angiotensin II and induce the expression of TIMP-1 and decrease the activation of the MMP-9. Collagen I and III synthesis are reduced, preventing distal heart fibrosis and glial deposition to protect heart function. DMN, dorsal motor nucleus; MMP-9, matrix metallopeptidase 9; NTS, nucleus tractus solitarius; taVNS, transcutaneous auricular vagus nerve stimulation; TGF-β1, transforming growth factor β1; TIMP-1, tissue inhibitors of metalloproteinase 1.

Figure 3

Functional anatomy of taVNS in regulating glucolipid metabolism. After taVNS activates the. NTS and DMN, vagal efferents reach the liver and pancreas. In the pancreas, insulin release is increased, promoting the conversion of glucose to glycogen in the liver and a decrease in blood glucose. Triglyceride output increases in the liver and de novo fat decreases. DMN, dorsal motor nucleus; NTS, nucleus tractus solitarius; taVNS, transcutaneous auricular vagus nerve stimulation.

Figure 4

Functional anatomy of taVNS in regulating gastrointestinal system. After activating the NTS. and DMN, through efferent vagus nerve, taVNS plays a role in the gastrointestinal system to regulate gastrointestinal motility, improve intestinal flora and reduce visceral pain. ACh, acetylcholine; CRH, corticotropin-releasing factor; DMN, dorsal motor nucleus; ICC, interstitial cells of Cajal; NTS, nucleus tractus solitarius; SMC, smooth muscle cells; taVNS, transcutaneous auricular vagus nerve stimulation; TRPV1, transient receptor potential vanilloid-1.

Figure 5

Functional anatomy of taVNS in regulating immunity. After activation of NTS and DMN by taVNS, vagal efferent nerves modulate splanchnic nerves via the coeliac ganglion. The splanchnic nerve endings release norepinephrine, which prompts T cells to secrete acetylcholine, which then binds to α7nAChR on macrophages, inhibiting the NF-κB pathway and exerting anti-inflammatory effects. α7nAChR, nicotinic acetylcholine receptor α7 subunit; β2AR, β2-adrenergic receptor; ACh, acetylcholine; DMN, dorsal motor nucleus; IL, interleukin; NE, norepinephrine; NF-κB: nuclear factor-κB; NTS, nucleus tractus solitarius; taVNS, transcutaneous auricular vagus nerve stimulation; TNF-α, tumor necrosis factor-α.