Current Directions in the Auricular Vagus Nerve Stimulation I - A Physiological Perspective

Eugenijus Kaniusas, Stefan Kampusch, Marc Tittgemeyer, Fivos Panetsos, Raquel Fernandez Gines, Michele Papa, Attila Kiss, Bruno Podesser, Antonino Mario Cassara, Emmeric Tanghe, Amine Mohammed Samoudi, Thomas Tarnaud, Wout Joseph, Vaidotas Marozas, Arunas Lukosevicius, Niko Ištuk, Antonio Šarolić, Sarah Lechner, Wlodzimierz Klonowski, Giedrius Varoneckas, Jozsef Constantin Széles, Eugenijus Kaniusas, Stefan Kampusch, Marc Tittgemeyer, Fivos Panetsos, Raquel Fernandez Gines, Michele Papa, Attila Kiss, Bruno Podesser, Antonino Mario Cassara, Emmeric Tanghe, Amine Mohammed Samoudi, Thomas Tarnaud, Wout Joseph, Vaidotas Marozas, Arunas Lukosevicius, Niko Ištuk, Antonio Šarolić, Sarah Lechner, Wlodzimierz Klonowski, Giedrius Varoneckas, Jozsef Constantin Széles

Abstract

Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging technology in the field of bioelectronic medicine with applications in therapy. Modulation of the afferent vagus nerve affects a large number of physiological processes and bodily states associated with information transfer between the brain and body. These include disease mitigating effects and sustainable therapeutic applications ranging from chronic pain diseases, neurodegenerative and metabolic ailments to inflammatory and cardiovascular diseases. Given the current evidence from experimental research in animal and clinical studies we discuss basic aVNS mechanisms and their potential clinical effects. Collectively, we provide a focused review on the physiological role of the vagus nerve and formulate a biology-driven rationale for aVNS. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the framework of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on physiological aspects - a discussion of engineering aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.

Keywords: animal research; auricular vagus nerve; biophysics; brain plasticity; clinical studies; inflammation; nerve stimulation.

Figures

FIGURE 1
FIGURE 1
Natural sensory innervation of the auricle versus its artificial stimulation. (A) The vagus nerve (VN) connects the brain with most of the organs within the thorax and abdomen. Afferent auricular branches (aVN) leave the cervical VN at the level of the jugular ganglion just outside the cranium and innervate the rather central regions of the pinna of the outer ear (Peuker and Filler, 2002). (B) Electric stimulation of aVN endings with needle electrodes located within these central regions. NTS, nucleus of the solitary tract; NSNT, nucleus spinalis of the trigeminal nerve; NA, nucleus ambiguous; DMN, dorsal motor nucleus. This figure and figure caption was originally published in the sister manuscript to this review (Kaniusas et al., 2019), which was published in Frontiers of Neuroscience under the creative commons attribution license CC BY 4.0.
FIGURE 2
FIGURE 2
Brain modulation via electrical stimulation of auricular vagus nerve (aVN) endings. (A) Intact feedback-loop which is composed out of efferent VN fibers (controlling different organs and functions) and afferent VN fibers (carrying sensory information back to the brain) for proper control of bodily organs and functions. (B) Different diseases may lead to a lost or impaired afferent feedback to the brain (e.g., due to neurodegeneration or maladaptive plasticity), which makes it impossible for the brain (the control station of the body) to adapt to changes in organs, functions, and/or environmental factors. (C) As a hypothesis, stimulation of aVN fibers substitutes the lost or impaired afferent feedback to the brain while inducing systemic regeneration processes. These processes, in turn, may lead to sustainable recovery of controlled organs and functions as well as recovery of the relevant sensory feedback-loop.
FIGURE 3
FIGURE 3
Reported clinical applications of the auricular vagus nerve stimulation (aVNS) in humans. The total area of the pie chart indicates the total number of publications reviewed, whereas individual pieces refer to the respective numbers of clinical trials, case studies, and reviews.

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