Current Directions in the Auricular Vagus Nerve Stimulation II - An Engineering 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, Sarah Lechner, Wlodzimierz Klonowski, Giedrius Varoneckas, Jozsef Constantin Széles, Antonio Šarolić, 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, Sarah Lechner, Wlodzimierz Klonowski, Giedrius Varoneckas, Jozsef Constantin Széles, Antonio Šarolić

Abstract

Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging electroceutical technology in the field of bioelectronic medicine with applications in therapy. Artificial modulation of the afferent vagus nerve - a powerful entrance to the brain - affects a large number of physiological processes implicating interactions between the brain and body. Engineering aspects of aVNS determine its efficiency in application. The relevant safety and regulatory issues need to be appropriately addressed. In particular, in silico modeling acts as a tool for aVNS optimization. The evolution of personalized electroceuticals using novel architectures of the closed-loop aVNS paradigms with biofeedback can be expected to optimally meet therapy needs. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the scope 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 engineering aspects - a discussion of physiological 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: auricular nerves; auricular transillumination; in silico modeling; personalized stimulation; stimulation optimization; stimulation patterns; vagus 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.
FIGURE 2
FIGURE 2
Wiring of vessels and nerves in the ear for the percutaneous aVNS. (A–C) High-resolution episcopic images of a volume biopsy in the cymba conchae of one male cadaver ear. Indicated blood vessels (in red) and nerves (green) reside apparently close to each other indicating their joint proliferation in the ear. (D) In order to find local auricular nerve branches, the outer ear is transilluminated to localize and visualize easily discernable auricular vessels which are less transparent than the surrounding tissue for green light. The visualized locations of vessels indicate the most likely regions of nerves, which serve for a personalized placement of stimulation needles.
FIGURE 3
FIGURE 3
CE-related regulatory pathway of aVNS medical devices.
FIGURE 4
FIGURE 4
Numerical modeling of aVNS with three stimulation electrodes. (A) Basic model of the tripolar stimulation with surface current electrodes. A single cathode carries the current i (=1 mA) and the two surrounding anodes i/2 each. The unmyelinated axon lays in parallel to electrodes at the depth of 2 mm. Activating functions f(x) are shown along the axon’s coordinate x, showing the influence of the electrode separation d. With decreasing d, the depolarized segment of the axon narrows [i.e., Δx decreases for f(x) > 0] while the local depolarization strength decreases [i.e., f(x) decreases for f(x) > 0]. (B) Advanced model of the tripolar stimulation with needle voltage electrodes. The spatial distribution of the local electric field E (in dB related to 150 V/m) is shown within the outer ear with the electric potential 1 V for the red electrode, –1 V for the blue, and 0 V for the green. In fact, the gradient of the electric field [proportional to f(x)] determines the potential excitation of straight nerves along x aligned typically along auricular vessels (Figure 2).
FIGURE 5
FIGURE 5
Personalized aVNS. (A) The closed-loop aVNS with the physiological biofeedback (e.g., magnitude of the pulse wave or HRV) which is used to control stimulation parameters of aVNS (e.g., the stimulus strength) in order to adhere to momentary therapeutic needs (e.g., optimal blood perfusion in legs). The biofeedback can also be used for a temporal synchronization of the applied stimuli with inner body rhythms (e.g., respiratory or cardiac cycle) to interfere constructively with the dynamics of the body. (B) aVNS of the afferent VN modulates activity of the efferent VN outflow to the heart, whereas the peripheral pulse wave arriving from the heart can be used as biofeedback to the stimulator of aVNS. (C) Personalized and optimized setting of stimulation needles and their stimulation patterns for the percutaneous aVNS based on an individualized ear model (Figure 4B) as derived from the transilluminated individual ear (Figure 2D). Therapy-relevant re-optimization of the stimulation patterns results when the closed-loop aVNS from the panels (A,B) operates. Here the level of the circle’s filling at each electrode position indicates the local stimulation strength which changes in the course of the closed-loop control.

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