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.

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.

Objective: Percutaneous stimulation of the auricular branch of the vagus nerve (pVNS) by miniaturized needle electrodes in the auricle gained importance as a treatment for acute and chronic pain. The objective is to establish a realistic numerical model of pVNS and investigate the effects of stimulation waveform, electrodes' depth, and electrodes' position on nerve excitation threshold and the percentage of stimulated nerves. Methods:Simulations were performed with Sim4Life. An electro-static solver and neural tissue models were combined for electromagnetic and neural simulation. The numerical model consisted of a realistic high resolution model of a human ear, blood vessels, nerves, and 3 needle electrodes. Results:A novel 3D ear model was established, including blood vessels and nerves. The electric field distribution was extracted and evaluated. Maximum sensitivity to needles' depth and displacement was evaluated to be 9.8% and 15.5% per 0.1mm, respectively. Stimulation was most effective using bi-phasic compared to mono-phasic pulses. Conclusion

Objective. While transcranial focused ultrasound is a very promising neuromodulation technique for its non-invasiveness and high spatial resolution, its application to the human deep brain regions such as the subthalamic nucleus (STN) is relatively new. The objective of this study is to design a simple ultrasound transducer and study the transcranial wave propagation through a highly realistic human head model. The effects of skull morphology and skull and brain tissue properties on the focusing performance and energy deposition must therefore be known. Approach. A full-wave finite-difference time-domain simulation platform was used to design and simulate ultrasound radiation from a singleelement focused transducer (SEFT) to the subthalamic nucleus. Simulations were performed using the state-of-the-art Multimodal Imaging-based and highly Detailed Anatomical (MIDA) head model. In addition, the impact of changes in sound speed, density, and tissue attenuation coefficients were assessed through a sensitivity analysis. Main results. A SEFT model was designed to deliver an intensity of around 100 / 2 to the STN region; 20% of the STN volume was sonicated with at least half of the maximum of the peak intensity and it was predicted that 61.5% of the volume of the beam (above half of the peak intensity) falls inside the STN region. The sensitivity analysis showed that the skull's sound speed is the most influential acoustic parameter, which must be known with less than 1.2% error to obtain an acceptable accuracy in intracranial fields and focusing (for less than 5% error).Significance. Ultrasound intensity delivery at the STN by a simple single element transducer is possible and could be a promising alternative to complex multi-element phased arrays, or more general, to invasive or less focused (non-acoustic) neuromodulation techniques. Accurate acoustic skull and brain parameters, including detailed skull geometry, are needed to ensure proper targeting in the deep brain region.

Percutaneous electrical stimulation of the auricular vagus nerve (pVNS) is an electroceutical technology. The selection of stimulation patterns is empirical, which may lead to under-stimulation or over-stimulation. The objective is to assess the efficiency of different stimulation patterns with respect to individual perception and to compare it with numerical data based on in-silico ear models. Methods: Monophasic (MS), biphasic (BS) and triphasic stimulation (TS) patterns were tested in volunteers. Different clinically-relevant perception levels were assessed. In-silico models of the human ear were created with embedded fibers and vessels to assess different excitation levels. Results: TS indicates experimental superiority over BS which is superior to MS while reaching different perception levels. TS requires about 57% and 35% of BS and MS magnitude, respectively, to reach the comfortable perception. Experimental thresholds decrease from non-bursted to bursted stimulation. Numerical results indicate a slight superiority of BS and TS over MS while reaching different excitation levels, whereas the burst length has no influence. TS yields the highest number of asynchronous action impulses per stimulation symbol for the used tripolar electrode setup. Conclusion: The comparison of experimental and numerical data favors the novel TS pattern. The analysis separates excitatory pVNS effects in the auricular periphery, as accounted by in-silico data, from the combination of peripheral and central pVNS effects in the brain, as accounted by experimental data. Significance: The proposed approach moves from an empirical selection of stimulation patterns towards efficient and optimized pVNS settings.