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Background Transcutaneous auricular Vagus Nerve Stimulation (taVNS) applies low-intensity electrical current to the ear with the intention of activating the auricular branch of the Vagus nerve. The sensitivity and selectivity of stimulation applied to the ear depends on current flow pattern produced by a given electrode montage (size and placement). Objective We compare different electrodes designs for taVNS considering both the predicted peak electric fields (sensitivity) and their spatial distribution (selectivity). Methods Based on optimized high-resolution (0.47 mm) T1 and T2 weighted MRI, we developed an anatomical model of the left ear and the surrounding head tissues including brain, CSF/meninges, skull, muscle, blood vessels, fat, cartilage, and skin. The ear was further segmented into 6 regions of interest (ROI) based on various nerve densities: cavum concha, cymba concha, crus of helix, tragus, antitragus, and earlobe. A range of taVNS electrode montages were reproduced spanning varied electrodes sizes and placements over the tragus, cymba concha, earlobe, cavum concha, and crus of helix. Electric field across the ear (from superficial skin to cartilage) for each montage at 1 mA or 2 mA taVNS, assuming an activation threshold of 6.15 V/m, 12.3 V/m or 24.6 V/m was predicted using a Finite element method (FEM). Finally, considering every ROI, we calculated the sensitivity and selectivity of each montage. Results Current flow patterns through the ear were highly specific to the electrode montage. Electric field was maximal at the ear regions directly under the electrodes, and for a given total current, increases with decreasing electrode size. Depending on the applied current and nerves threshold, activation may also occur in the regions between multiple anterior surface electrodes. Each considered montage was selective for one or two regions of interest. For example, electrodes across the tragus restricted significant electric field to the tragus. Stimulation across the earlobe restricted significant electric field to the earlobe and the antitragus. Because of this relative selectivity, use of control ear montages in experimental studies, support testing of targeting. Relative targeting was robust across assumptions of activation threshold and tissue properties. Discussion Computational models provide additional insight on how details in electrode shape and placement impact sensitivity (how much current is needed) and selectivity (spatial distribution), thereby supporting analysis of existing approaches and optimization of new devices. Our result suggest taVNS current patterns and relative target are robust across individuals, though (variance in) axon morphology was not represented.

Transcutaneous auricular vagus nerve electrical stimulation (taVNS) is an emerging adjuvant therapy for several clinical conditions. For example, taVNS has been shown to improve symptoms of drug-resistant epilepsy and drug-resistant major depression while being under investigation as a potential treatment for other clinical conditions including tinnitus and stroke. Moreover, taVNS is safe, and tolerable across different clinical and healthy populations. However, to date, a wide range of taVNS stimulation parameters have been used therapeutically and it is not clear which parameters provide the best therapeutic effect. This review aims to explore current evidence for therapeutic use of taVNS, identify stimulation parameters (active and sham) and report documented adverse events. This review will act as a guide for researchers considering who may safely benefit therapeutically from taVNS and under what protocol/s or parameters.

Evidence is pointing to a modulatory role of transcutaneous auricular vagus nerve stimulation (taVNS) on the LC-norepinephrine (NE) system. However, there is currently no reliable noradrenergic biomarker of taVNS that produces replicable results across studies (see Burger et al., 2020; Farmer et al., 2020). Possible reasons for this lack of replicability are relatively small sample sizes and the heterogeneity of stimulation procedures used across studies. The aim of the present study is to overcome these limitations by pooling existing data from a large sample of studies that examined the effects of taVNS on salivary-alpha amylase (sAA; as indirect marker for noradrenergic activity) in healthy subjects.

The vagus nerve transmits information between peripheral organs and the dorsal vagal complex in the brain stem, thereby affecting digestion (Teckentrup et al., 2020), mood (Ferstl et al., 2021), and motivation (Neuser et al., 2020). Intriguingly, there is growing evidence that the left and right vagus branch are anatomically and functionally distinct (Han et al., 2018; Wang, de Lartigue, & Page, 2020). We previously demonstrated gastric slowing after left-sided taVNS versus sham stimulation (Teckentrup et al., 2020). In line with our preliminary results, Hong et al. (2019) found a decreased gastric frequency after left-sided taVNS using invasive recordings during surgery. Furthermore, Anselmi, Toti, Bove, and Travagli (2017) reported reduced gastric tone and motility after dopamine administration to the left dorsal motor nucleus of the vagus which was abolished after vagotomy of the left vagus branch. This suggests that an afferent–efferent feedback loop mediates efferent effects of taVNS on digestion. In contrast to left-sided taVNS, evidence for effects of right-sided stimulation on digestion are scarce. In a recent preregistered study, we found no effect of right-sided taVNS on gastric frequency (Teckentrup et al., 2019). Previous work from our lab on the effects of taVNS vs. sham stimulation on mood showed that taVNS improved positive mood recovery independent of stimulation side in a post stimulation phase after receiving a food reward, but not during the stimulation. Thus, this delayed increase in positive mood might be associated with the altered metabolic state (Ferstl et al., 2021). Kraus et al. (2007) also reported mood enhancing effects of left-sided taVNS post stimulation without administering a food reward. Hence, it is currently unclear if the taVNS-induced improvement in mood recovery is mediated by the ingestion of a caloric load. Regarding motivation, we found that taVNS boosts the drive to work for food rewards independent of stimulation side, whereas it boosted the drive to work for monetary rewards only after stimulation on the right side (Neuser et al., 2020). In summary, preliminary results point to distinct functions of the right and left vagus branches in modulating digestion, mood, and motivation. However, lateralization effects of taVNS have not been investigated within individuals yet, and studies based on right-sided stimulation are missing. As taVNS is being discussed as a promising therapeutic tool (Liu et al., 2016; Tu et al., 2018; Wu et al., 2018), an investigation of lateralization and time-dependent effects within-person is crucial to maximize effectiveness. Thus, with the planned protocol of the study focusing on within-person dense sampling of metabolic, mood, and motivational states without impeding gastric measures, we aim to conclusively answer if there are side- or time-dependent effects of taVNS on digestion, mood, and motivation.

Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are incurable autoimmune diseases characterized by chronic inflammation of the gastrointestinal tract. There is increasing evidence that inappropriate interaction between the enteric nervous system and central nervous system and/or low activity of the vagus nerve, which connects the enteric and central nervous systems, could play a crucial role in their pathogenesis. Therefore, it has been suggested that appropriate neuroprosthetic stimulation of the vagus nerve could lead to the modulation of the inflammation of the gastrointestinal tract and consequent long-term control of these autoimmune diseases. In the present paper, we provide a comprehensive overview of (1) the cellular and molecular bases of the immune system, (2) the way central and enteric nervous systems interact and contribute to the immune responses, (3) the pathogenesis of the inflammatory bowel disease, and (4) the therapeutic use of vagus nerve stimulation, and in particular, the transcutaneous stimulation of the auricular branch of the vagus nerve. Then, we expose the working hypotheses for the modulation of the molecular processes that are responsible for intestinal inflammation in autoimmune diseases and the way we could develop personalized neuroprosthetic therapeutic devices and procedures in favor of the patients.

Neonates born premature or who suffer brain injury at birth often have oral feeding dysfunction and do not meet oral intake requirements needed for discharge. Low oral intake volumes result in extended stays in the hospital (>2 months) and can lead to surgical implant and explant of a gastrostomy tube (G-tube). Prior work suggests pairing vagus nerve stimulation (VNS) with motor activity accelerates functional improvements after stroke, and transcutaneous auricular VNS (taVNS) has emerged as promising noninvasive form of VNS. Pairing taVNS with bottle-feeding rehabilitation may improve oromotor coordination and lead to improved oral intake volumes, ultimately avoiding the need for G-tube placement. We investigated whether taVNS paired with oromotor rehabilitation is tolerable and safe and facilitates motor learning in infants who have failed oral feeding. We enrolled 14 infants [11 premature and 3 hypoxic–ischemic encephalopathy (HIE)] who were slated for G-tube placement in a prospective, open-label study of taVNS-paired rehabilitation to increase feeding volumes. Once-daily taVNS was delivered to the left tragus during bottle feeding for 2 weeks, with optional extension. The primary outcome was attainment of oral feeding volumes and weight gain adequate for discharge without G-tube while also monitoring discomfort and heart rate (HR) as safety outcomes. We observed no adverse events related to stimulation, and stimulation-induced HR reductions were transient and safe and likely confirmed vagal engagement. Eight of 14 participants (57%) achieved adequate feeding volumes for discharge without G-tube (mean treatment length: 16 ± 6 days). We observed significant increases in feeding volume trajectories in responders compared with pre-stimulation (p < 0.05). taVNS-paired feeding rehabilitation appears safe and may improve oral feeding in infants with oromotor dyscoordination, increasing the rate of discharge without G-tube, warranting larger controlled trials.

Metabolic feedback between the gut and the brain relayed via the vagus nerve contributes to energy homeostasis. We investigated in healthy adults whether non-invasive stimulation of vagal afferents impacts energy homeostasis via efferent effects on metabolism or digestion. In a randomized crossover design, we applied transcutaneous auricular vagus nerve stimulation (taVNS) while recording efferent metabolic effects using simultaneous electrogastrography (EGG) and indirect calorimetry. We found that taVNS reduced gastric myoelectric frequency (p =.008), but did not alter resting energy expenditure. We conclude that stimulating vagal afferents induces gastric slowing via vagal efferents without acutely affecting net energy expenditure at rest. Collectively, this highlights the potential of taVNS to modulate digestion by activating the dorsal vagal complex. Thus, taVNS-induced changes in gastric frequency are an important peripheral marker of brain stimulation effects.

Background: Insomnia is a prevalent sleep disorder and strong risk factor for poor quality of life, depression, and other lifestylerelated diseases. Objectives: To investigate the effect of the transcutaneous vagus nerve stimulation (taVNS) on sleep electroencephalographic (EEG) in the para-chlorophenylalanine (PCPA) insomnia rats. Methods: Rats were divided into control, model, taVNS and sham taVNS (stnVNS) (stimulate the auricular margin, as transcutaneous none VNS, stnVNS) group (n=6 in each group). A week before the experiment, the electrodes were fixed to the skull of all the rats for recording the sleep EEG. PCPA was used to establish insomnia models. The rats of taVNS and stnVNS group were treated via an electroacupuncture apparatus for seven consecutive days, and simultaneously, the sleep EEG were recorded for all groups after the treatment daily. And the power spectrum analysis was used in this experiment. Results: After modeling, the percentage of power spectrum of delta frequency band significantly decreased, while the theta, alpha, and beta frequency bands significantly increased in the model group compared to the control group. After intervention, the percentage of the delta frequency band significantly increased in the taVNS group as compared to the stnVNS group. Conclusion: These results suggest that taVNS can significantly modulate the power spectrum of the delta frequency band and may constitute a potential low-cost alternative for the treatment of insomnia.

Background Migraine is a common episodic neurological disorder. Literature has shown that transcutaneous auricular vagus nerve stimulation (taVNS) at 1 Hz can significantly relieve migraine symptoms. However, its underlying mechanism remains unclear. This study aims to investigate the neural pathways associated with taVNS treatment of migraine. Methods Twenty-nine patients with migraine were recruited from outpatient neurology clinics. Each patient attended two magnetic resonance imaging/functional magnetic resonance imaging (MRI/fMRI) scan sessions separated by one week. Each session included a pre-stimulation resting state fMRI scan, fMRI scans during real or sham 1 Hz taVNS (with block design), and a post-stimulation resting state fMRI scan. Results Twenty-six patients were included in the final analyses. Real taVNS evoked fMRI signal decreases in brain areas belonging to the default mode network (DMN) and brain stem areas including the locus coeruleus (LC), raphe nuclei, parabrachial nucleus, and solitary nucleus. Sham taVNS evoked fMRI signal decreases in brain areas belonging to the DMN. Compared to sham taVNS, real taVNS produced greater deactivation at the bilateral LC. Resting state functional connectivity (rsFC) analysis showed that after taVNS, LC rsFC with the right temporoparietal junction and left secondary somatosensory cortex (S2) significantly increased compared to sham taVNS. The increased rsFC of the left LC-left S2 was significantly negatively associated with the frequency of migraine attacks during the preceding month. Conclusion Our results suggest that taVNS at 1 Hz can significantly modulate activity/connectivity of brain regions associated with the vagus nerve central pathway and pain modulation system, which may shed light on the neural mechanisms underlying taVNS treatment of migraine., Highlights • taVNS at l HZ evoked fMRI signal decrease in the locus coeruleus in migraine. • After taVNS, LC rsFC with TPJ, hippocampus and S2 increased in migraine. • The increased LC-S2 rsFC negatively associated with the frequency of migraine attacks.

Background Recently, clinical observations reported the potential benefit of vagus nerve stimulation (VNS) for pediatric epilepsy. Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a newer non-invasive VNS, making it more accessible for treating pediatric epilepsy, yet there is limited clinical evidence for its effectiveness. Methods/Design A three-center, randomized, parallel, controlled trial will be carried out to evaluate whether ta-VNS improves pediatric epilepsy. Pediatric patients aged 2 to 14 years with epilepsy will be recruited and randomly assigned to transcutaneous auricular vagus nerve stimulation (ta-VNS) group, transcutaneous auricular non-vagus nerve stimulation (tan-VNS) group, and control group with a 1:1: sqrt(2) allocation, as per a computer generated randomization schedule stratified by study center using permuted blocks of random sizes. We will use Zelen’s design, in which randomization occurs before informed consent. Patients in the stimulation groups will receive tan-VNS or ta-VNS three times a day for 6 months. Patients in the control group will not be provided with any stimulation during the 6 months. The guardians of the patients are required to keep a detailed diary to record the data. Outcome assessment including seizure frequency, electroencephalogram (EEG), heart rate variability (HRV) analysis, quality of life (QOL) and adverse events will be made at baseline and 2, 4 and 6 months after ta-VNS initiation. The seizure frequency and adverse events will be followed up at 1 year and 1.5 years after ta-VNS initiation. Discussion Results of this trial will help clarify whether ta-VNS treatment is beneficial for pediatric patients, and will make clear whether the anticonvulsive effect of ta-VNS is correlated with the improvement of sympathovagal imbalance. Trial registration Clinical Trials Identifier: NCT02004340. Registration date: 13 November 2013. Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-0906-8) contains supplementary material, which is available to authorized users.