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Transcutaneous auricular vagus nerve stimulation (taVNS) bears therapeutic potential for a wide range of medical conditions. However, previous studies have found substantial interindividual variability in responsiveness to taVNS, and no reliable predictive biomarker for stimulation success has been developed so far. In this study, we investigate pupil size and event-related pupil response as candidate biomarkers. Both measures have a direct physiological link to the activity of the locus coeruleus (LC), a brainstem structure and the main source of norepinephrine in the brain. LC activation is considered one of the key mechanisms of action of taVNS, therefore, we expected a clear increase of the pupillary measures under taVNS compared to sham (placebo) stimulation, such that it could serve as a prospective predictor for individual clinical and physiological taVNS effects in future studies. We studied resting pupil size and pupillary responses to target stimuli in an auditory oddball task in 33 healthy young volunteers. We observed stronger pupil responses to target than to standard stimuli. However, and contrary to our hypothesis, neither pupil size nor the event-related pupil response nor behavioral performance were modulated by taVNS. We discuss potential explanations for this negative finding and its implications for future clinical investigation and development of taVNS.

•taVNS effects on brainstem activity are assessed during fMRI.•taVNS modulates activity in brainstem vagal afferent targets (including the NTS).•The signal dynamics over time indicates both acute, persistent and delayed effects of taVNS. Our increasing knowledge about gut-brain interaction is revolutionising the understanding of the links between digestion, mood, health, and even decision making in our everyday lives. In support of this interaction, the vagus nerve is a crucial pathway transmitting diverse gut-derived signals to the brain to monitor of metabolic status, digestive processes, or immune control to adapt behavioural and autonomic responses. Hence, neuromodulation methods targeting the vagus nerve are currently explored as a treatment option in a number of clinical disorders, including diabetes, chronic pain, and depression. The non-invasive variant of vagus nerve stimulation (VNS), transcutaneous auricular VNS (taVNS), has been implicated in both acute and long-lasting effects by modulating afferent vagus nerve target areas in the brain. The physiology of neither of those effects is, however, well understood, and evidence for neuronal response upon taVNS in vagal afferent projection regions in the brainstem and its downstream targets remain to be established. Therefore, to examine time-dependent effects of taVNS on brainstem neuronal responses in healthy human subjects, we applied taVNS during task-free fMRI in a single-blinded crossover design. During fMRI data acquisition, we either stimulated the left earlobe (sham), or the target zone of the auricular branch of the vagus nerve in the outer ear (cymba conchae, verum) for several minutes, both followed by a short ‘stimulation OFF’ period. Time-dependent effects were assessed by averaging the BOLD response for consecutive 1-minute periods in an ROI-based analysis of the brainstem. We found a significant response to acute taVNS stimulation, relative to the control condition, in downstream targets of vagal afferents, including the nucleus of the solitary tract, the substantia nigra, and the subthalamic nucleus. Most of these brainstem regions remarkably showed increased activity in response to taVNS, and these effect sustained during the post-stimulation period. These data demonstrate that taVNS activates key brainstem regions, and highlight the potential of this approach to modulate vagal afferent signalling. Furthermore, we show that carry-over effects need to be considered when interpreting fMRI data in the context of general vagal neurophysiology and its modulation by taVNS.

The present study investigated the effects of transcutaneous vagus nerve stimulation on cardiac vagal activity, the activity of the vagus nerve regulating cardiac functioning. We applied stimulation on the left cymba conchae and tested the effects of different stimulation intensities on a vagally-mediated heart rate variability pagerameter (i.e., the root mean square of successive differences) as well as on subjective ratings of strength of perceived stimulation intensity and unpleasantness due to the stimulation. Three experiments (within-subject designs, M = 61 healthy participants each) were carried out: In Experiment 1, to choose one fixed stimulation intensity for the subsequent studies, we compared three preset stimulation intensities (i.e., 0.5, 1.0 and 1.5 mA) with each other. In Experiment 2, we compared the set stimulation method with the free stimulation method, in which the participants were instructed to freely choose an intensity. In Experiment 3, to control for placebo effects, we compared both methods (i.e., set stimulation vs. free stimulation) with their respective sham stimulations. In the three experiments, an increase of cardiac vagal activity was found from resting to the stimulation phases. However, this increase in cardiac vagal activity was not dependent on stimulation intensity (Experiment 1), the method used to stimulate (i.e., set vs. free; Experiment 2), or whether stimulation was active or sham (Experiment 3). This pattern of results was solidly supported by Bayesian estimations. On the subjective level, higher stimulation intensities were perceived as significantly stronger and a stronger stimulation was generally also perceived as more unpleasant. The results suggest that cardiac vagal activity may be similarly influenced by afferent vagal stimuli triggered by active and sham stimulation with different stimulation intensities. Potential explanations for these findings and its implications for future research with tVNS are discussed.

In this randomized, double-blind, sham-controlled trial, we explored the effect of 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on gait impairments in Parkinson's disease (PD) patients and investigated the underlying neural mechanism. In total, 22 PD patients and 14 healthy controls were enrolled. PD patients were randomized (1:1) to receive active or sham taVNS (same position as active taVNS group but without releasing current) twice a day for 1 week. Meanwhile, all subjects were measured activation in the bilateral frontal and sensorimotor cortex during usual walking by functional near-infrared spectroscopy. PD patients showed instable gait with insufficient range of motion during usual walking. Active taVNS improved gait characteristics including step length, stride velocity, stride length, and step length variability compared with sham taVNS after completion of the 7-day therapy. No difference was found in the Unified Parkinson's Disease Rating Scale III, Timed Up and Go, Tinetti Balance, and Gait scores. Moreover, PD patients had higher relative change of oxyhemoglobin in the left dorsolateral prefrontal cortex, pre-motor area, supplementary motor area, primary motor cortex, and primary somatosensory cortex than HCs group during usual walking. Hemodynamic responses in the left primary somatosensory cortex were significantly decreased after taVNS therapy. taVNS can relieve gait impairments and remodel sensorimotor integration in PD patients.

The mechanisms underlying the association between positive emotions and physical health remain a mystery. We hypothesize that an upward-spiral dynamic continually reinforces the tie between positive emotions and physical health and that this spiral is mediated by people's perceptions of their positive social connections. We tested this overarching hypothesis in a longitudinal field experiment in which participants were randomly assigned to an intervention group that self-generated positive emotions via loving-kindness meditation or to a waiting-list control group. Participants in the intervention group increased in positive emotions relative to those in the control group, an effect moderated by baseline vagal tone, a proxy index of physical health. Increased positive emotions, in turn, produced increases in vagal tone, an effect mediated by increased perceptions of social connections. This experimental evidence identifies one mechanism—perceptions of social connections—through which positive emotions build physical health, indexed as vagal tone. Results suggest that positive emotions, positive social connections, and physical health influence one another in a self-sustaining upward-spiral dynamic.

This proof-of-concept study evaluated the acute effects of transcutaneous auricular vagus nerve stimulation (taVNS) on cardiac vagal activity in people living with HIV. Twenty-one men living with HIV on antiretroviral therapy participated in a single-blind, crossover clinical trial. Participants underwent two counterbalanced stimulation conditions (taVNS and sham) with a 48-hour washout period. Cardiac vagal activity was assessed using vagally-mediated heart rate variability (vmHRV) indices, including the root mean square of successive differences (rMSSD) and the percentage of differences between adjacent normal intervals greater than 50 ms (pNN50), recorded before, during, and after stimulation. No significant changes in vmHRV parameters were observed over time or between conditions. These findings suggest that an acute taVNS session does not modulate cardiac vagal activity in people living with HIV. We discuss potential explanations for these results and highlight considerations for future research on taVNS as a non-pharmacological approach to autonomic modulation.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising technique that potentially influences cortical activity, mainly increasing electroencephalography (EEG) power spectrum activity in low-frequency oscillations, and demonstrates potential therapeutic benefits for various pathologic conditions, like depression and chronic pain. To learn further about taVNS brain mechanisms, the present study investigated how using a single taVNS session can affect brain oscillations in healthy subjects. 44 healthy participants were included in this randomized, double-blind, sham-controlled trial. Participants were divided into the active and sham taVNS groups. Resting-state EEG power was analyzed across the frontal, central, and parietal regions in both hemispheres. Our findings demonstrated that active taVNS modulates low-frequency oscillations in the frontal areas of healthy subjects. After the intervention, the average delta power at the frontal region increased in the active group compared to the sham group. These changes were also observed with an increase in delta asymmetry (towards the right hemisphere) in the active group compared to the sham group. In healthy subjects, active taVNS selectively induces changes in the resting-state frontal brain oscillations. Our results suggest that taVNS increases homeostatic low-frequency oscillatory activity mainly over the right frontal hemisphere. Active taVNS induces activation of the fronto-vagal network, which has a therapeutic potential to generate salutogenic and balanced brain activity.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising noninvasive technique with potential beneficial effects on human emotion and cognition, including cortical arousal and alertness. However, it remains unclear how taVNS could improve cortical arousal and alertness, which are crucial for consciousness and daily task performance. Here, we aimed to estimate the modulatory effect of taVNS on cortical arousal and alertness and to reveal its underlying neural mechanisms. Sixty subjects were recruited and randomly assigned to either the taVNS group (receiving taVNS for 20 min) or the control group (receiving taVNS for 30 s). The effects of taVNS were evaluated behaviorally using a cue-target pattern task, and neurologically using a resting-state electroencephalogram (EEG). We found that taVNS facilitated the reaction time for the targets requiring right-hand responses and attenuated high-frequency alpha oscillations under the close-eye resting state. Importantly, taVNS-modulated alpha oscillations were positively correlated with the facilitated target detection performance, i.e., reduced reaction time. Furthermore, microstate analysis of the resting-state EEG when the eyes were closed illustrated that taVNS reduced the mean duration of microstate C, which has been proven to be associated with alertness. Altogether, this work provided novel evidence suggesting that taVNS could be an enhancer of both cortical arousal and alertness.

It has been demonstrated that acute vagus nerve stimulation (VNS) improves word recognition memory in epilepsy patients. Transcutaneous auricular vagus nerve stimulation (taVNS) has gained interest as a non-invasive alternative to improve cognition. In this prospective randomized cross-over study, we investigated the effect of both invasive VNS and taVNS on verbal memory performance in 15 patients with drug-resistant epilepsy. All patients conducted a word recognition memory paradigm in 3 conditions: VNS ON, VNS OFF and taVNS (3-period 3-treatment cross-over study design). For each condition, patients memorized 21 highlighted words from text paragraphs. Afterwards, the intervention was delivered for 30 s. Immediate recall and delayed recognition scores were obtained for each condition. This memory paradigm was repeated after 6 weeks of VNS therapy in 2 conditions: VNS ON and VNS OFF (2-period 2-treatment cross-over study design). Acute VNS and taVNS did not improve verbal memory performance. Immediate recall and delayed recognition scores were significantly improved after 6 weeks of VNS treatment irrespective of the acute intervention. We can conclude that the previously described positive effects of invasive VNS on verbal memory performance could not be replicated with invasive VNS and taVNS. An improved verbal memory performance was seen after 6 weeks of VNS treatment, suggesting that longer and more repetitive stimulation of the vagal pathway is required to modulate verbal memory performance. Clinical trial registration number : NCT05031208.

The present study examined the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on short-latency afferent inhibition (SAI), as indirect biomarker of cholinergic system activation. 24 healthy adults underwent intermittent taVNS (30 s on/30 s off, 30 min) or continuous taVNS at a frequency of 25 Hz (15 min) along with earlobe temporary stimulation (15 min or 30 min) were performed in random order. The efficiency with which the motor evoked potential from the abductor pollicis brevis muscle by transcranial magnetic stimulation was attenuated by the preceding median nerve conditioning stimulus was compared before taVNS, immediately after taVNS, and 15 min after taVNS. Continuous taVNS significantly increased SAI at 15 min post-stimulation compared to baseline. A positive correlation (Pearson coefficient = 0.563, p  = 0.004) was observed between baseline SAI and changes after continuous taVNS. These results suggest that 15 min of continuous taVNS increases the activity of the cholinergic nervous system, as evidenced by the increase in SAI. In particular, the increase after taVNS was more pronounced in those with lower initial SAI. This study provides fundamental insight into the clinical potential of taVNS for cholinergic dysfunction.