Effects of transcutaneous auricular vagus nerve stimulation on P300 magnitudes and salivary alpha-amylase during an auditory oddball task.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neurostimulation technique that is thought to modulate noradrenergic activity. Previous studies have demonstrated inconsistent effects of taVNS on noradrenergic activity, which is possibly due to insufficient statistical power, suboptimal stimulation parameter settings, and data collection procedures. In this preregistered within-subject experiment, 44 healthy participants received taVNS and sham (earlobe) stimulation during two separate experimental sessions. Stimulation intensity was individually calibrated to the maximum level below pain. During each session, participants received the stimulation continuously ten minutes before an auditory novelty oddball task till the end of the experimental session. The P3b component of the event-related potential served as a marker of phasic noradrenergic activity, whereas P3a magnitude was explored as an index of dopaminergic activity. Salivary alpha-amylase (sAA) was measured as an index of tonic noradrenergic activity before and at the end of the stimulation. The taVNS and sham conditions did not differ in P3a or P3b magnitudes, nor sAA secretion. These findings call into question whether taVNS, administered continuously at high, nonpainful stimulation intensities, reliably augments noradrenergic activity via the vagus nerve.

Expiratory-gated Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) does not Further Augment Heart Rate Variability During Slow Breathing at 0.1 Hz.

As cardiac vagal control is a hallmark of good health and self-regulatory capacity, researchers are seeking ways to increase vagally mediated heart rate variability (vmHRV) in an accessible and non-invasive way. Findings with transcutaneous auricular vagus nerve stimulation (taVNS) have been disappointing in this respect, as its effects on vmHRV are inconsistent at best. It has been speculated that combining taVNS with other established ways to increase vmHRV may produce synergistic effects. To test this idea, the present study combined taVNS with slow breathing in a cross-over design. A total of 22 participants took part in two sessions of breathing at 6 breaths/min: once combined with taVNS, and once combined with sham stimulation. Electrical stimulation (100 Hz, 400 µs) was applied during expiration, either to the tragus and cavum conchae (taVNS) or to the earlobe (sham). ECG was recorded during baseline, 20-minutes of stimulation, and the recovery period. Frequentist and Bayesian analyses showed no effect of taVNS (in comparison to sham stimulation) on the root mean square of successive differences between normal heartbeats, mean inter-beat interval, or spectral power of heart rate variability at a breathing frequency of 0.1 Hz. These findings suggest that expiratory-gated taVNS combined with the stimulation parameters examined here does not produce acute effects on vmHRV during slow breathing.

Short bursts of transcutaneous auricular vagus nerve stimulation enhance evoked pupil dilation as a function of stimulation parameters.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neurostimulatory technique hypothesised to enhance central noradrenaline. Currently, there is scarce evidence in support of a noradrenergic mechanism of taVNS and limited knowledge on its stimulation parameters (i.e., intensity and pulse width). Therefore, the present study aimed to test whether taVNS enhances pupil dilation, a noradrenergic biomarker, as a function of stimulation parameters. Forty-nine participants received sham (i.e., left ear earlobe) and taVNS (i.e., left ear cymba concha) stimulation in two separate sessions, in a counterbalanced order. We administered short bursts (5s) of seven stimulation settings varying as a function of pulse width and intensity and measured pupil size in parallel. Each stimulation setting was administered sixteen times in separate blocks. We expected short bursts of stimulation to elicit phasic noradrenergic activity as indexed by event-related pupil dilation and event-related temporal derivative. We hypothesised higher stimulation settings, quantified as the total charge per pulse (pulse width x intensity), to drive greater event-related pupil dilation and temporal derivative in the taVNS compared to sham condition. Specifically, we expected stimulation settings in the taVNS condition to be associated with a linear increase in event-related pupil dilation and temporal derivative. We found stimulation settings to linearly increase both pupil measures. In line with our hypothesis, the observed dose-dependent effect was stronger in the taVNS condition. We also found taVNS to elicit more intense and unpleasant sensations than sham stimulation. These results support the hypothesis of a noradrenergic mechanism of taVNS. However, future studies should disentangle whether stimulation elicited sensations mediate the effect of taVNS on evoked pupil dilation.

Evidence for a modulating effect of transcutaneous auricular vagus nerve stimulation (taVNS) on salivary alpha-amylase as indirect noradrenergic marker: A pooled mega-analysis.

BACKGROUND: Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has received tremendous attention as a potential neuromodulator of cognitive and affective functions, which likely exerts its effects via activation of the locus coeruleus-noradrenaline (LC-NA) system. Reliable effects of taVNS on markers of LC-NA system activity, however, have not been demonstrated yet. METHODS: The aim of the present study was to overcome previous limitations by pooling raw data from a large sample of ten taVNS studies (371 healthy participants) that collected salivary alpha-amylase (sAA) as a potential marker of central NA release. RESULTS: While a meta-analytic approach using summary statistics did not yield any significant effects, linear mixed model analyses showed that afferent stimulation of the vagus nerve via taVNS increased sAA levels compared to sham stimulation (b = 0.16, SE = 0.05, p = 0.001). When considering potential confounders of sAA, we further replicated previous findings on the diurnal trajectory of sAA activity. CONCLUSION(S): Vagal activation via taVNS increases sAA release compared to sham stimulation, which likely substantiates the assumption that taVNS triggers NA release. Moreover, our results highlight the benefits of data pooling and data sharing in order to allow stronger conclusions in research.

No evidence for a modulating effect of continuous transcutaneous auricular vagus nerve stimulation on markers of noradrenergic activity.

Although transcutaneous auricular vagus nerve stimulation (taVNS) is thought to increase central noradrenergic activity, findings supporting such mechanism are scarce and inconsistent. This study aimed to investigate whether taVNS modulates indirect markers of phasic and tonic noradrenergic activity. Sixty-six healthy participants performed a novelty auditory oddball task twice on separate days: once while receiving taVNS (left cymba concha), once during sham (left earlobe) stimulation. To maximize potential effects, the stimulation was delivered continuously (frequency: 25 Hz; width: 250 µs) at an intensity individually calibrated to the maximal level below pain threshold. The stimulation was administered 10 min before the oddball task and maintained throughout the session. Event-related pupil dilation (ERPD) to target stimuli and pre-stimulus baseline pupil size were assessed during the oddball task as markers of phasic and tonic noradrenergic activity, respectively. Prior to and at the end of stimulation, tonic pupil size at rest, cortisol, and salivary alpha-amylase were assessed as markers of tonic noradrenergic activity. Finally, we explored the effect of taVNS on cardiac vagal activity, respiratory rate, and salivary flow rate. Results showed a greater ERPD to both target and novelty compared to standard stimuli in the oddball task. In contrast to our hypotheses, taVNS did not impact any of the tested markers. Our findings strongly suggest that continuous stimulation of the cymba concha with the tested stimulation parameters is ineffective to increase noradrenergic activity via a vagal pathway.

Learn to breathe, breathe to learn? No evidence for effects of slow deep breathing at a 0.1 Hz frequency on reversal learning.

This study sought to investigate whether slow deep breathing (SDB) facilitates reversal learning. We also explored whether SDB modulates the renewal effect. After learning a series of cue-outcome associations (early acquisition phase) in a predictive learning task, 37 participants paced their breathing according to a normal (NPB group; 0.2 Hz) or a slow (SDB group; 0.1 Hz) pattern while completing the reversal and renewal phases. Response correctness, heart rate variability (HRV, i.e., Root mean square of successive differences), and respiratory rate were assessed. Findings indicated that both groups adopted the targeted breathing pattern. As expected, the SDB (vs. NPB) group displayed a steeper rise in HRV from early acquisition to the later phases of the task during which the breathing manipulation took place. However, the performance of the NPB and SDB groups did not significantly differ in any phase of the predictive learning task. Despite the inconclusive findings on the effect of SDB on reversal and renewal, these results confirm that SDB can be performed while performing a learning task.

Effects of transcutaneous auricular vagus nerve stimulation on reversal learning, tonic pupil size, salivary alpha-amylase, and cortisol.

This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) enhances reversal learning and augments noradrenergic biomarkers (i.e., pupil size, cortisol, and salivary alpha-amylase [sAA]). We also explored the effect of taVNS on respiratory rate and cardiac vagal activity (CVA). Seventy-one participants received stimulation of either the cymba concha (taVNS) or the earlobe (sham) of the left ear. After learning a series of cue-outcome associations, the stimulation was applied before and throughout a reversal phase in which cue-outcome associations were changed for some (reversal), but not for other (distractor) cues. Tonic pupil size, salivary cortisol, sAA, respiratory rate, and CVA were assessed at different time points. Contrary to our hypothesis, taVNS was not associated with an overall improvement in performance on the reversal task. Compared to sham, the taVNS group performed worse for distractor than reversal cues. taVNS did not increase tonic pupil size and sAA. Only post hoc analyses indicated that the cortisol decline was steeper in the sham compared to the taVNS group. Exploratory analyses showed that taVNS decreased respiratory rate but did not affect CVA. The weak and unexpected effects found in this study might relate to the lack of parameters optimization for taVNS and invite to further investigate the effect of taVNS on cortisol and respiratory rate.

Moving beyond belief: A narrative review of potential biomarkers for transcutaneous vagus nerve stimulation.

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive neurostimulation technique that is currently being tested as a potential treatment for a myriad of neurological and psychiatric disorders. However, the working mechanisms underlying tVNS are poorly understood and it remains unclear whether stimulation activates the vagus nerve for every participant. Finding a biological marker of tVNS is imperative, as it can help guide research on clinical applications and can inform researchers on optimal stimulation sites and parameters to further optimize treatment efficacy. In this narrative review, we discuss five potential biomarkers for tVNS and review currently available evidence for these markers for both invasive and tVNS. While some of these biomarkers hold promise from a theoretical perspective, none of the potential biomarkers provide clear and definitive indications that tVNS increases the vagal activity or augments activity in the locus coeruleus-noradrenaline network. We conclude the review by providing several recommendations for how to tackle the challenges and opportunities when researching potential biomarkers for the effects of tVNS.

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

Effects of (in)validation and plain versus technical language on the experience of experimentally induced pain: A computer controlled simulation paradigm.

BACKGROUND AND OBJECTIVES: Amongst social contextual influences on pain, the manner in which pain and painful procedures are communicated to patients is considered an important contributor to the subjective experience of pain. Threatening information, e.g., by the use of technical language, is suggested to increase pain reports. Validation, or communicating understanding towards another person reporting personal experiences, is suggested to reduce pain. The current study examines effects of both information language (technical vs. plain language) and validation (validation vs. invalidation) on the subjective experience of experimentally induced pain. METHODS: Pain-free participants (N = 132) were randomly assigned to one of four groups as formed by manipulations of validation and information language. After reading a description concerning the upcoming thermal stimulus formulated in technical or plain language, participants engaged in a computer controlled simulation (CCS; based on virtual reality technology). Participants received three thermal stimuli while interacting with an avatar who either validated or invalidated their experience during the CCS. Pain intensity and pain unpleasantness were assessed after each stimulus. RESULTS: The validation manipulation showed to be effective, but the information language manipulation did not induce differential threat expectancies. Results show no effect of validation or information language on subjective pain reports. LIMITATIONS: Suboptimality of the information language manipulation and shortcomings of the CCS procedure might account for current findings. CONCLUSIONS: The study offers an interesting model for the further experimental study of isolated and combined effects of (social) contextual factors on pain. Diverse future research avenues are discussed.