Transcutaneous vagus nerve stimulation does not affect verbal memory performance in healthy volunteers

Introduction: Invasive vagus nerve stimulation (VNS) improves word recognition memory in patients with epilepsy. Recent studies with transcutaneous VNS (tVNS) have also shown positive effects on various subdomains of cognitive functioning in healthy volunteers. In this randomized, controlled, crossover study, we investigated the effect of tVNS on a word recognition memory paradigm in healthy volunteers to further investigate the potential of tVNS in the treatment of cognitive disorders. Methods: We included 41 healthy participants aged between 18 and 30 years (young age group) and 24 healthy participants aged between 45 and 80 years (older age group). Each participant completed a word recognition memory paradigm during three different conditions: true tVNS, sham, and control. During true tVNS, stimulation was delivered at the cymba conchae. Sham stimulation was delivered by stimulating the earlobe. In the control condition, no stimulation was given. In each condition, participants were asked to remember highlighted words from three test paragraphs. Accuracy scores were calculated for immediate recall after each test paragraph and for delayed recognition at the end of the paradigm. We hypothesized that highlighted words from paragraphs in the true tVNS condition would be more accurately recalled and/or recognized compared to highlighted words from paragraphs in the sham or control condition. Results: In this randomized study, tVNS did not affect the accuracy scores for immediate recall or delayed recognition in both age groups. The younger group showed significantly higher accuracy scores than the older group. The accuracy scores improved over time, and the most recently learned words were better recognized. Participants rated true tVNS as significantly more painful; however, pain was not found to affect accuracy scores. Conclusion: In this study, tVNS did not affect verbal memory performance in healthy volunteers. Our results could not replicate the positive effects of invasive VNS on word recognition memory in epilepsy patients. Future research with the aim of improving cognitive function should focus on the rational identification of optimized and individualized stimulation settings primarily in patients with cognitive deficits

Transcutaneous vagus nerve stimulation via tragus or cymba conchae: Are its psychophysiological effects dependent on the stimulation area?

Efforts in optimizing transcutaneous vagus nerve stimulation (tVNS) are crucial to further develop its potential in improving cognitive and autonomic regulation. The present study focused on this topic. The aim was to compare for the first time the main stimulation areas of the ear currently used in studies with tVNS, taking cognitive as well as neurophysiological effects into account. The main areas to be compared with one another were tragus, cymba conchae, and earlobe (sham) stimulation. Post-error slowing, which has already been shown to be influenced by tVNS, was used to investigate the cognitive effects of tVNS when applied on the different auricular areas. On the neurophysiological level, we measured pupillary responses as an index of norepinephrine activity during post-error slowing, and cardiac vagal activity to investigate the activation of neural pathways involved in post-error slowing. Stimulation of different auricular areas led to no differences in post-error slowing and in pupillary responses. However, the neurological processes involved in post-error slowing could be observed, since norepinephrine activity increased after committing an error. Further, there was an increase in cardiac vagal activity over the test period that was independent of the stimulation areas. The results suggest that tVNS targeting the ear might have a non-specific effect on the processing of error commission, on pupillary responses, and on cardiac vagal activity. We conclude that it is necessary to consider alternatives for sham conditions other than electrical earlobe stimulation. [Abstract copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

The potential for autonomic neuromodulation to reduce perioperative complications and pain: a systematic review and meta-analysis

BACKGROUND: Autonomic dysfunction promotes organ injury after major surgery through numerous pathological mechanisms. Vagal withdrawal is a key feature of autonomic dysfunction, and it may increase the severity of pain. We systematically evaluated studies that examined whether vagal neuromodulation can reduce perioperative complications and pain. METHODS: Two independent reviewers searched PubMed, EMBASE, and the Cochrane Register of Controlled Clinical Trials for studies of vagal neuromodulation in humans. Risk of bias was assessed; I2 index quantified heterogeneity. Primary outcomes were organ dysfunction (assessed by measures of cognition, cardiovascular function, and inflammation) and pain. Secondary outcomes were autonomic measures. Standardised mean difference (SMD) using the inverse variance random-effects model with 95% confidence interval (CI) summarised effect sizes for continuous outcomes. RESULTS: From 1258 records, 166 full-text articles were retrieved, of which 31 studies involving patients (n=721) or volunteers (n=679) met the inclusion criteria. Six studies involved interventional cardiology or surgical patients. Indirect stimulation modalities (auricular [n=23] or cervical transcutaneous [n=5]) were most common. Vagal neuromodulation reduced pain (n=10 studies; SMD=2.29 [95% CI, 1.08-3.50]; P=0.0002; I2=97%) and inflammation (n=6 studies; SMD=1.31 [0.45-2.18]; P=0.003; I2=91%), and improved cognition (n=11 studies; SMD=1.74 [0.96-2.52]; P<0.0001; I2=94%) and cardiovascular function (n=6 studies; SMD=3.28 [1.96-4.59]; P<0.00001; I2=96%). Five of six studies demonstrated autonomic changes after vagal neuromodulation by measuring heart rate variability, muscle sympathetic nerve activity, or both. CONCLUSIONS: Indirect vagal neuromodulation improves physiological measures associated with limiting organ dysfunction, although studies are of low quality, are susceptible to bias and lack specific focus on perioperative patients

The Neuromodulatory and Hormonal Effects of Transcutaneous Vagus Nerve Stimulation as Evidenced by Salivary Alpha Amylase, Salivary Cortisol, Pupil Diameter, and the P3 Event-Related Potential

Background Transcutaneous vagus nerve stimulation (tVNS) is a new, non-invasive technique being investigated as an intervention for a variety of clinical disorders, including epilepsy and depression. It is thought to exert its therapeutic effect by increasing central norepinephrine (NE) activity, but the evidence supporting this notion is limited. Objective In order to test for an impact of tVNS on psychophysiological and hormonal indices of noradrenergic function, we applied tVNS in concert with assessment of salivary alpha amylase (SAA) and cortisol, pupil size, and electroencephalograph (EEG) recordings. Methods Across three experiments, we applied real and sham tVNS to 61 healthy participants while they performed a set of simple stimulus-discrimination tasks. Before and after the task, as well as during one break, participants provided saliva samples and had their pupil size recorded. EEG was recorded throughout the task. The target for tVNS was the cymba conchae, which is heavily innervated by the auricular branch of the vagus nerve. Sham stimulation was applied to the ear lobe. Results P3 amplitude was not affected by tVNS (Experiment 1A: N = 24; Experiment 1B: N = 20; Bayes factor supporting null model = 4.53), nor was pupil size (Experiment 2: N = 16; interaction of treatment and time: p = .79). However, tVNS increased SAA (Experiments 1A and 2: N = 25) and attenuated the decline of salivary cortisol compared to sham (Experiment 2: N = 17), as indicated by significant interactions involving treatment and time (p = .023 and p = .040, respectively). Conclusion These findings suggest that tVNS modulates hormonal indices but not psychophysiological indices of noradrenergic function

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

Influence of transcutaneous vagus nerve stimulation on cardiac vagal activity: Not different from sham stimulation and no effect of stimulation intensity

© 2019 Borges et al. 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 parameter (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

The Compassionate Vagus: effects of transcutaneous vagal nerve stimulation on cognition, emotion and heart rate variability during compassionate mind training

This clinical psychology doctoral thesis is structured into three chapters. The first chapter presents a systematic review of the cognitive and emotional domains affected by transcutaneous vagus nerve stimulation (tVNS). It also aims to present an overview of the experimental designs, psychological tasks, outcome measures, participant groups and stimulation parameters used in the field of tVNS. The second chapter is an empirical paper investigating the potential facilitatory effects of tVNS as an adjunct to compassionate mind training (CMT). The study investigates the effect of tVNS and CMT on state affect, self-compassion/criticism, vagally mediated heart rate variability and emotional face processing in healthy participants. The third chapter is a critical appraisal of the research process of chapter 1 and 2

Reduced Frontal Nogo-N2 With Uncompromised Response Inhibition During Transcutaneous Vagus Nerve Stimulation—More Efficient Cognitive Control?

We have previously shown invasive vagus nerve stimulation to improve attention and working memory and alter emotion-attention interaction in patients with refractory epilepsy, suggesting that VNS might be useful in the treatment of cognitive impairment. The current research focuses on whether non-invasive, transcutaneous vagus nerve stimulation (tVNS) has similar effects to VNS. Furthermore, we aimed to assess whether tVNS has an impact on cognitive control in general or on underlying brain physiology in a task that mimics everyday life demands where multiple executive functions are engaged while encountering intervening emotional stimuli. Event-related potentials (ERP) evoked in such a task, specifically centro-parietal P3 and frontal N2 were used as biomarkers for attention allocation and cognitive control required to carry out the task. A single-blinded, sham-controlled, within-subject study on healthy subjects (n = 25) was conducted using Executive Reaction Time Test (RT-test), a Go/NoGo task engaging multiple executive functions along with intervening threat-related distractors while EEG was recorded. tVNS at the left tragus and sham stimulation at the left ear lobe was alternately delivered throughout the task. To assess the impact of tVNS on neural activity underlying attention and cognitive control, centro-parietal P3 and frontal N2 peak amplitudes were measured in Go and NoGo conditions. Task performance was assessed with RTs and different error types reflecting cognitive control in general and distinct executive functions, such as working memory and response inhibition.No significant effects due to tVNS on performance in the Executive RT-test were observed. For N2 there was a main effect of stimulator status and a significant interaction of trial type (Go, NoGo) and stimulator status. Post hoc analysis revealed that tVNS resulted in a significant reduction of frontal N2 only in the NoGo condition. No significant effects were observed for P3 nor were there any effects of emotion. Diminished NoGo-N2 potential along with unaltered task performance during tVNS suggests fewer cognitive control resources were required to successfully withhold a prepotent response. Though caution is warranted, we suggest that tVNS may lead to more efficient neural processing with fewer resources needed for successful cognitive control, providing promise for its potential use in cognitive enhancement.Peer reviewe

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