Effects of Transcutaneous Auricular Vagus Nerve Stimulation on the P300: Do Stimulation Duration and Stimulation Type Matter?

Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has attracted increasing interest as a neurostimulation tool with potential applications in modulating cognitive processes such as attention and memory, possibly through the modulation of the locus-coeruleus noradrenaline system. Studies examining the P300 brain-related component as a correlate of noradrenergic activity, however, have yielded inconsistent findings, possibly due to differences in stimulation parameters, thus necessitating further investigation. In this event-related potential study involving 61 participants, therefore, we examined how changes in taVNS parameters, specifically stimulation type (interval vs. continuous stimulation) and duration, influence P300 amplitudes during a visual novelty oddball task. Although no effects of stimulation were found over the whole cluster and time window of the P300, cluster-based permutation tests revealed a distinct impact of taVNS on the P300 response for a small electrode cluster, characterized by larger amplitudes observed for easy targets (i.e., stimuli that are easily discernible from standards) following taVNS compared to sham stimulation. Notably, our findings suggested that the type of stimulation significantly modulated taVNS effects on the P300, with continuous stimulation showing larger P300 differences (taVNS vs. sham) for hard targets and standards compared to interval stimulation. We observed no interaction effects of stimulation duration on the target-related P300. While our findings align with previous research, further investigation is warranted to fully elucidate the influence of taVNS on the P300 component and its potential utility as a reliable marker for neuromodulation in this field.

Transcutaneous vagal nerve stimulation during lower body negative pressure.

BACKGROUND: Para-sympathetic vagal activation has profound influence on heart rate and other cardiovascular parameters. We tested the hypothesis that transcutaneous Vagal Nerve Stimulation (tVNS) through the auricular branch of the vagus nerve would attenuate the normal sympathetic response to central blood volume reduction by lower body negative pressure (LBNP). METHOD: 10 healthy volunteers (6 female; age 21 ± 2 years; weight 62 ± 13 kg; height 167 ± 12 cm) were included in this cross-over design trial. After 15 min rest in supine position, subjects underwent three 15-min periods of 30 mmHg LBNP intervention with and without cyclic tVNS stimulation. Continuous cardiovascular parameters (Nexfin) were recorded. RESULTS: Overall tVNS did not convincingly attenuate sympathetic response to central hypovolemia. Deactivation of the tVNS during LBNP resulted in increased MAP at 2.3 ± 0.5 mmHg (P < 0.001). Comparing the cyclic actual active stimulation periods to periods with pause during tVNS intervention showed a decrease in HR by 72.9 ± 11.2 to 70.2 ± 11.6 bpm (mean ± SD; P < 0.05), and concomitant increases in SV (86.0 ± 12.1 to 87.2 ± 12.6 mL; P < 0.05), MAP (82.9 ± 6.3 to 84.0 ± 6.2 mmHg; P < 0.05) and TPR (1116.0 ± 111.1 to 1153 ± 104.8 dyn*s/cm5; P < 0.05). CONCLUSION: tVNS in 30 s cycles during LBNP can selectively attenuate HR, prompting a compensatory augmented sympathetic response. It would appear the method used in this study at least, has an isolated cardiac inhibitory effect probably mediated by augmented vagal activity on the sinoatrial or atrio-ventricular node, possibly in combination with reduced activity in the sympathetic cardiac nerve.

Transcutaneous vagus nerve stimulation improves Long COVID symptoms in a female cohort: a pilot study.

Background: Long COVID, also known as Post-COVID-19 syndrome, is characterized by multisystemic symptoms that persists for weeks to years beyond acute infection. It disproportionately affects women and those with pre-existing anxiety/depression, conditions more prevalent in females. The vagus nerve, with its extensive innervation and regulation of critical bodily functions, has become a focal point for therapeutic interventions. Transcutaneous vagus nerve stimulation (t-VNS) has emerged as a promising non-invasive treatment for COVID-19 conditions. Methods: This pilot study assessed the efficacy of t-VNS in 24 female Long COVID patients (45.8 ± 11.7 years old; 20.2 ± 7.1 months since infection), who underwent a 10-day t-VNS intervention at home (30 min/session, twice a day). Cognition was considered the primary outcome, with anxiety, depression, sleep, fatigue, and smell as secondary outcomes. Outcomes were measured at baseline, post-intervention, and 1-month follow-up. Results: Significant improvements were observed in various cognitive functions, anxiety, depression, and sleep at post-intervention, with benefits remaining or progressing at 1-month follow-up. Improvements in fatigue were delayed, reaching statistical significance at 1-month follow-up compared to baseline. No significant changes were noted in olfactory performance. Conclusion: This pilot study provides preliminary evidence supporting the potential of t-VNS as a therapeutic intervention for female Long COVID patients. The encouraging results justify further rigorous investigation through larger, randomized controlled trials to confirm the efficacy of t-VNS, assess its generalizability to male cohorts, and explore biological markers to inform personalized treatment approaches. Our findings support the allocation of resources to conduct such trials and advance the understanding of t-VNS as a potential treatment for Long COVID.

Non-invasive vagus nerve stimulation conditions increased invigoration and wanting in depression.

BACKGROUND: Major depressive disorder (MDD) is often marked by impaired motivation and reward processing, known as anhedonia. Many patients do not respond to first-line treatments, and improvements in motivation can be slow, creating an urgent need for rapid interventions. Recently, we demonstrated that transcutaneous auricular vagus nerve stimulation (taVNS) acutely boosts effort invigoration in healthy participants, but its effects on depression remain unclear. OBJECTIVE: To assess the impact of taVNS on effort invigoration and maintenance in a sample that includes patients with MDD, evaluating the generalizability of our findings. METHODS: We used a single-blind, randomized crossover design in 30 patients with MDD and 29 matched (age, sex, and BMI) healthy control participants (HCP). RESULTS: Consistent with prior findings, taVNS increased effort invigoration for rewards in both groups during Session 1 (p = .040), particularly for less wanted rewards in HCP (pboot < 0.001). However, invigoration remained elevated in all participants, and no acute changes were observed in Session 2 (Δinvigoration = 3.3, p = .12). Crucially, throughout Session 1, we found taVNS-induced increases in effort invigoration (pboot = 0.008) and wanting (pboot = 0.010) in patients with MDD, with gains in wanting maintained across sessions (Δwanting = 0.06, p = .97). CONCLUSIONS: Our study replicates the invigorating effects of taVNS in Session 1 and reveals its generalizability to depression. Furthermore, we expand upon previous research by showing taVNS-induced conditioning effects on invigoration and wanting within Session 1 in patients that were largely sustained. While enduring motivational improvements present challenges for crossover designs, they are highly desirable in interventions and warrant further follow-up research.

Tonic and phasic transcutaneous auricular vagus nerve stimulation (taVNS) both evoke rapid and transient pupil dilation.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (tVNS or taVNS) is a non-invasive method of electrical stimulation of the afferent pathway of the vagus nerve, suggested to drive changes in putative physiological markers of noradrenergic activity, including pupil dilation. OBJECTIVE: However, it is unknown whether different taVNS modes can map onto the phasic and tonic modes of noradrenergic activity. The effects of taVNS on pupil dilation in humans are inconsistent, largely due to differences in stimulation protocols. Here, we attempted to address these issues. METHODS: We investigated pupil dilation under phasic (1 s) and tonic (30 s) taVNS, in a pre-registered, single-blind, sham-controlled, within-subject cross-over design, in the absence of a behavioural task. RESULTS: Phasic taVNS induced a rapid increase in pupil size over baseline, significantly greater than under sham stimulation, which rapidly declined after stimulation offset. Tonic taVNS induced a similarly rapid (and larger than sham) increase in pupil size over baseline, returning to baseline within 5 s, despite the ongoing stimulation. Thus, both active and sham tonic modes closely resembled the phasic effect. There were no differences in tonic baseline pupil size, and no sustained effects of stimulation on tonic baseline pupil size. CONCLUSIONS: These results suggest that both phasic- and tonic-like taVNS under the standard stimulation parameters may modulate primarily the phasic mode of noradrenergic activity, as indexed by evoked pupil dilation, over and above somatosensory effects. This result sheds light on the temporal profile of phasic and tonic stimulation, with implications for their applicability in further research.

Non-invasive vagus nerve stimulation and the motivation to work for rewards: A replication of Neuser et al. (2020, Nature Communications).

The vagus nerve is thought to be involved in the allostatic regulation of motivation and energy metabolism via gut-brain interactions. A recent study by Neuser and colleagues (2020) provided novel evidence for this process in humans, by reporting a positive effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the invigoration of reward-seeking behaviors, especially for food rewards. We conducted an independent direct replication of Neuser et al. (2020), to assess the robustness of their findings. Following the original study, we used a single-blind, sham-controlled, randomized cross-over design. We applied left-sided taVNS in healthy human volunteers (n = 40), while they performed an effort allocation task in which they had to work for monetary and food rewards. The replication study was purely confirmatory in that it strictly followed the analysis plans and scripts used by Neuser et al. Although, in line with Neuser et al., we found strong effects of task variables on effort invigoration and effort maintenance, we failed to replicate their key finding: taVNS did not increase the strength of invigoration (p = .62); the data were five times more likely (BF10 = 0.19) under the null hypothesis. We also found substantial evidence against an effect of taVNS on effort maintenance (p = .50; BF10 = 0.20). Our results provide evidence against the idea that left-sided taVNS boosts the motivational drive to work for rewards. Our study also highlights the need for direct replications of influential taVNS studies.

Remotely supervised at-home delivery of taVNS for autism spectrum disorder: feasibility and initial efficacy.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has potential clinical application for autism spectrum disorder (ASD). At-home sessions are necessary to allow delivery of repeated sessions, and remove burden on patients for daily visits, and reduce costs of clinic delivery. Our objective was to validate a protocol for remote supervised administration for home delivery of taVNS using specially designed equipment and platform. Methods: An open-label design was followed involving administration by caretakers to 12 patients with ASD (ages:7-16). Daily 1-h sessions over 2 weeks were administered under remote supervision. The primary outcome was feasibility, which was assessed by completion rate, stimulation tolerability, and confirmation of programmed stimulation delivery. The secondary measures were initial efficacy assessed by Childhood Anxiety Sensitivity Index-Revised (CASI-R), Parent Rated Anxiety Scale for Youth with ASD (PRAS-ASD), and Clinician Global Impression (CGI) scales. Sleep measures were also tracked using Cleveland Adolescent Sleep Questionnaire (CASQ). Results: Across 132 sessions, we obtained an 88.5% completion rate. A total of 22 expected adverse events were reported with headache being the most common followed by transient pain, itchiness, and stinging at the electrode site. One subject dropped out of the study unrelated to the stimulation or the study. Average scores of anxiety (CASI-R, PRAS-ASD, and CGI) and sleepiness (CASQ) were all improved at the 2 week time point. While not powered to determine efficacy, benefits were suggested in this open label pilot. Conclusion: Remotely supervised, proxy-administered, at-home delivery of taVNS is feasible in patients with ASD. Initial efficacy supports pursuing larger scale trials.

Impact of transcutaneous vagus nerve stimulation on healthy cognitive and brain aging.

Evidence for clinically meaningful benefits of transcutaneous vagus nerve stimulation (VNS) has been rapidly accumulating over the past 15 years. This relatively novel non-invasive brain stimulation technique has been applied to a wide range of neuropsychiatric disorders including schizophrenia, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, bipolar disorder, and Alzheimer's disease. More recently, non-invasive forms of VNS have allowed for investigations within healthy aging populations. These results offer insight into protocol considerations specific to older adults and how to translate those results into effective clinical trials and, ultimately, effective clinical care. In this review, we characterize the possible mechanisms by which non-invasive VNS may promote healthy aging (e.g., neurotransmitter effects, inflammation regulation, functional connectivity changes), special considerations for applying non-invasive VNS in an older adult population (e.g., vagus nerve changes with age), and how non-invasive VNS may be used in conjunction with existing behavioral interventions (e.g., cognitive behavioral therapy, cognitive training) to promote healthy emotional and cognitive aging.

Transcutaneous Vagus Nerve Stimulation (tVNS) applications in cognitive aging: a review and commentary.

Differentiating healthy from pathological aging trajectories is extremely timely, as the global population faces an inversion where older adults will soon outnumber younger 5:1. Many cognitive functions (e.g., memory, executive functions, and processing speed) decline with age, a process that can begin as early as midlife, and which predicts subsequent diagnosis with dementia. Although dementia is a devastating and costly diagnosis, there remains limited evidence for medications, therapies, and devices that improve cognition or attenuate the transition into dementia. There is an urgent need to intervene early in neurodegenerative processes leading to dementia (e.g., depression and mild cognitive impairment). In this targeted review and commentary, we highlight transcutaneous Vagus Nerve Stimulation (tVNS) as a neurostimulation method with unique opportunities for applications in diseases of aging, reviewing recent literature, feasibility of use with remote data collection methods/telehealth, as well as limitations and conflicts in the literature. In particular, small sample sizes, uneven age distributions of participants, lack of standardized protocols, and oversampling of non-representative groups (e.g., older adults with no comorbid diagnoses) limit our understanding of the potential of this method. We offer recommendations for how to improve representativeness, statistical power, and generalizability of tVNS research by integrating remote data collection techniques.

Left or right ear? A neuroimaging study using combined taVNS/fMRI to understand the interaction between ear stimulation target and lesion location in chronic stroke.

BACKGROUND: Implanted vagus nerve stimulation (VNS) and transcutaneous auricular VNS (taVNS) have been primarily administered clinically to the unilateral-left vagus nerve. This left-only convention has proved clinically beneficial in brain disorders. However, in stroke survivors, the presence of a lesion in the brain may complicate VNS-mediated signaling, and it is important to understand the laterality effects of VNS in stroke survivors to optimize the intervention. OBJECTIVE: To understand whether taVNS delivered to different ear targets relative to the lesion (ipsilesional vs contralesional vs bilateral vs sham) impacts blood oxygenation level dependent (BOLD) signal propagation in stroke survivors. METHODS: We enrolled 20 adults with a prior history of stroke. Each participant underwent a single visit, during which taVNS was delivered concurrently during functional magnetic resonance imaging (fMRI) acquisition. Each participant received three discrete active stimulation conditions (ipsilesional, contralesional, bilateral) and one sham condition in a randomized order. Stimulation-related BOLD signal changes in the active conditions were compared to sham conditions to understand the interaction taVNS and laterality effects. RESULTS: All active taVNS conditions deactivated the contralesional default mode network related regions compared to sham, however only ipsilesional taVNS enhanced the activations in the ipsilesional visuomotor and secondary visual cortex. Furthermore, we reveal an interaction in task activations between taVNS and cortical visuomotor areas, where ipsilesional taVNS significantly increased ipsilesional visuomotor activity and decreased contralesional visuomotor activity compared to sham. CONCLUSION: Laterality of taVNS relative to the lesion is a critical factor in optimizing taVNS in a stroke population, with ipsilesional stimulation providing largest direct brain activation and should be explored further when designing taVNS studies in neurorehabilitation.

Short-term transcutaneous vagus nerve stimulation increases pupil size but does not affect EEG alpha power: A replication of Sharon et al. (2021, Journal of Neuroscience).

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) has been tested as a potential treatment for pharmaco-resistant epilepsy and depression. Its clinical efficacy is thought to depend on taVNS-induced activation of the locus coeruleus and other neuromodulator systems. However, unlike for invasive VNS in rodents, there is little evidence for an effect of taVNS on noradrenergic activity. OBJECTIVE: We attempted to replicate recently published findings by Sharon et al. (2021), showing that short bursts of taVNS transiently increased pupil size and decreased EEG alpha power, two correlates of central noradrenergic activity. METHODS: Following the original study, we used a single-blind, sham-controlled, randomized cross-over design. Human volunteers (n = 29) received short-term (3.4 s) taVNS at the maximum level below the pain threshold, while we collected resting-state pupil-size and EEG data. To analyze the data, we used scripts provided by Sharon and colleagues. RESULTS: Consistent with Sharon et al. (2021), pupil dilation was significantly larger during taVNS than during sham stimulation (p = .009; Bayes factor supporting the difference = 7.45). However, we failed to replicate the effect of taVNS on EEG alpha power (p = .37); the data were four times more likely under the null hypothesis (BF10 = 0.28). CONCLUSION: Our findings support the effectiveness of short-term taVNS in inducing transient pupil dilation, a correlate of phasic noradrenergic activity. However, we failed to replicate the recent finding by Sharon et al. (2021) that taVNS attenuates EEG alpha activity. Overall, this study highlights the need for continued research on the neural mechanisms underlying taVNS efficacy and its potential as a treatment option for pharmaco-resistant conditions. It also highlights the need for direct replications of influential taVNS studies.

Transcutaneous vagus nerve stimulation at nonspecific timings during training can compromise motor adaptation in healthy humans.

Adding afferent vagus nerve stimulation to motor training via implanted electrodes can modify neuromotor adaptation depending on the stimulation timing. This study aimed to understand neuromotor adaptations when transcutaneous vagus nerve stimulation (tVNS) is applied at nonspecific timings during motor skill training in healthy humans. Twenty-four healthy young adults performed visuomotor training to match a complex force trajectory pattern with the index and little finger abduction forces concurrently. Participants were assigned to the tVNS group receiving tVNS at the tragus or the sham group receiving sham stimulation to the earlobe. The corresponding stimulations were applied at nonspecific timings throughout the training trials. Visuomotor tests were performed without tVNS or sham stimulation before and after training sessions across days. The reduction in the root mean square error (RMSE) against the trained force trajectory was attenuated in the tVNS group compared with the sham group, while its in-session reduction was not different between groups. The reduction of RMSE against an untrained trajectory pattern was not different between groups. No training effect was observed in corticospinal excitability or GABA-mediated intracortical inhibition. These findings suggest that adding tVNS at nonspecific timings during motor skill training can compromise motor adaptation but not transfer in healthy humans.NEW & NOTEWORTHY Adding vagus nerve stimulation via implanted electrodes during motor training can facilitate motor recovery in disabled animals and humans. No study examined the effect of transcutaneous vagus nerve stimulation (tVNS) during training on neuromotor adaptation in healthy humans. We have found that adding tVNS at nonspecific timings during motor skill training can compromise motor adaptation but not transfer in healthy humans.

Motor Activated Auricular Vagus Nerve Stimulation as a Potential Neuromodulation Approach for Post-Stroke Motor Rehabilitation: A Pilot Study.

BACKGROUND: Implanted vagus nerve stimulation (VNS), when synchronized with post-stroke motor rehabilitation improves conventional motor rehabilitation training. A non-invasive VNS method known as transcutaneous auricular vagus nerves stimulation (taVNS) has emerged, which may mimic the effects of implanted VNS. OBJECTIVE: To determine whether taVNS paired with motor rehabilitation improves post-stroke motor function, and whether synchronization with movement and amount of stimulation is critical to outcomes. METHODS: We developed a closed-loop taVNS system for motor rehabilitation called motor activated auricular vagus nerve stimulation (MAAVNS) and conducted a randomized, double-blind, pilot trial investigating the use of MAAVNS to improve upper limb function in 20 stroke survivors. Participants attended 12 rehabilitation sessions over 4-weeks, and were assigned to a group that received either MAAVNS or active unpaired taVNS concurrently with task-specific training. Motor assessments were conducted at baseline, and weekly during rehabilitation training. Stimulation pulses were counted for both groups. RESULTS: A total of 16 individuals completed the trial, and both MAAVNS (n = 9) and unpaired taVNS (n = 7) demonstrated improved Fugl-Meyer Assessment upper extremity scores (Mean ± SEM, MAAVNS: 5.00 ± 1.02, unpaired taVNS: 3.14 ± 0.63). MAAVNS demonstrated greater effect size (Cohen's d = 0.63) compared to unpaired taVNS (Cohen's d = 0.30). Furthermore, MAAVNS participants received significantly fewer stimulation pulses (Mean ± SEM, MAAVNS: 36 070 ± 3205) than the fixed 45 000 pulses unpaired taVNS participants received (P < .05). CONCLUSION: This trial suggests stimulation timing likely matters, and that pairing taVNS with movements may be superior to an unpaired approach. Additionally, MAAVNS effect size is comparable to that of the implanted VNS approach.

CPVT and Complete Atrio-Ventricular Block: The Flipside of the Same Coin.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare electrical genetic disease characterized by ventricular polymorphic tachycardia and/or bidirectional ventricular tachycardia induced by the release of catecholamines caused by intense physical or emotional stress in structurally normal hearts. Mostly, it is caused by mutations in genes that are involved in calcium homeostasis, in particular in the gene encoding for cardiac ryanodine receptor (RyR2). Our observation is the first description of familial CPVT caused by mutation of the RyR2 gene, linked to the complete AV block.

Synergistic effects of transcutaneous vagus nerve stimulation and inhibitory control training on electrophysiological performance in healthy adults.

Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive nerve stimulation technique that exerts a positive "exogenous" online neuromodulatory effect on inhibitory control (IC). Additionally, IC training (ICT) is an effective approach for enhancing IC via the "endogenous" activation of brain regions implicated in this process. The aim of the present study was to examine the synergistic effects of tVNS and ICT on IC enhancement. For this, we measured the changes in neural activity in frontal, fronto-central, and central regions in the time domain of the N2 component and the frequency domain of alpha power during the stop signal task. A total of 58 participants were randomly divided into four groups that received five sessions of either ICT or sham ICT with either online tVNS or sham tVNS. No differences in N2 amplitude were detected after any of the interventions. However, N2 latency shortened after tVNS + ICT in frontal, fronto-central, and central regions. N2 latency shortened after the intervention of sham tVNS + ICT in frontal region. Moreover, alpha power after tVNS + ICT intervention was larger than those of the other interventions in frontal, fronto-central, and central regions. The obtained electrophysiological data suggested that combining tVNS with ICT has synergistic ameliorative effects on IC, and provide evidence supporting the IC-enhancing potential of tVNS combined with ICT.

The Effects of Transcutaneous Vagus Nerve Stimulation on Functional Connectivity Within Semantic and Hippocampal Networks in Mild Cognitive Impairment.

Better treatments are needed to improve cognition and brain health in people with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Transcutaneous vagus nerve stimulation (tVNS) may impact brain networks relevant to AD through multiple mechanisms including, but not limited to, projection to the locus coeruleus, the brain's primary source of norepinephrine, and reduction in inflammation. Neuropathological data suggest that the locus coeruleus may be an early site of tau pathology in AD. Thus, tVNS may modify the activity of networks that are impaired and progressively deteriorate in patients with MCI and AD. Fifty patients with MCI (28 women) confirmed via diagnostic consensus conference prior to MRI (sources of info: Montreal Cognitive Assessment Test (MOCA), Clinical Dementia Rating scale (CDR), Functional Activities Questionnaire (FAQ), Hopkins Verbal Learning Test - Revised (HVLT-R) and medical record review) underwent resting state functional magnetic resonance imaging (fMRI) on a Siemens 3 T scanner during tVNS (left tragus, n = 25) or sham control conditions (left ear lobe, n = 25). During unilateral left tVNS, compared with ear lobe stimulation, patients with MCI showed alterations in functional connectivity between regions of the brain that are important in semantic and salience functions including regions of the temporal and parietal lobes. Furthermore, connectivity from hippocampi to several cortical and subcortical clusters of ROIs also demonstrated change with tVNS compared with ear lobe stimulation. In conclusion, tVNS modified the activity of brain networks in which disruption correlates with deterioration in AD. These findings suggest afferent target engagement of tVNS, which carries implications for the development of noninvasive therapeutic intervention in the MCI population.

Advances in Non-Invasive Neuromodulation: Designing Closed-Loop Devices for Respiratory-Controlled Transcutaneous Vagus Nerve Stimulation.

Studies suggest non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) as a potential therapeutic option for various pathological conditions, such as epilepsy and depression. Exhalation-controlled taVNS, which synchronizes stimulation with internal body rhythms, holds promise for enhanced neuromodulation, but there is no closed-loop system in the literature capable of performing such integration in real time. In this context, the objective was to develop real-time signal processing techniques and an integrated closed-loop device with sensors to acquire physiological data. After a conditioning stage, the signal is processed and delivers synchronized electrical stimulation during the patient's expiratory phase. Additional modules were designed for processing, software-controlled selectors, remote and autonomous operation, improved analysis, and graphical visualization. The signal processing method effectively extracted respiratory cycles and successfully attenuated signal noise. Heart rate variability was assessed in real time, using linear statistical evaluation. The prototype feedback stimulator device was physically constructed. Respiratory peak detection achieved an accuracy of 90%, and the real-time processing resulted in a small delay of up to 150 ms in the detection of the expiratory phase. Thus, preliminary results show promising accuracy, indicating the need for additional tests to optimize real-time processing and the application of the prototype in clinical studies.

Ear your heart: transcutaneous auricular vagus nerve stimulation on heart rate variability in healthy young participants.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) stimulating the auricular branch of the vagus nerve along a well-defined neuroanatomical pathway, has promising therapeutic efficacy. Potentially, taVNS can modulate autonomic responses. Specifically, taVNS can induce more consistent parasympathetic activation and may lead to increased heart rate variability (HRV). However, the effects of taVNS on HRV remain inconclusive. Here, we investigated changes in HRV due to brief alteration periods of parasympathetic-vagal cardiac activity produced by taVNS on the cymba as opposed to control administration via the helix. Materials and Methods: We compared the effect of 10 min of active stimulation (i.e., cymba conchae) to sham stimulation (i.e., helix) on peripheral cardiovascular response, in 28 healthy young adults. HRV was estimated in the time domain and frequency domain during the overall stimulation. Results: Although active-taVNS and sham-taVNS stimulation did not differ in subjective intensity ratings, the active stimulation of the cymba led to vagally mediated HRV increases in both the time and frequency domains. Differences were significant between active-taVNS and both sham-taVNS and resting conditions in the absence of stimulation for various HRV parameters, but not for the low-frequency index of HRV, where no differences were found between active-taVNS and sham-taVNS conditions. Conclusion: This work supports the hypothesis that taVNS reliably induces a rapid increase in HRV parameters when auricular stimulation is used to recruit fibers in the cymba compared to stimulation at another site. The results suggest that HRV can be used as a physiological indicator of autonomic tone in taVNS for research and potential therapeutic applications, in line with the established effects of invasive VNS. Knowledge of the physiological effect of taVNS short sessions in modulating cardiovagal processing is essential for enhancing its clinical use.

Brain effect of transcutaneous vagal nerve stimulation: A meta-analysis of neuroimaging evidence.

BACKGROUND: Dysfunction in the autonomic nervous system is common throughout many functional gastrointestinal diseases (FGIDs) that have been historically difficult to treat. In recent years, transcutaneous vagal nerve stimulation (tVNS) has shown promise for improving FGID symptoms. However, the brain effects of tVNS remain unclear, which we investigated by neuroimaging meta-analysis. METHODS: A total of 157 studies were identified, 4 of which were appropriate for inclusion, encompassing 60 healthy human participants. Using activation likelihood analysis estimation, we statistically quantified functional brain activity changes across three domains: (1) tVNS vs. null stimulation, (2) tVNS vs. sham stimulation, and (3) sham stimulation vs. null stimulation. KEY RESULTS: tVNS significantly increased activity in the insula, anterior cingulate, inferior and superior frontal gyri, caudate and putamen, and reduced activity in the hippocampi, occipital fusiform gyri, temporal pole, and middle temporal gyri, when compared to null stimulation (all corrected p < 0.005). tVNS increased activity in the anterior cingulate gyrus, left thalamus, caudate, and paracingulate gyrus and reduced activity in right thalamus, posterior cingulate cortex, and temporal fusiform cortex, when compared to sham stimulation (all corrected p < 0.005). Sham stimulation significantly increased activity in the insula and reduced activity in the posterior cingulate and paracingulate gyrus (all corrected p < 0.001), when contrasted to null stimulation. CONCLUSIONS: Brain effects of tVNS localize to regions associated with both physiological autonomic regulation and regions whose activity is modulated across numerous FGIDs, which may provide a neural basis for efficacy of this treatment. Functional activity differences between sham and null stimulation illustrate the importance of robust control procedures for future trials.

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.