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.

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.

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.

Establishment of Emotional Memories Is Mediated by Vagal Nerve Activation: Evidence from Noninvasive taVNS.

Emotional memories are better remembered than neutral ones, but the mechanisms leading to this memory bias are not well understood in humans yet. Based on animal research, it is suggested that the memory-enhancing effect of emotion is based on central noradrenergic release, which is triggered by afferent vagal nerve activation. To test the causal link between vagus nerve activation and emotional memory in humans, we applied continuous noninvasive transcutaneous auricular vagus nerve stimulation (taVNS) during exposure to emotional arousing and neutral scenes and tested subsequent, long-term recognition memory after 1 week. We found that taVNS, compared with sham, increased recollection-based memory performance for emotional, but not neutral, material. These findings were complemented by larger recollection-related brain potentials (parietal ERP Old/New effect) during retrieval of emotional scenes encoded under taVNS, compared with sham. Furthermore, brain potentials recorded during encoding also revealed that taVNS facilitated early attentional discrimination between emotional and neutral scenes. Extending animal research, our behavioral and neural findings confirm a modulatory influence of the vagus nerve in emotional memory formation in humans.SIGNIFICANCE STATEMENT Emotionally relevant information elicits stronger and more enduring memories than nonrelevant information. Animal research has shown that this memory-enhancing effect of emotion is related to the noradrenergic activation in the brain, which is triggered by afferent fibers of the vagus nerve (VN). In the current study, we show that noninvasive transcutaneous auricular VN stimulation enhances recollection-based memory formation specifically for emotionally relevant information as indicated by behavioral and electrophysiological indices. These human findings give novel insights into the mechanisms underlying the establishment of emotional episodic memories by confirming the causal link between the VN and memory formation which may help understand the neural mechanisms underlying disorders associated with altered memory functions and develop treatment options.

Transcutaneous Vagus Nerve Stimulation in Humans Induces Pupil Dilation and Attenuates Alpha Oscillations.

Vagus nerve stimulation (VNS) is widely used to treat drug-resistant epilepsy and depression. While the precise mechanisms mediating its long-term therapeutic effects are not fully resolved, they likely involve locus coeruleus (LC) stimulation via the nucleus of the solitary tract, which receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline levels, whereas LC lesions suppress VNS therapeutic efficacy. Noninvasive transcutaneous VNS (tVNS) uses electrical stimulation that targets the auricular branch of the vagus nerve at the cymba conchae of the ear. However, the extent to which tVNS mimics VNS remains unclear. Here, we investigated the short-term effects of tVNS in healthy human male volunteers (n = 24), using high-density EEG and pupillometry during visual fixation at rest. We compared short (3.4 s) trials of tVNS to sham electrical stimulation at the earlobe (far from the vagus nerve branch) to control for somatosensory stimulation. Although tVNS and sham stimulation did not differ in subjective intensity ratings, tVNS led to robust pupil dilation (peaking 4-5 s after trial onset) that was significantly higher than following sham stimulation. We further quantified, using parallel factor analysis, how tVNS modulates idle occipital alpha (8-13Hz) activity identified in each participant. We found greater attenuation of alpha oscillations by tVNS than by sham stimulation. This demonstrates that tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, thus supporting the hypothesis that tVNS elevates noradrenaline and other arousal-promoting neuromodulatory signaling, and mimics invasive VNS.SIGNIFICANCE STATEMENT Current noninvasive brain stimulation techniques are mostly confined to modulating cortical activity, as is typical with transcranial magnetic or transcranial direct/alternating current electrical stimulation. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to stimulate subcortical arousal-promoting nuclei, though previous studies yielded inconsistent results. Here we show that short (3.4 s) tVNS pulses in naive healthy male volunteers induced transient pupil dilation and attenuation of occipital alpha oscillations. These markers of brain arousal are in line with the established effects of invasive VNS on locus coeruleus-noradrenaline signaling, and support that tVNS mimics VNS. Therefore, tVNS can be used as a tool for studying how endogenous subcortical neuromodulatory signaling affects human cognition, including perception, attention, memory, and decision-making; and also for developing novel clinical applications.

Non-invasive vagus nerve stimulation boosts mood recovery after effort exertion.

BACKGROUND: Mood plays an important role in our life which is illustrated by the disruptive impact of aberrant mood states in depression. Although vagus nerve stimulation (VNS) has been shown to improve symptoms of depression, the exact mechanism is still elusive, and it is an open question whether non-invasive VNS could be used to swiftly and robustly improve mood. METHODS: Here, we investigated the effect of left- and right-sided transcutaneous auricular VNS (taVNS) v. a sham control condition on mood after the exertion of physical and cognitive effort in 82 healthy participants (randomized cross-over design) using linear mixed-effects and hierarchical Bayesian analyses of mood ratings. RESULTS: We found that 90 min of either left-sided or right-sided taVNS improved positive mood [b = 5.11, 95% credible interval, CI (1.39-9.01), 9.6% improvement relative to the mood intercept, BF10 = 7.69, pLME = 0.017], yet only during the post-stimulation phase. Moreover, lower baseline scores of positive mood were associated with greater taVNS-induced improvements in motivation [r = -0.42, 95% CI (-0.58 to -0.21), BF10 = 249]. CONCLUSIONS: We conclude that taVNS boosts mood after a prolonged period of effort exertion with concurrent stimulation and that acute motivational effects of taVNS are partly dependent on initial mood states. Collectively, our results show that taVNS may help quickly improve affect after a mood challenge, potentially by modulating interoceptive signals contributing to the reappraisal of effortful behavior. This suggests that taVNS could be a useful add-on to current behavioral therapies.

Neuromodulation in drug-resistant epilepsy: A review of current knowledge.

Nearly 1% of the global population suffers from epilepsy. Drug-resistant epilepsy (DRE) affects one-third of epileptic patients who are unable to treat their condition with existing drugs. For the treatment of DRE, neuromodulation offers a lot of potential. The background, mechanism, indication, application, efficacy, and safety of each technique are briefly described in this narrative review, with an emphasis on three approved neuromodulation therapies: vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS), and closed-loop responsive neurostimulation (RNS). Neuromodulatory approaches involving direct or induced electrical currents have been developed to lessen seizure frequency and duration in patients with DRE since the notion of electrical stimulation as a therapy for neurologic diseases originated in the early nineteenth century. Although few people have attained total seizure independence for more than 12 months using these treatments, more than half have benefitted from a 50% drop in seizure frequency over time. Although promising outcomes in adults and children with DRE have been achieved, challenges such as heterogeneity among epilepsy types and etiologies, optimization of stimulation parameters, a lack of biomarkers to predict response to neuromodulation therapies, high-level evidence to aid decision-making, and direct comparisons between neuromodulatory approaches remain. To solve these existing gaps, authorize new kinds of neuromodulation, and develop personalized closed-loop treatments, further research is needed. Finally, both invasive and non-invasive neuromodulation seems to be safe. Implantation-related adverse events for invasive stimulation primarily include infection and pain at the implant site. Intracranial hemorrhage is a frequent adverse event for DBS and RNS. Other stimulation-specific side-effects are mild with non-invasive stimulation.

Toward Diverse or Standardized: A Systematic Review Identifying Transcutaneous Stimulation of Auricular Branch of the Vagus Nerve in Nomenclature.

OBJECTIVES: After 20 years of development, there is confusion in the nomenclature of transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN). We performed a systematic review of transcutaneous stimulation of ABVN in nomenclature. MATERIALS AND METHODS: A systematic search of the literature was carried out, using the bibliographic search engine PubMed. The search covered articles published up until June 11, 2020. We recorded the full nomenclature and abbreviated nomenclature same or similar to transcutaneous stimulation of ABVN in the selected eligible studies, as well as the time and author information of this nomenclature. RESULTS: From 261 studies, 67 full nomenclatures and 27 abbreviated nomenclatures were finally screened out, transcutaneous vagus nerve stimulation and tVNS are the most common nomenclature, accounting for 38.38% and 42.06%, respectively. In a total of 97 combinations of full nomenclatures and abbreviations, the most commonly used nomenclature for the combination of transcutaneous vagus nerve stimulation and tVNS, accounting for 30.28%. Interestingly, the combination of full nomenclatures and abbreviations is not always a one-to-one relationship, there are ten abbreviated nomenclatures corresponding to transcutaneous vagus nerve stimulation, and five full nomenclatures corresponding to tVNS. In addition, based on the analysis of the usage habits of nomenclature in 21 teams, it is found that only three teams have fixed habits, while other different teams or the same team do not always use the same nomenclature in their paper. CONCLUSIONS: The phenomenon of confusion in the nomenclature of transcutaneous stimulation of ABVN is obvious and shows a trend of diversity. The nomenclature of transcutaneous stimulation of ABVN needs to become more standardized in the future.

A Comprehensive Review of Vagus Nerve Stimulation for Depression.

OBJECTIVES: Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression. MATERIALS AND METHODS: Using PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS. RESULTS: VNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS. CONCLUSIONS: The mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.

Recognizing emotions in bodies: Vagus nerve stimulation enhances recognition of anger while impairing sadness.

According to the Polyvagal theory, the vagus nerve is the key phylogenetic substrate that supports efficient emotion recognition for promoting safety and survival. Previous studies showed that the vagus nerve affects people's ability to recognize emotions based on eye regions and whole facial images, but not static bodies. The purpose of this study was to verify whether the previously suggested causal link between vagal activity and emotion recognition can be generalized to situations in which emotions must be inferred from images of whole moving bodies. We employed transcutaneous vagus nerve stimulation (tVNS), a noninvasive brain stimulation technique that stimulates the vagus nerve by a mild electrical stimulation to the auricular branch of the vagus, located in the anterior protuberance of the outer ear. In two sessions, participants received active or sham tVNS before and while performing three emotion recognition tasks, aimed at indexing their ability to recognize emotions from static or moving bodily expressions by actors. Active tVNS, compared to sham stimulation, enhanced the recognition of anger but reduced the ability to recognize sadness, regardless of the type of stimulus (static vs. moving). Convergent with the idea of hierarchical involvement of the vagus in establishing safety, as put forward by the Polyvagal theory, we argue that our findings may be explained by vagus-evoked differential adjustment strategies to emotional expressions. Taken together, our findings fit with an evolutionary perspective on the vagus nerve and its involvement in emotion recognition for the benefit of survival.

A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: challenges and future directions.

Brain stimulation approaches are important to gain causal mechanistic insights into the relevance of functional brain regions and/or neurophysiological systems for human cognitive functions. In recent years, transcutaneous vagus nerve stimulation (tVNS) has attracted considerable popularity. It is a noninvasive brain stimulation technique based on the stimulation of the vagus nerve. The stimulation of this nerve activates subcortical nuclei, such as the locus coeruleus and the nucleus of the solitary tract, and from there, the activation propagates to the cortex. Since tVNS is a novel stimulation technique, this literature review outlines a brief historical background of tVNS, before detailing underlying neurophysiological mechanisms of action, stimulation parameters, cognitive effects of tVNS on healthy humans, and, lastly, current challenges and future directions of tVNS research in cognitive functions. Although more research is needed, we conclude that tVNS, by increasing norepineprine (NE) and gamma-aminobutyric acid (GABA) levels, affects NE- and GABA-related cognitive performance. The review provides detailed background information how to use tVNS as a neuromodulatory tool in cognitive neuroscience and outlines important future leads of research on tVNS.

Modulating auditory selective attention by non-invasive brain stimulation: Differential effects of transcutaneous vagal nerve stimulation and transcranial random noise stimulation.

Selective attention is a basic process required to maintain goal-directed behavior by appropriately responding to target stimuli and suppressing reactions to non-target stimuli. It has been proposed that auditory selective attention is linked to the activity of the locus coeruleus-norepinergic (LC-NE) system and a large-scale fronto-parietal cortical network, but there is still sparse causal evidence for these assumptions. By applying transcutaneous vagal nerve stimulation (tVNS) and transcranial random noise stimulation (tRNS) over the frontal cortex, we systematically assessed the involvement of these subcortical and cortical components in the regulation of auditory selective attention. Using a single-blinded, sham-controlled, within-subject design we analyzed online effects of tVNS and tRNS in 20 healthy participants during an auditory oddball paradigm. We show significant stimulation-dependent modulations of auditory selective attention on the behavioral and electrophysiological level. Compared to sham, tVNS increased the P3 amplitude, while tRNS reduced the reaction time to target stimuli. Moreover, both techniques reduced the P3 latency. Our data provide evidence for the functional relevance of the subcortical NE system in the regulation of neural resources that allows a phasic response to incoming target stimuli. They indicate that frontal cortex structures are crucially involved in the successful evaluation of the respective information. Moreover, our results are in favor of the LC-P3 hypothesis claiming the vital role of the NE system in auditory selective attention and in the generation of the P3. Of note, the effects of tVNS on auditory selective attention are comparable with those evoked by pharmacological interventions and invasive vagal nerve stimulation.

Transcutaneous vagus nerve stimulation (tVNS) enhances conflict-triggered adjustment of cognitive control.

Response conflicts play a prominent role in the flexible adaptation of behavior as they represent context-signals that indicate the necessity for the recruitment of cognitive control. Previous studies have highlighted the functional roles of the affectively aversive and arousing quality of the conflict signal in triggering the adaptation process. To further test this potential link with arousal, participants performed a response conflict task in two separate sessions with either transcutaneous vagus nerve stimulation (tVNS), which is assumed to activate the locus coeruleus-noradrenaline (LC-NE) system, or with neutral sham stimulation. In both sessions the N2 and P3 event-related potentials (ERP) were assessed. In line with previous findings, conflict interference, the N2 and P3 amplitude were reduced after conflict. Most importantly, this adaptation to conflict was enhanced under tVNS compared to sham stimulation for conflict interference and the N2 amplitude. No effect of tVNS on the P3 component was found. These findings suggest that tVNS increases behavioral and electrophysiological markers of adaptation to conflict. Results are discussed in the context of the potentially underlying LC-NE and other neuromodulatory (e.g., GABA) systems. The present findings add important pieces to the understanding of the neurophysiological mechanisms of conflict-triggered adjustment of cognitive control.

Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study.

Despite many pharmacological and psychosocial treatment options, schizophrenia remains a debilitating disorder. Thus, new treatment strategies rooted in the pathophysiology of the disorder are needed. Recently, vagus nerve stimulation (VNS) has been proposed as a potential treatment option for various neuropsychiatric disorders including schizophrenia. The objective of this study was to investigate for the first time the feasibility, safety and efficacy of transcutaneous VNS in stable schizophrenia. A bicentric randomized, sham-controlled, double-blind trial was conducted from 2010 to 2012. Twenty schizophrenia patients were randomly assigned to one of two treatment groups. The first group (active tVNS) received daily active stimulation of the left auricle for 26 weeks. The second group (sham tVNS) received daily sham stimulation for 12 weeks followed by 14 weeks of active stimulation. Primary outcome was defined as change in the Positive and Negative Symptom Scale total score between baseline and week 12. Various other secondary measures were assessed to investigate safety and efficacy. The intervention was well tolerated with no relevant adverse effects. We could not observe a statistically significant difference in the improvement of schizophrenia psychopathology during the observation period. Neither psychopathological and neurocognitive measures nor safety measures showed significant differences between study groups. Application of tVNS was well tolerated, but did not improve schizophrenia symptoms in our 26-week trial. While unsatisfactory compliance questions the feasibility of patient-controlled neurostimulation in schizophrenia, the overall pattern of symptom change might warrant further investigations in this population.

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.

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.

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 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.

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.

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.