Phasic, Event-Related Transcutaneous Auricular Vagus Nerve Stimulation Modifies Behavioral, Pupillary, and Low-Frequency Oscillatory Power Responses.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed to activate the locus ceruleus-noradrenaline (LC-NA) system. However, previous studies failed to find consistent modulatory effects of taVNS on LC-NA biomarkers. Previous studies suggest that phasic taVNS may be capable of modulating LC-NA biomarkers such as pupil dilation and alpha oscillations. However, it is unclear whether these effects extend beyond pure sensory vagal nerve responses. Critically, the potential of the pupillary light reflex as an additional taVNS biomarker has not been explored so far. Here, we applied phasic active and sham taVNS in 29 subjects (16 female, 13 male) while they performed an emotional Stroop task (EST) and a passive pupil light reflex task (PLRT). We recorded pupil size and brain activity dynamics using a combined Magnetoencephalography (MEG) and pupillometry design. Our results show that phasic taVNS significantly increased pupil dilation and performance during the EST. During the PLRT, active taVNS reduced and delayed pupil constriction. In the MEG, taVNS increased frontal-midline theta and alpha power during the EST, whereas occipital alpha power was reduced during both the EST and PLRT. Our findings provide evidence that phasic taVNS systematically modulates behavioral, pupillary, and electrophysiological parameters of LC-NA activity during cognitive processing. Moreover, we demonstrate for the first time that the pupillary light reflex can be used as a simple and effective proxy of taVNS efficacy. These findings have important implications for the development of noninvasive neuromodulation interventions for various cognitive and clinical applications.SIGNIFICANCE STATEMENT taVNS has gained increasing attention as a noninvasive neuromodulation technique and is widely used in clinical and nonclinical research. Nevertheless, the exact mechanism of action of taVNS is not yet fully understood. By assessing physiology and behavior in a response conflict task in healthy humans, we demonstrate the first successful application of a phasic, noninvasive vagus nerve stimulation to improve cognitive control and to systematically modulate pupillary and electrophysiological markers of the noradrenergic system. Understanding the mechanisms of action of taVNS could optimize future clinical applications and lead to better treatments for mental disorders associated with noradrenergic dysfunction. In addition, we present a new taVNS-sensitive pupillary measure representing an easy-to-use biomarker for future taVNS studies.

Preliminary evidence of transcutaneous vagus nerve stimulation effects on sleep in veterans with post-traumatic stress disorder.

Sleep problems are common among veterans with post-traumatic stress disorder and closely associated with hyperarousal symptoms. Transcutaneous vagus nerve stimulation (tVNS) may have potential to improve sleep quality in veterans with PTSD through effects on brain systems relevant to hyperarousal and sleep-wake regulation. The current pilot study examines the effect of 1 h of tVNS administered at "lights out" on sleep architecture, microstructure, and autonomic activity. Thirteen veterans with PTSD completed two nights of laboratory-based polysomnography during which they received 1 h of either active tVNS (tragus) or sham stimulation (earlobe) at "lights out" with randomised order. Sleep staging and stability metrics were derived from polysomnography data. Autonomic activity during sleep was assessed using the Porges-Bohrer method for calculating respiratory sinus arrhythmia (RSAP-B ). Paired t-tests revealed a small decrease in the total sleep time (d = -0.31), increase in N3 sleep (d = 0.23), and a small-to-moderate decrease in REM sleep (d = -0.48) on nights of active tVNS relative to sham stimulation. tVNS was also associated with a moderate reduction in cyclic alternating pattern (CAP) rate (d = -0.65) and small-to-moderate increase in RSAP-B during NREM sleep. Greater NREM RSAP-B was associated with a reduced CAP rate and NREM alpha power. This pilot study provides preliminary evidence that tVNS may improve sleep depth and stability in veterans with PTSD, as well as increase parasympathetically mediated nocturnal autonomic activity. These results warrant continued investigation into tVNS as a potential tool for treating sleep disturbance in veterans with PTSD.

Influence of a 2-week transcutaneous auricular vagus nerve stimulation on memory: findings from a randomized placebo controlled trial in non-clinical adults.

PURPOSE: Memory plays an essential role in daily life and is one of the first functions to deteriorate in cognitive impairment and dementia. Transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic method; however, its ability to enhance memory is underexplored, especially considering long-term stimulation. We aimed to investigate the effect of a 2-week course of auricular tVNS (taVNS) on memory in a non-clinical population. METHODS: This single-blind randomized placebo-wait-list controlled trial recruited 76 participants (30 men; mean age 48.32 years) and randomized them into four groups: early active/sham taVNS and late active/sham taVNS. Participation in the study lasted 4 weeks; early groups underwent 2 weeks intervention immediately following the first study site visit (days 0-13) and late groups 2 weeks after the first study site visit (days 14-27). Active and sham taVNS included 2 weeks of daily 4-h neurostimulation at the tragus or earlobe, respectively. To assess memory, we used the Rey Auditory Verbal Learning Test. RESULTS: Two weeks of active taVNS, but not sham taVNS, improved immediate recall and short-term memory score both in early and late groups. Furthermore, the improvements persisted over subsequent follow-up in early active taVNS. Importantly, the effect of active taVNS was superior to sham for immediate recall in both early and late groups. There were no statistical differences in delayed recall. CONCLUSION: Our findings suggest that taVNS has potential to improve memory, particularly immediate recall, and may be an effective method in preventing memory loss and mitigating cognitive aging.

Effects of transcutaneous vagus nerve stimulation on chronic low back pain: a systematic review.

BACKGROUND: Chronic low back pain (CLBP) is a frequent disease. It is a critical health concern that can influence functional capacity by restricting living activities. OBJECTIVES: The current study is to investigate the effects of transcutaneous vagus nerve stimulation (TVNs) in the management of CLBP. METHODS: We searched the databases on Google Scholar, PubMed, Web of Science, Cochrane, and Pedro for randomized clinical trial (RCT) studies published in any language that looked at the effectiveness of TVNs in people with chronic LBP. The inclusion criteria were PICO. Participants in the research were people (≥ 18 years) diagnosed with persistent low back pain for more than 3 months. Study quality was assessed using Cochrane ROB 2. RESULTS: Our database search found 1084 RCT. A number of studies that were not necessary for the issue were removed, and the overall outcome was six trials. Risk of bias (ROB) evaluations at the study level (derived from outcomes) are reported. In the six studies, two (33.3%) had an overall uncertain ROB (i.e., some concerns), whereas one (16.7%) had a high overall ROB. Three trials (50%) had a low overall RoB. CONCLUSION: There is still no evidence to support the use of transcutaneous vagus nerve stimulation as a viable therapeutic rehabilitation strategy. Therefore, we recommend high-quality trials and long-term follow-up to evaluate disability, quality of life, and pain outcomes in these patients.

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.

Transcutaneous Auricular Vagus Nerve Stimulation in Pediatric Patients: A Systematic Review of Clinical Treatment Protocols and Stimulation Parameters.

BACKGROUND: Noninvasive transcutaneous vagus nerve stimulation (tVNS) has promising therapeutic potential in a wide range of applications across somatic and psychiatric conditions. Compared with invasive vagus nerve stimulation, good safety and tolerability profiles also support the use of tVNS in pediatric patients. Potential neurodevelopment-specific needs, however, raise concerns regarding the age-appropriate adjustment of treatment protocols and applied stimulation parameters. OBJECTIVE: In this study, we aimed to review registered trials and published studies to synthesize existing tVNS treatment protocols and stimulation parameters applied in pediatric patients. MATERIALS AND METHODS: A systematic search of electronic data bases (PubMed, Scopus, MEDLINE, Cochrane Library, and PsycINFO) and ClinicalTrials was conducted. Information on patient and study-level characteristics (eg, clinical condition, sample size), the tVNS device (eg, brand name, manufacturer), stimulation settings (eg, pulse width, stimulation intensity), and stimulation protocol (eg, duration, dosage of stimulation) was extracted. RESULTS: We identified a total of 15 publications (four study protocols) and 15 registered trials applying tVNS in pediatric patients (<18 years of age). Most of these studies did not exclusively address pediatric patients. None of the studies elaborated on neurodevelopmental aspects or justified the applied protocol or stimulation parameters for use in pediatric patients. CONCLUSIONS: No dedicated pediatric tVNS devices exist. Neither stimulation parameters nor stimulation protocols for tVNS are properly justified in pediatric patients. Evidence on age-dependent stimulation effects of tVNS under a neurodevelopment framework is warranted. We discuss the potential implications of these findings with clinical relevance, address some of the challenges of tVNS research in pediatric populations, and point out key aspects in future device development and research in addition to clinical studies on pediatric populations.

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.

Auricular Transcutaneous Vagus Nerve Stimulation Diminishes Alpha-Band-Related Inhibitory Gating Processes During Conflict Monitoring in Frontal Cortices.

BACKGROUND: Pursuing goals is compromised when being confronted with interfering information. In such situations, conflict monitoring is important. Theoretical considerations on the neurobiology of response selection and control suggest that auricular transcutaneous vagus nerve stimulation (atVNS) should modulate conflict monitoring. However, the neurophysiological-functional neuroanatomical underpinnings are still not understood. METHODS: AtVNS was applied in a randomized crossover study design (n = 45). During atVNS or sham stimulation, conflict monitoring was assessed using a Flanker task. EEG data were recorded and analyzed with focus on theta and alpha band activity. Beamforming was applied to examine functional neuroanatomical correlates of atVNS-induced EEG modulations. Moreover, temporal EEG signal decomposition was applied to examine different coding levels in alpha and theta band activity. RESULTS: AtVNS compromised conflict monitoring processes when it was applied at the second appointment in the crossover study design. On a neurophysiological level, atVNS exerted specific effects because only alpha-band activity was modulated. Alpha-band activity was lower in middle and superior prefrontal regions during atVNS stimulation and thus lower when there was also a decline in task performance. The same direction of alpha-band modulations was evident in fractions of the alpha-band activity coding stimulus-related processes, stimulus-response translation processes, and motor response-related processes. CONCLUSIONS: The combination of prior task experience and atVNS compromises conflict monitoring processes. This is likely due to reduction of the alpha-band-associated inhibitory gating process on interfering information in frontal cortices. Future research should pay considerable attention to boundary conditions affecting the direction of atVNS effects.

Increased Concentrations of Circulating Interleukins following Non-Invasive Vagus Nerve Stimulation: Results from a Randomized, Sham-Controlled, Crossover Study in Healthy Subjects.

OBJECTIVE: The vagus nerve constitutes the main component of the parasympathetic nervous system and plays an important role in the regulation of neuro-immune responses. Invasive stimulation of the vagus nerve produces anti-inflammatory effects; however, data on humoral immune responses of transcutaneous vagus nerve stimulation (tVNS) are rare. Therefore, the present study investigated changes in serum cytokine concentrations of interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor α (TNFα) following a short-term, non-invasive stimulation of the vagus nerve. METHODS: Whole blood samples were collected before and after a short-lived application of active tVNS at the inner tragus as well as sham stimulation of the earlobe. Cytokine serum concentrations were determined in two healthy cohorts of younger (n = 20) and older participants (n = 19). Differences between active and sham conditions were analyzed using linear mixed models and post hoc F tests after applying Yeo-Johnson power transformations. This trial was part of a larger study registered on ClinicalTrials.gov (NCT05007743). RESULTS: In the young cohort, IL-6 and IL-1ß concentrations were significantly increased after active stimulation, whereas they were slightly decreased after sham stimulation (IL-6: p = 0.012; IL-1ß: p = 0.012). Likewise, in the older cohort, IL-1ß and IL-8 concentrations were significantly elevated after active stimulation and reduced after sham application (IL-8: p = 0.007; IL-1ß: p = 0.001). In contrast, circulating TNFα concentrations did not change significantly in either group. CONCLUSION: Our results show that active tVNS led to an immediate increase in the serum concentrations of certain pro-inflammatory cytokines such as IL-1ß, IL-6, and/or IL-8 in two independent cohorts of healthy study participants.

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.

Investigating the Effect of Transcutaneous Auricular Vagus Nerve Stimulation on Cortical Excitability in Healthy Males.

OBJECTIVES: As a potential treatment for epilepsy, transcutaneous auricular vagus nerve stimulation (taVNS) has yielded inconsistent results. Combining transcranial magnetic stimulation with electromyography (TMS-EMG) and electroencephalography (TMS-EEG) can be used to investigate the effect of interventions on cortical excitability by evaluating changes in motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). The goal of this study is to objectively evaluate the effect of taVNS on cortical excitability with TMS-EMG and TMS-EEG. These findings are expected to provide insight in the mechanism of action and help identify more optimal stimulation paradigms. MATERIALS AND METHODS: In this prospective single-blind cross-over study, 15 healthy male subjects underwent active and sham taVNS for 60 min, using a maximum tolerated stimulation current. Single and paired pulse TMS was delivered over the right-sided motor hotspot to evaluate MEPs and TEPs before and after the intervention. MEP statistical analysis was conducted with a two-way repeated measures ANOVA. TEPs were analyzed with a cluster-based permutation analysis. Linear regression analysis was implemented to investigate an association with stimulation current. RESULTS: MEP and TEP measurements were not affected by taVNS in this study. An association was found between taVNS stimulation current and MEP outcome measures indicating a decrease in cortical excitability in participants who tolerated higher taVNS currents. A subanalysis of participants (n = 8) who tolerated a taVNS current ≥2.5 mA showed a significant increase in the resting motor threshold, decrease in MEP amplitude and modulation of the P60 and P180 TEP components. CONCLUSIONS: taVNS did not affect cortical excitability measurements in the overall population in this study. However, taVNS has the potential to modulate specific markers of cortical excitability in participants who tolerate higher stimulation levels. These findings indicate the need for adequate stimulation protocols based on the recording of objective outcome parameters.

Transcutaneous Vagus Nerve Stimulation in Patients With Severe Traumatic Brain Injury: A Feasibility Trial.

OBJECTIVES: Preclinical studies have shown that surgically implanted vagus nerve stimulation (VNS) promotes recovery of consciousness and cognitive function following experimental traumatic brain injury (TBI). The aim of this study is to report the feasibility and safety of a noninvasive transcutaneous vagus nerve stimulation (tVNS) in patients with persistent impairment of consciousness following severe TBI. MATERIALS AND METHODS: The feasibility of tVNS was evaluated in five patients presenting with diffuse axonal injury and reduced dominant EEG activity one month following severe TBI. tVNS was applied to the left cymba conchae of the external ear using a skin electrode four hours daily for eight weeks. Possible effects of tVNS on physiological parameters and general side effects were recorded. In addition, we report the rate of recovery using coma recovery scale revised (CRS-R). RESULTS: The tVNS regime of four hours daily for eight weeks was feasible and well tolerated with little side effects and no clinically relevant effects on physiological parameters. Three patients showed improvements (>3 points) in the CRS-R following eight weeks tVNS. CONCLUSION: We demonstrated that tVNS is a feasible and safe VNS strategy for patients following severe TBI. Controlled studies are needed to clarify whether tVNS has a potential to promote recovery of consciousness following severe TBI.

Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa): a prospective clinical trial.

PURPOSE: Postoperative ileus (POI) is a common complication after abdominal surgery. Invasive stimulation of the cervical vagus nerve is known to reduce inflammatory response and ameliorated POI after surgery in a mouse model. However, the transcutaneous vagus nerve stimulation (tVNS) is a possible non-invasive approach. In this clinical study, we aimed to investigate the effect of tVNS on the activation of the stomach muscle in humans. METHODS: Patients requiring open laparotomy were screened for this prospective proof of concept clinical study. After open laparotomy, muscle activity of the stomach was measured by a free running electromyography (EMG) before and during tVNS on the ear. Frequency and amplitude of compound gastric action potentials were the electrophysiological parameters we assessed to reveal the changes in electro motor gastric activity. Gastrin levels as a surrogate marker for vagus nerve activation was analyzed before, 1 and 3 h after tVNS. RESULTS: Fourteen patients were included, no severe adverse events and no medical device related adverse events occurred. tVNS led to significant reduction of action potential frequency and significant elevation of action potential amplitude in the stomach compared to control. Gastrin levels were significantly elevated 3 h after tVNS compared to levels before tVNS. CONCLUSION: Application of tVNS is a safe and feasible procedure during surgical intervention. Our results provide evidence that tVNS activates efferent visceral vagal fibers. Therefore, this low risk and easy to perform method could be useful to prevent postoperative ileus. CLINICAL TRIAL REGISTER NUMBER: DRKS00013340.

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 vagus nerve stimulation (tVNS) modulates flow experience.

Flow has been defined as a pleasant psychological state that people experience when completely absorbed in an activity. Previous correlative evidence showed that the vagal tone (as indexed by heart rate variability) is a reliable marker of flow. So far, it has not yet been demonstrated that the vagus nerve plays a causal role in flow. To explore this we used transcutaneous vagus nerve stimulation (tVNS), a novel non-invasive brain stimulation technique that increases activation of the locus coeruleus (LC) and norepinephrine release. A sham/placebo-controlled, randomized cross-over within-subject design was employed to infer a causal relation between the stimulated vagus nerve and flow as measured using the Flow Short-Scale in 32 healthy young volunteers. In both sessions, while being stimulated, participants had to rate their flow experience after having performed a task for 30 min. Active tVNS, compared to sham stimulation, decreased flow (as indexed by absorption scores). The results can be explained by the network reset theory, which assumes that high-phasic LC activity promotes a global reset of attention over exploitation of the current focus of attention, allowing rapid behavioral adaptation and resulting in decreased absorption scores. Furthermore, our findings corroborate the hypothesis that the vagus nerve and noradrenergic system are causally involved in flow.

Optimization of Transcutaneous Vagus Nerve Stimulation Using Functional MRI.

OBJECTIVE/HYPOTHESIS: Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, depression, and a number of other disorders. Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) has been considered as a non-invasive alternative. Several functional magnetic resonance imaging (fMRI) studies on the effects of tVNS used different stimulation parameters and locations in the ear, which makes it difficult to determine the optimal tVNS methodology. The present study used fMRI to determine the most effective location for tVNS. MATERIALS AND METHODS: Four stimulation locations in the ear were compared: the inner tragus, inferoposterior wall of the ear canal, cymba conchae, and earlobe (sham). Thirty-seven healthy subjects underwent two 6-min tVNS stimulation runs per electrode location (monophasic rectangular 500 µs pulses, 25 Hz). General linear model was performed using SPM; region-of-interest analyses were performed for the brainstem areas. RESULTS: Stimulation at the ear canal resulted in the weakest activation of the nucleus of solitary tract (NTS), the recipient of most afferent vagal projections, and of the locus coeruleus (LC), a brainstem nucleus that receives direct input from the NTS. Stimulation of the inner tragus and cymba conchae activated these two nuclei as compared to sham. However, ROI analysis showed that only stimulation of the cymba conchae produced a significantly stronger activation in both the NTS and LC than did the sham stimulation. CONCLUSIONS: These findings suggest that tVNS at the cymba conchae properly activates the vagal pathway and results in its strongest activation, and thus may be the optimal location for tVNS therapies applied to the auricle.

A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy.

This study explored the efficacy and safety of transcutaneous vagus nerve stimulation (t-VNS) in patients with pharmacoresistant epilepsy. A total of 60 patients were randomly divided into two groups based on the stimulation zone: the Ramsay-Hunt zone (treatment group) and the earlobe (control group). Before and after the 12-month treatment period, all patients completed the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the Liverpool Seizure Severity Scale (LSSS), and the Quality of Life in Epilepsy Inventory (QOLIE-31). Seizure frequency was determined according to the patient's seizure diary. During our study, the antiepileptic drugs were maintained at a constant level in all subjects. After 12 months, the monthly seizure frequency was lower in the treatment group than in the control group (8.0 to 4.0; P=0.003). This reduction in seizure frequency was correlated with seizure frequency at baseline and duration of epilepsy (both P>0.05). Additionally, all patients showed improved SAS, SDS, LSSS, and QOLIE-31 scores that were not correlated with a reduction in seizure frequency. The side effects in the treatment group were dizziness (1 case) and daytime drowsiness (3 cases), which could be relieved by reducing the stimulation intensity. In the control group, compared with baseline, there were no significant changes in seizure frequency (P=0.397), SAS, SDS, LESS, or QOLIE-31. There were also no complications in this group.

Transcutaneous vagus nerve stimulation effects on chronic pain: systematic review and meta-analysis.

Chronic pain is one of the major causes of disability with a tremendous impact on an individual's quality of life and on public health. Transcutaneous vagus nerve stimulation (tVNS) is a safe therapeutic for this condition. We aimed to evaluate its effects in adults with chronic pain. A comprehensive search was performed, including randomized controlled trials published until October 2023, which assessed the effects of noninvasive tVNS. Cohen's d effect size and 95% confidence intervals (CIs) were calculated, and random-effects meta-analyses were performed. Fifteen studies were included. The results revealed a mean effect size of 0.41 (95% CI 0.17-0.66) in favor of tVNS as compared with control, although a significant heterogeneity was observed (χ2 = 21.7, df = 10, P = 0.02, I 2 = 53.9%). However, when compared with nonactive controls, tVNS shows a larger effect size (0.79, 95% CI 0.25-1.33), although the number of studies was small (n = 3). When analyzed separately, auricular tVNS and cervical tVNS against control, it shows a significant small to moderate effect size, similar to that of the main analysis, respectively, 0.42 (95% CI 0.08-0.76, 8 studies) and 0.36 (95% CI 0.01-0.70, 3 studies). No differences were observed in the number of migraine days for the trials on migraine. This meta-analysis indicates that tVNS shows promise as an effective intervention for managing pain intensity in chronic pain conditions. We discuss the design of future trials to confirm these preliminary results, including sample size and parameters of stimulation.

Transcutaneous auricular vagus nerve stimulation to acutely reduce emotional vulnerability and improve emotional regulation in borderline personality disorder (tVNS-BPD): study protocol for a randomized, single-blind, sham-controlled trial.

BACKGROUND: Borderline personality disorder (BPD) is considered a disorder of emotion regulation resulting from the expression of a biologically determined emotional vulnerability (that is, heightened sensitivity to emotion, increased emotional intensity/reactivity, and a slow return to emotional baseline) combined with exposure to invalidating environments. Vagal tone has been associated with activity in cortical regions involved in emotion regulation and a lower resting state of vagal tone has been observed in BPD patients relative to healthy controls. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been shown to reduce temper outbursts in adults with Prader-Willi Syndrome, to enhance recognition of emotions in healthy students, and to improve depressive and anxiety symptoms. Furthermore, a single session of taVNS has been shown to acutely alter the recognition of facial expressions of negative valence in adolescents with MDD and increase emotion recognition in controls. However, the effect of taVNS on emotional vulnerability and regulation in individuals diagnosed with BPD has not been investigated. Our aims are to determine if taVNS is effective in acutely reducing emotional vulnerability and improve emotional regulation in BPD patients. METHODS: Forty-two patients will be randomized to a single session of taVNS or sham-taVNS while going through an affect induction procedure. It will consist of the presentation of one neutral and three negative affect-evoking 4-min-long videos in sequence, each of which is followed by a 4-min post-induction period during which participants will rate the quality and intensity of their current self-reported emotions (post-induction ratings) and the perceived effectiveness in managing their emotions during the video presentation. The rating of the current self-reported emotions will be repeated after every post-induction period (recovery ratings). Mixed models with individuals as random effect will be used to investigate the ratings at each stage of the study, taking into account the repeated measures of the same individuals at baseline, pre-induction, post-induction, and recovery. DISCUSSION: The study has potential to yield new insights into the role of vagal tone in emotion dysregulation in BPD and offer preliminary data on the effectiveness of taVNS as a possible non-invasive brain stimulation to treat a core symptom of BPD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05892900. Retrospectively registered on Jun 07, 2023.