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Background: Previous studies have evaluated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of Parkinson's disease (PD). However, the mechanism underlying the effect of taVNS on PD remains to be elucidated. This study aimed to investigate the immediate effects of taVNS in PD patients. Methods: This crossover self-controlled study included 50 PD patients. Each patient underwent three sessions of resting-state functional magnetic resonance imaging (rs-fMRI) under three conditions: real taVNS, sham taVNS, and no taVNS intervention. We analyzed whole-brain amplitude of low-frequency fluctuations (ALFF) from preprocessed fMRI data across different intervention conditions. ALFF values in altered brain regions were correlated with clinical symptoms in PD patients. Results: Forty-seven participants completed the study and were included in the final analysis. Real taVNS was associated with a widespread decrease in ALFF in the right hemisphere, including the superior parietal lobule, precentral gyrus, postcentral gyrus, middle occipital gyrus, and cuneus (voxel p < 0.001, GRF corrected). The ALFF value in the right superior parietal lobule during real taVNS was negatively correlated with the Unified Parkinson's Disease Rating Scale Part III (r = −0.417, p = 0.004, Bonferroni corrected). Conclusion: TaVNS could immediately modulate the functional activity of brain regions involved in superior parietal lobule, precentral gyrus, postcentral gyrus, middle occipital gyrus, and cuneus. These findings offer preliminary insights into the mechanism of taVNS in treating PD and bolster confidence in its long-term therapeutic potential. TaVNS appears to reduce ALFF values in specific brain regions, suggesting a potential modulation mechanism for treating PD. [ABSTRACT FROM AUTHOR]

Aims: Transcutaneous auricular vagus nerve stimulation (taVNS) is widely used to treat a variety of disorders because it is noninvasive, safe, and well tolerated by awake patients. However, long‐term and repetitive taVNS is difficult to achieve in awake mice. Therefore, developing a new taVNS method that fully mimics the method used in clinical settings and is well‐tolerated by awake mice is greatly important for generalizing research findings related to the effects of taVNS. The study aimed to develop a new taVNS device for use in awake mice and to test its reliability and effectiveness. Methods: We demonstrated the reliability of this taVNS device through retrograde neurotropic pseudorabies virus (PRV) tracing and evaluated its effectiveness through morphological analysis. After 3 weeks of taVNS application, the open field test (OFT) and elevated plus maze (EPM) were used to evaluate anxiety‐like behaviors, and the Y‐maze test and novel object recognition test (NORT) were used to evaluate recognition memory behaviors, respectively. Results: We found that repetitive taVNS was well tolerated by awake mice, had no effect on anxiety‐like behaviors, and significantly improved memory. Conclusion: Our findings suggest that this new taVNS device for repetitive stimulation of awake mice is safe, tolerable, and effective. [ABSTRACT FROM AUTHOR]

Transcutaneous auricular vagus nerve stimulation (taVNS) targets subcutaneous axons in the auricular branch of the vagus nerve at the outer ear. Its non‐invasive nature makes it a potential treatment for various disorders. taVNS induces neuromodulatory effects within the nucleus of the solitary tract (NTS), and due to its widespread connectivity, the NTS acts as a gateway to elicit neuromodulation in both higher‐order brain regions and other brainstem nuclei (e.g. spinal trigeminal nucleus; Sp5). Our objective was to examine stimulation parameters on single‐neuron electrophysiological responses in α‐chloralose‐anaesthetized Sprague–Dawley rats within NTS and Sp5. taVNS was also compared to traditional cervical VNS (cVNS) on single neuronal activation. Specifically, electrophysiological extracellular recordings were evaluated for a range of frequency and intensity parameters (20–250 Hz, 0.5–1.0 mA). Neurons were classified as positive, negative or non‐responders based on increased activity, decreased activity or no response during stimulation, respectively. Frequency‐dependent analysis showed that 20 and 100 Hz generated the highest proportion of positive responders in NTS and Sp5 with 1.0 mA intensities eliciting the greatest magnitude of response. Comparisons between taVNS and cVNS revealed similar parameter‐specific activation for caudal NTS neuronal populations; however, individual neurons showed different activation profiles. The latter suggests that cVNS and taVNS send afferent input to NTS via different neuronal pathways. This study demonstrates differential parameter‐specific taVNS responses and begins an investigation of the mechanisms responsible for taVNS modulation. Understanding the neuronal pathways responsible for eliciting neuromodulatory effects will enable more tailored taVNS treatments in various clinical disorders. Key points: Transcutaneous auricular vagus nerve stimulation (taVNS) offers a non‐invasive alternative to invasive cervical vagus nerve stimulation (cVNS) by activating vagal afferents in the ear to induce neuromodulation.Our study evaluated taVNS effects on neuronal firing patterns in the nucleus of the solitary tract (NTS) and spinal trigeminal nucleus (Sp5) and found that 20 and 100 Hz notably increased neuronal activity during stimulation in both nuclei.Increasing taVNS intensity not only increased the number of neurons responding in Sp5 but also increased the magnitude of response, suggesting a heightened sensitivity to taVNS compared to NTS.Comparisons between cVNS and taVNS revealed similar overall activation but different responses on individual neurons, indicating distinct neural pathways.These results show parameter‐specific and nuclei‐specific responses to taVNS and confirm that taVNS can elicit responses comparable to cVNS at the neuronal level, but it does so through different neuronal pathways. [ABSTRACT FROM AUTHOR]

Background: Premature Ventricular Complexes (PVCs) are very common in clinical practice, with frequent PVCs (more than 30 beats per hour) or polymorphic PVCs significantly increasing the risk of mortality. Previous studies have shown that vagus nerve stimulation improves ventricular arrhythmias. Stimulation of the auricular distribution of the vagus nerve has proven to be a simple, safe, and effective method to activate the vagus nerve. Transcutaneous au ricular vagus nerve stimulation (taVNS) has shown promise in both clinical and experimental setting for PVCs; however, high-quality clinical studies are lacking, resulting in insufficient evidence of efficacy. Methods: The study is a prospective, randomized, parallel-controlled trial with a 1:1 ratio between the two groups. Patients will be randomized to either the treatment group (taVNS) or the control group (Sham-taVNS) with a 6-week treatment and a subsequent 12-week follow-up period. The primary outcome is the proportion of patients with a ≥ 50% reduction in the number of PVCs monitored by 24-hour Holter. Secondary outcomes include the proportion of patients with a ≥ 75% reduction in PVCs, as well as the changes in premature ventricular beats, total heartbeats, and supraventricular premature beats recorded by 24-hour Holter. Additional assessments compared score changes in PVCs-related symptoms, as well as the score change of self-rating anxiety scale (SAS), self-rating depression scale (SDS), and 36-item short form health survey (SF-36). Discussion: The TASC-V trial will help to reveal the efficacy and safety of taVNS for frequent PVCs, offering new clinical evidence for the clinical practice. Trial registration: Clinicaltrials.gov: NCT04415203 (Registration Date: May 30, 2020). [ABSTRACT FROM AUTHOR]

Background: Treatment of disorders of consciousness (DOC) poses a huge challenge for clinical medicine. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation method, which shows potential in improving recovery of DOC. However, the evidence came from single-center, small-sample randomized controlled trial, which is insufficient to form a conclusion. Thereby, we propose a prospective, multicenter, doubleblind, stratified, two-arm randomized controlled trial protocol to investigate the efficacy and safety of bilateral synchronous taVNS for treatment of DOC. Methods: We aim to recruit 382 patients with prolonged DOC, and divide them into an active stimulation group and a sham stimulation group. The patients in the active stimulation group will receive bilateral synchronous taVNS with a 200  μs pulse width, 20  Hz frequency, and personal adjusted intensity. The sham stimulation group will wear the same stimulator but without current output. Both groups will receive treatment for 30  min per session, twice per day, 6 days per week lasting for 4 weeks. The clinical assessment including Coma Recovery Scale-Revised (CRS-R), Full Outline of Unresponsiveness (FOUR), Glasgow Coma Scale (GCS), and Extended Glasgow Outcome Scale (GOS-E) will be conducted to evaluate its efficacy. Heart rate variability (HRV), blood pressure, and adverse events will be recorded to evaluate its safety. Discussion: These results will enable us to investigate the efficacy and safety of taVNS for DOC. This protocol will provide multicenter, large-sample, highquality Class II evidence to support bilateral synchronous taVNS for DOC, and will advance the field of treatment options for DOC [ABSTRACT FROM AUTHOR]

The aim of this study was to clarify the effects of transcutaneous auricular vagus nerve stimulation (taVNS) to the left cymba concha on the pain perception using nociceptive withdrawal reflex (NWR), which is known to be associated with chronic pain, and to investigate whether there is a relationship between taVNS‐induced suppression of the NWR and parasympathetic activation. We applied either 3.0 mA, 100 Hz taVNS for 120 s on the left cymba concha (taVNS condition) or the left earlobe (Sham condition) for 20 healthy adults. NWR threshold was measured before (Baseline), immediately after (Post 0), 10 min (Post 10) and 30 min after (Post 30) stimulation. The NWR threshold was obtained from biceps femoris muscle by applying electrical stimulation to the sural nerve. During taVNS, electrocardiogram was recorded, and changes in autonomic nervous activity measured by heart rate variability (HRV) were analyzed. We found that the NWR thresholds at Post 10 and Post 30 increased compared with baseline in the taVNS group (10 min after: p =.008, 30 min after: p =.008). In addition, increased parasympathetic activity by taVNS correlated with a greater increase in NWR threshold at Post 10 and Post 30 (Post 10: p =.003; Post 30: p =.001). The present results of this single‐blinded study demonstrate the pain‐suppressing effect of taVNS on NWR threshold and suggest that the degree of parasympathetic activation during taVNS may predict the pain‐suppressing effect of taVNS after its application. [ABSTRACT FROM AUTHOR]

Background. tVNS is a technique of electrical stimulation of vagus nerve afferents that is used as a therapy for chronic pain. This study aims to analyze the effect of adding tVNS to exercise therapy on dynamic balance in chronic LBP patients measured by Maximized Reach Distance (%MAXD) and composite score of Modified Star Excursion Balance Test (MSEBT). Method. The method is an experimental study with a pretest-posttest randomized control group study. 22 people with mechanical chronic LBP aged 16-55 years who were randomly allocated into an exercise group (control group) and an exercise plus tVNS group (intervention group). MSEBT dynamic balance was measured before and after intervention. Results. In the intervention group the average MSEBT anterior right and left leg before (74.57±14.72;73.53±15.0) after (86.45±15.98; 86.98±15.9), posteromedial right and left before (88.23±16.76; 75.15±15.04) after (99.65±14.56, 92.19±11.91), right and left posterolateral before (76.66±13.89, 78.02±13.44) after (84.00±17.25, 84.30±13.90) there was a significant difference (p <0.05). Comparing anterior AMSEBT, right composite score and left posteromedial posterolateral AMSEBT between groups, there was a significant difference (p <0.05), not significant in right posteromedial posterolateral AMSEBT. Conclusion. The addition of tVNS to exercise therapy after 2 weeks on dynamic balance with MSEBT assessment showed a significant improvement in the intervention group. The results were better in the intervention group than in the control group. Further research is still needed to investigate the potential of adding tVNS to chronic LBP. [ABSTRACT FROM AUTHOR]

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is considered a safe and promising tool for limb rehabilitation after stroke, but its effect on cough has never been studied. It is known that the ear and larynx share vagal afferent pathways, suggesting that stimulating the ear with taVNS might have effects on cough sensitivity. The specific stimulation parameters used can influence outcomes. Objective: To investigate the effect of various stimulation parameters on change in cough sensitivity, compared to the reference parameter of 25 Hz stimulation at the left concha (most commonly-used parameter for stroke rehabilitation). Design, setting, and participants: Randomized, single-blind, active-controlled, eight-period cross-over design conducted March to August 2022 at a New Zealand research laboratory with 16 healthy participants. Interventions: All participants underwent eight stimulation conditions which varied by stimulation side (right ear, left ear), zone (ear canal, concha), and frequency (25 Hz, 80 Hz). Main outcome measures: Change in natural and suppressed cough threshold (from baseline to after 10 min of stimulation) assessed using a citric acid cough reflex test. Results: When compared to the reference parameter of 25 Hz stimulation at the left concha, there was a reduction in natural cough threshold of -0.16 mol/L for 80 Hz stimulation at the left canal (p = 0.004), indicating increased sensitivity. For the outcome measure of suppressed cough threshold, there was no significant effect of any of the stimulation conditions compared to the active reference. Conclusion: Since stroke patients often have cough hyposensitivity with resulting high risk of silent aspiration, using 80 Hz taVNS at the left canal may be a better choice for future stroke rehabilitation studies than the commonly used 25 Hz taVNS at the left concha. Treatment parameters should be manipulated in future sham-controlled trials to maximize any potential treatment effect of taVNS in modulating cough sensitivity. [ABSTRACT FROM AUTHOR]

Emotional experiences are a part of our lives. The maladaptive functioning of an individual's emotional field can lead to emotional disturbances of various kinds, such as anxiety and depression. Currently, there is an increasing prevalence of emotional disorders that cause great human suffering and high socioeconomic costs. Emotional processing has a biological basis. The major neuroscientific theories of emotion are based on biological functioning, and all of them take into account the anatomy and function of the tenth cranial nerve: the vagus nerve. The vagus nerve connects the subdiaphragmatic and supradiaphragmatic areas and modulates emotional processing as the basis of interoceptive functioning. Auricular vagus nerve stimulation is a new and innovative neuromodulation technique based on the function of the vagus nerve. Several interventions have shown that this new neurostimulation technique is a very promising resource for treating emotional disorders. In this paper, we summarise three neuroscientific theories of emotion, explain what transcutaneous auricular nerve stimulation is, and present arguments for its use and continued research. [ABSTRACT FROM AUTHOR]

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a potentially effective neuromodulation technique for addressing neurological disorders, including disorders of consciousness. Expanding upon our prior clinical study, which demonstrated the superior effectiveness of a 4-week taVNS treatment in patients with minimally conscious state (MCS) compared to those in a vegetative state/unresponsive wakefulness state, the aim of this investigation was to evaluate the safety and therapeutic efficacy of taVNS in individuals with MCS through a sham-controlled randomized double-blind clinical trial. Methods: A cohort of 50 adult patients (male = 33, female = 17) diagnosed with a MCS were randomly assigned to either the active taVNS (N = 25) or sham taVNS (N = 25) groups. The treatment period lasted for 4 weeks, followed by an 8-week follow-up period. The Coma Recovery Scale-Revised (CRS-R) and Glasgow Coma Scale (GCS) were administered at baseline and weekly during the initial 4 weeks. Additionally, the Disability Rating Scale (DRS) was used to assess the patients’ functional abilities via telephone at week 12. Furthermore, various neurophysiological measures, including electroencephalogram (EEG), upper-limb somatosensory evoked potentials (USEP), brainstem auditory evoked potentials (BAEP), and P300 event-related potentials (P300), were employed to monitor changes in brain activity and neural conduction pathways. Results: The scores for the active taVNS group in the CRS-R and GCS showed greater improvement over time compared to the sham taVNS group (CRS-R: 1-week, Z = −1.248, p = 0.212; 2-week, Z = −1.090, p = 0.276; 3-week, Z = −2.017, p = 0.044; 4-week, Z = −2.267, p = 0.023. GCS: 1-week, Z = −1.325, p = 0.185; 2-week, Z = −1.245, p = 0.213; 3-week, Z = −1.848, p = 0.065; 4-week, Z = −1.990, p = 0.047). Additionally, the EEG, USEP, BAEP, and P300 also demonstrated significant improvement in the active taVNS group compared to the sham taVNS group at week 4 (EEG, Z = −2.086, p = 0.037; USEP, Z = −2.014, p = 0.044; BAEP, Z = −2.298, p = 0.022; P300 amplitude, Z = −1.974, p = 0.049; P300 latency, t = 2.275, p = 0.027). Subgroup analysis revealed that patients with MCS derived greater benefits from receiving taVNS treatment earlier (CRS-R, Disease duration ≤ 1-month, mean difference = 8.50, 95% CI = [2.22, 14.78], p = 0.027; GCS, Disease duration ≤ 1-month, mean difference = 3.58, 95% CI = [0.14, 7.03], p = 0.044). By week 12, the active taVNS group exhibited lower Disability Rating Scale (DRS) scores compared to the sham taVNS group (Z = −2.105, p = 0.035), indicating a more favorable prognosis for MCS patients who underwent taVNS. Furthermore, no significant adverse events related to taVNS were observed during treatment. Conclusion: The findings of this study suggest that taVNS may serve as a potentially effective and safe intervention for facilitating the restoration of consciousness in individuals diagnosed with MCS. This therapeutic approach appears to enhance cerebral functioning and optimize neural conduction pathways. [ABSTRACT FROM AUTHOR]

Objective: In this randomized, double‐blind, sham‐controlled trial, we explored the effect of 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on gait impairments in Parkinson's disease (PD) patients and investigated the underlying neural mechanism. Methods: In total, 22 PD patients and 14 healthy controls were enrolled. PD patients were randomized (1:1) to receive active or sham taVNS (same position as active taVNS group but without releasing current) twice a day for 1 week. Meanwhile, all subjects were measured activation in the bilateral frontal and sensorimotor cortex during usual walking by functional near‐infrared spectroscopy. Results: PD patients showed instable gait with insufficient range of motion during usual walking. Active taVNS improved gait characteristics including step length, stride velocity, stride length, and step length variability compared with sham taVNS after completion of the 7‐day therapy. No difference was found in the Unified Parkinson's Disease Rating Scale III, Timed Up and Go, Tinetti Balance, and Gait scores. Moreover, PD patients had higher relative change of oxyhemoglobin in the left dorsolateral prefrontal cortex, pre‐motor area, supplementary motor area, primary motor cortex, and primary somatosensory cortex than HCs group during usual walking. Hemodynamic responses in the left primary somatosensory cortex were significantly decreased after taVNS therapy. Conclusion: taVNS can relieve gait impairments and remodel sensorimotor integration in PD patients. [ABSTRACT FROM AUTHOR]

Transcutaneous auricular vagus nerve stimulation (taVNS) is used for treating depression but the efficacy and safety have not been well assessed. This study was conducted to evaluate the efficacy and safety of taVNS in depression. The retrieval databases included English databases of PubMed, Web of Science, Embase, the Cochrane Library and PsycINFO, and Chinese databases of CNKI, Wanfang, VIP and Sino Med, and the retrieval period was from their inception to November 10, 2022. The clinical trial registers (ClinicalTrials.gov and Chinese Clinical Trial Registry) were also searched. Standardized mean difference and the risk ratio were used as the effect indicator and the effect size was represented by the 95 % confidence interval. Revised Cochrane risk-of-bias tool for randomized trials and the Grades of Recommendation, Assessment, Development and Evaluation system were used to assess the risk of bias and quality of evidence respectively. Totally, 12 studies of 838 participants were included. taVNS could significantly improve depression and reduce Hamilton Depression Scale scores. Low to very low evidence showed that taVNS had higher response rates than sham-taVMS and comparable response rates compared to antidepressants (ATD) and that taVNS combined with ATD had comparable efficacy to ATD with fewer side effects. The number of studies in subgroups was small and the evidence quality was low to very low. taVNS is an effective and safe method for alleviating depression scores and had a comparable response rate to ATD. • taVNS is an effective and safe method for mild to moderate depression. • taVNS has significantly higher response rate than sham-taVNS. • taVNS has comparable effect than antidepressants in reducing Hamilton Depression Scale scores with less side effects. [ABSTRACT FROM AUTHOR]

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has recently been explored for the treatment of Disorders of consciousness (DoC) caused by traumatic brain injury. The evidence of taVNS during the consciousness recovery has been recently reported. However, the mechanism of taVNS in the recovery of consciousness is not clear. This study attempts to investigate the effectiveness of taVNS in DoC by means of Coma Recovery Scale-Revised (CRS-R), Magnetic resonance imaging (MRI), Electrophysiology (EEG), and Single-molecular array (Simoa). Methods/design: Nighty patients with DoC acquired brain injury are randomized into one of three groups receiving sham taVNS or active taVNS (just left and left or right), respectively. Each of the three groups will experience a 40dayscycle (every 10days for a small period, baseline 2weeks, intervention 2weeks, 40min per day, 5days per week, then no intervention for 2weeks, intervention 2weeks, 40min per day, and 5days per week). Primary outcomes (CRS-R) will be recorded five times during every period. Secondary outcomes will be recorded at the first and at the last period [MRI, EEG, Phosphorylated tau (P-tau), and Neurofilament light chain (NFL)]. We will take notes the adverse events and untoward effects during all cycles. Discussion: Transcutaneous auricular vagus nerve stimulation as a painless, noninvasive, easily applied, and effective therapy was applied for treatment of patients with depression and epilepsy several decades ago. Recent progress showed that taVNS has behavioral effects in the consciousness recovery. However, there is no clinical evidence to support the effects of taVNS on brain activity. Therefore, we will design a randomized controlled trial to evaluate the effectiveness and safety of taVNS therapy for DoC, and explore neural anatomy correlated to taVNS during the consciousness recovery. Finally, this protocol also tests some biomarkers along with the recovery of consciousness. [ABSTRACT FROM AUTHOR]

The human brain exhibits the remarkable ability to categorize speech sounds into distinct, meaningful percepts, even in challenging tasks like learning non-native speech categories in adulthood and hearing speech in noisy listening conditions. In these scenarios, there is substantial variability in perception and behavior, both across individual listeners and individual trials. While there has been extensive work characterizing stimulus-related and contextual factors that contribute to variability, recent advances in neuroscience are beginning to shed light on another potential source of variability that has not been explored in speech processing. Specifically, there are task-independent, moment-to-moment variations in neural activity in broadly-distributed cortical and subcortical networks that affect how a stimulus is perceived on a trial-by-trial basis. In this review, we discuss factors that affect speech sound learning and moment-to-moment variability in perception, particularly arousal states—neurotransmitter-dependent modulations of cortical activity. We propose that a more complete model of speech perception and learning should incorporate subcortically-mediated arousal states that alter behavior in ways that are distinct from, yet complementary to, top-down cognitive modulations. Finally, we discuss a novel neuromodulation technique, transcutaneous auricular vagus nerve stimulation (taVNS), which is particularly well-suited to investigating causal relationships between arousal mechanisms and performance in a variety of perceptual tasks. Together, these approaches provide novel testable hypotheses for explaining variability in classically challenging tasks, including non-native speech sound learning. [ABSTRACT FROM AUTHOR]

Negative stress significantly impacts major depressive disorder (MDD), given the shared brain circuitry between the stress response and mood. Thus, interventions that target this circuitry will have an important impact on MDD. The aim of this study was to evaluate the acute effects of a novel respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique in the modulation of brain activity and connectivity in women with MDD in response to negative stressful stimuli. Twenty premenopausal women with recurrent MDD in an active episode were included in a cross-over experimental study that included two functional MRI visits within one week, randomized to receive exhalatory- (e-RAVANS) or inhalatory-gated (i-RAVANS) at each visit. Subjects were exposed to a visual stress challenge that preceded and followed RAVANS. A Factorial analysis was used to evaluate the effects of RAVANS on brain activity and connectivity and changes in depressive and anxiety symptomatology post-stress. Compared with i-RAVANS, e-RAVANS was significantly associated with increased activation of subgenual anterior cingulate, orbitofrontal and ventromedial prefrontal cortices and increased connectivity between hypothalamus and dorsolateral prefrontal cortex, and from nucleus tractus solitarii to locus coeruleus and ventromedial prefrontal cortex. Changes in brain activity and connectivity after e-RAVANS were significantly associated with a reduction in depressive and anxiety symptoms. Our study suggests exhalatory-gated RAVANS effectively modulates brain circuitries regulating response to negative stress and is associated with significant acute reduction of depressive and anxiety symptomatology in women with recurrent MDD. Findings suggest a potential non-pharmacologic intervention for acute relief of depressive symptomatology in MDD. • Exhalation-gated taVNS (e-RAVANS) upregulates brain response to negative stress. • e-RAVANS has significant acute antidepressant and anxiolytic effects in MDD subjects. • Respiration-gating may optimize taVNS therapeutic effects on major depression. [ABSTRACT FROM AUTHOR]

Protracted alcohol withdrawal symptoms (PAWS), characterized by the presence of substance-specific signs and symptoms (including anxiety, irritability, mood instability, insomnia, and cravings), make alcohol abstinence difficult and increase the risk of relapse in recovering alcoholics. The goal of this study was to evaluate the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on PAWS and plasma brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and leptin levels in patients with alcohol dependency. A total of 114 patients with alcohol dependence were randomly divided into two groups: the treatment group and the control group. The patients in the treatment group were treated with taVNS of the bilateral auricular concha using an ear vagus nerve stimulator. The Pennsylvania Alcohol Craving Scale was used to evaluate the extent of craving for alcohol. The Self-Rating Anxiety Scale and Self-Rating Depression Scale (SDS) were used to evaluate the extent of anxiety and depression symptoms, respectively. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. Enzyme-linked immunosorbent assay was used to measure plasma BDNF, IL-6, TNF-α, and leptin levels. The results showed that the SDS and PSQI scores were significantly lower in the treatment group than in the control group. Moreover, compared with the control group, the average BDNF levels in the treatment group were significantly increased. These results suggest that taVNS could improve the depression symptoms and sleep quality in alcohol-dependent patients after withdrawal, which might be related to the upregulation of plasma BDNF levels. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence suggests that transcutaneous auricular vagus nerve stimulation (taVNS) may relieve symptoms of migraineurs. Frequency is one of the key stimulation parameters. The aim of this study is to investigate the modulation effect of taVNS frequency on the descending pain modulation system (DPMS) in patients with migraine.Methods: Twenty-four episodic migraineurs without aura (21 females) were recruited for the single-blind, crossover, functional magnetic resonance imaging (fMRI) study. Each participant attended two separate fMRI scan sessions, one for 1 Hz and another for 20 Hz taVNS, in a random order. Seed-based functional connectivity analysis was applied using the ventrolateral periaqueductal gray (PAG) as the region of interest.Results: Compared with the pre-taVNS resting state, continuous 1 Hz taVNS (during) produced a significant increase in functional connectivity between the PAG and the bilateral middle cingulate cortex (MCC), right precuneus, left middle frontal gyrus (MFG), and left cuneus. Compared with 20 Hz taVNS, 1 Hz taVNS produced greater PAG connectivity increases with the MCC, right precuneus/posterior cingulate cortex, left insula, and anterior cingulate cortex (ACC). A significant negative correlation was observed between the number of migraine attacks in the previous 4 weeks and the PAG-MCC functional connectivity in the pre-taVNS resting-state before 1 Hz taVNS.Conclusions: Our findings suggest that taVNS with different frequencies may produce different modulation effects on the descending pain modulation system, demonstrating the important role of stimulation frequency in taVNS treatment. [ABSTRACT FROM AUTHOR]

Purpose: Transcutaneous auricular vagus nerve stimulation (taVNS) has been considered for the treatment of sympathetically mediated disorders. However, the optimal mode of stimulation is unknown. This study aimed to compare the cardiovascular effects of respiratory-gated taVNS in healthy subjects. Methods: The examination included expiratory-gated, inspiratory-gated, and non-respiratory-gated taVNS trials. Subjects were examined twice (the order of expiratory- and inspiratory-gated taVNS was changed). taVNS trials started with controlled breathing without stimulation (pre-stimulatory recording) followed by controlled breathing with taVNS (stimulatory recording). Synchronizing taVNS with the respiratory phase was computer-controlled. Heart rate (HR) was calculated from ECG. Systolic blood pressure (SBP) and systemic vascular resistance (SVR) were recorded continuously and noninvasively. Baroreflex sensitivity based on rising (BRS-UP) or falling SBP sequences (BRS-DOWN) or all sequences (BRS-ALL) and heart rate variability (HRV) were analyzed. Results: Seventy-two taVNS trials were obtained from 12 subjects (age 23 ± 3 years). Pre-stimulatory HR correlated with change in HR (r = − 0.25) and SVR (r = 0.24, both p < 0.05). There were no differences between three stimulatory conditions in (1) the changes of hemodynamic parameters, (2) BRS-UP and BRS-ALL, or (3) HRV indices (all p > 0.20). However, in the group of high pre-stimulatory HR trials, HR change differed between inspiratory-gated (0.11 ± 0.53%) and both expiratory-gated (− 1.30 ± 0.58%, p = 0.06) and non-respiratory-gated taVNS (− 1.69 ± 0.65, p = 0.02). BRS-DOWN was higher in inspiratory- vs. non-respiratory-gated taVNS (15.4 ± 1.3 vs. 14.1 ± 0.9 ms/mmHg, p = 0.03). Conclusions: Expiratory-gated and non-respiratory-gated taVNS exert clear cardioinhibitory effects in healthy subjects with high pre-stimulatory HR, whereas inspiratory-gated taVNS does not affect HR. Cardiac and vascular effects of taVNS depend on pre-stimulatory HR. [ABSTRACT FROM AUTHOR]

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

Neonates born premature or who suffer brain injury at birth often have oral feeding dysfunction and do not meet oral intake requirements needed for discharge. Low oral intake volumes result in extended stays in the hospital (>2 months) and can lead to surgical implant and explant of a gastrostomy tube (G-tube). Prior work suggests pairing vagus nerve stimulation (VNS) with motor activity accelerates functional improvements after stroke, and transcutaneous auricular VNS (taVNS) has emerged as promising noninvasive form of VNS. Pairing taVNS with bottle-feeding rehabilitation may improve oromotor coordination and lead to improved oral intake volumes, ultimately avoiding the need for G-tube placement. We investigated whether taVNS paired with oromotor rehabilitation is tolerable and safe and facilitates motor learning in infants who have failed oral feeding. We enrolled 14 infants [11 premature and 3 hypoxic–ischemic encephalopathy (HIE)] who were slated for G-tube placement in a prospective, open-label study of taVNS-paired rehabilitation to increase feeding volumes. Once-daily taVNS was delivered to the left tragus during bottle feeding for 2 weeks, with optional extension. The primary outcome was attainment of oral feeding volumes and weight gain adequate for discharge without G-tube while also monitoring discomfort and heart rate (HR) as safety outcomes. We observed no adverse events related to stimulation, and stimulation-induced HR reductions were transient and safe and likely confirmed vagal engagement. Eight of 14 participants (57%) achieved adequate feeding volumes for discharge without G-tube (mean treatment length: 16 ± 6 days). We observed significant increases in feeding volume trajectories in responders compared with pre-stimulation (p < 0.05). taVNS-paired feeding rehabilitation appears safe and may improve oral feeding in infants with oromotor dyscoordination, increasing the rate of discharge without G-tube, warranting larger controlled trials. [ABSTRACT FROM AUTHOR]

Primary insomnia (PI) is associated with increased spontaneous neuronal activity. Transcutaneous auricular vagus nerve stimulation (taVNS) modulates brain function, and it is an effective treatment for primary insomnia. However, whether taVNS alleviates insomnia through modulating spontaneous neuronal activity is not fully clarified. This study aims to investigate the instant effect of taVNS in modulating spontaneous neuronal activity in PI patients using resting-state functional magnetic resonance imaging (rs-fMRI). Twenty-two PI subjects underwent rs-fMRI scanning prior and immediately after 30 min treatment of taVNS controlled by twenty healthy adults. Amplitude of low frequency fluctuations (ALFF) analysis was employed to assess the difference in spontaneous neuronal activity between PI patients and healthy adults, as well as between pre-treatment and post-treatment of taVNS. The taVNS-induced altered ALFF brain areas were then selected as regions of interest to perform the resting state functional connectivity (RSFC) analysis in PI patients. The right precuneus showed significantly increased ALFF in PI patients. After immediate taVNS treatment, the ALFF was significantly decreased in the right precuneus and increased in the left middle occipital gyrus. The RSFC in right precuneus with right angular, right superior frontal gyrus, and right middle frontal gyrus was significantly decreased. This study provides insights into the instant brain effects of taVNS on PI patients. [ABSTRACT FROM AUTHOR]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a relatively non-invasive alternative treatment for patients suffering from major depressive disorder (MDD). It has been postulated that acupuncture may achieve its treatment effects on MDD through suppression of vagal nerve inflammatory responses. Our previous research established that taVNS significantly increases amygdala-dorsolateral prefrontal cortex connectivity, which is associated with a reduction in depression severity. However, the relationship between taVNS and the central/peripheral functional state of the immune system, as well as changes in brain neural circuits, have not as yet been elucidated. In the present paper, we outline the anatomic foundation of taVNS and emphasize that it significantly modulates the activity and connectivity of a wide range of neural networks, including the default mode network, executive network, and networks involved in emotional and reward circuits. In addition, we present the inflammatory mechanism of MDD and describe how taVNS inhibits central and peripheral inflammation, which is possibly related to the effectiveness of taVNS in reducing depression severity. Our review suggests a link between the suppression of inflammation and changes in brain regions/circuits post taVNS. [ABSTRACT FROM AUTHOR]

The present work was undertaken to study the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on 1, 2-dimethyhydrazine (DMH) induced colon cancer and role of the cholinergic anti-inflammatory pathways (CAP) in the same. Groups of rats were randomly divided into ten groups (n = 8). DMH administration was very well apparent for autonomic dysfunction as observed through distorted hemodynamic (electrocardiogram and heart rate variability), increased aberrant crypt foci and flat neoplastic lesions (methylene blue staining, scanning electron microscopy and Hematoxylin and eosin staining). DMH administration was also recorded for per-oxidative damage. taVNS application restored the autonomic function, cellular morphology and curtailed the oxidative damage. DMH application conspicuously inhibited the mitochondrial apoptosis which was restored back after taVNS application, when scrutinized through immunoblotting and quantitative real time polymerase chain reaction studies. taVNS application up-regulated the CAP as perceived through increased expression for α7 nicotinic acetylcholine receptor(α7nAchR) and decreased expression for nuclear factor kappa-ligand-chain-enhancer of activated B cells (NFκBp65), tissue necrosis factor-α and high mobility group box-1 at protein and mRNA levels. All in all, taVNS up-surged the CAP to counteract DMH induced colon carcinogenesis. Among all the stimulation parameters used, taVNS 3 (pulse width-1 ms, frequency-6 Hz, voltage-6 v, duration-240 min) was observed to be the most effective. Since only chemotherapy and surgery are available options for management of CRC, which are troublesome and painful, there is currently no non-invasive method available for management of CRC. Results of the current study affirmed the effectiveness of taVNS against DMH induced colon cancer. The present study established taVNS as a novel and non-invasive approach toward the management of CRC. [ABSTRACT FROM AUTHOR]

Background: Depression presents a significant burden to both patients and society. One treatment that has emerged is vagus nerve stimulation (VNS), an FDA-approved physical treatment for depressive disorders. However, the application of this intervention has been limited by the involvement of surgery and potential side effects. The aim of this study is to explore the effectiveness of stimulating the superficial branches of the vagus nerve as a solo treatment for MDD.Methods: This is a nonrandomized, controlled study. The first cohort of patients (n=91) only received transcutaneous auricular VNS (taVNS) for 12 weeks. In the second cohort (n=69), patients first received 4 weeks of sham taVNS followed by 8 weeks of taVNS. All treatments were self-administered by the patients at home after they received training from the hospitals. The primary outcome measurement was the 24-item Hamilton Depression Rating Scale measured at weeks 0, 4, 8, and 12. Data analysis included a timelag analysis comparing (1) real and sham taVNS groups at week 4; (2) the real taVNS group at week 4 vs the sham taVNS group at week 8 (fourth week of real taVNS following 4 weeks of sham); and (3) the real taVNS group at week 8 vs the sham taVNS group at week 12 (eighth week of real taVNS following sham).Results: After four weeks of treatment, MDD patients in the taVNS group showed greater improvement than patients in the sham taVNS group as indicated by Hamilton score changes as well as response and remission rates at week four. In addition, we also found that the clinical improvements continued until week 12 during taVNS.Limitations: Patients were not randomized in this study.Conclusions: Our results suggest that taVNS is a promising, safe, and cost-effective therapeutic method for mild and moderate MDD. [ABSTRACT FROM AUTHOR]

Background: Recently, clinical observations reported the potential benefit of vagus nerve stimulation (VNS) for pediatric epilepsy. Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a newer non-invasive VNS, making it more accessible for treating pediatric epilepsy, yet there is limited clinical evidence for its effectiveness. Methods/Design: A three-center, randomized, parallel, controlled trial will be carried out to evaluate whether ta-VNS improves pediatric epilepsy. Pediatric patients aged 2 to 14 years with epilepsy will be recruited and randomly assigned to transcutaneous auricular vagus nerve stimulation (ta-VNS) group, transcutaneous auricular non-vagus nerve stimulation (tan-VNS) group, and control group with a 1:1: sqrt(2) allocation, as per a computer generated randomization schedule stratified by study center using permuted blocks of random sizes. We will use Zelen's design, in which randomization occurs before informed consent. Patients in the stimulation groups will receive tan-VNS or ta-VNS three times a day for 6 months. Patients in the control group will not be provided with any stimulation during the 6 months. The guardians of the patients are required to keep a detailed diary to record the data. Outcome assessment including seizure frequency, electroencephalogram (EEG), heart rate variability (HRV) analysis, quality of life (QOL) and adverse events will be made at baseline and 2, 4 and 6 months after ta-VNS initiation. The seizure frequency and adverse events will be followed up at 1 year and 1.5 years after ta-VNS initiation. Discussion: Results of this trial will help clarify whether ta-VNS treatment is beneficial for pediatric patients, and will make clear whether the anticonvulsive effect of ta-VNS is correlated with the improvement of sympathovagal imbalance. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We investigated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of pediatric epilepsy. Methods: Fourteen pediatric patients with intractable epilepsy were treated by ta-VNS of the bilateral auricular concha using an ear vagus nerve stimulator. The baseline seizure frequency was compared with that after 8weeks, from week 9 to 16 and from week 17 to the end of week 24, according to the seizure diaries of the patients. Results: One patient dropped out after 8weeks of treatment due to lack of efficacy, while the remaining 13 patients completed the 24-week study without any change in medication regimen. The mean reduction in seizure frequency relative to baseline was 31.83% after week 8, 54.13% from week 9 to 16 and 54.21% from week 17 to the end of week 24. The responder rate was 28.57% after 8weeks, 53.85% from week 9 to 16 and 53.85% from week 17 to the end of week 24. No severe adverse events were reported during treatment. Conclusion: Transcutaneous auricular VNS may be a complementary treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy and should be further studied. [Copyright &y& Elsevier]

The vagus nerve plays a vital role in the regulation of food intake and vagal afferent signals may help regulate food cue reactivity by providing negative homeostatic feedback. Despite strong evidence from preclinical studies on vagal afferent "satiety" signals in guiding food intake, evidence from human studies is largely inconclusive to date. Here, we investigated the acute effects of left or right transcutaneous auricular vagus nerve stimulation (taVNS) on subjective ratings of wanting and liking of various food and non-food items in 82 healthy participants (46 women, MBMI = 23.1 kg/m2). In contrast to previous reports in patients with depression, we found moderate to anecdotal evidence supporting the absence of taVNS-induced changes in food ratings. To test whether the absence of taVNS effects on food ratings is due to heterogeneity in the sample, we conducted post hoc subgroup analyses by splitting the data according to stimulation side and sex (between-subject factors) as well as caloric density, perceived healthiness, and flavor (sweet vs. savory) of the food (within-subject factors). This multiverse analysis largely supported the absence of taVNS-induced changes since the strongest subgroup effects provided only anecdotal evidence in favor of taVNS-induced changes. We conclude that acute taVNS only has a marginal effect on subjective ratings of food, suggesting that it is an unlikely mechanism for the reported long-term effects of VNS on body weight. In light of an absence of acute taVNS effects on conscious food liking and wanting, our results call for future research on the correspondence between acute and chronic effects of vagal afferent stimulation. [ABSTRACT FROM AUTHOR]

Transcutaneous auricular vagus nerve stimulation (taVNS) modulates central and peripheral neurophysiology. Specifically, taVNS increases heart rate variability (HRV) indicating a shift in autonomic function towards parasympathetic predominance. However, knowledge on the influence of stimulation parameters and targets is scarce. We hypothesized that the location and charge per phase of taVNS influences HRV. In thirteen healthy subjects, six different stimulation targets were investigated, i.e., cymba conchae, cavum conchae, outer tragus, inner tragus, crus helicis, and fossa triangularis. At each target, 24 parameter combinations were studied: Eight different electrical charges per phase were evaluated by investigating three pulse durations and eight charge-balanced current intensities, i.e., 100 μs (0.250-2 mA in steps of 0.250 mA), 260 μs (0.096–0.769 mA in steps of 0.096 mA), and 500 μs (0.050–0.400 mA in steps of 0.050 mA). In a parallel group design, left and right taVNS were compared to each other. 30 bursts at each parameter combination were applied with a periodicity of 1 Hz. Each burst consisted of five pulses applied at 25 Hz. HRV increased in a charge-dependent way with significant differences between the right and left ear. The targets with the strongest effects were the cymba conchae and fossa triangularis, and to a lesser extent the inner tragus. HRV is suitable to define taVNS parameters and targets for research and therapeutic purposes. Bursts of taVNS with a pulse duration of 100 μs and a current intensity of 2 mA are comfortable for the participants and effective in increasing HRV when applied at specific auricular locations. These findings need to be replicated in larger cohorts, and with longer stimulation and off-periods between conditions. Since results may differ in conditions with an impaired autonomic tone, future studies should also consider aged and patient populations. • Transcutaneous auricular vagus nerve stimulation modulates heart rate variability. • The location and charge of taVNS influences HRV. • Stimulating cymba conchae, fossa triangularis or inner tragus has strong effects. • 25 Hz bursts applied at a periodicity of 1 Hz effectively increase HRV. • 100 μs pulse duration and 2 mA current intensity are comfortable and effective. [ABSTRACT FROM AUTHOR]

Autonomic nervous system (ANS) dysfunction is a well-known feature of cardiovascular diseases (CVDs). Studies on heart rate variability (HRV), a non-invasive method useful in investigating the status of cardiovascular autonomic control, have shown that a predominance of sympathetic modulation not only contributes to the progression of CVDs but has a pivotal role in their onset. Current therapies focus more on inhibition of sympathetic activity, but the presence of drug-resistant conditions and the invasiveness of some surgical procedures are an obstacle to complete therapeutic success. On the other hand, targeting the parasympathetic branch of the autonomic nervous system through invasive vagus nerve stimulation (VNS) has shown interesting results as alternative therapeutic approach for CVDs. However, the invasiveness and cost of the surgical procedure limit the clinical applicability of VNS and hinder the research on the physiological pathway involved. Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) seems to represent an important non-invasive alternative with effects comparable to those of VNS with surgical implant. Thus, in the present narrative review, we illustrate the main studies on tVNS performed in healthy subjects and in three key examples of CVDs, namely heart failure, hypertension and atrial fibrillation, highlighting the neuromodulatory effects of this technique. [ABSTRACT FROM AUTHOR]

Epilepsy is a common chronic neurological disease with a high burden of illness. Invasive vagus nerve stimulation (iVNS) is a well-established treatment option in patients with epilepsy (PWE). More recently, transcutaneous vagus nerve stimulation (tVNS) was introduced, an alternative option which is particularly interesting because it does not require surgery and is instantaneously removable. Here, we thoroughly reviewed clinical data on efficacy and safety of tVNS in epilepsies. Five prospective trials in 118 patients with drug-resistant epilepsies and 3 randomized controlled trials in 280 patients with drug-resistant epilepsies were carried out. Study protocols were heterogeneous in terms of patients' characteristics, used device, stimulation parameters, study duration and endpoints. Seizure reduction amounted up to 64%, with responder rates (seizure reduction ≥50%) up to 65%. Seizure freedom was reached in up to 24%, and even to 31% in a small pediatric study group. Seizure severity scores were provided in 4 studies, showing significant improvement in two of them. Adverse side effects were mostly headache, ear pain and skin alteration and rated as mild to moderate. Drowsiness might be depend on stimulation intensity. Quality of life scores reflecting burden of illness showed significant improvement in two studies. Efficacy and safety of tVNS in PWE has to be interpreted as promising. Multicenter randomized double-blind clinical trials with standardized stimulation protocols and long-term follow-up studies are necessary to finally assess tVNS treatment outcome in drug-resistant epilepsies. • TaVNS shows promising results concerning reduction of seizure frequency and seizure severity in PWE. • Adverse effects of taVNS are mild or moderate and mostly reversible. • Randomized double-blind clinical trials are needed for assessing efficacy and safety of taVNS in greater detail. • Mode of action is not fully understood yet. [ABSTRACT FROM AUTHOR]

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed as a potential new tool in the treatment of major depressive disorder. Prior studies have demonstrated that taVNS enhances cognitive control and is able to modulate brain activity in key regions involved in cognitive emotion regulation, such as the anterior cingulate and medial prefrontal cortex, which is known to be impaired in depressed patients. Preclinical studies are lacking but may provide important insights into the working mechanisms of taVNS on cognitive emotion regulatory processes. In this between-subject study, 83 healthy subjects underwent a single-session of active taVNS or sham stimulation, after which cognitive reappraisal was examined using a computer-based cognitive emotion regulation task. Our results indicate that participants receiving active taVNS, compared to sham, were better at using cognitive reappraisal and rated their response to emotion-eliciting pictures as less intense. Yet, even though we found significant differences in behavioral measures of cognitive emotion regulation, no differences between groups were found in terms of physiological responses to the emotional stimuli. Overall, these findings suggest a positive effect of taVNS on the cognitive reappraisal of emotions, but future studies assessing objective measures of neural activity during cognitive emotion regulation following taVNS are warranted. • Effects of transcutaneous auricular vagus nerve stimulation (taVNS) on emotion regulation. • Sham-controlled study in healthy subjects performing an emotion regulation task. • Behavioral and psychophysiological indices of emotion regulation were assessed. • taVNS enhances cognitive reappraisal. • taVNS did not affect the physiological response to emotional stimuli. [ABSTRACT FROM AUTHOR]