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.

Investigating neuromodulatory effect of transauricular vagus nerve stimulation on resting-state electroencephalography.

Purpose: The purpose of this study was to investigate the neuromodulatory effects of transauricular vagus nerve stimulation (taVNS) and determine optimal taVNS duration to induce the meaningful neuromodulatroty effects using resting-state electroencephalography (EEG). Method: Fifteen participants participated in this study and taVNS was applied to the cymba conchae for a duration of 40 min. Resting-state EEG was measured before and during taVNS application. EEG power spectral density (PSD) and brain network indices (clustering coefficient and path length) were calculated across five frequency bands (delta, theta, alpha, beta and gamma), respectively, to assess the neuromodulatory effect of taVNS. Moreover, we divided the whole brain region into the five regions of interest (frontal, central, left temporal, right temporal, and occipital) to confirm the neuromodulation effect on each specific brain region. Result: Our results demonstrated a significant increase in EEG frequency powers across all five frequency bands during taVNS. Furthermore, significant changes in network indices were observed in the theta and gamma bands compared to the pre-taVNS measurements. These effects were particularly pronounced after approximately 10 min of stimulation, with a more dominant impact observed after approximately 20-30 min of taVNS application. Conclusion: The findings of this study indicate that taVNS can effectively modulate the brain activity, thereby exerting significant effects on brain characteristics. Moreover, taVNS duration of approximately 20-30 min was considered appropriate for inducing a stable and efficient neuromodulatory effects. Consequently, these findings have the potential to contribute to research aimed at enhancing cognitive and motor functions through the modulation of EEG using taVNS. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-024-00361-8.

Age as an Effect Modifier of the Effects of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) on Heart Rate Variability in Healthy Subjects.

Background: Evidence suggests that vagus nerve stimulation can modulate heart rate variability (HRV). However, there is a lack of mechanistic studies in healthy subjects assessing the effects of bilateral transcutaneous auricular vagus nerve stimulation (taVNS) on HRV. Our study aims to investigate how taVNS can influence the HRV response, including the influence of demographic variables in this response. Methods: Therefore, we conducted a randomized controlled study with 44 subjects, 22 allocated to active and 22 to sham taVNS. Results: Our results showed a significant difference between groups in the high-frequency (HF) metric. Active taVNS increased the HF metric significantly as compared to sham taVNS. Also, we found that age was a significant effect modifier of the relationship between taVNS and HF-HRV, as a larger increase in HF-HRV was seen in the older subjects. Importantly, there was a decrease in HF-HRV in the sham group. Conclusions: These findings suggest that younger subjects can adapt and maintain a constant level of HF-HRV regardless of the type of stimulation, but in the older subjects, only the active taVNS recipients were able to maintain and increase their HF-HRV. These results are important because they indicate that taVNS can enhance physiological regulation processes in response to external events.

Evidence of bottom-up homeostatic modulation induced taVNS during emotional and Go/No-Go tasks.

Bilateral transcutaneous auricular vagus nerve stimulation (taVNS) - a non-invasive neuromodulation technique - has been investigated as a safe and feasible technique to treat many neuropsychiatric conditions. such as epilepsy, depression, anxiety, and chronic pain. Our aim is to investigate the effect of taVNS on neurophysiological processes during emotional and Go/No-Go tasks, and changes in frontal alpha asymmetry. We performed a randomized, double-blind, sham-controlled trial with 44 healthy individuals who were allocated into two groups (the active taVNS group and the sham taVNS group). Subjects received one session of taVNS (active or sham) for 60 min. QEEG was recorded before and after the interventions, and the subjects were assessed while exposed to emotional conditions with sad and happy facial expressions, followed by a Go/No-Go trial. The results demonstrated a significant increase in N2 amplitude in the No-Go condition for the active taVNS post-intervention compared to the sham taVNS after adjusting by handedness, mood, and fatigue levels (p = 0.046), significantly reduced ERD during sad conditions after treatment (p = 0.037), and increased frontal alpha asymmetry towards the right frontal hemisphere during the emotional task condition (p = 0.046). Finally, we observed an interesting neural signature in this study that suggests a bottom-up modulation from brainstem/subcortical to cortical areas as characterized by improved lateralization of alpha oscillations towards the frontal right hemisphere, and changes in ERP during emotional and Go/No-Go tasks that suggests a better subcortical response to the tasks. Such bottom-up effects may mediate some of the clinical effects of taVNS.

Effects of Transcutaneous Auricular Vagus Nerve Stimulation on Cortical Excitability in Healthy Adults.

OBJECTIVE: Vagus nerve stimulation (VNS) has recently been reported to exert additional benefits for functional recovery in patients with brain injury. However, the mechanisms underlying these effects have not yet been elucidated. This study examined the effects of transcutaneous auricular VNS (taVNS) on cortical excitability in healthy adults. MATERIALS AND METHODS: We recorded subthreshold and suprathreshold single- and paired-pulse motor-evoked potentials (MEPs) in the right-hand muscles of 16 healthy adults by stimulating the left primary motor cortex. Interstimulus intervals were set at 2 milliseconds and 3 milliseconds for intracortical inhibition (ICI), and 10 milliseconds and 15 milliseconds for intracortical facilitation (ICF). taVNS was applied to the cymba conchae of both ears for 30 minutes. The intensity of taVNS was set to a maximum tolerable level of 1.95 mA. MEPs were measured before stimulation, 20 minutes after the beginning of the stimulation, and 10 minutes after the cessation of stimulation. RESULTS: The participants' age was 33.25 ± 7.08 years, and nine of 16 were male. No statistically significant changes were observed in the mean values of the single-pulse MEPs before, during, or after stimulation. Although the ICF showed an increasing trend after stimulation, the changes in ICI and ICF were not significant, primarily because of the substantial interindividual variability. CONCLUSIONS: The effect of taVNS on cortical excitability varied in healthy adults. An increase in ICF was observed after taVNS, although the difference was not statistically significant. Our findings contribute to the understanding of the mechanisms by which taVNS is effective in patients with brain disorders.

A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis.

OBJECTIVE: We aimed to conduct a systematic review and meta-analysis assessing the antiinflammatory effects of various VNS methods while exploring multiple antiinflammatory pathways. MATERIALS AND METHODS: We included clinical trials that used electrical stimulation of the vagus nerve and assessed inflammatory markers up to October 2022. We excluded studies lacking control groups, those with combined interventions, or abstracts without full text. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews. For each inflammatory marker, a random-effects meta-analysis using the inverse variance method was performed. Methods used include transcutaneous auricular VNS (taVNS), transcutaneous cervical VNS (tcVNS), invasive cervical VNS (iVNS), and electroacupuncture VNS (eaVNS). Main reported outcomes included tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), and IL-10. Risk of bias was evaluated using the Cochrane Collaboration Tool (RoB 2.0). RESULTS: This review included 15 studies, involving 597 patients. No statistically significant general VNS effect was observed on TNF-α, IL-6, and IL-1ß. However, CRP, IL-10, and interferon (IFN)-γ were significantly modulated by VNS across all methods. Subgroup analysis revealed specific stimulation techniques producing significant results, such as taVNS effects in IL-1ß and IL-10, and iVNS in IL-6, whereas tcVNS and eaVNS did not convey significant pooled results individually. Cumulative exposure to VNS, higher risk of bias, study design, and pulse width were identified as effect size predictors in our meta-regression models. CONCLUSIONS: Pooling all VNS techniques indicated the ability of VNS to modulate inflammatory markers such as CRP, IL-10, and IFN-γ. Individually, methods such as taVNS were effective in modulating IL-1ß and IL-10, whereas iVNS modulated IL-6. However, different VNS techniques should be separately analyzed in larger, homogeneous, and powerful studies to achieve a clearer and more consistent understanding of the effect of each VNS method on the inflammatory system.

Changes in Otitis Media During COVID-19.

OBJECTIVES: During the COVID-19 pandemic, various non-pharmaceutical interventions such as individual hygiene practices like hand washing, social distancing, and mandates for the use of masks in public spaces were implemented to reduce the spread of the disease. Otitis media (OM) is a common infectious disease. How the changed environment due to the COVID-19 pandemic has influenced the prevalence of infectious diseases like OM is not known. This study aimed to investigate how OM prevalence and trends changed during COVID-19 in Korea. METHODS: OM patient data from 2017 to 2021 were extracted from the Health Insurance Review and Assessment Service database. Patients diagnosed with disease code H66 (suppurative and unspecified otitis media) were selected for analysis. Data on OM prevalence, gender, region, medical institution, and number of ventilating-tube prescriptions were analyzed. All age groups were included, and ages were categorized into 5-year ranges. RESULTS: The number of patients diagnosed with the OM disease code decreased continuously from 2017 to 2021 (1 598 205, 1 560 178, 1 520 948, 983 701, and 734 901). The average OM prevalence per 1000 persons decreased by 45.0% from 30.2 in 2017 to 2019 to 16.6 in 2020 to 2021. The change of OM prevalence was greater for the 0 to 5 age group than other age groups. The decrease in average prevalence per 1000 persons was greatest in the 0 to 5 age group (48.6% decrease from 358.2 in 2017-2019 to 184.1 in 2020-2021). The impact of environmental changes on ventilation-tube insertion was smaller than on OM prevalence. The average number of ventilating-tube insertions decreased by 28.1% from 27 311 in 2017 to 2019 to 19 650 in 2020 to 2021. CONCLUSIONS: OM prevalence decreased by 45.0%, and the number of ventilating-tube insertions decreased by 28.1% in Korea during COVID-19.

Consensus Statements on the Definition, Classification, and Diagnostic Tests for Tinnitus: A Delphi Study Conducted by the Korean Tinnitus Study Group.

BACKGROUND: Tinnitus is a bothersome condition associated with various symptoms. However, the mechanisms of tinnitus are still uncertain, and a standardized assessment of the diagnostic criteria for tinnitus is required. We aimed to reach a consensus on diagnosing tinnitus with professional experts by conducting a Delphi study with systematic review of the literature. METHODS: Twenty-six experts in managing tinnitus in Korea were recruited, and a two-round modified Delphi study was performed online. The experts evaluated the level of agreement of potential criteria for tinnitus using a scale of 1-9. After the survey, a consensus meeting was held to establish agreement on the results obtained from the Delphi process. Consensus was defined when over 70% of the participants scored 7-9 (agreement) and fewer than 15% scored 1-3 (disagreement). To analyze the responses of the Delphi survey, the content validity ratio and Kendall's coefficient of concordance were evaluated. RESULTS: Consensus was reached for 22 of the 38 statements. For the definition of tinnitus, 10 out of 17 statements reached consensus, with three statements achieving complete agreement including; 1) Tinnitus is a conscious perception of an auditory sensation in the absence of a corresponding external stimulus, 2) Tinnitus can affect one's quality of life, and 3) Tinnitus can be associated with hearing disorders including sensorineural hearing loss, vestibular schwannoma, Meniere's disease, otosclerosis, and others. For the classification of tinnitus, 11 out of 18 statements reached consensus. The participants highly agreed with statements such as; 1) Vascular origin is expected in pulse-synchronous tinnitus, and 2) Tinnitus can be divided into acute or chronic tinnitus. Among three statements on the diagnostic tests for tinnitus only Statement 3, "There are no reliable biomarkers for sensory or emotional factors of tinnitus." reached consensus. All participants agreed to perform pure-tone audiometry and tinnitus questionnaires, including the Tinnitus Handicap Inventory and Tinnitus Questionnaire. CONCLUSION: We used a modified Delphi method to establish a consensus-based definition, a classification, and diagnostic tests for tinnitus. The expert panel reached agreement for several statements, with a high level of consensus. This may provide practical information for clinicians in managing tinnitus.

Abnormal quantitative sudomotor axon reflex test results in patients with tinnitus as a possible indicator of small fiber neuropathy.

A few cases of small fiber neuropathy (SFN) and tinnitus (TN) associated with coronavirus disease 2019 have been reported. However, the relationship between SFN and TN has not been studied. This study investigated a possible relationship between SFN and patients with TN (PwTNs) using autonomic function tests (AFTs) including quantitative sudomotor axon reflex tests (QSART). We performed QSARTs and other AFTs such as the Sympathetic skin response (SSR), Valsalva ratio (VR), and heart rate variability (HRV). The QSART results, obtained at seven hospitals using same protocols, were compared between PwTNs and healthy controls. We confirmed the abnormalities in SSR, VR, and HRV in PwTNs, although those parasympathetic AFTs were not performed in healthy controls. Additionally, we checked Tinnitus handicap inventory (THI) scores for PwTNs and ~50% of PwTNs had low-grade disability, whereas 9.3% had high-grade disability. Data from 57 PwTNs and 122 healthy controls were analyzed. The sweat volumes of QSART in the older age group tended to be higher in the PwTNs than in age-matched healthy controls, and significant differences between the PwTN and control groups were observed in the feet in both sexes (p < 0.001) and in the arms in women (p = 0.013). In the younger age group, the sweat volumes in the feet of men were higher in PwTNs than in healthy controls (p = 0.017). No association was observed between THI and QSART scores. In this study, the sweat volumes in QSARTs were higher in PwTNs than in healthy controls. However, abnormal SSR, HRV, and VR results were not commonly observed in PwTNs. Although the results should be interpreted with caution because of limitations in study, PwTNs might also have SFN apart from dysautonomia. This is the first study to perform QSART with other parasympathetic AFTs in PwTNs. However, larger and more rigorously controlled studies will be needed to reveal the relationship between SFN and TN in the future.

Understanding the Effects of Non-Invasive Transauricular Vagus Nerve Stimulation On EEG and HRV.

Several studies have demonstrated promising results of transcutaneous auricular vagus nerve stimulation (taVNS) in treating various disorders; however, no mechanistic studies have investigated this technique's neural network and autonomic nervous system effects. This study aims to describe how taVNS can affect EEG metrics, HRV, and pain levels. Healthy subjects were randomly allocated into two groups: the active taVNS group and the sham taVNS group. Electroencephalography (EEG) and Heart Rate Variability (HRV) were recorded at baseline, 30 min, and after 60 min of 30 Hz, 200-250 µs taVNS, or sham stimulation, and the differences between the metrics were calculated. Regarding vagal projections, some studies have demonstrated the role of the vagus nerve in modulating brain activity, the autonomic system, and pain pathways. However, more data is still needed to understand the mechanisms of taVNS on these systems. In this context, this study presents methods to provide data for a deeper discussion about the physiological impacts of this technique, which can help future therapeutic investigations in various conditions.