There are 9.9 million new cases of dementia in the world every year. Short-term conversion rate from mild cognitive impairment (MCI) to dementia is between 20% and 40%, but long-term in 5-10 years ranges from 60% to 100%. It is particularly important to prevent or prolong the development of MCI into dementia. Both auriculotherapy and vagus nerve stimulation are effective on improving cognitive functions. However, there is no double blinded randomized clinical trial to support the effectiveness of transcutaneous electrical stimulation of auricular acupoints in patients with MCI. This randomized controlled trial involved patients with MCI, aged from 55 to 75 years old. Patients were randomly allocated to transcutaneous auricular vagus nerve stimulation (taVNS) group or sham taVNS group. In the taVNS group, two auricular acupoints were stimulated, including heart (concha, CO₁₅) and kidney (CO₁₀), which are in the distribution of vagus nerve. While in the sham taVNS group, two other auricular acupoints were stimulated, including elbow (scaphoid fossa, SF₃) and shoulder (SF_4,5), which are out of the distribution of vagus nerve. The primary outcome was the Montreal cognitive assessment-basic, MOCA-B. The secondary outcomes included auditory verbal learning test-HuaShan version (AVLT-H), shape trails test A&B (STT-A&B), animal fluence test (AFT), Boston naming test (BNT), Pittsburgh sleep quality index (PSQI), rapid eye movement sleep behavior disorder screening questionnaire (RBDSQ), Epworth sleepiness scale (ESS) and functional activities questionnaire (FAQ). These outcome measures were taken at baseline, 24 weeks later. After 24 weeks of intervention, the data of 52 patients were intended for analysis. After intervention, there was significant difference in the overall scores of MoCA-B between taVNS group and sham taVNS group (p = 0.033 < 0.05). In taVNS group, compared with before intervention, the overall scores of MOCA-B increased significantly after intervention (p < 0.001). As for N5 and N7, the two sub-indicators of AVLT-H, in taVNS group, compared with before intervention, both N5 and N7 increased significantly after intervention (both ps < 0.001). As for STTB, in taVNS group, compared with before intervention, STTB was significantly reduced after intervention (p = 0.016). For BNT, in taVNS group, compared with before intervention, BNT increased significantly after intervention (p < 0.001). In taVNS group, compared with before intervention, PSQI, RBDSQ, ESS and FAQ decreased significantly after intervention (p = 0.002, 0.025, <0.001, 0.006 respectively). 1 patient with a history of tympanic membrane perforation in taVNS group was reported with mild adverse reactions which disappeared a week after termination of taVNS. The intervention of taVNS is effective on increasing the overall scores of MoCA-B, N5 and N7. The clinical trial demonstrated that taVNS can improve cognitive performance in patients with MCI. This inexpensive, effective and innovative method can be recommended as a therapy for more patients with MCI in the prevention or prolonging of its development into dementia, but it is still required to be further investigated. http://www.chictr.org.cn. (ID: ChiCTR2000038868).

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is a vital neuromodulation for the treatment of depression, but its antidepressant molecular mechanism is unclear. The α7 nicotinic acetylcholine receptor (α7nAchR) is a key mediator of the vagus nerve that mediates its anti‐inflammatory efficacy. Here, we investigated whether the antidepressant effect of taVNS in chronic unpredicted mild stress (CUMS)‐exposed rats works through the α7nAchR/JAK2/STAT3/NF‐κB pathway.Methods: The depression model was established by CUMS for continuous 6 weeks in rats. From the 4th week of the experiment, CUMS‐exposed rats were subjected to taVNS for 3 weeks. To clarify the role of α7nAchR in the antidepressant effect of taVNS, we used α7nAchR^−/− gene knockout rats. The sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST) were used to evaluate depression‐like behaviors of rats. Immunofluorescent staining was used to observe the morphology of microglia in the hypothalamus. Western blot was used to examine the protein expression of α7nAchR, p‐JAK2, p‐STAT3, IL‐1β, NF‐κB p65, and p‐NF‐κB p65 in the hypothalamus.Results: Depression‐like behaviors in CUMS‐exposed rats were manifested by decreased SPT ratio, increased FST immobility time, decreased total distance, vertical movement score, and activity time of OFT. Hypothalamic neuroinflammation in CUMS‐exposed rats was manifested by an amoebic‐like activated state of microglia, downregulated expression of α7nAchR, p‐JAK2, p‐STAT3, and upregulated expression of NF‐κB p65, p‐NF‐κB p65, and IL‐1β. TaVNS could significantly reverse the above‐mentioned phenomena, but had a poor improvement effect for CUMS‐exposed α7nAchR^−/− rats.Conclusion: The hypothalamic α7nAchR/JAK2/STAT3/NF‐κB signaling pathway may play an important role in the antidepressant‐like behavior of taVNS.

IMPORTANCE: Evidence from randomized clinical trials of transcutaneous auricular vagus nerve stimulation (taVNS) for chronic insomnia disorder is lacking.OBJECTIVE: To evaluate the efficacy and safety of taVNS for chronic insomnia compared with the sham taVNS.DESIGN, SETTING, and PARTICIPANTS: This randomized clinical trial was conducted from October 2021 to December 2022 at a single center in Beijing, China. Patients with chronic insomnia disorder with a Pittsburgh Sleep Quality Index (PSQI) of at least 8 were enrolled. Statistical analysis was performed from June to September 2023.INTERVENTIONS: Patients were allocated to the active taVNS group or sham taVNS group with a 1:1 ratio. Both groups received the stimulation for 30 minutes each time, twice a day, 5 consecutive days a week, with an 8-week treatment and a 12-week follow-up.MAIN OUTCOMES AND MEASURES: The primary end point was the mean change from baseline through week 8 in PSQI scores. Minimal clinically important difference was 2.5 points. Secondary outcomes included mental health, sleepiness, and fatigue. Safety was also evaluated.RESULTS: A total of 72 participants were randomized to either active taVNS group (36 participants; mean [SD] age, 45.2 [14.5] years; 27 [75.0%] female) or the sham taVNS group (36 participants; mean [SD] age, 44.6 [13.9] years; 31 [86.1%] female); 68 participants completed the 8-week intervention. The least-square mean changes from baseline to week 8 in PSQI were −8.2 (95% CI, −9.3 to −7.0) points in the taVNS group and −3.9 (95% CI, −5.1 to −2.7) points in the sham group. Both groups experienced statistically significant improvements from before to after the intervention. However, active taVNS showed a clinically meaningful 4.2-point greater reduction (95% CI, −5.9 to −2.6 points; P < .001; Cohen d effect size, 1.2) in PSQI compared with the sham group (minimal clinically important difference = 2.5 points). Secondary outcomes, including mental health and fatigue, showed similar favorable results. The efficacy of taVNS was sustained throughout the 20-week study period.CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, taVNS significantly reduced insomnia severity. Clinically meaningful enhancements in PSQI scores were observed compared with sham stimulation, with the benefits of taVNS sustained over a 20-week period. Future multicenter clinical trials with large sample sizes are needed to validate its effectiveness across diverse populations.Trial Registration: Chinese Clinical Trial Registry: ChiCTR2100051319

As an emerging neuromodulation therapy, transcutaneous auricular vagus nerve stimulation (taVNS) has been proven to be safe and effective for epilepsy, major depressive disorders, insomnia, glucose...

Transcutaneous auricular vagus nerve stimulation was recently reported to have a therapeutic potential for functional dyspepsia (FD). This study aimed to explore the integrative effects and mechanisms of auricular vagus nerve stimulation (aVNS) in a rodent model of FD. Methods: We evaluated the effects of aVNS on visceral hypersensitivity, gastric motility and open field test (OFT) activity in iodoacetamide (IA)-treated rats. The autonomic function was assessed; blood samples and tissues were collected and analyzed by an enzyme-linked immunosorbent assay and western blot. Vagotomy was performed to investigate the role of vagal efferent nerve. Results: aVNS reduced the electromyography response to gastric distension, improved gastric emptying and increased the horizontal and vertical motion scores of the OFT in IA-treated rats. The sympathovagal ratio was increased in IA-treated rats but normalized with aVNS. The serum cytokines TNF-α, IL-6, IL-1β and NF-κBp65 were increased in IA-treated rats and decreased with aVNS. The hypothalamus–pituitary–adrenal axis was hyperactive in IA-treated rats but inhibited by aVNS. The expression of duodenal desmoglein 2 and occludin were all decreased in IA-treated rats and increased with aVNS but not sham-aVNS. Vagotomy abolished the ameliorating effects of aVNS on gastric emptying, horizontal motions, serum TNF-α and duodenal NF-κBp65. Conclusion: aVNS improves gastric motility and gastric hypersensitivity probably by anti-inflammatory mechanisms via the vago-vagal pathways. A better understanding on the mechanisms of action involved with aVNS would lead to the optimization of the taVNS methodology and promote taVNS as a non-pharmacological alternative therapy for FD.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is effective for treating major depressive disorder (MDD). We aimed to explore the modulating effect of prolonged longitudinal taVNS on the striatal subregions’ functional connectivity (FC) in MDD patients. Methods: Sixteen MDD patients were enrolled and treated with taVNS for 8 weeks. Sixteen healthy control subjects (HCs) were recruited without intervention. The resting-state FC (rsFC) based on striatal subregion seed points and the Hamilton Depression Scale (HAMD) were evaluated in the MDD patients and HCs at baseline and after 8 weeks. A two-way ANCOVA test was performed on each rsFC metric to obtain the (group-by-time) interactions. Results: The rsFC values between the left ventral caudate (vCa) and right ventral prefrontal cortex (vPFC), and between the right nucleus accumbens (NAc) and right dorsal medial prefrontal cortex (dmPFC) and ventrolateral prefrontal cortex (vlPFC) are lower in the MDD patients compared to the HCs at baseline, and increase following taVNS; the rsFC values between the left vCa and right, superior occipital gyrus (SOG), and between the left dorsal caudate (dCa) and right cuneus are higher in MDD patients and decrease following taVNS. Conclusions: Prolonged longitudinal taVNS can modulate the striatum rsFC with the prefrontal cortex, occipital cortex, temporal cortex, and intra-striatum, and these changes partly underlie any symptomatic improvements. The results indicate that prolonged longitudinal taVNS may produce beneficial treatment effects by modulating the cortical striatum circuitry in patients with MDD.