The Efficacy and Safety of Transcutaneous Auricular Vagus Nerve Stimulation in Patients with Mild Cognitive Impairment: A Double Blinded Randomized Clinical Trial

Background: 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 from 20% to 40%, but long-term in 5 to 10 years increases to the extent from 60% to 100%. It is particularly important to prevent or prolong the development of MCI to dementia. Both auriculotherapy and vagus nerve stimulation are effective in improving cognitive functions. However, there is no double blinded randomized clinical trial to support the effectiveness of transcutaneous electrical stimulation of auricular acupuncture points in patients with MCI. Methods: This randomized controlled trial involved patients with mild cognitive impairment, aged from 55 to 75 years old. Patients were randomized to be allocated to transcutaneous auricular vagus nerve stimulation (taVNS) group or sham taVNS group. In the taVNS group, two auricular acupuncture points (AAPs) were stimulated, including heart (concha, CO15) and kidney (CO10), in the distribution of vagus nerve. While in the sham taVNS group, two other AAPs were stimulated, including elbow (scaphoid fossa, SF3) and shoulder (SF4,5), 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. Results: 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). Referring to N5 and N7 (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 to 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). There were mild adverse reactions (that disappeared a week after termination of taVNS) reported by 1 patient with a history of tympanic membrane perforation in taVNS group. The intervention of taVNS is effective in increasing the overall scores of MoCA-B, N5 and N7. Conclusion: It demonstrates that taVNS can improve cognitive performance in patients with MCI. This inexpensive, effective innovative method can be recommended to be applied for more patients with MCI in order to prevent or prolong the development to dementia, but it is still required to be further investigated.