| Objective:(1)To observe the clinical efficacy of transcutaneous auricular vagus nerve stimulation(taVNS)for the treatment of mild cognitive impairment using a randomized double-blind(patient and evaluator blinded)controlled clinical study.(2)Observing the difference in brain function between MCI patients and healthy subjects based on resting-state fMRI technique.(3)To explore the brain effects in MCI patients treated with 24 weeks’taVNS by the resting state fMRI,and analyze the correlation between the brain effects and the clinical symptoms.Methods:sIn the clinical study,36 patients with MCI were prospectively included according to the principles of a randomized double-blind controlled trial and randomly assigned to the taVNS and sham taVNS groups in a 1:1 ratio,and 20 healthy controls matched with gender,age,and years of education were included.Patients who were excluded as well as those still under treatment were excluded,and 22 patients were finally included for analysis.taVNS group stimulated the heart and kidneys in the vagal distribution of the auricular cavity,while sham taVNS group stimulated the elbow and shoulder in the non-vagal distribution of the ear canal.In both groups,the stimulation waveform was sparse and dense,the frequency was 20/100Hz,the current intensity was adjusted in the range of 3-14mA,patient should be able to tolerate it without significant pain,and the patient was treated at home for 30 minutes each morning and evening for 5 days a week for 24 weeks.The Montreal Cognitive Assessment-Basic(MoCA-B)(the primary efficacy indicators),the Auditory Verbal Learning Test-Huashan Version(AVLT-H),the Shape Trails Test A&B(STT A&B),the Animal Fluency Test(AFT),and Boston Naming Test(BNT)(secondary efficacy indicators),and adverse effects were recorded.In the brain effect mechanism study,36 patients and 20 healthy controls in Study 1 were conducted with the resting-state fMRI scan.The two-sample t-test was performed on the preprocessed completed image results.Twenty-two patients who completed the experiment participated in the resting state fMRI scan after 24 weeks of treatment.The results of the preprocessed images were compared and analyzed,and the baseline results were used as seed points for functional linkage analysis,and the significant differences in the brain region were obtained for post hoc analysis,Bonferroni correction was used,and finally correlated with the clinical scale..Results:Study I:The clinical study of taVNS for MCI.A total of 36 patients with MCI and 20 healthy controls were included at baseline.Four cases were drop-out and 10 others were still under treatment due to the impact of the COVID-19 epidemic,so a total of 22 MCI patients were included for pre-and post-treatment comparisons at 24 weeks(6 months),10 in the taVNS group and 12 in the sham taVNS group.At baseline,there were no statistically significant differences between the taVNS group,sham,taVNS group and HCs group in terms of gender,age,and years of education;Differences in MoCA-B scores between the three groups:taVNS group<HCs group(P<0.001)and sham taVNS group<HCs group(P<0.001);Differences in AVLT-H(N5)scores between the three groups:taVNS group<HCs group(P<0.001),sham taVNS group<HCs group(P<0.001);Differences in AVLT-H(N7)scores between the three groups:taVNS group<HCs group(P=0.031),sham taVNS group<HCs group(P=0.009);Differences in STT-A time consumption:taVNS group>HCs group(P=0.001),sham taVNS group>HCs group(P=0.003);Differences in STT-B time consumption:taVNS group>HCs group(P=0.003),sham taVNS group>HCs group(P=0.003);Differences in AFT scores:taVNS group<HCs group(P=0.014),sham taVNS group<HCs group(P=0.007);However,the difference in BNT scores between the three groups was not statistically significant(F=2.065,P=0.137).Functional Activities Questionnaire(FAQ),17-item Hamilton Depression Scale(HAMD-17),and Hamilton Anxiety Scale(HAMA)scores were all within the normal range.Efficacy evaluation result:After 24 weeks of treatment,repeated measures ANOVA showed a significant group*time point interaction effect(F=36.130,P=<0.001,partialη2=0.644),a significant group main effect(F=6.330,P=0.033,partial η2=0.413),and a non-significant time point main effect for MoCA-B scores in the taVNS and sham taVNS groups,post hoc analysis showed a statistically significant(P<0.001)improvement in the taVNS group post-treatment compared to pre-treatment scores,with a 1.933(95%CI:-4.202 to 0.336,P=0.030)point improvement in the mean of the taVNS group post-treatment compared to the sham taVNS group,but the difference was not significant.The AVLT-H(N5)score group*time point interaction effect was significant in both groups(F=4.801,P=0.040,partial η2=0.194),the time point main effect was significant(F=9.309,P=0.014,partial η2=0.508),the group main effect was not significant,and the post hoc analysis showed that the taVNS group had an improved score after treatment compared to the pre-treatment group,and the difference was statistically significant(P=0.012),and the post-treatment taVNS group had improved scores compared to the sham taVNS group,with a statistically significant difference(P<0.001).The group*time point interaction effect for STT-A time use in both groups was significant(F=6.967,P=0.016,partialη2=0.258),the group main effect was significant(F=6.674,P=0.030,partialη2=0.426),the time point main effect was not significant,and the post hoc analysis showed a statistically significant difference in time consumption after treatment in the taVNS group compared to the pre-treatment group(P=0.002),and a statistically significant difference in time use in the post-treatment taVNS group compared to the sham taVNS group(P=0.003).In addition,the main and interaction effects of AVLT-H(N7)score,STT-B time consumption,AFT score and BNT score were not significant in both groups.Regarding the assessment of adverse effects of treatment,no significant adverse effects occurred during the treatment period in all patients except for 1 patient who experienced pain when the current flow was adjusted too high at the beginning of the treatment(no discomfort after the current flow was turned down).Study Ⅱ:Mechanism of resting-state brain effects of taVNS for MCI.Baseline and 24-week pre-and post-treatment comparisons included the same subjects as in Study 1.Two patients were excluded for excessive head movement on fMRI,and the actual number of patients included in the 24-week pre-and post-treatment statistics was 20,including 10 in the taVNS group and 10 in the sham taVNS group.At baseline,there were no statistically significant differences between the taVNS group,sham taVNS group and HCs group in terms of gender,age,and years of education;Differences in MoCA-B scores between the three groups:taVNS group<HCs group(P<0.001)and sham taVNS group<HCs group(P<0.001);Differences in AVLT-H(N5)scores between the three groups:taVNS group<HCs group(P<0.001),sham taVNS group<HCs group(P<0.001),taVNS group>sham taVNS group(P=0.031);Differences in AVLT-H(N7)scores between the three groups:taVNS group<HCs group(P<0.001),sham taVNS group<HCs group(P=0.005);Differences in STT-A time consumption:taVNS group>HCs group(P=0.001);sham taVNS group>HCs group(P=0.002);Differences in STT-B time consumption:taVNS group.>HCs group(P=0.002),sham taVNS group>HCs group(P=0.001);Differences in AFT scores:taVNS group<HCs group(P=0.008),sham taVNS group<HCs group(P=0.018);However,the difference in BNT scores between the three groups was not statistically significant(F=2.111,P=0.135).FAQ,HAMD-17,and HAMA scores were in the normal range.Clinical datas of MCI patients before and after treatment were same as in Study I.The fMRI results showed that the fALFF of the left anterior cingulate was significantly lower in MCI patients compared with healthy controls.After 24 weeks of treatment,the right inferior parietal gyrus fALFF was significantly higher in the taVNS group compared with that before treatment,and there was a significant difference between the taVNS and sham taVNS groups after treatment;the FC of the left anterior cingulate and the right middle cingulate were significantly enhanced in the taVNS group compared with the sham taVNS group after treatment,and the enhanced FC was significantly and negatively correlated with STT-A time consumption(r=-0.812,P=0.004).Conclusions:(1)taVNS improved the overall cognitive function of MCI patients,especially for the improvement of episodic memory and executive function.(2)MCI patients have local brain function abnormalities,as evidenced by reduced fALFF values in the left ACC.taVNS modulated local brain function in the right inferior parietal gyrus.(3)taVNS may improve the cognitive function of patients with MCI by regulating the functional connectivity of left ACC and right MCC,and the cingulate gyrus may be an important therapeutic target in the regulation of MCI by taVNS,preliminarily verifying our hypothesis. |
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