| Objective:To compare the clinical efficacy of auricular electro-acupuncture(transcutaneous auricular vagus nerve stimulation,taVNS)in treatment-resistant depression(TRD)and refractory depression(MDD),and to explore the related emotion-cognition brain network interactionsvia resting-state functional magnetic resonance imaging(rs-fMRI).Methods:23 patients with TRD(TRD group,TRD)and 13 patients with MDD refractory depression,control group,MDD)were recruited and treated with taVNS for 8 weeks with vagus nerve stimulator(SDZ-?B,Huatuo Brand,Jiangsu Medical Instrument Company)and bilateral ear concha as stimulation sites.The patients were interviewed and followed up before treatment(week 0),2 weeks ±3 days after treatment,4 weeks±3 days,and at the end of treatment(8 weeks±3 days).The severity of symptoms and side effects were evaluated.The reduction rate of HAMD-17 score before and after treatment was taken as the primary outcome.Using SPSS24.0 software,the data were analyzed by chi-square test;firstly,the normal distribution of each group was analyzed,if it was normal distribution,the analysis of variance was conducted,if the variance was uniform,and the independent sample t-test was used;the variance was uneven,and the rank sum test was employed.The measurement data of normal distribution are expressed by mean ±standard deviation(X±s)and disobeyed by median ±quartile spacing(M±QR).One-way ANOVA-LSD-t test(normal distribution and uniform variance)and Dunnett-t test(uneven variance)were used for pairwise comparison.Bilateral test,?=0.05.13 TRD patients(6 males,7 females,mean age 45.7 years),11 patients with relapsed depression(5 males,6 females,mean age 39.8 years),and 13 healthy volunteers matched in gender and age(6 males,7 females,mean age 38.6 years)were enrolled in the fMRI study.Resting state magnetic resonance imaging(rs-fMRI)was performed at baseline and after 8 week,respectively.Image data pre-processing and region of interest:rs-fMRI data processing and analysis was performed using SPM8 and DPABI software under the Matlab platform.The right middle frontal gyrus?left orbital prefrontal gyrus were selected as the region of interest(ROIs)respectively.Excluding the interference of covariates of age,gender and education level,the statistical methods of analysis of variance and Post hoc test were used to analyze the statistical differences of the average(mean of z-map's of the statistical charts extracted by the three groups,and the brain regions with differences among three groups were found.The statistical results of fMRI were corrected by GRF,and the difference was statistically significant at voxel level(P<0.001)and cluster level(P<0.05).The average value of the extracted time series was compared between TRD group and MDD group,TRD group and healthy control,MDD group and healthy control by using SPSS 24.0 statistical software.Bilateral test,?=0.05.rs-FC changes in TRD group and MDD group after 8 weeks of treatment:paired t-test was used.The results were corrected by GRF,and the difference was statistically significant between voxel level(P<0.001)and cluster level(P<0.05).Spearman coefficient analysis was used to analyze the correlation between HAMD-17 score reduction rate and brain function changes in TRD group and MDD group after 8 weeks treatment.Results:1.Clinical studyIn the course of the trial,3 cases in the TRD group fell off,1 case terminated the trial due to the aggravation of symptom,and 19 cases actually completed the treatment.In MDD group,2 cases were terminated because of taking medicine in the halfway,and 11 cases actually completed the follow-up and treatment.1.1Baseline:There was no significant difference in age,gender,course of disease and HAMD-17,HAMA,SDS,SAS,PQSI,RRS and WCST between two groups.1.2 Effectiveness in TRD group.After 8 weeks of treatment with auricular electro-acupuncture combined with basic antidepressants in TRD group,5 cases were clinically cured(5/19),8 cases were significantly improved,4 cases were improved,2 cases were ineffective,and the total response rate was 89.47%.After 2 weeks of treatment,the HAMD score reduction rate was 32.78%and 54.21%after 4 weeks and 62.18%after 8 weeksThe scores of HAMD,HAMA,SDS and SAS in TRD group at 2,4 and 8 weeks after treatment were significantly different from those before treatment(P<0.001).After 8 weeks,the scores of PSQI,RRS and WCST were significantly different from those before treatment(P<0.005).1.3Effectiveness in MDD groupAfter 8 weeks of auricular electro-acupuncture treatment in MDD group,6 cases were cured,4 cases were significantly improved,1 case was improved,0 cases showed ineffective,and the total response rate was 100%.After 2 weeks of treatment,the reduction rate of HAMD score was 43.56%.58.9%after 4 weeks and 75.11%after 8 weeks.After 2,4 and 8 weeks,the scores of HAMD,HAMA,SDS and SAS were significantly different from those before treatment(P<0.05).After 8 weeks,the scores of PSQI,RRS and WCST were significantly different from those before treatment(P<0.05).2.Research on Brain functional network:2.1 Comparison of ALFF baselines among three groups:The ALLF values of right dorsolateral superior frontal gyrus,left precuneus,left angular gyrus and right middle frontal gyrus in TRD patients were higher than those in healthy controls,suggesting that TRD patients may have excessive compensatory response of interacting between emotion and cognitionThe ALFF value of calcarine in patients with TRD and MDD is low,which can also be supported by the clinical PQSI scale involving in sleep problems in patients with TRD and MDD2.2 Brain functional network after 8 weeks of treatment in TRD.After auricular electro-acupuncture treatment,FC in right inferior temporal gyrus,right insular inferior frontal gyrus,left medial superior frontal gyrus,left medial superior frontal gyrus,right anterior lobe and right middle frontal gyrus increased,and FC in right superior occipital gyrus and left orbitofrontal gyrus increased in TRD group,indicating that the therapeutic mechanism of auricular electro-acupuncture involves emotional and cognitive related brain areas,and provides evidence for the improvement of memory and cognition in patients with TRD2.3 The rs-FC changes in MDD group after 8 weeks of treatment:After 8 weeks of auricular electro-acupuncture,the FC of bilateral medial superior frontal gyrus and right middle frontal gyrus increased in patients with MDD,suggesting that regulating the functional activity of DMN may be an important mechanism of auricular electro-acupuncture in the treatment of MDD.2.4 Analysis of the correlation between the decrease rate of HAMD-17 score and the changes of brain function in 3.TRD group and MDD group after 8 weeks.In TRD group,the enhancement of FC from left orbitofrontal gyrus to right superior occipital gyrus was positively correlated with HAMD-17 score reduction rate after 8 weeks of treatment.No correlation was found between the changes of brain regions and the difference of HAMD-17 in MDD group after 8 weeks of treatment.Conclusion:1.TaVNS was effective in both of TRD and the relapsed MDD,but the effect for the later was better.2.TaVNS can improve the Anxiety,impaired Sleep and Cognition conditions for Depression patients.3.There are brain functional abnormalities involving in emotion and cognition in patients with Depression patients4.TaVNS can modulate the brain activities in the emotion-cognition network of TRD or MDD. |
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