| Objective1.To observe the clinical efficacy of auricular electroacupuncture(transcutaneous auricular vagus nerve stimulation,taVNS)in treatment-resistant depression(TRD)and non-refractory depression(non-TRD).2.To compare the efficacy of taVNS treatment in patients with TRD and non-TRD.3.To analyze the differences in resting-state functional connectivity(rsFC)in TRD,non-TRD,and healthy control(HC)subjects at the baseline.4.To analyze the changes of rs-FC after 8 weeks of treatment with taVNS in TRD group and non-TRD group.5.To analyze the correlation between clinical efficacy and changes in rsFC after 8 weeks in TRD and non-TRD groups.We aimed to provide a scientific basis of brain function for the therapeutic mechanism of taVNS in patients with TRD.MethodsClinical TrialWe recruited 20 patients with TRD and 16 patients w ith non-TRD.The Huatuo brand transcutaneous auricular vagus nerve stimulation(taVNS,SDZ-IIB)were used to stimulate bilateral ear concha for treatment.The stimulator's ear electrode clips were attached to bilateral ear concha twice a day(in the morning and evening),each for 30 minutes with following parameters:intensity in 4-6 mA,dense wave with frequency in 5 Hz:20 Hz,wave width less than 1 ms,preferably with a maximum current that does not cause pain.Patients in the TRD group were treated with taVNS on the basis of keeping the original antidepressant drugs while the non-TRD group were only treated with taVNS.The patient took the taVNS instrument home after the doctor's told him/her how to use it.Under the supervision of the family,the patient strictly followed the treatment method,and recorded diary about the treatment time and reaction every day for 8 weeks.It was observed for two groups of patients in four psychological scale scores before treatment(week 0),in the period of treatment(2 weeks ± 3 days,4 weeks ± 3 days,8 weeks ± 3 days),including 17-item Hamilton Depression Scale(HAMD-17),14-item Hamilton Anxiety Scale(HAMA-14),self-Rating Depression Scale(SDS),and self-Rating Anxiety Scale(SAS)scores.Every scale was compared between two groups.The Pittsburgh Sleep Quality Index(PSQI)and the Ruminative Response Scale(RRS)scores were evaluated in each group before treatment(week 0)and after treatment(week 8±3 days).It was also compared between two groups.Statistical analyses were conducted using SPSS 20.0.The HAMD-17 reduction scores rate after treatment was used as the clinical efficacy evaluation standard.HAMD reduction score rate=[(pre-treatment score-post-treatment score)/pre-treatment score]×100%.The reduction rate>75%was diagnosed as clinical recovery;the significantly improved was evaluated as the reduction rate from 50%to 74%;however,the improvement meaned the reduction rate from 25%to 49%,while reduction rate<25%is invalid.The response rates was defined as a HAMD reduction rate>25%/the sample size of the group.fMRI study on taVNSUsing blood oxygen level-dependent functional magnetic resonance imaging(BOLD-fMRI)technique.Patients were randomized enrolled for clinical trial,including 9 patients with TRD,4 males and 5 females,with an average age of 43.7 years(28-55 y);14 non-TRD patients,male 6,female 8,with an average age of 38.8 years(31-52 y).The rs-fMRI scans were performed on a 3.0 T MRI scanner(Magnetom Skyra,Siemens.Germany)before and after 8-week taVNS.In addition,16 healthy volunteers were recruited as control,male 3 and female 10,with an average age of 45.6 years(29-59 y).The rs-fMRI data were collected at the time of enrollment.The trial was approved by the Ethics Committee of Guang'anmen Hospital,and each subject completed the informed consent form before the trial.fMRI Data Analysis:rs-fMRI data preprocessing:rs-fMRI data processing and analysis using DPABI software version 4.3 of the Matalab software SPM8 platform.We selected the bilateral rACC as the seed regions given its central role in emotional and cognitive processing.The left and right rACC were defined with the central coordinates(-4,37,0;4.37,0)and in a radius of 3 mm.One-way ANOVA were used to analyze the differential brain regions of the TRD group,the non-TRD group,and the HC group.We extracted the mean time courses of signals of the seed regions and computed their correlations with the rest of the whole brain.Using SPSS 20.0 statistical software,paired t-tests were performed between the three groups:TRD group vs.non-TRD group,TRD group vs.HC group,non-TRD group vs.HC group.The paired t-test was used to analyze the changes of rs-FC in TRD group or non-TRD group after 8 weeks of treatment respectively.Spearman coefficient analysis was used to analyze the correlation between changes HAMD-17 and rs-FC in TRD and non-TRD respectively.Differences in rsFC before and after treatment beyond a given threshold level(0.5)cluster size(100 voxels)were considered to have a significant change.ResultsClinical TrialSeventeen subjects completed treatments with follow-up in TRD group,in which two dropped off and one subjects stoped the trial due to suddenly increase in severity.15 subjects completed their treatments with follow-up in non-TRD group,and only one subjects stoped the trial due to self-administered oral antidepressants.There were no significant differences in age,gender,duration of disease,and scores of HAMD-17,HAMA,SDS,SAS,PQSI,and RRS in baseline level before treatment between the two groups.1.Efficacy in TRD group:The reduction rate of HAMD scores were 44.68%/53.74%/76.87%after 2/4/8 weeks of treatment.8 subjects reached the clinical recovery,6 subjects showed their symptoms improved significantly,2 subjects was improved,but 1 subject was ineffective.The response rates is 94.1%;Comparing the HAMD,HAMA,SDS,SAS scores between 0 week and 2/4/8 weeks after treatment individually,the differences show the statistical significance(P<0.001).Comparing the RRS/PSQI scores between 0 week and 8 weeks after treatment,the differences show statistically significant(P<0.005).2.Efficacy in non-TRD group:The reduction rate of HAMD scores were 45.16%/64.12%/79.8%after 2/4/8 weeks of treatment.10 subjects reached clinical recovery,4 subjects' symptoms showed improved significantly,1 subjects was improved,and no subject was ineffective.The response rates is 100%;when comparing the HAMD,HAMA,SDS,SAS scores between 0 week and 2/4/8 weeks after treatment individually,the differences show statistically significant(P<0.001).Comparing the RRS/PSQI scores between 0 week and 8 weeks after treatment individuallv,the differences show statistically significant(P<0.001).3.Comparison between TRD group and non-TRD group:There was no significant difference in response rates between the two groups(P>0.05).There was no significant differences in HAMD,HAMA,SDS,SAS scores between the two groups in diffiences at 2/4/8 weeks post-treatment and 0 weeks pre-treatment individually(P>0.05).There was no significant differences in RRS?PSQI scores between the two groups when comparing the scores at 8 weeks(post-treatment)and 0 weeks(pre-treatment)(P>0.05).fMRI study on taVNSDue to the adjustment of fMRI parameters in the beghinning of experiment,the data of 3 subjects with inconsistent parameters were removed.Finally 13 HC subjects,9 TRD subjects,14 non-TRD subjects were included.1.Comparison of the rsFC in baselines between three groups:1.1 Brain activity areas in HC>non-TRD:Between the right rACC and a set of regions including left middle frontal gyrus/Frontal_Sup_R(aal)/left Superior Frontal Gyrus;and left middle frontal gyrus/Precentral Gyrus Postcentral_L(aal)/right Middle Frontal Gyrus/Supp_Motor_Area_L(aal).1.2 Brain activity areas in HC>TRD:Between the right rACC and right lingual gyrus,and right lingual gyrus.1.3 Brain activity areas in non-TRD>TRD:Between the right rACC and a set of regions including left Middle Frontal Gyrus/Frontal Sup R(aal)/left Superior Frontal Gyrus/Paracentral_Lobule_L(aal)/Precuneus_L(aal);and left Middle Frontal Gyrus/Precentral Gyrus Postcentral_L(aal)/right Middle Frontal Gyrus/Supp_Motor_Area_L(aal)/Paracentral_Lobule_L(aal)/Paracentral_Lobule_R(aal)/Supp_Motor_Area_R(aal).2.fMRI study of rsFC after 8 weeks of treatment2.1 Brain activity regions in the rs-FC changes after 8 weeks in the TRD group:FC increased between the right rACC and a set of regions including the left Precuneus/Postcentral_L(aal).and left Lingual Gyrus/left Precuneus/Postcentral_L(aal);FC decreased between the left rACC and the right Precuneus.2.2 Brain activity regions in the rs-FC changes after 8 weeks in the non-TRD group:FC increased between the right rACC and right Lingual Gyrus;FC decreased between the right rACC and Insula_R/Insula_L/Frontal_Inf_Orb_R(aal)/left Cingulate Gyrus,and Insula_R/Insula_L/right Inferior Frontal Gyrus/Frontal_Mid_L(aal)/left Anterior Cingulate.3.Correlation analysis between HAMD-17 reduction and rs-FC changes after 8 weeks'treatment.3.1 TRD group:After 8 weeks of treatment in the TRD group,the FC increases between the left rACC and left lingual gyrus was significantly positively associated with the HAMD-17 score reduction(r=0.840,P=0.005).No correlation was found in other brain regions(P>0.05).3.2 Non-TRD group:No correlation was found in non-TRD group.Conclusion1.TaVNS was effective in the treatment of TRD,and there was no significant difference in efficacy compared with the non-TRD group,but it showed the trend that that the TRD group seems more difficult to be alleviated.2.Prior to taVNS treatment,TRD patients had significant abnormal FC in the rACC-frontal/lingual gyrus,which may be associated with treatment resistance.3.After 8 weeks of taVNS treatment,FC increased in rACC-precuneus/postcentral/lingual gyrus,especially in the lingual gyrus and precuneus in TRD patients.4.After 8 weeks of taVNS treatment,FC decreased in default mode network and prefrontal-limbic network may be the important network contributing to the improvement of depressive symptoms in non-TRD patients. |
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