The Clinical And Brain Mechanism Study Of Transcutaneous Auricular Vagus Nerve Stimulation For Treating The Treatment Resistant Depression Using BOLD/MRS Multimodal FMRI

Purposes1.To observe the clinical efficacy of transcutaneous auricular vagus nerve stimulation(taVNS)in treating the treatment resistant depression(TRD)and non-treatment resistant depression(nTRD).2.To compare the pathological mechanism of depression between the TRD group and nTRD by using the resting-state functional connectivity and magnetic resonance spectroscopy.Furthermore,to explore the therapeutic mechanism of taVNS in treating TRD and nTRD in 8 weeks.Methods30 TRD patients(TRD group)and 22 nTRD patients(nTRD group)were recruited.All were treated by the transcutaneous auricular vagus nerve stimulation for 8 weeks.The taVNS treatment was performed twice a day for 30 minutes each time,7 days a week.The clinical scales including Hamilton Depression Rating Scale(HAMD-17),Hamilton Anxiety Scale(HAMA),Self-Rating Depression Scale(SDS),Self-Rating Anxiety Scale(SAS)were scored before treatment(week 0),after 2,4,8 weeks’ treatment,respectively,and Ruminative Response Scale(RRS),Pittsburgh Sleep Quality Index(PSQI),and Wisconsin Card Sorting Test(WCST)were evaluated before treatment(week 0)and at the 8th weekend.The score reduction rate of HAMD-17 before and after treatment was used as the main outcome indicator.To compare the differences of Regional Homogeneity(ReHo)of brain function among the TRD group,nTRD and healthy subjects at baseline in order to explore the pathological mechanism of depression.Furthermore,the changes of functional connectivity(FC)after 8 weeks’ taVNS treament were analyzed to clarify the brain mechanisms of taVNS on TRD and nTRD respectively.Part of the clinical subjects were included to participate in the resting state-functional Magnetic(rs-fMRI)study:23 TRD patients and 20 nTRD patients participated in the brain fMRI scan at the 0 week and the 8th weekend.In addition,26 healthy subjects were recruited and participated in the rs-fMRI scan once.Part of the subjects who participated in the function Magnetic Resonance Imaging(rs-fMRI)study were recruited in the Magnetic Resonance Spectroscopy(MRS)study:16 TRD patients,11 nTRD patients and 10 healthy subjects.To observe the baseline differences of y-aminobutyric acid(GABA)and glutamic acid(Glu)among TRD,nTRD and healthy subjects,and then to explore the relationship between GABA,Glu and clinical symptoms of TRD.ResultsA total of 30 cases were recruited in the TRD group,three cases of TRD patients fell off,27 cases of TRD patients finished the 8 weeks’ taVNS treatment.A total of 22 cases were enrolled in the nTRD group,two cases of nTRD patients fell off,20 cases completed the taVNS treatment.After enrollment,there were no significant differences in age,gender,the course of disease,and in the baseline scores of HAMD-17,HAMA,SDS,SAS,PSQI,and WCST between the two groups.The Efficacy was evaluated after the 8 weeks’ taVNS on TRD or nTRD.In TRD group the reduction score rate of HAMD-17 was 67.73%for TRD.13 cases were clinically cured,8 cases improved significantly,4 cases improved,and 2 cases were ineffective.The overall response rate was 92.59%.In non-TRD group the reduction rate of HAMD was 100%.HAMD-17,HAMA,SDS,SAS,and RRS、PSQI scales’ scores were significantly differed from the baseline for both patient groups(P<0.05).The results for Resting state fMRI-BOLD.The value of ReHo in the healthy group was larger than in the TRD group including left lingual gyrus,inferior parietal lobules,inferior occipital gyrus,bilateral talar gyrus,right central posterior gyrus.The higher values of ReHo when healthy group comparing with the nTRD group were left lingual gyrus,inferior parietal lobule,middle occipital gyrus,bilateral calcarine gyrus,right central posterior gyrus.The ReHo values of left superior temporal pole in TRD group were larger than in healthy group.The left cerebellum 4/5,9,10,vermis 3,and right cerebellum 5 showed higher values in nTRD group than in the healthy group.The brain regions of the TRD whose ReHo value were greater than that of the nTRD included left cerebellum 1,left cerebellum 2.The rs-FC value decreased between the right insula with the left superior frontal gyrus or the middle frontal gyrus after 8 weeks of treatment in the TRD group,and the decreased FC were significantly negatively correlated with the HAMD-17 reduction in the TRD group(P=0.012,r=-0.512),while the rs-FC values between the right insular lobe and bilateral anterior cingulate gyrus was increased,and the increased values were significantly negatively correlated with the changes of the HAMD-17 reduction in the nTRD group(P=0.026,r=-0.496).MRS study:There was no significant difference in the baseline values of GABA and Glu between three groups of TRD,nTRD,and healthy subjects.The baseline value of GABA in the TRD group was significantly positively correlated with the baseline SAS score(P=0.021,r=0.610).There was a significant positive correlation between the baseline value of GABA and the reduction rate of SAS score before and after 8 weeks of taVNS treatment(P=0.012,r=0.755).The the baseline value of Glu was negatively correlated with the baseline value of PSQI(P=0.025,r=-0.573).There was no significant difference in the GABA and Glu values before and after the treatment of taVNS for 8 weeks.Conclusions:1.taVNS is effective in treating TRD and nTRD respectively.2.The abnormal ReHo in cerebellum function may be the different pathological mechanism between TRD and nTRD,The brain function and network’ changes in the right insular lobe may be the similar neuromechanism of taVNS treating TRD or nTRD.3.GAB A and Glu in TRD are associated with symptoms with anxiety,sleep,and rumination.They may be the targets of neurotransmitter modulated by taVNS on TRD.