| Background:Major Depressive Disorder(MDD)is a mood disorder characterized by persistent depression.According to Traditional Chinese Medicine(TCM)theory,MDD belongs to the categories of Depressive Psychosis,Melancholia,Hysteria,Lily disease,Plum-stone qi ea al.About onethird of MDD patients failed to respond to drugs,adverse effects also limits its application.Therefore,there is an urgent need to develop a safe,effective,non-drug treatment for MDD.Transcutaneous Electrical Cranial-Auricular Acupoints Stimulation(TECAS),a new noninvasive physical therapy for depression,was first proposed for the following reasons:①The clinical symptoms of MDD were manifested as "Shen Tui" according to TCM theory,to adjust the heart and brain is the key to treat MDD;②A large number of studies have found that inflammation promotes the occurrence of MDD,and acupuncture has immunomodulatory effects;③Cranial acupoints(such as Baihui point and Yintang Point)and aricular points are recommended by dvidence-based guidelines of acupuncture and moxibustion in treating MDD;④Peripheral afferent fibers and cholinergic anti-inflammatory pathways are associated with the therapeutic effects of acupuncture;⑤Transcutaneous electrical acupoints stimulation is a portabe and non-invasive therapy,which has similar efficacy to traditional acupuncture.⑥"Neuro-inflammation" plays an important role in the physiopathology of MDD."Enlightening the Spirit by Modulating Pivot" is highly recommended by TCM for treating MDD.In this study,the clinical efficacy of TEC AS in treating MDD is verified,then the potential modulational effects of TECAS on "immune-neuro-psychological" axis were also explored,which is expected to clarify the acting mechanisms of TEC AS.At last,the biomarkers for longitudinal therapeutic effects of TECAS were also identified.Objectives:To observe the antidepressant efficacy and characteristics of TECAS.To compare the differences in serum inflammatory factors between MDD patients and Healthy Controls(HCs).To clarify whether the abnormal inflammatory factors at baseline could distinguish the suitable population for TEC AS.To screen the brain regions influenced by the peripheral inflammatory factors in MDD patients.To find the abnormal brain areas by comparing the MDD patients and HC whitin the inflammation-related brain regions.To observe the modulating effect of TEC AS on inflammation-related brain regions.To explore the correlation between the severity of MDD,the alleviated symptoms and fMRI values.To clarify the predicting effects of the baseline fMRI values on the TEC AS’ anti-depressive effect.To explore whether baseline inflammatory factors could contribute to the predicting accuracy.Methods:The data collected in this study were from a multicenter randomized controlled trial funded by the National Key Researsh and Development Program.Subjects who completed fMRI scanning and serum inflammatory factors(IL-6,TNF-α,hsCRP)were included.MDD patients were consist of three groups(ie G1:TECAS group;G2:Escitalopram group;G3:combind TECAS and existing antidepressants group);Twenty-four HCs were recruits at the same time(see Research roadmap).Study 1:The clinical efficacy of TECAS on MDDThe baseline clinical charactors of 3 MDD groups and HC group were observed before and after treatment.Subgroup analysis was performed according to gender,age,education level,first-episode or recurrence MDD,and inflammatory factor levels.Study 2:Abnormal inflammation-related brain regions in MDD patientsDifferent voxel-based analyses were performed on fMRI data.The correlation analyses between the fMRI data and the inflammatory factors were performed to identified the inflammatory brain regions(inflammatory brain mask).Within this mask,two-sample t-test were performed to identify the abnormal brain regions.Study 3:Modulating effects of TECAS on the inflammation-related brain regions in MDD patientsThe abnormal inflammation-related brain regions found in study 2 would be used in the following seed-based analyses.Mixed-ANCOVA would be performed to compare the group(i.e.,each MDD group,HCs group)-by time(weeks 0 and 8)interactions.The correlation between the baseline FC values and the severity of symptoms,as well as the correlation between the FC changes and the efficacy of TEC AS were explored.Study 4:Study on predicting TECAS’ antidepressant effectAt baseline,the predicting effects of the brain regions modulated by TECAS were explored.MDD patients were divided into immune-abnormal/immune-normal subgroup according to the baseline serum inflammatory factors.The predicting accuracy between the subgroup was explored.Results:Study 1:Characters:at baseline,a total of 80 MDD patients were recruit(43 in G1 group,39 in G2 group and 15 in G3 group).After 8 weeks,9 of the 80 MDD patients drop out(4 in G1 group,3 in G2 group and 2 in G3 group).Sixy-seven MDD patients(G1 group:33;G2 group:19 cases;G3 group:13 MDD patients)and 24 HCs completed 2 qualified fMRI and serum inflammatory factors examinations.A total of 14 adverse events were reported(including skin rush at stimulation site in 8 cases and drug-related adverse effects in 6 cases).No serious adverse events related to the study occurred.Twenty-four healthy subjects were included.At baseline,serum TNF-α and hsCRP in G1 and G2 groups were higher than those of G3 and HC groups,while there was no difference between G1 and G2 and there was no difference between G3 and HC.There were no between-group differences in IL-6 among the MDD and HC groupsTwo-way repeated measure ANOVA showed similar decreases in HAMD and HAMA scale scores among the three MDD groups after 8 weeks,while there was no difference in the HAMD or HAMA remission rate among the three groups.In the subgroup of recurrent MDD,the HAMD and HAMA remission rate in G2 group were lower than those in G1 and G3 group.Other subgroup analysis showed no significant difference.Study 2:① Brain regions influenced by peripheral inflammationDifferent voxel-based analyses showed similar results,inflammation affected the default mode network,reward network,frontal parietal network,dorsal attention network and emotional network.②MDD patients showed abnormal ventral striatum compared to HCsIt was found abnormal ventral striatum in MDD group within the inflammation-related brain regions when compared to HCs group.Study 3:① TECAS normalized the ventral striatum FCIn G1 group,TEC AS normalized the FCs between ventral striatum and precuneus and lingual gyrus.At baseline,the FC values between the ventral striatum and lingual gyrus and precuneus were correlated with the baseline HAMD and HAMA scores.② The modulating effects of TECAS were associated with the therapeutic effectThe FC value changes between the ventral striatum and lingual gyrus,and between the ventral striatum and precuneus were correlated with the HAMD and HAMA score changes.Study 4:①Baseline FC values between ventral striatum and precuneus predict the antidepressant efficacy of TEC AS in G1 group.At baseline,FCs between ventral striatum and precuneus in MDD patients was associated with HAMD and HAMA remission rates after TECAS treatment for 8 weeks.(2)Baseline TNF-α and hsCRP affect the predicting effectsIn the subgroups with elevated TNF-α or hsCRP,FC values between ventral striatum and precuneus show stronger correlations with the HAMD and HAMA score decrease.Conclusion:①TECAS show similar HAMD and HAMA decrease to escitalopram.Baseline Clinical characters do not distinguish TECAS antidepressant candidates.② The ventral striatum,the core brain region of reward network,was the inflammation-related brain region.FC values between the ventral striatum and precuneus and lingual gyrus were related to the severity of MDD symptoms.③ TECAS increased the FC values between ventral striatum and dorsal attention network,and decreased the FC values between ventral striatum and precuneus.The FC changes were correlated with its antidepressant effect.④ Baseline FC values between the ventral striatum and precuneus predicted the patients remission.Elevated TNF-α and hsCRP contribute to the predicton. |
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