The Clinical And Rs-fMRI Study On Mild-to-moderate Primary Depression Treated With Electro-acupuncture At GV24 And GV29

BackgroundDepression is a common mental disorder with losing interest to most things or activities as the main performances. The World Health Organization (WHO) predicted that depression would become the second largest disease burden comparing to AIDS by 2030. In China, the incidence of depression has risen to 5.3% by the 2010, and the risk of depression in college freshmen reached up to 24.8%. Because of its high prevalence, high risk of suicide, high disabling and high disease burden, the prevention and the mechanism researches of depression are extremely urgent.As the principal treatment of depression, the antidepressants have been widely used in clinic. However, there were many limitations such as long onset time, low response and side effects, etc. Less than one third of the patients had response to the antidepressants for the first treatment. Thus, other complementary and alternative therapies have been sought to control the side effects, and improve the clinical curative effect. Evidence-based medicine showed that the electro-acupuncture had similar curative effect of antidepressants and fewer side effects. In many reports, GV24 and GV29 had been chosen as the main points to lead Yang into Yin, latent liver Yang, tranquilize mind, and restore consciousness.At present, the pathogenesis of depression has been unclear and developing in western medicine. The blood oxygen leveldependent functional Magnetic Resonance Imaging(BOLD-fMRI), could show the brain function changes noninvasively, intuitively, and systematically. Based on the technology of resting-state functional magnetic resonance imaging (Rs-fMRI), brain network researches have been developed and shown its important application value in exploring the pathological mechanism of depression. Brain function network theory considered that the changes in cognitive control network, the default network and emotion regulating network were consistent with clinical symptoms. According to the "confusion of brain spirit", "correlation of meridian specificity and the brain" hypothesis in TCM theory and pathogenesis of abnormal changes of "brain function network" in western medicine theory, this study selected the Rs-fMRI technology to explore the mechanism of depression treated with electro-acupuncture.Above all, in this research, at first the meta analysis was used to study the efficacy and safety on depression treated with combination of acupuncture with SSRIs comparing to 5-serotonin reuptake inhibitors (SSRIs), and evaluate the quality of each study and the level of the evidence. Then, with primary depression pateients as the objects, single blind and randomized controlled clinical research was taken to compare the curative effect, onset time and side effects among different interventions: electro-acupuncture at GV24 and GV29, electro-acupuncture at GV24 and GV29 combined with antidepressant, and antidepressant. At last Rs-fMRI was used to observe the change of brain function of the primary depression pateients treated by electro-acupuncture at GV24 and GV29, in order to explore the curative mechanism of treatment of primary depression with electro-acupuncture at GV24 and GV29.ObjectiveStudy the efficacy and safety of the combination of electro-acupuncture with antidepressant on depression by meta analysis. Observe the efficicency and safety of electro-acupuncture at GV24 and GV29 on primary depression with randomized controlled clinical trial. Explore the Brain function mechanism of electro-acupuncture at GV24 andGV29 on primary depression with Rs-fMRI.Methods1. Meta analysisThe Chinese databases as CNKI, VIP, WanFang database, CBM and English databases as Ovid Lww, PubMed and the Cochrane library were respectively retrieved with the proposal. The retrieval time was until March 31,2014.According to inclusion and exclusion criterias, Chinese and English literatures of randomized controlled trials (RCT) with high quality were included. All the literatures were about comparison on the safety of primary curative effect of depression treated by combination of acupuncture with SSRIs vs SSRIs. The quality of literatures was evaluated by the modified Jadad scale. The RevMan 5.2 software (Cochrance cooperation website) was used to analyse the 17-iterm of Hamilton Depression Scale, HAMD (HAMD-17) scores, Self-rating depression scale (SDS) scores and Rating Scale for Side Effects (SERS) scors, Treatment Emergent Symptom Scale (TESS) scors. The GRADE system recommended rating method was used to evaluate quality of the evidences.2. Clinical researchAccording to inclusion and exclusion criterias,195 patients with mild-to-moderate primary depression were included. All the patients were randomized into electro-acupuncture group, integrative group and drug group. Electro-acupuncture was received in electro-acupuncture group and integrative group three times a week, while Paroxetine was taken in integrative group and drug group daily.2.1 Intervention methodThe main acupoints were GV24 and GV29. The matching acupoints were GV16, both GB20, GV14, both PC6, and both SP6. Acupuncture order:First GV14 was needled with 30-second twirling, and then slowly withdrawing the needle. Second GV16 was needled with 30-second twirling, and then slowly withdrawing the needle. The rest of the points were needled in the order from head to foot. GV24 and GV26, double GB20 were respectively connected to the HANS acupoint nerve stimulator (LH-202-H) electrodes, stimulating with density alternate wave of the frequency of 2/15Hz, with current intensity within tolerance of the patients (skin slight jitter),30 minutes a time. The needles at the rest acupoints were retained and twirledl time per 15min.2.2 Evaluation methodEffective rate was evaluated by the reductive ratio of HAMD-17 total score: reductive ratio= (total score before treatment-total score after treatment)/total score before treatment× 100%. Effective was defined as the reductive ratio> 50%, while invalid as≤50%. HAMD-17 and SDS were respectively observed at 5 time points of the beginning and 1,2,4,6 weeks during the course, while SERS was observed at 4 time points of the beginning and 2,4,6 weeks during the cours. Adverse events were recorded.2.3 Statistical methodsThe software of SPSS 20.0 for Windows was used. Two-tailed test with α=0.05 and 95% confidence interval were used to inference all statistical. Parameter method was used as far as possible. When the parameter conditions couldn’t be satisfied, the data was transformed to meet the conditions. If it is still not satisfied, non-parametric test could be considered to use.3. Rs-fMRI researchAccording to inclusion and exclusion criterias,12 patients with mild-to-moderate primary depression and 12 cases of normal subjects were included respectively.3.1 acupuncture programHua-tuo disposable needle (25 mm X 0.30 mm) were horizontal inserted backward 0.5 inches at GV24, and 0.5 inches at GV29. The two needles were twirled to De Qi, and then respectively connected to HANS acupoint nerve stimulator (LH-202-H) for 30 minutes, with 2/15Hz stimulating frequency alternate wave, current intensity within patients’ tolerance degrees.3.2 Scanning SolutionsGE 3.0 T MRI scanner (GE signa Excite system, American) and standard GE EPI functional head coil were used to collect brain function data. After conventional three plane position, sagittal T1WI-FLAIR was scanned to obtain anatomical images, with anterior and posterior commissure as the scanning reference, TR/TE= 2300ms/21ms. Thirty slices were scanned to include the range from parietal to foramen magnum, with slice thickness 5.0 mm/1.0 mm intervals, FOV=240 mm×240 mm,256×256 resolution. Single echo planar imaging gradient echo sequence (GRE EPI) was used for functional imaging acquisition with the same slices of anatomy image, total scanning 6 min, TR/TE=3000ms/20ms, FA=90°, thickness 5.0mm/1.0 mm intervals, FOV=240mm× 240mm,96 × 96 resolution.3D sequence was scanned by T1 FSPGR, TR=2.7ms, TE=3.39ms, FOV=256 mm × 256 mm,256×256 resolution, FA=7°, thickness 1 mm, as reference chart of the function scanning. Image acquisition time: before and 15 minunts after the elctro-acupuncture.3.3 Data AnalysisBased on MATLAB R2009a platform, DPARSFA with SPM 8, REST 1.8 software were used to preprocess the Rs-fMRI raw data, including format conversion, the first 10 point data removing, Slice timing, Realign, Normalization and Smooth,6 steps. Then the REST 1.8 was used for whole brain low frequency amplitude (ALFF) and regional homogeneity (ReHo) analysis. REST 1.8 was used to compare the standardization ReHo and ALFF in each group between two time points with paired samples t-test respectively, and between groups with the two independent samples t-test. The xjview 8.0 was used to set statistical threshold as 0.05, with AlphaSim correction (P=0.05, the Cluster size=228 voxels). Finally the ReHo and ALFF changes of above the brain regions before and after electro-acupuncture were obtained, and the statistical significance brain regions were presented as image form. Clinical trial data was analysed by SPSS 20.0 for Windows.Results1 Meta analysisEventually,5 RCT literatures, with relatively high methodological quality and small sample size, were included in the study. Totally,371 patients of primary depression from the ward or outpatient clinic were included. Subgroup analysis showed that HAMD-17 and SDS scores at 1,2,4 weeks after treatment in the acupuncture combined with SSRIs group were significantly less than SSRIs group. Analysis of the safety showed that, the SERS score at 2,4 weeks after treatment in the acupuncture combined with SSRIs group were significantly lower than SSRIs group. Descriptive analysis showed that the TESS score at 1,2,4 weeks in he acupuncture combined with SSRIs group was significantly lower than SSRIs group. Evaluation of evidence quality by GRADE showed that, the outcomes of 2 groups were demoted to medium quality due to heterogeneity, while the other 6 groups remaining high quality.2 Clinical researchThe effective rate as the main efficacy evaluation index was evaluated by the reductive ratio of HAMD-17 total scores. The results showed that there were significant differences among different time points before and after the treatment in each group (P<0.001), and at the 6-week of the treatment, the reductive ratios of HAMD-17 were significantly different among 3groups (χ2= 9.783, P=0.008).Within-group comparison showed that, at different time points after the treatment, the HAMD-17 scores were significantly lower than that before the treatment (P<0.001). Comparison among groups showed significant difference among 3 groups at each time point (P<0.05). At 1-week during the treatment,3.55±0.39 of HAMD-17 score had been reduced in the electro-acupuncture group, with significant difference than the other two groups. At 2-to 4-week during the treatment, the changes of integrative group were most obvious (6.34±0.55,10.27±0.65). The electro-acupuncture group was better than drug group at 2-week, while drug group was better than electro-acupuncture group at 4-week, both without significant differences. At 6-week of treatment, HAMD-17 score changes were 12.48±0.68 in integrative group,11.89 ±0.60 in drug group, and 9.42±0.50 in electro-acupuncture group. There was significant difference of electro-acupuncture group than the other 2 groups.Within-group comparison showed that, SDS standard score was significantly reduced at different time points after treatment than that before in each group (P<0v.001). Comparison among groups showed significant difference among 3 groups at each time point. At 1-week, integrative group showed significant difference with the other 2 groups (both P<0.001), without difference between the other 2 groups. At 2-week, change value of integrative group was much higher than that of drug group (P=0.002), without difference between other 2 groups. At 4-and 6-week, there was no significant difference among 3 groups (P>0.05).SERS score analysis showed that the electric acupuncture can obviously decrease the patients’SERS score (P<0.001), since 2-week until 6-week of the treatment, the SERS score in integrative group was significantly lower than drug group (P=0.027,0.021,0.031).3. Rs-fMRI researchComparison of ALFF and ReHo data before electro-acupuncture between depression patients and normal subjects showed that:the ALFF values of left inferior temporal gyrus, caudate nucleus, anterior and posterior lobe of depression patients were significantly increased than normal subjects, while those of left medial frontal gyrus, the right medial frontal gyrus, posterior cingulate, precuneus and supramarginal gyrus were significantly reduced. The ReHo values of the right inferior frontal gyrus, the left postcentral gyrus, and lingual gyrus of depression patients were significantly increased than normal subjects, while those of the right posterior cingulate, the brain after anterior cingulate gyrus, anterior lobe of cerebellum and both inferior temporal gyrus, dorsolateral prefrontal cortex were significantly reduced.The ALFF and ReHo data of normal subjects after electro-acupuncture were compared with that before. After electro-acupuncture, the ALFF value of left posterior lobe of cerebellum was significantly increased, while thosee of precuneus, posterior cingutate and the right middle frontal gyrus were significantly reduced. The ReHo values of posterior lobe of cerebellum, middle occipital Gyrus, thalamus and left posterior central gyrus, middle temporal gyrus were significantly increased, while those of left dorsolateral frontal gyrus, posterior cingulate, precuneus, and right supramarginal gyrus were decreased significantly.The ALFF and ReHo data of depression patients after electro-acupuncture were compared with that before. The ALFF values of right precuneus, middle frontal gyrus were increased significantly. The ReHo values of right middle frontal gyrus, Edge angular gyrus, and left middle temporal gyrus were significantly increased, while that of right caudatum was decreased significantly.Conclusion1. Compared with SSRIs drugs, electro-acupuncture combined with SSRIs therapy showed shorter onset time and higher safety on treating primary depression.2. Electro-acupuncture at GV24 and GV29 could rapidly improve the symptoms of patients with depression in the first 2 weeks; however, its curative effect at the 6th week was inferior to antidepressant and electro-acupuncture combined with antidepressant. In the first 2 weeks, the patients with integrative therapy felt more obvious improvement; meanwhile, electro-acupuncture could reduce the side effect of antidepressants in the integrative therapy.3. Depression patients’ Frontal lobes, cingulate gyrus, precuneus, supramarginal gyrus, which brain areas are associated with emotional and cognitive have insufficient activation. It may be the pathogenesis related with depression. Electro-acupuncture at GV24 and GV29 could target and regulate the depression related brain regions in the frontal lobe, precuneus. This might be the barin functional mechanism for the treatment on depression with electro-acupuncture at GV24 and GV29.