| Objectives:Major depressive disorder(MDD)is a popular psychiatric disorder commonly showing abnormal spontaneous brain activity,yet little is known about its alterations in dynamic spontaneous brain activity and the molecular mechanisms associated with these changes.Here,based on the resting-state functional MRI data of 65 first-episode,treatment-naive patients with MDD and 66 healthy controls,we compared dynamic regional homogeneity(dReHo)of spontaneous brain activity between the two groups,and gene expression profiles associated with dReHo alterations in MDD were investigated by leveraging transcriptional data from the Allen Human Brain Atlas and weighted gene co-expression network analysis to investigate complex mechanism of MDDMaterials and Methods:In this study,136 subjects were recruited(131 subjects finally included)with 67 first-episode,treatment-naive patients with MDD(65 MDD patients finally included)and 69 age-and gender-matched healthy controls(66 healthy controls finally included)All participants aged 18-65 years and their MRI images were obtained using a 3.0-Tesla Discovery MR750 scanner(General Electric,Milwaukee,WI)in Tianjin Medical University General Hospital.The rs-fMRI data were preprocessed using the Data Processing Assistant for Resting-State fMRI(DPARSF)based on Statistical Parametric Mapping 12.Then dReHo was calculated using sliding window approach with Data Processing&Analysis of Brain Imaging(DPABI)toolbox and voxel-wise two-sample t-tests were performed to identify dReHo differences between the two groups,and t-statistical map was generated.In addition,the 10185 genes were clustered into consensus modules by applying weighted genes co-expression network analysis(WGCNA)based on four left hemispheres and two bi-hemishperes from AHBA Finally,for each module,Pearson correlation was conducted between ME and t-value across brain tissue samples and,then,stable consensus modules related to MDD were obtained.These modules were finally annotated by pathways and cell-type enrichment analysis.Results:1.Based on the window length of 50 TRs,compared with healthy controls,voxel-wise two-sample t-tests revealed significantly decreased dReHo in bilateral inferior temporal gyrus,fusiform gyrus,hippocampus,parahippocampal gyrus,temporal pole(superior)and insula,left amygdala and Rolandic operculum,and right putamen in patients with MDD(q<0.05,FDR corrected).The results of the intergroup comparisons were similar using the other two window lengths(34 TRs and 66 TRs)2.Nineteen consensus modules were identified from WGCNA analysis based on four left hemispheres and two bi-hemispheres expression data.Pearson’s correlation was calculated between MEs and across-sample t values in each module to show the consistent correlation pattern of modules across the two expression data sets and the three windows lengths.The results showed that there were 17 preserved MDD-related modules,14 of them were correlated with dReHo difference in cortical samples and 8 of them in subcortical samples(overlapped 5 modules by cortical and subcortical analyses)3.The genes in the stable modules were significantly enriched in pathways related to synaptic signaling,immune response,axon ensheathment and central nervous system development and were preferentially expressed in neurons,astrocyte and microglia.Conclusions:1.In this study,we found that first-episode,treatment-naive MDD patients had decreased dReHo mainly in the limbic areas that have frequently been reported to be abnormal in MDD2.The case-control differences in dReHo showed replicable spatial correlations with expression profiles of gene modules associated with various cell types,biological functions and pathways,indicating that MDD may be developed via complex polygenetic and polypathway mechanisms. |
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