The Effects Of TNF-α Gene Polymorphism On Brain Networks Related With Working Memory In Major Depressive Disorder

[Objective]Depression has been the leading cause of global disease burden,nevertheless,the pathogenesis remains unclear.Tumor necrosis factor-α(TNF-α)has shown close association with the pathogenesis and development of major depressive disorder(MDD).Single nucleotide polymorphisms(SNP)of TNF-α may affect the protein expression and then lay influence on the brain synaptic plasticity,which can be revealed partly by structural and functional neuroimages.Moreover,anti-TNF-α therapy can improve the depressive symptoms and cognitive impairements of patients with depression.Accordingly,we hypothese an SNP of TNF-α,rs1799724,may influence the brain structure and function of patients with MDD through affecting synaptic plasticity,which might be associated with the cognitive and social dysfunction of MDD.The aims of this study were to investigate whether the SNP of TNF-α could affect the brain structure and functional network associated with working memory across patients with MDD and HC using structural and task magnetic resonance imaging(MRI)analyses,and further explore their association with cognitive and social function.[Method]Section 1: Effects of tumor necrosis factor-α polymorphism on the brain structural changes of the patients with major depressive disorder.We totally recruited 256 patients with MDD and 135 healthy controls(HC)with genotyping data,and compared their clinical and cognitive features between groups of diagnoses and genotypes.Then structural analyses were performed on good-quality T1 images of 109low-risk MDD,34 high-risk MDD,84 low-risk HC,and 29 high-risk HC.Voxel-based morphometry(VBM)analysis followed by graph theory based structural covariance analysis was applied to locate diagnosis x genotype interactions.Eigenvalues of significant regions were extracted and the correlation with cognitive function and social function were analysed.Section 2: Effects of TNF-α polymorphism on the functional networks related with working memory of the patients with major depressive disorder.Task MRI data with good quality were preprocessed and analysed,consisting of 105 low-risk MDD,33high-risk MDD,84 low-risk HC,and 29 high-risk HC.Two-back task with two load levels,0-back(baseline)and 2-back,was performed during MRI scan.Activiation and deactiviation patterns across all the participants were calculated,and independent component analyses(ICA)were carried out to identify brain networks involved in working memory process.Network engagement(beta weights)and between-network interaction(functional network connectivity,FNC)were calculated based on load contrast 2-back > 0-back,and then statistical analyses were conducted to see the effects of diagnosis and genotype on network engagement and FNC.Finally,the association between network features and cognitive function as well as social function were tested.[Results]Section 1: Effects of tumor necrosis factor-α polymorphism on the brain structural changes of the patients with major depressive disorder.Diagnosis x genotype interaction was exclusively localized to the visual cortex(right superior occipital gyrus,FDR correction,p<0.05).The same region also showed reduced volume in patients with MDD than HC(main effect of diagnosis),with this effect being most pronounced in patients carrying the high-risk genotype.Irrespective of diagnosis,individuals with the high-risk genotype(T-carriers)had reduced volume in left angular gyrus(low-risk<high-risk,FDR correction,p=0.05).However,neither global nor regional topography of structural covariant network was found to have group difference.The volume of right superior occipital gyrus was positively correlated with cognitive function in low-risk MDD and high-risk HC,and was positively correlated with social dysfunction in low-risk MDD.The volume of left angular gyrus was negatively correlated with cognitive function in low-risk participants(MDD and HC),was positively correlated with social function across all the patients with MDD,but negatively correlated with life quality in low-risk HC.Section 2: Effects of TNF-α polymorphism on the functional networks related with working memory of the patients with major depressive disorder.No significant effects of TNF-α was found on activity of single brain region during working memory task in patients with MDD or HCs.Across participants of MDD and HC,visual network(VN),default mode network(DMN),frontoparietal network(FPN)and salience network(SN)may be involved in working memory task.The engagement of DMN was significantly different between low-risk participants and high-risk participants(main effect of genotype,F=4.852,p=0.029),with low-risk HC<high-risk HC and low-risk HC<high-risk MDD in detail.The engagement of FPN was significantly different between MDD and HC(main effect of diagnosis,F=4.327,p=0.039)with low-risk MDD > low-risk HC pattern.FNC between FPN and VN were significantly different between MDD and HC(main effect of diagnosis,F=7.681,p=0.006)with low-risk MDD< low-risk HC and low-risk MDD < high-risk HC significantly.DMN engagement was negatively correlated with cognitive function across all the groups,but was negatively correlated with days lost to work only in high-risk MDD.[Conclusions]Among the depressed and healthy subjects,a genetic variation which can increase TNF-α expression selectively affects the anatomy of the grey matter volume of right superior occipital gyrus and left angular gyrus and the engagement of DMN in Two-back working memory task.Additionally,significant associations were found between bran structural and functional characteristics and cognitive or social function.