The Resting-state Functional Activation And Functional Connectivity In Major Depressive Disorder And The Correlations With LHPP Gene Polymorphism

Objective: Major depressive disorder(MDD)is a common mental illness with high recurrence rate and high disability,and the pathophysiological mechanism is unclear.More and more neuroimaging studies have shown that MDD patients had abnormal brain spontaneous activities and functional connection.Previous studies always use less cases to explore the f MRI in MDD,and the results were inconsistent.Based on the complex genetic characteristics of MDD,many genetic imaging studies have already demonstrated that risk genes may affect the brain neural circuits in MDD.A single-nucleotide polymorphism at the LHPP gene(rs35936514)in Chinese has been reported in genome-wide association studies to be associated with MDD.However,the neural system effects of rs35936514 that mediate the association are unknown.We hypothesized that LHPP gene polymorphism may increase the risk of MDD by affecting the brain regions and neural circuits.We collected single-center large sample to explore the resting state functional activation and functional connectivity in MDD.The present work also explored the association of neural circuitry and the LHPP rs35936514 polymorphism in MDD.We tried to discuss the biological mechanisms of MDD.Methods: Magnetic resonance imaging was performed on a GE Signa HDX 3.0T MRI scanner with a standard head coil.Resting-state functional magnetic resonance imaging(rs-f MRI)data were acquired from 202 MDD patients and 231 healthy controls(HC)matched for gender,age and education.Demographic data and blood samples were collected.The resting-state f MRI data were preprocessed using DPARSF and SPM8.The ALFF and FC values of BOLD signal for each participant was calculated.Two sample t-tests were used to compare ALFF and FC values between MDD and HC groups(P < 0.05).The genotypes of the SNP at rs35936514 were determined using Sanger sequencing method.Subjects were further divided into two groups: a CC group homozygous for the C allele and risk T-carrier group(CT/TT genotypes).Hardy-Weinberg equilibrium were used to test genotype frequencies.A voxelwise ANOVA(2 × 2 ANOVA: diagnosis × genotypes)was used to determine the interaction effects and main genotype effect on ALFF and FC values.Correction for multiple comparisons was based on Monte Carlo simulation(AFNI).Spearman correlation analyses were performed to assess the correlation of illness duration and HAMD-17 score with the ALFF and FC values in the regions that were significantly different between MDD and HC groups(P < 0.05).Results:(1)No significant difference between the MDD and HC groups was found in age,sex or education.Genotype frequencies were consistent with Hardy-Weinberg equilibrium expectation.(2)Compared with HCs,MDD patients showed significantly increased ALFF in the limbic system(left hippocampus,left amygdala),paralimbic system(left parahippocampal gyrus,bilateral OFC),hetero-modal cortical(bilateral DLPFC,left MPFC,bilateral ITG,MTG,left IPL,right supramarginal gyrus)and primary cortex(right STG,left precentral gyrus and left postcentral gyrus);MDD patients showed significantly decreased ALFF in primary cortex(bilateral cuneus,calcarine gyri,bilateral lingual gyri,left precentral gyrus and bilateral postcentral gyri).MDD patients showed increased FC in the hippocampal-paralimbic system(bilateral insula,bilateral ACC,right frontal pole,right temporal pole,bilateral OFC),subcortical nuclei(left putamen),hetero-modal cortical(right DLPFC),bilateral MPFC and primary auditory cortex(bilateral STG);MDD patients showed significantly decreased FC classical emotional processing brain regions including hippocampal-visual cortex(left cuneus,bilateral calcarine gyri,bilateral lingual gyri)and somatic motor and sensory cortex(bilateral precentral gyri and left postcentral gyrus,left paracentral lobule),paralimbic system(right CC,bilateral OFC).These findings correspond to a corrected p < 0.05 by Alpha Sim correction.(3)T-carrier group showed increased ALFF in the primary auditory cortex(left STG),primary motor cortex(left precentral gyrus)and paralimbic system(left temporal pole).T allele with MDD patients had significantly lower ALFF values in primary visual cortex(bilateral lingual gyri).ALFF were highest in the classical emotional processing brain regions(bilateral DLPFC,left MPFC).These findings correspond to a corrected p <0.05 by Alpha Sim correction.The T-carrier group showed decreased hippocampal-FC in the DMN(bilateral precuneus,PCC,MPFC)and hetero-modal cortical(the left DLPFC)and increased hippocampal-FC in the visual cortex(left occipital cortex).T allele with MDD patients showed extensive abnormal hippocampal-FC in the primary cortex,(bilateral ITG,bilateral postcentral gyrus,bilateral supplementary motor area,bilateral cuneus,bilateral lingual gyri,bilateral calcarine sulcus,precuneus),the classical emotional processing brain regions including hetero-modal cortical(right angular gyrus,DLPFC),as well as paralimbic system(bilateral OFC,ACC),bilateral MPFC.These findings correspond to a corrected P<0.05 by Alpha Sim correction.(4)Left MTG/STG showed a positive association between ALFF and illness duration,bilateral occipital cortex showed a negative association between ALFF and illness duration;Bilateral occipital cortex showed a positive association between FC and HAMD scores(P<0.05).Correlation analyses did not show any significant associations in other groups(>0.05).Conclusions:(1)There were widespread abnormalities in the ALFF and hippocampus-FC in MDD patients.Compared with HCs,MDD patients showed abnormal ALFF in the limbic and paralimbic system,hetero-modal cortical and primary cortex;MDD patients showed significant abnormal FC in the hippocampal-classical emotional processing brain regions including paralimbic system,subcortical nuclei,bilateral MPFC and primary auditory cortex,visual cortex and somatic motor and sensory cortex,paralimbic system.It is suggested that these brain regions and neural circuits may be involved in the pathophysiological mechanism of MDD.(2)The abnormal ALFF in the primary auditory cortex(left superior temporal gyrus),primary motor cortex(left precentral gyrus)and paralimbic system(left temporal pole),and abnormal hippocampal-FCs in the DMN(bilateral precuneus,PCC,MPFC),hetero-modal cortical(the left DLPFC),were related to LHPP gene polymorphism.It is suggested that LHPP gene polymorphism may affect neural circuits and affect emotional regulation.T allele with MDD patients had abnormal ALFFs in primary visual cortex(bilateral lingual gyri),the classical emotional processing brain regions(bilateral DLPFC,left MPFC),and abnormal hippocampal-FCs in the primary cortex,including the primary visual cortex,auditory cortex,motor cortex,the somatosensory cortex,the classical emotional processing brain regions including hetero-modal cortical,as well as paralimbic system,which were related to LHPP gene polymorphism.We suggested that LHPP gene polymorphism may affect neural circuits and emotional regulation and play an important role in the pathophysiological mechanism of MDD.We provided a new approach to explore the pathophysiological mechanism of MDD.