MRI Study On Brain Neuronetwork Connections In Early Onset Schizophrenia And DNA Copy Number Variations In Major Psychosis

PART-ⅠMRI study on brain neuronetwork connections in early onset schizophreniaObject The aim of this study was to explore the brain default network function connection and white matter integrity in first-episode early onset schizophrenia(EOS),by blood oxygenation level dependent functional magnetic resonance imaging(BOLD-fMRI) and diffusion tensor imaging(DTI) techniques.Methods First-episode adolescences with EOS(early onset schizophrenia) according to the diagnosis criteria of CCMD-Ⅲand DSM-Ⅳ) and age and gender-matched healthy controls were tested in a resting-state fMRI scan and diffusion tensor imaging scan.Functional connectivity analysis was used to reconstruct the default network in patients and healthy volunteers.Differences were examined between two groups.Functional connectivity analysis also was evaluated between the default network and other regions of the brains.Fractional anisotropy(FA) was measured in EOS and healthy volunteers with an automated voxel-based method of analysis.Results Forty-one first-episode patients and forty-two controls finished MRI scan.After excluding data from subjects with head movement,26 EOS(13 females and 13 males) and 28 age and gender-matched healthy volunteers were remained for fMRI analysis;35 EOS(17females and 18 males) and 33 age and gender-matched healthy volunteers were analyzed in DTI analysis.1.Default network analysis: the default network included the posterior cingulate/precuneus,left and right Superior Frontal gyrus,Caudate,the dorsal and ventral medial prefrontal cortex(MPFC),left and right angular gyrus,left and right Inferior Temporal Gyrus,left Parahippocampa Gyrus,right Inferior Semi-Lunar Lobule,and Cerebellar Tonsil.By comparing the functional connections within the default network between groups,we found five significantly abnormal connections comparing the patients group with controls.Three increased connections in patients are the connections between:ventral MPFC and right Inferior Temporal Gyrus (p=0.0078),ventral MPFC and left angular gyrus(p=0.0091),ventral MPFC and dorsal MPFC(p=0.0163).Two decreased connections in patients are the connections between:right angular gyrus and right Inferior Semi-Lunar Lobule(p=0.0223),left Superior Frontal gyrus and Cerebellar Tonsil(p=0.0294)。Comparing the connections of the default network and the other regions of the whole brain in two groups,the bilateral orbital middle frontal gyrus showed increased positive correlation with the default network in patients.2.DTI analysis: Comparing with controls,EOS patients exhibited significantly decreased fractional anisotropy(FA) values in right caudate,right anterior cingulate, right middle frontal gyrus,left superior frontal gyrus,left inferior Parietal lobe and left thalamus/hippocampus.There are no regions showing significantly increased FA in EOS patients.Conclusions 1.To my knowledge,this is the first study reporting that functional disintegration of the default network in first-episode EOS.Within the default network,the major abnormal connections were correlated to MPFC,and showed increased positive connections in EOS patients.The bilateral orbital inferior frontal gyrus showed increased positive correlation with the default network in patients. The abnormalities could be the source of the abnormal of introspectively oriented mental actives.2.EOS showed decreased fractional anisotropy in prefrontal and sub cortical regions suggested that widespread structural dysconnectivity,including the subcortical region,is already present in their first episode of illness. PARTⅡDNA copy number variations in major psychosisObject The aim of this study was to identify copy number variations(CNVs) in schizophrenia,bipolar disorder and major depression,and to test correlations between CNVs and these diseases.Methods Postmortem brain tissue from individuals with DSM-IV diagnosed SZ(n = 50),BD(n = 49),major depression(15) and matched controls(n = 49),provided by the Stanley Medical Research Institute Brain-Array and Consortium Collections.DNA was extracted from each specimen and purified.The Affymetrix 5.0 SNP array was hybridized to the genomic DNA sample of each subject.Assays were carried out according to the manufacturer's protocol.Partek software was used to obtain estimates of copy number variations(CNVs).First,copy number baseline was created from pools of all control samples,and the intensity of each sample's data was normalized to the copy number baseline.Then, CNVs were detected using a Hidden Markov Model,with a region defined as consistent variation in at least three adjacent probes.This finds the most likely state at each genomic locus by assigning a hidden state at each locus based on the observed data and the neighboring states. Secondary analyses of the genomic DNA hybridization data were performed,on allele signal ratio and loss of heterozygosity(LOH),which can give support information on CNVs.Results 2502 CNVs(from 1226 loci) were detected from autosomes. 22 CNVs(from 20 loci) were detected from X chromosome.The average number of CNVs detected per individual was 15.5.Of 2524 CNVs,1148 CNVs were heterozygous deletions,562 CNVs were homozygous deletions,and 814 CNVs were duplications.The median size of CNVs was 31kb,and the mean size was 189 kb.Three large CNVs on chromosome 9 were detected in schizophrenia and bipolar diseases. We compared the CNVs identified in our analysis to those present in the Database of Genomic Variants(DGV).156 CNVs(96 loci) in our data were novel CNVs.Of 2524 CNVs,906 CNVs are singleton CNVs,and 1618 CNVs were non-singleton CNVs.In tests for association for 43 common CNVs(frequency＞5%),CNV-304 has marginal significant P value(p=0.086) after Bonferroni correction.We further investigated genes that were deleted or duplicated exclusively in patients(ie,not observed in controls in our study,and not present in the Database of Genomic Variants).35 genes in CNVs were recorded exclusively in patients with major psychosis:6 in bipolar disorder,8 in major depression and 21 in schizophrenia.Conclusions 1.We found three very big CNVs in schizophrenia and bipolar diseases which suggested that these big CNVs may contribute genetic risk to these diseases.2.CNVs-304 is has marginal association with schizophrenia(Simulation P=0.002,Bonferroni P=0.086).3.There are 35 genes exclusively in major psychosis,which suggested these genes are valuable candidate genes for further study.