A Study On Neural Mechanisms Of Schizophrenia And Its Core Symptoms Based On New MRI Techniques

Part 1: Altered resting-state cerebral blood flow and its connectivity in schizophrenia ?Purpose? Small sample sizes and large inter-subject variations result in inconsistent findings in resting-state cerebral blood flow(CBF)in schizophrenia.The CBF connectivity alterations in schizophrenia remain unclear.In this study,we aimed to clarify the following issues:(1)the CBF alteration patterns in schizophrenia;(2)the associations between CBF alterations and clinical parameters;(3)whether the brain regions with altered CBF also exhibited CBF connectivity changes in schizophrenia.?Methods? A three-dimensional pseudo-continuous arterial spin labeling(3D-pcASL)imaging was performed to measure resting-state CBF in 100 schizophrenia patients and 94 healthy comparison subjects.The normalized CBF was used to reduce inter-subject variations.Both group comparisons in the CBF and correlations between CBF alterations and clinical parameters were assessed.CBF connectivity of brain regions with regional CBF differences was also compared between groups.?Results? Compared with healthy controls,schizophrenia patients exhibited increased CBF in the bilateral inferior temporal gyri,thalami and putamen and decreased CBF in the left insula and middle frontal gyrus and the bilateral anterior cingulate cortices and middle occipital gyri.These results remained significant even after gray matter volume correction.In schizophrenia patients,significant correlations were found between CBF and clinical parameters.Importantly,schizophrenia patients exhibited CBF disconnections between the left thalamus and right medial superior frontal gyrus and between the left insula and left postcentral gyrus.?Conclusion?Our findings suggest that schizophrenia patients may exhibit both regional CBF abnormalities and deficits in CBF connectivity,which may underlie clinical symptoms of schizophrenia.Part 2: Performance of diffusion kurtosis imaging in detecting white matter abnormality in schizophrenia ?Purpose?Diffusion kurtosis imaging(DKI)is an extension of traditional diffusion tensor imaging(DTI),exhibiting improved sensitivity and specificity in detecting developmental and pathological changes in neural tissues.In this study,we aimed to evaluate the performance of DKI and DTI in detecting white matter abnormality in schizophrenia.?Methods?DKI and DTI were performed in 94 schizophrenia patients and 91 sexand age-matched healthy controls.White matter integrity was assessed by fractional anisotropy(FA),mean diffusivity(MD),axial diffusivity(AD),radial diffusivity(RD),mean kurtosis(MK),axial kurtosis(AK)and radial kurtosis(RK)of DKI and FA,MD,AD and RD of DTI.Group differences in these parameters were compared using tract-based spatial statistics(TBSS).?Results?The sensitivities in detecting white matter abnormality(abnormal voxels/total voxels of the brain white matter skeleton)in schizophrenia were RD(37%)> MK(34%)> FA(24%)> MD(21%)> AK(20%)> RK(3%)for DKI,and RD(43%)> FA(30%)> MD(21%)for DTI.DKI-derived diffusion parameters(RD,FA and MD)were sensitive to detect abnormality in white matter regions(the corpus callosum and anterior limb of internal capsule)with coherent fiber arrangement;however,the kurtosis parameters(MK and AK)were sensitive to reveal abnormality in white matter regions(the juxtacortical white matter and corona radiata)with complex fiber arrangement.In schizophrenia,the decreased AK suggests axonal damage;however,the increased RD indicates myelin impairment.?Conclusion?These findings suggest that diffusion and kurtosis parameters could provide complementary information and they should be jointly used to reveal pathological changes in schizophrenia.Part 3: Distinct disruptions of resting-state functional brain networks in familial and sporadic schizophrenia ?Purpose?Clinical and brain structural differences have been reported between patients with familial and sporadic schizophrenia;however,little is known about the brain functional differences between the two subtypes of schizophrenia.In this study,we aimed to investigate the patterns of disruptions of resting-state functional brain networks in familial and sporadic schizophrenia.?Methods?Twenty-six patients with familial schizophrenia(PFS),26 patients with sporadic schizophrenia(PSS)and 26 healthy controls(HC)underwent a resting-state functional magnetic resonance imaging(fMRI).The whole-brain functional network was constructed and analyzed using graph theoretical approaches.Topological properties(including global,nodal and edge measures)were compared among the three groups.?Results?We found that PFS,PSS and HC exhibited common small-world architecture of the functional brain networks.However,at a global level,only PFS showed significantly lower normalized clustering coefficient,small-worldness,and local efficiency,indicating a randomization shift of their brain networks.At a regional level,PFS and PSS disrupted different neural circuits,consisting of abnormal nodes(increased or decreased nodal centrality)and edges(decreased functional connectivity strength),which were widely distributed throughout the entire brain.Furthermore,some of these altered network measures were significantly correlated with severity of psychotic symptoms.?Conclusion?These results suggest that familial and sporadic schizophrenia had segregated disruptions in the topological organization of the intrinsic functional brain network,which may be due to different etiological contributions.Part 4: Neural substrates underlying delusions in schizophrenia ?Purpose?Delusions are cardinal positive symptoms in schizophrenia;however,the neural substrates of delusions remain unknown.In the present study,we aimed to investigate the neural correlates of delusions in schizophrenia using multi-modal MRI techniques.?Methods?Diffusion,structural and perfusion MRIs were performed in 19 schizophrenia patients with severe delusions,30 patients without delusions and 30 healthy controls.Fractional anisotropy(FA),gray matter volume(GMV)and cerebral blood flow(CBF)were voxel-wisely compared among the three groups.?Results?Although patients without delusions exhibited decreased FA in white matter regions and decreased GMV in gray matter regions relative to controls,patients with severe delusions demonstrated comparable FA in all of these white matter regions and similar GMV in most of these gray matter regions.Compared with the healthy control group,the two patient subgroups consistently showed reduced GMV in the anterior cingulate cortex and amygdala,reduced CBF in the middle frontal gyrus and insula,and increased CBF in the right precuneus.More importantly,schizophrenia patients with severe delusions had further reduced CBF in the ACC than patients without delusions.?Conclusion?These findings suggest that schizophrenia patients with severe delusions have relatively normal structural integrity.Importantly,the excessively reduced perfusion in the anterior cingulate cortex may be associated with the development of delusions in schizophrenia.Part 5: Cerebral blood flow alterations specific to auditory verbal hallucinations in schizophrenia ?Purpose?Auditory verbal hallucinations(AVH)have been associated with deficits in auditory and speech-related networks.However,the resting-state CBF alterations specific to AVH in schizophrenia remain unknown.In this study,we aimed to explore AVH-related CBF alterations in individuals with schizophrenia.?Methods?35 individuals with schizophrenia with AVH,41 individuals with schizophrenia without AVH and 50 controls underwent arterial spin labeling MRI.The CBF differences were voxel-wise compared across the three groups.?Results?Compared with healthy control group,both schizophrenia groups showed an overlapping reduction of CBF in the bilateral occipital regions,the left lateral prefrontal and insular cortices,and the right anterior cingulate cortex and an overlapping increase of CBF in the bilateral lateral temporal regions and putamen,the left middle cingulate cortex,and the right thalamus,which were defined as common CBF alterations shared by patients with and without AVH.Compared with both patients without AVH and healthy controls,patients with AVH exhibited decreased CBF in the bilateral occipital and left parietal regions and increased CBF in the right superior temporal gyrus and caudate,which were defined as exclusive CBF alterations in patients with AVH.?Conclusion?The AVH-specific CBF increase in the auditory and striatal areas and CBF reduction in the visual and parietal areas suggest that there exists a CBF redistribution associated with AVH.