| Objective:Although brain structural abnormalities in patients with schizophrenia,especially brain changes in the early stage and after short-term antipsychotics,have been widely reported.However,the reports of disharmony between gray matter loss and white matter microstructure abnormality,and abnormal changes of brain function and structural abnormalities are still not consistent.It is not clear whether there are different brain structural and functional alterations between chronic never treated and different antipsychotics long-term treated patients,and whether the change trend of the brain network between the long-term antipsychotics treated and never-treated patients with chronic schizophrenia is more consistent with the change pattern of gray matter or white matter.These will provide important information for finding brain target therapy for long-term antipsychotic effects and new drug development.Many studies have confirmed that the pathophysiology of schizophrenia is related to the abnormal changes of immune cells,and the ratio of different kinds of immune cells is related to the symptoms and remission of schizophrenia.However,it is not clear whether the changes of peripheral blood immune cell ratio in patients with schizophrenia tend to be normalized after long-term antipsychotics treatment,and whether there is a correlation between brain network graph theory metrics and peripheral blood immune cell ratio.Therefore,we proposed research contents of three aspects:(1)To explore the different patterns of gray matter alterations among chronic never treated patients with schizophrenia and those stable patients treated with risperidone and clozapine monotherapy,and to verify whether there are characteristic or specific gray matter changes in long-term never-treated chronic schizophrenia and chronic schizophrenia patients treated with different antipsychotics.(2)To further explore whether there are differences in white matter between never-treated patients with chronic schizophrenia,risperidone-treated and clozapine-treated stable patients with chronic schizophrenia and healthy controls,whether there are inconsistent characteristic changes in white matter between patients with chronic schizophrenia treated with risperidone and clozapine,and whether the white matter changes of these differences are correlated with clinical symptoms,illness duration and dosage.These findings will help to determine whether the alteration trend of white matter is consistent with that of gray matter.(3)To explore whether there is a difference in brain network between never-treated chronic schizophrenia patients and stable chronic schizophrenia patients treated with long-term risperidone monotherapy,and to analyze the relationship between network graph theory metrics with significant differences between groups and peripheral blood immune cell ratio,cognitive function and symptoms,and to explore the mechanism of risperidone therapy and immunity from the perspective of brain functional network.(4)To explore the relationship between the changes of gray matter,white matter structure and functional network in never-treated chronic schizophrenia patients and stable chronic schizophrenia patients treated with long-term risperidone monotherapy.Materials and Methods:The first chapter of this study recruited 35 never-treated chronic schizophrenia patients(average illness durations 242.86±148.87 months),20 illness duration-matched risperidone monotherapy for more than 5 years(average illness durations 202.08±99.63 months),20 clozapine monotherapy for more than 5 years(average illness durations 236.75±105.71 months)patients with stable schizophrenia and 55 age-matched healthy controls.All MRI data were collected by 3.0T GE Signa Excite MRI scanner for axial high resolution T1 weighted imaging.On the day of MRI scan,the symptom severity was evaluated by positive and negative symptom scale(PANSS),and the drug dose and illness duration were collected.The T1 images were preprocessed by Free Surfer analysis software,and the average cortical volume,cortical thickness and surface area of 68 regions of interest(ROI)and the average subcortical volumes of 14 ROI were extracted.Analysis of covariance was conducted using a general linear model followed by post hoc pairwise comparisons after controlling for age and sex.Pearson correlation analyses among the gray matter measures and drug dose,PANSS scores,and illness duration were performed in never treated group,risperidone treatment group and clozapine treatment group.The multiple comparisons of each of 68 cortical measurements and 14 subcortical volumes were corrected by a false discovery rate(FDR)criterion,P < 0.05 was considered to be statistically significant.The second chapter of this study recruited 27 never-treated chronic schizophrenia patients(average illness durations 218.30 ±140.26 months),20 illness duration-matched risperidone monotherapy for more than 5 years(average illness durations 202.08±99.63 months),17 clozapine monotherapy for more than 5 years(average illness durations 236.88 ±113.59 months)patients with stable schizophrenia and 24 age-matched healthy controls according to the inclusion and exclusion criteria.All MRI data were collected by 3.0T GE Signa Excite MRI scanner for diffusion tensor imaging(DTI).On the day of MRI scan,the symptom severity was evaluated by PANSS,and the drug dose and illness duration were collected.The DTI images were processed by PANDA software,and the values of anisotropy fraction(FA)and mean diffusivity(MD)were extracted by 20-tract Johns Hopkins University white matter template.Analysis of covariance was conducted using a general linear model followed by post hoc pairwise comparisons after controlling for age and sex.Pearson correlation analyses among the DTI measures of fiber bundles and drug dose,PANSS scores,and illness duration were performed in schizophrenia patient groups.The FA and MD values of 20 fiber bundles were compared between groups using the correction criterion of FDR to make multiple comparison correction,P < 0.05 was considered to be statistically significant.The third chapter of this study recruited 23 never-treated chronic schizophrenia patients(average illness durations 226.00±144.98 months),18 illness duration-matched risperidone monotherapy for more than 5 years(average illness durations 195.33±101.97 months),and 22 age-matched healthy controls according to evaluate the brain functional network by the resting state functional MRI.All MRI data were collected by 3.0T GE Signa Excite MRI scanner for resting state brain function MRI.On the day of MRI scan,the symptom severity was evaluated by PANSS,cognitive ability was assessed with the Brief Assessment of Cognition in Schizophrenia,and the peripheral blood,drug dose and illness duration were collected.The functional MRI image pre-processing is carried out by GRETNA software,and 246 ROI are selected to obtain the measures of network metric based on graph theory analysis.Peripheral blood immune cell ratio analysis uses specific differential methylation regions as immune cell recognition markers to calculate the composition of cell types in peripheral blood samples,including monocytes,CD8+T cells,CD4+T cells,NK cells,B cells,neutrophils and eosinophils.For network metrics analyses,analysis of covariance was conducted to compare network metric values for group differences,followed by post hoc pairwise comparisons after controlling for age and sex.The peripheral blood immune cell ratio was compared between groups by t-test(normal distribution)or rank sum test(non-normal distribution).Partial correlation analyses among the network metrics of significant group differences and peripheral blood immune cell ratio,PANSS scores,cognition functional scores,drug dose,and illness duration were performed by controlling for the differences of the covariates of age and sex.The measures of 246 brain regions were compared between groups using the correction criterion of FDR to make multiple comparison correction,P < 0.05 was considered to be statistically significant.Finally,the gray matter,white matter and brain network measures of the different brain regions between the never-treated patient group and the risperidone-treated patient group in the three chapters of this study were performed by correlation analyses to explore their change trend.Results:In the first chapter of this study,the alterations of cerebral gray matter in patients with stable chronic schizophrenia treated with different antipsychotics in MRI study showed that relative to the healthy control group,both risperidone-treated,clozapine-treated and never-treated chronic schizophrenia patients showed reduced gray matter(GM)mainly involving the left banks superior temporal sulcus,left fusiform,left medial orbitofrontal,bilateral rostral anterior cingulate gyrus,and bilateral rostral middle frontal cortex and increased GM in the left cuneus.Compared with the never-treated patient group,both treated chronic patient groups showed reductions mainly in bilateral prefrontal,temporal and left inferior parietal cortex.The clozapine-treated patient group showed more decreased GM than the risperidone-treated patient group in bilateral prefrontal and the left cuneus cortex,but less decreased GM in the left temporal cortex.The reduction of gray matter was negatively correlated with dosage,illness duration and severity of symptoms in the risperidone-treated patient group and clozapine-treated patient group.In the second chapter of this study,the alterations of cerebral white matter in patients with stable chronic schizophrenia treated with different antipsychotics in MRI study showed that relative to the healthy control group,both risperidone-treated,clozapine-treated and never-treated chronic schizophrenia patient groups showed reduced FA values.Relative to the healthy control group,the MD values of the other19 fasciculus except the left arcuate fasciculus increased significantly in the never-treated patient group and clozapine treatment group,but there was no significant difference between the healthy control group and risperidone-treated patient group.Compared with the never-treated patient group,the FA values of the other 19 fasciculus except the left arcuate fasciculus were significantly increased in the risperidone-treated patient group,and the MD values of bilateral corticospinal tract,bilateral cingulum-hippocampus pathway,bilateral inferior fronto-occipital fasciculus,left anterior thalamic radiation,left cingulum-cingulate pathway,left inferior longitudinal fasciculus,left superior longitudinal fasciculus,right uncinate fasciculus,the splenium and the genu of the corpus callosum were significantly decreased in the risperidone-treated patient group.There was no significant difference in FA and MD values between the never-treated patient group and clozapine-treated patient group.Compared with the clozapine-treated patient group,the risperidone-treated patient group showed FA values significantly increased involving bilateral anterior thalamic radiation,bilateral superior longitudinal fasciculus,bilateral inferior fronto-occipital fasciculus,left corticospinal tract,left uncinate fasciculus,right arcuate fasciculus,right cingulum-hippocampus pathway,the splenium and the genu of the corpus callosum,and the MD values significantly decreased involving bilateral inferior frontal-occipital tract,bilateral uncinate fasciculus,left inferior longitudinal fasciculus and right cingulum-hippocampus pathway.The FA value of white matter microstructure was negatively correlated with the severity of symptoms in the patients with chronic schizophrenia,while the MD value was positively correlated with the severity of symptoms.In the third chapter of this study,the correlation study between brain function alterations and peripheral blood immune cell ratio in patients with stable chronic schizophrenia treated with long-term risperidone found that both risperidone-treated and never-treated chronic schizophrenia patient groups had significantly decreased nodal centrality than the healthy control group mainly in local efficiency,nodal centrality of left superior and inferior temporal gyrus,and bilateral cingulate gyrus,and significantly increased nodal centrality in the left middle frontal gyrusand bilateral thalamus.Compared with the never-treated patient group,the risperidone-treated patient group had significantly increased nodal centrality in the bilateral paracentral lobule,right parahippocampal gyrus,and right middle temporal gyrus,and significantly decreased nodal centrality in the left middle frontal gyrus,left orbital gyrus,right inferior temporal gyrus,bilateral superior parietal lobule,bilateral precuneus,left ventral caudate,and left rostral temporal thalamus.Compared with the healthy control group,the ratio of CD4+T cells and NK cells in peripheral blood was lower in the risperidone-treated patient group.The nodal centrality of bilateral thalamus-dominated subregions are related to the ratio of CD4+T cells and NK cells in peripheral blood,cognitive function and clinical symptoms.Based on the correlation analysis of gray matter,white matter and brain network changes between the never-treated group and risperidone-treated group in three chapters of this study,we found that there was a synergistic relationship between the abnormal changes of functional connection and the gray matter and integrity of white matter in long-term never-treated patients with schizophrenia.There was a correlation between the changes of gray matter and white matter in patients with chronic schizophrenia treated with risperidone,while the abnormal changes between the functional network and the gray matter,the functional network and integrity of white matter are relatively independent.Conclusion:Both long-term treated and never-treated chronic schizophrenia patients showed cortical gray matter reductions,white matter microstructure defects and abnormal changes of brain network.The patients who received long-term antipsychotic treatment showed more severe gray matter loss and less defects to the white matter microstructure than those without antipsychotic treatment,suggesting that the change of white matter was not consistent with that of gray matter in patients with long-term antipsychotic trearment.These findings indirectly supported the hypothesis of incoordination between gray matter and white matter in schizophrenia.Patients with long-term clozapine monotherapy displayed more severe and extensive GM loss and white matter microstructure defects than patients with risperidone monotherapy,suggesting that different antipsychotics had different effects on gray matter and white matter.These findings provide new insights into the long-term antipsychotics treatment of chronic schizophrenia and the different brain structural alterations after different antipsychotics,and may provide evidence for the development of new medications or potential treatment targets for long-term treatment in schizophrenia patients.There were differences in brain network alterations involving prefrontal lobe,temporal lobe,superior parietal lobule and thalamus between never-treated and long-term risperidone-treated patients with chronic schizophrenia,which could still indicate that long-term risperidone therapy has effect on the brain network of patients with schizophrenia.The brain network alterations of subregions in thalamus are related to the ratio of immune cells in peripheral blood,cognitive function and clinical symptoms,which provide an objective basis for the mechanism of antipsychotic medications and immunological markers in patients with schizophrenia.To sum up,the different changes of gray matter,white matter and functional network in never-treated and risperidone-treated schizophrenic patients suggest that long-term antipsychotic treatment will affect the change trend of the gray matter,white matter and functional network.Therefore,these findings show that the effect of antipsychotics on the brain changes of schizophrenia requires a comprehensive analysis from multiple levels and perspectives to draw conclusions. |
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