Yuan Xiao

Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change

Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129 non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesis-driven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in early-course patients, predictive of symptoms and diagnostic classification, but less evidence for “hypoconnectivity.” At the whole-brain level, we observed “hyperconnectivity” around areas centered on the default system, with modest overlap with PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n = 25), which also predicted immediate symptom improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may decrease longitudinally, could have prognostic and therapeutic implications.

Resting-state brain function in schizophrenia and psychotic bipolar probands and their first-degree relatives.

BACKGROUND Schizophrenia (SCZ) and psychotic bipolar disorder (PBD) share considerable overlap in clinical features, genetic risk factors and co-occurrence among relatives. The common and unique functional cerebral deficits in these disorders, and in unaffected relatives, remain to be identified. METHOD A total of 59 healthy controls, 37 SCZ and 57 PBD probands and their unaffected first-degree relatives (38 and 28, respectively) were studied using resting-state functional magnetic resonance imaging (rfMRI). Regional cerebral function was evaluated by measuring the amplitude of low-frequency fluctuations (ALFF). Areas with ALFF alterations were used as seeds in whole-brain functional connectivity analysis. We then tested whether abnormalities identified in probands were present in unaffected relatives. RESULTS SCZ and PBD probands both demonstrated regional hypoactivity in the orbital frontal cortex and cingulate gyrus, as well as abnormal connectivity within striatal-thalamo-cortical networks. SCZ probands showed greater and more widely distributed ALFF alterations including the thalamus and bilateral parahippocampal gyri. Increased parahippocampal ALFF was related to positive symptoms and cognitive deficit. PBD patients showed uniquely increased functional connectivity between the thalamus and bilateral insula. Only PBD relatives showed abnormal connectivity within striatal-thalamo-cortical networks seen in both proband groups. CONCLUSIONS The present findings reveal a common pattern of deficits in frontostriatal circuitry across SCZ and PBD, and unique regional and functional connectivity abnormalities that distinguish them. The abnormal network connectivity in PBD relatives that was present in both proband groups may reflect genetic susceptibility associated with risk for psychosis, but within-family associations of this measure were not high.

Altered Cortical Thickness Related to Clinical Severity But Not the Untreated Disease Duration in Schizophrenia

Although previous studies have reported deficits in the gray matter volume of schizophrenic patients, it remains unclear whether these deficits occur at the onset of the disease, before treatment, and whether they are progressive over the duration of untreated disease. Furthermore, the gray matter volume represents the combinations of cortical thickness and surface area; these features are believed to be influenced by different genetic factors. However, cortical thickness and surface area in antipsychotic-naive first-episode schizophrenic patients have seldom been investigated. Here, the cortical thicknesses and surface areas of 128 antipsychotic-naive first-episode schizophrenic patients were compared with 128 healthy controls. The patients exhibited significantly lower cortical thickness, primarily in the bilateral prefrontal and parietal cortex, and increased thickness in the bilateral anterior temporal lobes, left medial orbitofrontal cortex, and left cuneus. Furthermore, decreased cortical thickness was related to positive schizophrenia symptoms but not to the severity of negative symptoms and the untreated disease duration. No significant difference of surface area was observed between the 2 groups. Thus, without the confounding factors of medication and illness progression, this study provides further evidence to support anatomical deficits in the prefrontal and parietal cortex early in course of the illness. The increased thicknesses of the bilateral anterior temporal lobes may represent a compensatory factor or may be an early-course neuronal pathology caused by preapoptotic osmotic changes or hypertrophy. Furthermore, these anatomical deficits are crucial to the pathogenesis of positive symptoms and relatively stable instead of progressing during the early stages of the disease.

Two Patterns of White Matter Abnormalities in Medication-Naive Patients With First-Episode Schizophrenia Revealed by Diffusion Tensor Imaging and Cluster Analysis.

IMPORTANCE Accumulating evidence supports the hypothesis that cerebral white matter abnormalities are involved in the pathophysiology of schizophrenia; however, findings from in vivo neuroimaging studies have been inconsistent. Besides confounding factors, including age, illness duration, and medication effects, an additional cause for the inconsistent results may be heterogeneity in the nature of white matter alterations associated with the disorder. OBJECTIVE To investigate whether different patterns of white matter abnormalities exist in a large cohort of medication-naive patients with first-episode schizophrenia and the relationship between such patterns and clinical parameters. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional diffusion tensor imaging study of 113 medication-naive patients with first-episode schizophrenia and 110 demographically matched healthy control individuals. The study was conducted in the mental health center of West China Hospital, Sichuan University, Chengdu, China, from January 2006 to June 2014. MAIN OUTCOMES AND MEASURES The patterns of white matter abnormalities revealed by tract-specific analysis in conjunction with hierarchical clustering. RESULTS With diffusion features extracted from 18 fiber tracts, cluster analysis revealed 2 patterns of abnormalities. One pattern (42.5% of patient sample) showed widespread white matter abnormalities compared with matched healthy control individuals, while another pattern (57.5% of patient sample) only showed circumscribed regional white matter abnormalities, mainly in the left superior longitudinal fasciculus. Patients in these subgroups did not differ in demographic features; however, negative symptoms were more severe in patients with widespread white matter abnormalities. CONCLUSIONS AND RELEVANCE Two distinct patterns of white matter abnormalities exist at the early phase of schizophrenia, with those having global abnormalities experiencing more severe negative symptoms. The finding that distinct subgroups of patients with schizophrenia have different forms of white matter pathology may reflect qualitatively distinct genetic influences or neurodevelopmental alterations and thus represents a promising strategy for resolving neurobiological heterogeneity in the schizophrenia syndrome.

Brain Structural Abnormalities in a Group of Never-Medicated Patients With Long-Term Schizophrenia

OBJECTIVE This study investigated brain morphometry in chronically ill but never-medicated schizophrenia patients and whether the relation of age to morphometric abnormalities differed from that in healthy subjects. METHOD In a cross-sectional design, high-resolution T1-weighted images were acquired from 25 schizophrenia patients with untreated chronic illness lasting 5 to 47 years and 33 matched healthy comparison subjects. Cortical thickness and gray matter volume were compared in the two groups. In regions with significant group differences, nonlinear modeling of age-related effects was used to test for accelerated decline in the patients. RESULTS Schizophrenia patients had less cortical thickness in the bilateral ventromedial prefrontal cortices, left superior temporal gyrus, and right pars triangularis, relative to comparison subjects, and greater cortical thickness in the left superior parietal lobe. The relation of age to cortical thickness indicated faster age-related cortical thinning in the right ventromedial prefrontal cortex, left superior temporal gyrus, and right pars triangularis in patients than in comparison subjects, but slower thinning in the left superior parietal lobe. Gray matter volume was greater in the putamen bilaterally and smaller in the right middle temporal gyrus and right lingual gyrus of the patients, but age-related effects did not differ from those of the comparison subjects. CONCLUSIONS The accelerated age-related decline in prefrontal and temporal cortical thickness in never-medicated schizophrenia patients suggests a neuroprogressive process in some brain regions. Slower age-related cortical thinning of the superior parietal cortex and striatal volumetric abnormalities unrelated to age suggest different pathological processes over time in these regions.

Brain structural plasticity in survivors of a major earthquake.

BACKGROUND Stress responses have been studied extensively in animal models, but effects of major life stress on the human brain remain poorly understood. The aim of this study was to determine whether survivors of a major earthquake, who were presumed to have experienced extreme emotional stress during the disaster, demonstrate differences in brain anatomy relative to individuals who have not experienced such stressors. METHODS Healthy survivors living in an area devastated by a major earthquake and matched healthy controls underwent 3-dimentional high-resolution magnetic resonance imaging (MRI). Survivors were scanned 13-25 days after the earthquake; controls had undergone MRI for other studies not long before the earthquake. We used optimized voxel-based morphometry analysis to identify regional differences of grey matter volume between the survivors and controls. RESULTS We included 44 survivors (17 female, mean age 37 [standard deviation (SD) 10.6] yr) and 38 controls (14 female, mean age 35.3 [SD 11.2] yr) in our analysis. Compared with controls, the survivors showed significantly lower grey matter volume in the bilateral insula, hippocampus, left caudate and putamen, and greater grey matter volume in the bilateral orbitofrontal cortex and the parietal lobe (all p < 0.05, corrected for multiple comparison). LIMITATIONS Differences in the variance of survivor and control data could impact study findings. CONCLUSION Acute anatomic alterations could be observed in earthquake survivors in brain regions where functional alterations after stress have been described. Anatomic changes in the present study were observed earlier than previously reported and were seen in prefrontal-limbic, parietal and striatal brain systems. Together with the results of previous functional imaging studies, our observations suggest a complex pattern of human brain response to major life stress affecting brain systems that modulate and respond to heightened affective arousal.

Similar and Different Gray Matter Deficits in Schizophrenia Patients and Their Unaffected Biological Relatives

Neuroimaging studies have revealed significant reductions in the gray matter (GM) of several brain regions in patients with schizophrenia, a neuropsychiatric disorder with high hereditability. However, it is unclear whether unaffected relatives have GM abnormalities in common with their affected relatives, which may relate to susceptibility to developing schizophrenia. To address this issue, we conducted two separate meta-analyses of voxel-based morphometry to investigate GM abnormalities in schizophrenia patients and their unaffected relatives. One meta-analysis compared a patient group with healthy controls, whereas the other meta-analysis compared the unaffected relatives with healthy controls. Eight studies comprising 495 patients with schizophrenia, 584 unaffected relatives of patients, and 596 healthy controls were systematically included in the present study. Compared to healthy controls, the patient group showed decreased GM in the right cuneus, the right superior frontal gyrus, the right insula and the left claustrum, and increased GM in the bilateral putamen, the right parahippocampal gyrus, the left precentral gyrus, the left inferior temporal gyri, and the right cerebellar tonsil. The comparison between unaffected relatives and healthy controls showed a GM reduction in the left claustrum, the bilateral parahippocampal gyri, the left fusiform gyrus, the right inferior temporal gyrus, and the bilateral medial prefrontal cortices, whereas increased GM was observed in the right hippocampus, the right fusiform gyrus, the right precentral gyrus, and the right precuneus. Thus, our meta-analyses show that the GM changes in schizophrenia patients and their unaffected relatives are largely different, although there is subtle overlap in some regions.

Dose-dependent effects of isoflurane on regional activity and neural network function: A resting-state fMRI study of 14 rhesus monkeys: An observational study

The dose-dependent effect of isoflurane on cerebral regional activity and functional connectivity (FC) in 14 rhesus monkeys was investigated using resting-state functional MRI. Amplitude of low-frequency fluctuations (ALFF) decreased in the cerebellum, visual cortex, and cortico-subcortical network when the isoflurane dose changed from 1.0 to 1.3 MAC. ALFF decreased in the arousal system, cerebellum, sensory, visual areas, cortico-subcortical network and default mode network and increased in the bilateral dorsal prefrontal cortices, frontal eye fields and motor-related areas from 1.0 to 1.6 MAC. FC of the default mode network, frontal-parietal, cortico-subcortical, motor, sensory, auditory and visual areas was reduced when isoflurane increased from 1.0 to 1.3 MAC. FC decreased in more widespread areas, especially in regions of cortico-subcortical networks and limbic systems, when isoflurane further increased from 1.0 to 1.6 MAC. Both dose-dependent decreased and increased ALFF were separately observed, while FC deteriorated as the anesthesia deepened. These results suggest that changes continue to occur past the loss of consciousness, and the dose-dependent effects of isoflurane are different with regard to regional function and neural network integration.

Common pattern of gray-matter abnormalities in drug-naive and medicated first-episode schizophrenia: a multimodal meta-analysis.

Studies of schizophrenia at drug-naive state and on antipsychotic medication have reported a number of regions of gray-matter (GM) abnormalities but the reports have been inconsistent. The aim of this study was to conduct multimodal meta-analysis to compare the cross-sectional voxel-based morphometry studies of brain GM in antipsychotic-naive first-episode schizophrenia (AN-FES) and those with antipsychotic treatment within 1 year (AT-FES) to determine the similarities and differences in these groups. We conducted two separate meta-analyses containing 24 studies with a sample size of 801 patients and 957 healthy controls. A multimodal meta-analysis method was used to compare the findings between AN-FES and AT-FES. Meta-regression analyses were done to determine the influence of different variables including age, duration of illness, and positive and negative symptom scores. Finally, jack-knife analyses were done to test the robustness of the results. AN-FES and AT-FES showed common patterns of GM abnormalities in frontal (gyrus rectus), superior temporal, left hippocampal and insular cortex. GM in the left supramarginal gyrus and left middle temporal gyrus were found to be increased in AN-FES but decreased in AT-FES, whereas left median cingulate/paracingulate gyri and right hippocampus GM was decreased in AN-FES but increased in AT-FES. Findings suggest that both AN-FES and AT-FES share frontal, temporal and insular regions as common anatomical regions to be affected indicating these to be the primary regions of GM abnormalities in both groups.

Gray Matter Abnormalities in Non-comorbid Medication-naive Patients with Major Depressive Disorder or Social Anxiety Disorder

Background An overlap of clinical symptoms between major depressive disorder (MDD) and social anxiety disorder (SAD) suggests that the two disorders exhibit similar brain mechanisms. However, few studies have directly compared the brain structures of the two disorders. The aim of this study was to assess the gray matter volume (GMV) and cortical thickness alterations between non-comorbid medication-naive MDD patients and SAD patients. Methods High-resolution T1-weighted images were acquired from 37 non-comorbid MDD patients, 24 non-comorbid SAD patients and 41 healthy controls (HCs). Voxel-based morphometry analysis of the GMV (corrected with a false discovery rate of p < 0.001) and vertex-based analysis of cortical thickness (corrected with a clusterwise probability of p < 0.001) were performed, and group differences were compared by ANOVA followed by post hoc tests. Outcomes Relative to the HCs, both the MDD patients and SAD patients showed the following results: GMV reductions in the bilateral orbital frontal cortex (OFC), putamen, and thalamus; cortical thickening in the bilateral medial prefrontal cortex, posterior dorsolateral prefrontal cortex, insular cortex, left temporal pole, and right superior parietal cortex; and cortical thinning in the left lateral OFC and bilateral rostral middle frontal cortex. In addition, MDD patients specifically showed a greater thickness in the left fusiform gyrus and right lateral occipital cortex and a thinner thickness in the bilateral lingual and left cuneus. SAD patients specifically showed a thinner cortical thickness in the right precentral cortex. Interpretation Our results indicate that MDD and SAD share common patterns of gray matter abnormalities in the orbitofrontal-striatal-thalamic circuit, salience network and dorsal attention network. These consistent structural differences in the two patient groups may contribute to the broad spectrum of emotional, cognitive and behavioral disturbances observed in MDD patients and SAD patients. In addition, we found disorder-specific involvement of the visual processing regions in MDD and the precentral cortex in SAD. These findings provide new evidence regarding the shared and specific neuropathological mechanisms that underlie MDD and SAD.