S. E. Chua

A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia.

BACKGROUND Diffusion tensor imaging (DTI) can be used to investigate cerebral structural connectivity in never-medicated individuals with first-episode schizophrenia. METHOD Subjects with first-episode schizophrenia according to DSM-IV-R who had never been exposed to antipsychotic medication (n=25) and healthy controls (n=26) were recruited. Groups were matched for age, gender, best parental socio-economic status and ethnicity. All subjects underwent DTI and structural magnetic resonance imaging (MRI) scans. Voxel-based analysis was performed to investigate brain regions where fractional anisotropy (FA) values differed significantly between groups. A confirmatory region-of-interest (ROI) analysis of FA scores was performed in which regions were placed blind to group membership. RESULTS In patients, FA values significantly lower than those in healthy controls were located in the left fronto-occipital fasciculus, left inferior longitudinal fasciculus, white matter adjacent to right precuneus, splenium of corpus callosum, right posterior limb of internal capsule, white matter adjacent to right substantia nigra, and left cerebral peduncle. ROI analysis of the corpus callosum confirmed that the patient group had significantly lower mean FA values than the controls in the splenium but not in the genu. The intra-class correlation coefficient (ICC) for independent ROI measurements was 0.90 (genu) and 0.90 (splenium). There were no regions where FA values were significantly higher in the patients than in the healthy controls. CONCLUSIONS Widespread structural dysconnectivity, including the subcortical region, is already present in neuroleptic-naive patients in their first episode of illness.

White matter fractional anisotrophy differences and correlates of diagnostic symptoms in autism

BACKGROUND Individuals with autism have impairments in 3 domains: communication, social interaction and repetitive behaviours. Our previous work suggested early structural and connectivity abnormalities in prefrontal-striato-temporal-cerebellar networks but it is not clear how these are linked to diagnostic indices. METHOD Children with autism (IQ > 70) aged 6 to 14 years old and matched typically developing controls were studied using diffusion tensor imaging. Voxel-based methods were used to compare fractional anisotrophy (FA) measures in each group and to correlate FA measures in the autism group with the diagnostic phenotype described by the Autism Diagnostic Interview - Revised (ADI-R) algorithm for ICD-10. RESULTS After controlling for the effects of age and white matter volume, we found that FA in the autism group was significantly lower than controls in bilateral prefrontal and temporal regions, especially in the right ventral temporal lobe adjacent to the fusiform gyrus. FA was greater in autism in the right inferior frontal gyrus and left occipital lobe. We observed a tight correlation between lower FA and higher ADI-R diagnostic algorithm scores across white matter tracts extending from these focal regions of group difference. Communication and social reciprocity impairments correlated with lower FA throughout fronto-striato-temporal pathways. Repetitive behaviours correlated with white matter indices in more posterior brain pathways, including splenium of the corpus callosum and cerebellum. CONCLUSIONS Our data support the position that diagnostic symptoms of autism are associated with a core disruption of white matter development.

Differential effects on white-matter systems in high-functioning autism and Asperger's syndrome

BACKGROUND Whether autism spectrum maps onto a spectrum of brain abnormalities and whether Aspergers syndrome (ASP) is distinct from high-functioning autism (HFA) are debated. White-matter maldevelopment is associated with autism and disconnectivity theories of autism are compelling. However, it is unknown whether children with ASP and HFA have distinct white-matter abnormalities. METHOD Voxel-based morphometry mapped white-matter volumes across the whole brain in 91 children. Thirty-six had autism spectrum disorder. A history of delay in phrase speech defined half with HFA; those without delay formed the ASP group. The rest were typically developing children, balanced for age, IQ, gender, maternal language and ethnicity. White-matter volumes in HFA and ASP were compared and each contrasted with controls. RESULTS White-matter volumes around the basal ganglia were higher in the HFA group than ASP and higher in both autism groups than controls. Compared with controls, children with HFA had less frontal and corpus callosal white matter in the left hemisphere; those with ASP had less frontal and corpus callosal white matter in the right hemisphere with more white matter in the left parietal lobe. CONCLUSIONS HFA involved mainly left hemisphere white-matter systems; ASP affected predominantly right hemisphere white-matter systems. The impact of HFA on basal ganglia white matter was greater than ASP. This implies that aetiological factors and management options for autism spectrum disorders may be distinct. History of language acquisition is a potentially valuable marker to refine our search for causes and treatments in autism spectrum.

The default mode network is disrupted in parkinson's disease with visual hallucinations

Background: Visual hallucinations (VH) are one of the most striking nonmotor symptoms in Parkinsons disease (PD), and predict dementia and mortality. Aberrant default mode network (DMN) is associated with other psychoses. Here, we tested the hypothesis that DMN dysfunction contributes to VH in PD. Methods: Resting state functional data was acquired from individuals with PD with VH (PDVH) and without VH (PDnonVH), matched for levodopa drug equivalent dose, and a healthy control group (HC). Independent component analysis was used to investigate group differences in functional connectivity within the DMN. In addition, we investigated whether the functional changes associated with hallucinations were accompanied by differences in cortical thickness. Results: There were no group differences in cortical thickness but functional coactivation within components of the DMN was significantly lower in both PDVH and PDnonVH groups compared to HC. Functional coactivation within the DMN was found to be greater in PDVH group relative to PDnonVH group. Conclusion: Our study demonstrates, for the first time that, within a functionally abnormal DMN in PD, relatively higher “connectivity” is associated with VH. We postulate that aberrant connectivity in a large scale network affects sensory information processing and perception, and contributes to “positive” symptom generation in PD. Hum Brain Mapp 35:5658–5666, 2014.

Early striatal hypertrophy in first-episode psychosis within 3 weeks of initiating antipsychotic drug treatment

BACKGROUND We and others have reported that patients experiencing their first episode of psychosis already have significant structural brain abnormalities. Antipsychotics seem to reverse subcortical volume deficits after months of treatment. However, the early impact of medication on brain morphology is not known. METHOD Forty-eight individuals in their first episode of psychosis underwent magnetic resonance imaging (MRI) brain scanning. Twenty-six were antipsychotic naive and 22 were newly treated with antipsychotic medication for a median period of 3 weeks. In each group, 80% of subjects received a diagnosis of schizophrenia. The two groups were balanced for age, sex, handedness, ethnicity, height, years of education, paternal socio-economic status (SES) and Positive and Negative Syndrome Scale (PANSS) score. Group differences in whole-brain grey matter were compared voxel by voxel, using Brain Activation and Morphological Mapping (BAMM) software. We also conducted testing of group differences with region-of-interest (ROI) measurements of the caudate nucleus. RESULTS Relative to the untreated group, those receiving antipsychotic medication for 3-4 weeks had significantly greater grey-matter volumes in the bilateral caudate and cingulate gyri, extending to the left medial frontal gyrus. ROI analysis confirmed that, in treated patients, the right and left caudate nuclei were significantly larger by 10% (p<0.039, two-tailed) and 9% (p<0.048, two-tailed) respectively. CONCLUSIONS Early striatal grey-matter enlargement may occur within the first 3-4 weeks of antipsychotic treatment. Possible reasons for putative striatal hypertrophy and its implications are discussed.

Abnormalities in connectivity of white-matter tracts in patients with familial and non-familial schizophrenia

BACKGROUND Abnormalities in the connectivity of white-matter (WM) tracts in schizophrenia are supported by evidence from post-mortem investigations, functional and structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). The aims of this study were to explore the microstructural changes in first-episode schizophrenia in a Han Chinese population and to investigate whether a family history of psychiatric disorder is related to the severity of WM tract integrity abnormalities in these patients. METHOD T1-weighted MR and DT images were collected in 68 patients with first-episode schizophrenia [22 with a positive family history (PFH) and 46 with a negative family history (NFH)] and 100 healthy controls. Voxel-based analysis was performed and WM integrity was quantified by fractional anisotropy (FA). Cluster- and voxel-level analyses were performed by using two-sample t tests between patients and controls and/or using a full factorial model with one factor and three levels among the three sample groups (patients with PFH or NFH, and controls), as appropriate. RESULTS FA deficits were observed in the patient group, especially in the left temporal lobe and right corpus callosum. This effect was more severe in the non-familial schizophrenia than in the familial schizophrenia subgroup. CONCLUSIONS Overall, these findings support the hypothesis that loss of WM integrity may be an important pathophysiological feature of schizophrenia, with particular implications for brain dysmaturation in non-familial and familial schizophrenia.

Brain morphological abnormality in schizophrenia is independent of country of origin

Objective: The disorder schizophrenia has a worldwide prevalence of 1% and is generally associated with lateral cerebral ventricular enlargement. Whether there is a relationship between these two findings is unclear but has aetiological relevance.

Extensive brain structural network abnormality in first-episode treatment-naive patients with schizophrenia: morphometrical and covariation study

BACKGROUND Alterations in gray matter (GM) are commonly observed in schizophrenia. Accumulating studies suggest that the brain changes associated with schizophrenia are distributed rather than focal, involving interconnected networks of areas as opposed to single regions. In the current study we aimed to explore GM volume (GMV) changes in a relatively large sample of treatment-naive first-episode schizophrenia (FES) patients using optimized voxel-based morphometry (VBM) and covariation analysis. METHOD High-resolution T1-weighted images were obtained using 3.0-T magnetic resonance imaging (MRI) from 86 first-episode drug-naive patients with schizophrenia and 86 age- and gender-matched healthy volunteers. Symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS). GMV was assessed using optimized VBM and in 16 regions of interest (ROIs), selected on the basis of a previous meta-analysis. The relationships between GMVs in the ROIs were examined using an analysis of covariance (ANCOVA). RESULTS The VBM analysis revealed that first-episode patients showed reduced GMV in the hippocampus bilaterally. The ROI analysis identified reductions in GMV in the left inferior frontal gyrus, bilateral hippocampus and right thalamus. The ANCOVA revealed different patterns of regional GMV correlations in patients and controls, including of inter- and intra-insula, inter-amygdala and insula-postcentral gyrus connections. CONCLUSIONS Schizophrenia involves regional reductions in GMV and changes in GMV covariance in the insula, amygdala and postcentral gyrus. These findings were evident at the onset of the disorder, before treatment, and therefore cannot be attributable to the effects of chronic illness progression or medication.

Quantitative susceptibility mapping as an indicator of subcortical and limbic iron abnormality in Parkinson's disease with dementia

Late stage Parkinsons disease (PD) patients were commonly observed with other non-motor comorbidities such as dementia and psychosis. While abnormal iron level in the substantia nigra was clinically accepted as a biomarker of PD, it was also suggested that the increased iron deposition could impair other brain regions and induce non-motor symptoms. A new Magnetic Resonance Imaging (MRI) called Quantitative Susceptibility Mapping (QSM) has been found to measure iron concentration in the grey matter reliably. In this study, we investigated iron level of different subcortical and limbic structures of Parkinsons disease (PD) patients with and without dementia by QSM. QSM and volumetric analysis by MRI were performed in 10 PD dementia (PDD) patients (73 ± 6 years), 31 PD patients (63 ± 8 years) and 27 healthy controls (62 ± 7 years). No significant differences were observed in the L-Dopa equivalent dosage for the two PD groups (p = 0.125). Putative iron content was evaluated in different subcortical and limbic structures of the three groups, as well as its relationship with cognitive performance. One-way ANCOVA with FDR adjustment at level of 0.05, adjusted for age and gender, showed significant group differences for left and right hippocampus (p = 0.015 & 0.032, respectively, BH-corrected for multiple ROIs) and right thalamus (p = 0.032, BH-corrected). Post-hoc test with Bonferronis correction suggested higher magnetic susceptibility in PDD patients than healthy controls in the left and right hippocampus (p = 0.001 & 0.047, respectively, Bonferronis corrected), while PD patients had higher magnetic susceptibility than the healthy controls in right hippocampus and right thalamus (p = 0.006 & 0.005, respectively, Bonferronis corrected). PDD patients also had higher susceptibility than the non-demented PD patients in left hippocampus (p = 0.046, Bonferronis corrected). The magnetic susceptibilities of the left and right hippocampus were negatively correlated with the Mini-Mental State Examination score (r = −0.329 & -0.386, respectively; p < 0.05). This study provides support for iron accumulation in limbic structures of PDD and PD patients and its correlation with cognitive performance, however, its putative involvement in development of non-motor cognitive dysfunction in PD pathogenesis remains to be elucidated.

Bilateral recruitment of speech and language areas on a verbal fluency task using FMRI in Schizophrenic subjects

The IXth International Congress on Schizophrenia Research, Colorado Springs, Colorado, USA, 29 March - 2 April 2003. In Schizophrenia Research, 2003, v. 60 n. 1, suppl., p. 215