Person:

Bouix, Sylvain

Background—Abnormalities within language-related anatomical structures have been associated with clinical symptoms and with language and memory deficits in schizophrenia. Recent studies suggest disruptions in functional connectivity within the Inferior Frontal Gyrus (IFG) network in schizophrenia. However, due to technical challenges, anatomical connectivity abnormalities within this network and their involvement in clinical and cognitive deficits have not been studied. Material and Methods—Diffusion and anatomical scans were obtained from 23 chronic schizophrenia patients and 23 matched controls. The IFG was automatically segmented, and its white matter connections extracted and measured with newly-developed stochastic tractography tools. Correlations between anatomical structures and measures of semantic processing were also performed. Results—White Matter connections between the IFG and posterior brain regions followed two distinct pathways: dorsal and ventral. Both demonstrated left lateralization, but ventral pathway abnormalities were only found in schizophrenia. IFG volumes also showed left lateralization andabnormalities in schizophrenia. Further, despite similar laterality and abnormality patterns, IFG volumes and white matter connectivity were not correlated with each other in either group. Interestingly, measures of semantic processing correlated with white matter connectivity in schizophrenia and with gray matter volumes in controls. Finally, hallucinations were best predicted by both gray matter and white matter measures together. Conclusions—Our results suggest abnormalities within the ventral IFG network in schizophrenia, with white matter abnormalities better predicting semantic deficits. The lack of a statistical relationship between coexisting gray and white matter deficits might suggest their different origin and the necessity for a multimodal approach in future schizophrenia studies.

Background: Overall neocortical gray matter (NCGM) volume has not been studied in first-episode schizophrenia (FESZ) at first hospitalization or longitudinally to evaluate progression, nor has it been compared with first-episode affective psychosis (FEAFF). Methods: Expectation-maximization/atlas-based magnetic resonance imaging (MRI) tissue segmentation into gray matter, white matter (WM), or cerebrospinal fluid (CSF) at first hospitalization of 29 FESZ and 34 FEAFF, plus 36 matched healthy control subjects (HC), and, longitudinally ∼1.5 years later, of 17 FESZ, 21 FEAFF, and 26 HC was done. Manual editing separated NCGM and its lobar parcellation, cerebral WM (CWM), lateral ventricles (LV), and sulcal CSF (SCSF). Results: At first hospitalization, FESZ and FEAFF showed smaller NCGM volumes and larger SCSF and LV than HC. Longitudinally, FESZ showed NCGM volume reduction (−1.7%), localized to frontal (−2.4%) and temporal (−2.6%) regions, and enlargement of SCSF (7.2%) and LV (10.4%). Poorer outcome was associated with these LV and NCGM changes. FEAFF showed longitudinal NCGM volume increases (3.6%) associated with lithium or valproate administration but without clinical correlations and regional localization. Conclusions: Longitudinal NCGM volume reduction and CSF component enlargement in FESZ are compatible with post-onset progression. Longitudinal NCGM volume increase in FEAFF may reflect neurotrophic effects of mood stabilizers.

We introduce a mathematical framework for computing geometrical properties of white matter fibres directly from diffusion tensor fields. The key idea is to isolate the portion of the gradient of the tensor field corresponding to local variation in tensor orientation, and to project it onto a coordinate frame of tensor eigenvectors. The resulting eigenframe-centered representation then makes it possible to define scalar indices (or measures) that describe the local white matter geometry directly from the diffusion tensor field and its gradient, without requiring prior tractography. We derive new scalar indices of (1) fibre dispersion and (2) fibre curving, and we demonstrate them on synthetic and in vivo data. Finally, we illustrate their applicability to a group study on schizophrenia.

Two of the most frequently investigated regions in diffusion tensor imaging studies in chronic schizophrenia are the uncinate fasciculus (UF) and cingulum bundle (CB). The purpose of the present study was to determine whether UF and CB white matter integrity were altered at the early stage of illness and specific to schizophrenia. Fifteen schizophrenia subjects and 15 affective psychosis within 4 years of first hospitalization (12 patients with schizophrenia and 12 patients with affective psychosis during their first hospitalization), and 15 psychiatrically healthy controls underwent line-scan diffusion tensor imaging. Fractional anisotropy (FA) and mean diffusivity (D(m)) were used to quantify water diffusion, and cross-sectional area was defined with a directional threshold method. Bilaterally reduced FA, but not D(m), was present in the UF of schizophrenia compared with healthy controls. Affective psychosis was intermediate between schizophrenia subjects and healthy controls, but not significantly different from either. For CB, there was no significant group difference for FA or D(m). These findings suggest that UF, but not CB, white matter integrity is altered at the early stage of illness in schizophrenia although it may not be specific to schizophrenia. The CB abnormalities reported in chronic schizophrenia may develop during the later course of the disease.

Background: Superior temporal gyrus (STG) volume reduction is one of the most consistent findings in schizophrenia. The goal of this study was to conduct the first diffusion tensor imaging (DTI) study to investigate altered structural integrity in STG gray and white matter in patients with chronic schizophrenia compared with healthy controls. Methods: Magnetic resonance imaging (MRI) and DTI were acquired in 21 male patients with schizophrenia and 22 age-, handedness-, and parental social economic status-matched male comparison subjects. After manual segmentation of gray and white matter, mean diffusivity and fractional anisotropy were measured within STG. Correlational analyses were also conducted to test possible associations between DTI and clinical measures, including positive and negative symptoms of schizophrenia. Results: Compared with controls, patients demonstrated reduced volume, bilaterally, in STG gray matter but not in white matter. For DTI measures, patients showed increased mean diffusivity, bilaterally, in STG gray matter, and in left-sided STG white matter. In addition, mean diffusivity in left-sided STG white matter showed statistically significant correlations with auditory hallucinations and attentional impairments in patients. Conclusions: These findings suggest a disruption of tissue integrity in STG gray and white matter in schizophrenia. In addition, increased water diffusivity in left-side STG, which was associated with auditory hallucinations and attentional impairments, suggests the possibility of a disconnection among auditory/language processing regions in schizophrenia.

Individuals with 22q11.2 deletion syndrome (22q11.2DS) evince a 30% incidence of schizophrenia. We compared the white matter (WM) of 22q11.2DS patients without schizophrenia to a group matched healthy controls using Tract-Based-Spatial-Statistics (TBSS). We found localized reduction of Fractional Anisotropy (FA) and Axial Diffusivity (AD; measure of axonal integrity) in WM underlying the left parietal lobe. No changes in Radial Diffusivity (RD; measure of myelin integrity) were observed. Of note, studies in chronic schizophrenia patients report reduced FA, no changes in AD, and increases in RD in WM. Our findings suggest different WM microstructure in 22q11.2DS than in patients with schizophrenia.

A progressive post-onset decrease in gray matter volume 1.5 years after first hospitalization in schizophrenia has been shown in superior temporal gyrus (STG). However, it is still controversial whether progressive volume reduction occurs in chronic schizophrenia in the STG and amygdala– hippocampal complex (AHC), structures found to be abnormal in chronic schizophrenia. These structures were measured at two time points in 16 chronic schizophrenia patients and 20 normal comparison subjects using manual tracing with high spatial resolution magnetic resonance imaging (MRI).Average interscan interval was 3.1 years for schizophrenia patients and 1.4 years for healthy comparison subjects. Cross-sectional comparisons showed smaller relative volumes in schizophrenia compared with controls in posterior STG and AHC. An ANCOVA with interscan interval as a covariate showed there was no statistically significant progression of volume reduction in either the STG or AHC in the schizophrenia group compared with normal subjects. In the schizophrenia group, volume change in the left anterior AHC significantly correlated with PANSS negative symptoms. These data, and separately reported first episode data from our laboratory, suggest marked progression at the initial stage of schizophrenia, but less in chronic schizophrenia.

Objectives—The interhemispheric auditory pathway has been shown to play a crucial role in the processing of acoustic stimuli, and alterations of structural and functional connectivity between bilateral auditory areas are likely relevant to the pathogenesis of auditory verbal hallucinations (AVHs). The aim of this study was to examine this pathway in patients with chronic schizophrenia regarding their lifetime history of AVHs. Methods—DTI scans were acquired from 33 healthy controls (HC), 24 schizophrenia patients with a history of AVHs (LT-AVH) and 9 schizophrenia patients without any lifetime hallucinations (N-LT-AVH). The interhemispheric auditory fibre bundles were extracted using streamline tractography. Subsequently, diffusivity indices, namely Fractional Anisotropy (FA), Trace, Mode, Axial and Radial Diffusivity, were calculated.Results—FA was decreased over the entire pathway in LT-AVH compared with N-LT-AVH. Moreover, LT-AVH displayed decreased FA and Mode as well as increased Radial Diffusivity in the midsagittal section of the fibre tract. Conclusions—These findings indicate complex microstructural changes in the interhemispheric auditory pathway of schizophrenia patients with a history of AVHs. Alterations appear to be absent in patients who have never hallucinated.

CNTNAP2 is a gene on chromosome 7 that has shown associations with autism andschizophrenia, and there is evidence that it plays an important role for neuronal synchronization and brain connectivity. In this study, we assessed the relationship between Diffusion Tensor Imaging (DTI), a putative marker of anatomical brain connectivity, and multiple single nucleotide polymorphisms (SNPs) spread out over this large gene. 81 healthy controls and 44 patients with schizophrenia (all Caucasian) underwent DTI and genotyping of 31 SNPs within CNTNAP2. We employed Tract-based Spatial Statistics (TBSS) for inter-subject brain registration and computed average diffusivity values for six major white matter tracts. Analyses of Covariance (ANCOVAs) were computed to test for possible associations with genotypes. The strongest association, which survived rigorous Bonferroni correction, was between rs2710126 genotype and Fractional Anisotropy (FA) in the uncinate fasciculus (p=.00003). This anatomical location is particularly interesting given the enriched fronto-temporal expression of CNTNAP2 in the developing brain. For this SNP, no phenotype association has been reported before. There were several further genotype-DTI associations that were nominally significant but did not survive Bonferroni correction, including an association between axial diffusivity in the dorsal cingulum bundle and a region in intron 13 (represented by rs2710102, rs759178, rs2538991), which has previously been reported to be associated with anterior-posterior functional connectivity. We present new evidence about the effects of CNTNAP2 on brain connectivity, whose disruption has been hypothesized to be central to schizophrenia pathophysiology.