Background
Impairments in structural and functional connections are demonstrated in schizophrenia. Certain disconnectional patterns may be biomarkers of elevated risk for schizophrenia. Convergent examination of multiple diffusion parameters and cognitive performance better illustrates pathophysiological significance of such disconnectional patterns.
Methods
Diffusion Tensor Imaging data on 39 early-course schizophrenia subjects, 21 adolescent/young adult first-degree relatives (FDR) of schizophrenia subjects and 29 healthy controls (HC) were examined for threshold-free clusters of fractional anisotropy (FA) and radial diffusivity (RD) differences correcting for multiple comparisons. Regression models examined the variance contributed by anisotropy differences, age and sex. Group-wise differences on sustained attention, verbal memory and executive functions were examined and correlated with diffusivity measures controlling for age and sex.
Results
Schizophrenia subjects showed significantly decreased FA and increased RD in the forceps minor and superior longitudinal fasciculus (SLF) compared to HC. FDR showed decreased forceps minor FA compared to HC, and decreased SLF RD compared to HC and schizophrenia subjects. Quantitative RD differences were 2–3 fold higher compared to FA. Besides, forceps minor RD was inversely correlated with sustained attention in schizophrenia.
Conclusions
Schizophrenia and FDR subjects show different patterns of white matter diffusivity compared to HC. While forceps minor changes may be a disease marker, SLF changes may be risk markers. In addition, RD may be a more robust risk marker than FA.
Schizophrenia is proposed as a ‘disconnection syndrome’ (Friston and Frith, 1995). Systematic mapping of the ‘disconnection’ could elucidate pathophysiology, risk for psychoses and endophenotypes. Diffusion tensor imaging (DTI) is a promising non-invasive approach to characterize anisotropy of water diffusion reflecting tissue microstructure. DTI relies on the principle that water tends to diffuse more freely along the longitudinal axis (λ1) than along the transverse axes (λ2 and λ3) of axons. Fractional anisotropy (FA; relative changes in diffusion along the λ1 compared to λ2 and λ3) and radial diffusivity (RD; mean diffusion perpendicular to the axonal orientation) are frequently used to characterize altered anisotropy ( Beaulieu, 2002), myelination ( Kubicki et al., 2005 and Klawiter et al., 2011) and tract coherence ( Kubicki et al., 2005). Altered FA alone does not clearly depict changes in white matter microarchitecture. Simultaneously examining multiple diffusivity measures more clearly suggest white matter pathology ( Hasan, 2006).
Functional and DTI studies suggest ‘disconnected’ networks among schizophrenia subjects and first-degree relatives of schizophrenia subjects (FDR) who have about 10% risk for schizophrenia (Gottesman, 1991) compared to healthy controls (HC). Increased prefrontal and thalamic activations during episodic memory processing among schizophrenia subjects and FDR compared to HC suggest an impaired fronto-temporal and fronto-thalamic connectivity (Stolz et al., 2012). Resting fMRI studies report altered functional connectivity among schizophrenia subjects and FDR (Whitfield-Gabrieli and Ford, 2012). DTI studies report altered anisotropy in the association (superior longitudinal fasciculus (SLF), uncinate fasciculus) (Friedman et al., 2008), commissural (corpus callosum, forceps minor) (Friedman et al., 2008) and projection (internal capsule and cingulum) (Ellison-Wright and Bullmore, 2009) fibers in schizophrenia compared to controls. A combined structural and functional connectivity study showed lower coherence between the two although there was globally decreased anatomical connectivity (Skudlarski et al., 2010). The nature of diffusivity differences suggests that schizophrenia subjects in general show decreased FA (Bora et al., 2011 and Fitzsimmons et al., 2013) and increased mean diffusivity (Fitzsimmons et al., 2013) that may be contributed by increased RD but not axial diffusivity (Seal et al., 2008 and Scheel et al., 2013). Anisotropy differences among FDR were intermediate between schizophrenia and HC (Skudlarski et al., 2013). Decreased FA in the SLF among ultra-high risk (UHR) subjects at baseline (Karlsgodt et al., 2009) and in those who later developed psychosis (Bloemen et al., 2010) suggest that reduced anisotropy in the SLF may be a biomarker of risk for psychosis. Another DTI study on UHR subjects reported decreased FA and increased RD among UHR subjects compared to HC in the SLF along with other regions; progressive reduction in FA in the frontal white matter was noted among UHR subjects who later developed psychosis compared to those who did not suggesting that the frontal white matter may also be a risk biomarker (Carletti et al., 2012). It is unclear whether the nature of changes in diffusivity patterns or variations in specific tracts among the diagnostic groups contributes to the heterogeneity of the disorder.
We comprehensively examined multiple diffusivity measures among early-course schizophrenia subjects, FDR and HC. We hypothesized that the: (a) fronto-temporal, fronto-parietal and fronto-thalamic tracts would show reduced FA and increased RD within the same regions among schizophrenia subjects compared to HC, (b) FA and RD in the above tracts among FDR subjects would be intermediate between that of schizophrenia and HC subjects, and (c) diffusivity differences in these tracts would correlate with cognitive performance.
