Abnormal white matter microstructure in schizophrenia: A voxelwise analysis of axial and radial diffusivity

Abstract

Diffusion Tensor Imaging (DTI) investigations in schizophrenia have provided evidence of impairment in white matter as indicated by reduced fractional anisotropy (FA). However, the neuropathological implications of these findings remain unclear. In the current study, we conducted a voxelwise analysis of the constituent parameters of FA, Axial (λ_||) and Radial Diffusivity (λ_┴), in 14 male participants with schizophrenia and 14 age, gender, education, and premorbid intelligence matched healthy controls. Significantly reduced FA and higher Radial Diffusivity were concurrently observed in several major white matter tracts in the schizophrenia group. This finding suggests that the loss of white matter integrity in schizophrenia is the result of demyelination and/or changes to the axonal cytoskeleton rather than gross axonal damage.

Introduction

While neuropathological investigations of white matter in schizophrenia have identified abnormalities at the cellular level, in vivo characterization of such abnormalities has been hampered by a lack of adequate measures of microscopic pathology (Walterfang et al., 2006). In this context, the recent development of Diffusion Tensor Imaging (DTI) has provided a non-invasive means to examine white matter microstructure in vivo by estimating the extent to which the diffusion of water molecules is restricted in neural tissue.

Recent DTI investigations in schizophrenia have demonstrated impaired white matter integrity as indicated by reduced Fractional Anisotropy (FA; for a recent review see Kubicki et al., 2007). However, these findings have been inconsistent and occasionally contradictory, and the underlying cause of abnormal FA remains unclear (Kanaan et al., 2005). Fractional Anisotropy is a composite measure, derived from a combination of estimates of axial diffusivity (λ_||) and radial diffusivity (λ_┴), which are known to index distinct forms of white matter pathology and disease processes (Wozniak and Lim, 2006). Axonal damage such as that following ischemia (Song et al., 2003) leads to a marked decrease in λ_|| and only modest decreases in λ_┴. In contrast, demyelination of axons such as in multiple sclerosis results in an increase in λ_┴ without changing λ_|| (Song et al., 2005). As such, examining these diffusivity measures independently should provide complementary information about white matter pathology.

In this study we concurrently examined axial and radial diffusivity in a group of subjects with established schizophrenia and matched healthy controls using a newly developed method for voxelwise mapping of diffusion changes; Tract Based Spatial Statistics (TBSS, Smith et al., 2006, Smith et al., 2007). This approach enabled us to examine the nature of pathological changes along major white matter tracts across the entire brain while avoiding the confounds associated with traditional voxel-based approaches (Jones et al., 2005).