Abnormal white matter microstructure in schizophrenia: A voxelwise analysis of axial and radial diffusivity
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).
Section snippets
Participants
DTI data were acquired from fourteen participants with established schizophrenia and fourteen age-matched healthy controls. Groups were matched for age, gender, premorbid IQ and total years of education (see Table 1). All clinical participants were chronic, stable outpatients with a current diagnosis of schizophrenia as determined by the SCID (First et al., 1994). Current symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987). All subjects with
Results
Compared to the healthy control group significantly reduced FA was observed in several major white matter tracts in the schizophrenia group including the external capsule (superior longitudinal fasciculus, uncinate fasciculus, and inferior occipital-frontal fasciculus), internal capsule and thalamic regions (see Fig. 1). Importantly, the large portions of the external capsule were also identified as regions where the schizophrenia group demonstrated higher Radial Diffusivity (λ┴) bilaterally.
Discussion
In this study we clarified the nature of reported diffusivity abnormalities in white matter microstructure in schizophrenia. To the best of our knowledge this is the first published study to concurrently examine axial and radial diffusivity in a voxelwise analysis in schizophrenia. Overall the reported findings of reduced FA in major white matter tracts using TBSS in this sample are broadly consistent with the regions identified in previous DTI studies of schizophrenia (Kanaan et al., 2005,
Role of funding source
The identified funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Marc L Seal, Murat Yücel, Alex Fornito, Stephen J Wood, Ben J Harrison, Mark Walterfang, Gaby S Pell, Christos Pantelis designed the study and wrote the protocol. Murat Yücel supervised data collection. Gaby S Pell designed and validated the DTI acquisition sequence. Marc L Seal, Murat Yücel, and Alex Fornito managed the literature searches and undertook the statistical analysis, and Marc L Seal wrote the first draft of the manuscript. All authors contributed to and have approved the final
Conflict of interest
All authors know of no conflicts of interest pertaining to this manuscript.
Acknowledgement
This research was supported by the National Health & Medical Research Council (NH&MRC) of Australia (Project Grant I.D. 236175 and Program Grant I.D. 350241). Dr Seal is supported by a Ronald Phillip Griffith Fellowship from the Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne. Dr Yücel is supported by a NHMRC Program Grant (I.D. 350241) and the Colonial Foundation. Dr Fornito is supported by a JN Peters Research Fellowship. Dr Wood is supported by a Career
References (21)
- et al.
The influence of sulcal variability on morphometry of the human anterior cingulate and paracingulate cortex
NeuroImage
(2006) - et al.
The effect of filter size on VBM analyses of DT-MRI data
NeuroImage
(2005) - et al.
Diffusion tensor imaging in schizophrenia
Biol. Psychiatry
(2005) - et al.
Tract-specific anisotropy measurements in diffusion tensor imaging
Psychiatry Res.
(2006) - et al.
A review of diffusion tensor imaging studies in schizophrenia
J. Psychiatr. Res.
(2007) - et al.
Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data
NeuroImage
(2006) - et al.
Demyelination increases radial diffusivity in corpus callosum of mouse brain
NeuroImage
(2005) - et al.
Neuropathological, neurogenetic and neuroimaging evidence for white matter pathology in schizophrenia
Neurosci. Biobehav. Rev.
(2006) - et al.
Advances in white matter imaging: a review of in vivo magnetic resonance methodologies and their applicability to the study of development and aging
Neurosci. Biobehav. Rev.
(2006) - et al.
Paracingulate morphologic differences in males with established schizophrenia: a magnetic resonance imaging morphometric study
Biol. Psychiatry
(2002)
Cited by (101)
Enhanced carbonyl stress and disrupted white matter integrity in schizophrenia
2020, Schizophrenia ResearchWhite Matter Microstructural Properties Associated with Impaired Attention in Chronic Schizophrenia: A Multi-Center Study
2020, Psychiatry Research - NeuroimagingA multimodal imaging study of brain structural correlates of schizotypy dimensions using the MSS
2020, Psychiatry Research - Neuroimaging