Diffusion tensor imaging with tract-based spatial statistics reveals local white matter abnormalities in preterm infants
Introduction
Infants born preterm often suffer long-term morbidity that is more severe with prolonged exposure to the extrauterine environment (Bhutta et al., 2002) and more severe in boys than in girls (Marlow et al., 2005); functional outcomes that are matched with poorly defined neuroanatomical changes (Kapellou et al., 2006). At 30 months of age impairment can be identified in half of all infants born at 25 weeks gestational age or less (Wood et al., 2000), and as many as 52% of these children will later require some form of special needs or educational support because of learning difficulties (Rivkin, 2000). Impairments often continue into adolescence, with a high prevalence of behavioral problems reported, including psychiatric and attention deficit disorders (Indredavik et al., 2005).
Motor difficulties are well characterized, with approximately 10% of very low birth weight infants developing cerebral palsy (Hack and Fanaroff, 2000), usually associated with focal abnormalities on ultrasound or MR (magnetic resonance) imaging. However, motor impairments are uncommon compared to cognitive and behavioral problems, for which the neuroimaging correlates are poorly defined. There is evidence that cognitive impairment may be associated with more subtle abnormalities of cerebral white matter, which can appear as diffuse increased high signal on T2-weighted images or increases in the apparent diffusion coefficient on diffusion-weighted imaging (Dyet et al., 2006).
Diffusion tensor imaging (DTI) depends on the Brownian motion of water molecules (Le Bihan et al., 1986), which is restricted within the brain by structural barriers including macromolecules and cell membranes. The preferential direction of water diffusion within cerebral white matter occurs along the axons allowing DTI to identify the location and direction of white matter tracts (Moseley et al., 1990). By calculating the eigenvalues of the diffusion tensor, diffusion parallel and perpendicular to the white matter tracts can be measured, which provide non-subjective measurements that reflect tissue microstructure.
Although regions of interest (ROIs) can be drawn directly onto unregistered diffusion tensor images to measure diffusion parameters in different areas of the brain, the complex global spatiotemporal changes occurring in the developing neonatal brain cannot be fully captured by such analyses. Furthermore, ROI studies are subjective, manually intensive, require a priori definitions of the spatial locations of different brain structures and often have significant intra- and inter-subject variability which does not easily allow for comparison of many brain regions or large subject groups.
Tract-based spatial statistics (TBSS) is an automated observer-independent approach for assessing groupwise microstructural differences in the major white matter pathways of the brain (Smith et al., 2006). The aim of this study was to determine if TBSS could be implemented in the preterm population, and to test the hypothesis that preterm infants have microstructural differences in cerebral white matter compared to term-born control infants in the absence of focal abnormalities such as cystic periventricular leukomalacia (cPVL) or hemorrhagic parenchymal infarction (HPI) on conventional MR imaging.
Section snippets
Materials and methods
Ethical permission for MR imaging was granted by the Hammersmith Hospital Research Ethics Committee. Written parental consent was obtained prior to imaging for each subject.
Results
We found that regions within the centrum semiovale, frontal white matter and the genu of the corpus callosum had a significantly lower FA in preterm infants imaged at term equivalent age compared to term-born controls (voxelwise thresholding uncorrected for multiple comparisons, t > 3, p < 0.05) (Figs. 1a–d). Those infants born at less than or equal to 28 weeks gestational age (n = 11) displayed additional reductions in FA in the posterior aspect of the posterior limb of the internal capsule, the
Discussion
In this study we used DTI and automated tract-based analysis to investigate brain microstructure in preterm infants imaged at term equivalent age. We found that the centrum semiovale, frontal white matter and genu of the corpus callosum had significantly lower FA compared to age- and sex-matched term-born controls. The most immature infants (i.e., those infants born ≤ 28 weeks gestational age) displayed additional and more extensive reductions in FA, suggesting more severe white matter
Acknowledgments
We are grateful to the Department of Health, Medical Research Council (UK), the Academy of Medical Sciences, The Health Foundation and Philips Medical Systems, for research grant support. We thank the staff of the Neonatal Unit, Hammersmith Hospital for their help in this study.
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