Diffusion tensor imaging of normal white matter maturation from late childhood to young adulthood: Voxel-wise evaluation of mean diffusivity, fractional anisotropy, radial and axial diffusivities, and correlation with reading development

Abstract

Using diffusion tensor MR imaging (DTI) and advanced voxel-wise analysis tools, we study diffusivity and anisotropy changes of white matter from late childhood to young adulthood, and correlate quantitative diffusion indices with Chinese and English reading performance scores. Seventy-five normal healthy school going ethnic Chinese students and young adults of three age groups were recruited (group 1, n = 24, mean ± SD = 7.4 ± 0.3 years; group 2, n = 27, mean ± SD = 10.3 ± 0.5 years; group 3, n = 24, mean ± SD = 22.8 ± 2.3 years). DTI was performed with 3 mm isotropic resolution to cover the entire brain. Voxel-wise analysis was performed using Tract-Based Spatial Statistics (TBSS) to localize regions of white matter showing significant changes of fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities between groups. We found increased FA and decreased MD with increasing age in regions of cerebellar white matter, right temporal white matter, and a large portion of the superior frontal and parietal white matter driven by both the reduction of radial diffusivity and axial diffusivity with the former to a greater extent. Changes were continual from late childhood to young adulthood. Findings were confirmed by region-of-interest analysis in specific white matter tracts. After controlling for the effect of age, significant correlation was found between diffusion indices of the anterior limb of the left internal capsule and Chinese reading score (p = 0.05), and of the corona radiata and English reading score (p = 0.026 and p = 0.029 for left and right, respectively).These DTI indices likely reflect the multiple biological processes that occur during brain development which provide the neural substrate for ongoing functional connectivity including for reading development.

Introduction

The human brain continues to undergo complex and prolonged development after birth. The study of this process can help identify key maturational milestones and provide a valuable reference with which various pathologies can be compared to and characterized (Huppi and Dubois, 2006, Toga et al., 2006). Multiple MR imaging techniques have been applied to evaluate noninvasively the various aspects of normal brain development. Volumetric studies have demonstrated that gray matter volume increases dramatically until late childhood (6–9 years) and subsequently declines gradually, while white matter volume increases dramatically up to adolescence (12–15 years) and continues to increase at a slower rate until as late as the 4th decade of life (Courchesne et al., 2000). It is also known that brain maturation follows a spatially and temporally ordered pattern; with cortical maturation generally following a posterior to anterior gradient (Gogtay et al., 2004, Sowell et al., 2002, Toga et al., 2006), and white matter tract myelination also following distinct temporal patterns (Barkovich et al., 1988, Kinney et al., 1988).

Diffusion tensor MR imaging (DTI) can estimate water diffusivities in tissues along the three orthogonal principle diffusion directions (Basser et al., 1994). It is unique in its sensitivity to alterations of tissue microstructure and the ability to illustrate neural pathways (Wakana et al., 2004). In structured tissue such as white matter, water diffusion is less restricted along the fiber than perpendicular to it due to barriers such as axon membrane and myelin. The overall diffusivity and the degree of directionality of diffusion in a tissue can be quantified by mean diffusivity (MD) and fractional anisotropy (FA), respectively (Beaulieu, 2002). Due to its superb sensitivities to whiter matter changes, DTI has been used to study brain maturation from infancy to childhood and until adulthood (Ben et al., 2005, Huang et al., 2006, Huppi et al., 1998, Mukherjee et al., 2001, Schneider et al., 2004). It has been found that white matter maturation is manifested as nonlinearly increased FA and decreased mean diffusivity (MD) with the most dramatic changes taking place during the first 2–3 years of life. Several studies have been carried out to investigate brain maturation specifically from late childhood to adolescence and young adulthood (Barnea-Goraly et al., 2005, Bonekamp et al., 2007, Giorgio et al., 2008, Klingberg et al., 1999, Schmithorst et al., 2002, Snook et al., 2005, Snook et al., 2007). This period is critical for emotional and cognitive development and the ongoing maturation of neural pathways is important in the development of functional connectivity. It is generally agreed that white matter maturation during this period is characterized by continual widespread changes of decreased MD and increased FA. Apart from quantification of FA and MD, recent studies have shown that directional diffusivities such as axial diffusivity (presumed to be the diffusivity along the axon) and radial diffusivity (presumed to be the diffusivity perpendicular to the axon) are more specific to underlying biological processes, such as myelin and axonal changes (Song et al., 2002). In general, the relationship between these diffusivities, FA and MD, is such that FA increases when radial diffusivity decreases and/or axial diffusivity increases while MD increases when axial diffusivity and/or radial diffusivity increases, and vice versa.

The previously used conventional method of voxel-wise analysis to evaluate DTI indices, including FA, is limited by the use of registration methods with low dimensional transformations which restricts the accuracy in establishing correspondence of anatomical points between individuals, largely due to the heterogeneous signal intensity of the FA map. Furthermore, the requirement of image smoothing and the arbitrary selections of smoothing kernel and statistical thresholds may lead to different, and even contradictory results (Jones et al., 2005). Tract-Based Spatial Statistics (TBSS) (Smith et al., 2006) is a recent advancement in voxel-wise analysis of DTI data, which can overcome the limitations encountered with conventional methods. This is achieved by using a nonlinear registration method and also, by projecting the center of fiber tracts of individual subjects into a common white matter skeleton, residual misregistration issues can be greatly circumvented. Furthermore, the method does not require image smoothing and uses nonparametric statistical test with a correction of multiple comparisons, instead of assuming unjustified Gaussian distribution of DTI indices as conventional methods do, thereby delivering better localization ability and providing a solid ground for the validity of the results.

The structural changes found by MR imaging during brain development from childhood to young adulthood may provide the neural substrate for the development of functional connectivity, including for higher cognitive functions and reading development. From an on-going study of reading development in Chinese children from late childhood to young adulthood, we evaluate DTI parameters FA, MD, and axial and radial diffusivities by TBSS analysis of three age groups at different stages of reading development, and determine the relationships with reading performance.