Changes in white matter microstructure during adolescence

Abstract

Postmortem histological studies have demonstrated that myelination in human brain white matter (WM) continues throughout adolescence and well into adulthood. We used in vivo diffusion-weighted magnetic resonance imaging to test for age-related WM changes in 42 adolescents and 20 young adults. Tract-Based Spatial Statistics (TBSS) analysis of the adolescent data identified widespread age-related increases in fractional anisotropy (FA) that were most significant in clusters including the body of the corpus callosum and right superior corona radiata. These changes were driven by changes in perpendicular, rather than parallel, diffusivity. These WM clusters were used as seeds for probabilistic tractography, allowing us to identify the regions as belonging to callosal, corticospinal, and prefrontal tracts. We also performed voxel-based morphometry-style analysis of conventional T1-weighted images to test for age-related changes in grey matter (GM). We identified a cluster including right middle frontal and precentral gyri that showed an age-related decrease in GM density through adolescence and connected with the tracts showing age-related WM FA increases. The GM density decrease was highly significantly correlated with the WM FA increase in the connected cluster. Age-related changes in FA were much less prominent in the young adult group, but we did find a significant age-related increase in FA in the right superior longitudinal fascicle, suggesting that structural development of this pathway continues into adulthood. Our results suggest that significant microstructural changes in WM continue throughout adolescence and are associated with corresponding age-related changes in cortical GM regions.

Introduction

The notion that myelination in brain white matter is not complete by childhood, but continues throughout adolescence and adulthood, has been demonstrated by both conventional structural magnetic resonance imaging (MRI) studies (Courchesne et al., 2000, Paus et al., 1999, Pfefferbaum et al., 1994) and postmortem histological analysis (Benes et al., 1994). In recent years, diffusion tensor magnetic resonance imaging (DTI) has been applied to address this issue, by providing sensitive measures of the changes in the microstructure of white matter (WM) in the brain that occur over childhood.

DTI is sensitive to the self-diffusion of water molecules. By fitting a model (such as the diffusion tensor model) to the diffusion measurements at each voxel, it is possible to estimate useful parameters such as the fractional anisotropy (FA) and the three principal diffusivities of the diffusion tensor (eigenvalues: λ₁, λ₂ and λ₃) (Basser, 1995). FA is a measure of the degree of diffusion directionality and ranges from 0 (isotropic diffusion) to 1 (anisotropic diffusion). Increasing FA values over development can indicate an increased compactness or density of the fibre bundles or an increased myelination (Beaulieu, 2002), although interpretation of changes in diffusion parameters is not always straightforward, and other factors such as tract geometry will influence FA. The eigenvalues of the diffusion tensor, parallel (λ₁) or perpendicular (λ₂ and λ₃) to white matter tracts, are also important indices useful for a better characterization of the changes in tissue microenvironment (Cader et al., 2007, Oh et al., 2004, Schonberg et al., 2006).

Volumetric MRI studies have established that there are gross morphological changes in both grey and white matter structure during childhood (Giedd et al., 1999, Reiss et al., 1996) and adolescence (Giedd et al., 1999), although specific findings are inconsistent. DTI studies in childhood have suggested that changes in white matter microstructure occur with development (Barnea-Goraly et al., 2005, Schmithorst et al., 2005, Snook et al., 2005), but there is not yet a consensus regarding the distribution and extent of these changes. More limited DTI data are available regarding age-related changes in brain white matter during adolescence and, again, specific findings are mixed. Positive correlations between age and FA have been reported in groups which extend from childhood to adolescence in the internal capsule, pyramidal tracts, left arcuate fascicle and right inferior longitudinal fascicle (Schmithorst et al., 2002), and also in the ventral visual pathways, basal ganglia, thalamic pathways and corpus callosum (Barnea-Goraly et al., 2005). Investigation of the time course of these changes suggests that in general FA increases are steepest before the age of 10 and begin to plateau in later childhood and adolescence (Ben Bashat et al., 2005). Certain structures, however, such as the centrum semiovale and splenium of the corpus callosum show strongest FA changes in adolescence (Ben Bashat et al., 2005).

Although numerous studies have reported decline in white matter FA with ageing beyond the age of 50 (Abe et al., 2002, Bhagat and Beaulieu, 2004, Moseley, 2002, Nusbaum et al., 2001, Pfefferbaum et al., 2000, Salat et al., 2005), few studies have investigated age-related white matter changes in younger adults. Age-related changes in young adulthood are much less pronounced than those observed in children and elderly adults. One study found a global increase in mean FA based on histogram analyses of white matter in subjects aged 20 to 40 (Yoshiura et al., 2005), while a localized increase in FA in the right centrum semiovale has been reported for subjects between the ages of 21 and 27 (Snook et al., 2005). Increasing FA in the right centrum semiovale was associated with a decline in perpendicular diffusivities, rather than an increase in the parallel diffusivity (Snook et al., 2005), consistent with the hypothesis that increasing fibre compactness and/or myelination drives the FA increase.

In summary, although age-related changes in white matter microstructure have been much studied in early childhood and late adulthood, changes occurring in adolescence and early adulthood are less well characterized. In the present study, we sought to define age-related structural white matter changes in adolescents (13.5–21 years) and young adults (23–42 years) using a novel DTI approach to test for voxelwise correlations between diffusion parameters and age within each group.