Changes in white matter microstructure during adolescence
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.
Section snippets
Data acquisition
We acquired MR data in two groups: a group of forty-two healthy adolescent subjects (22 males, 20 females; age range 13.5–21 years; 40 right-handed, 2 left-handed) and a group of twenty adult subjects (11 males, 9 females; age range 23–42 years; all right-handed). The age chosen to differentiate between adolescence and young adulthood varies by a few years between studies, but is typically between 17 and 22 years; our choice of 21 years is broadly consistent with previous work (Giedd et al.,
Adolescent group: Within-group correlations between age and diffusion measures
To test for global age-related change in diffusion measures, we tested for correlations between age and diffusion measures averaged across the whole white matter skeleton. Within the adolescent group, we found a significant positive correlation between age and mean FA across the skeleton (r = 0.42, p < 0.01) (Fig. 1A). This correlation remained significant if FA across all WM voxels was considered (rather than only those voxels within the skeleton) (r = 0.41, p < 0.01).
Increases in FA with age could be
Discussion
We found widespread age-related increases in whole brain white matter FA in a group of adolescents (13.5–21 years). Stringent testing for local correlations between age and FA revealed the most significant changes to be in the right body of corpus callosum and in the right superior region of corona radiata. In a group of young adults (23–42 years), age-related changes in FA were less pronounced: we did not find evidence for global changes in FA, but a local positive correlation between age and
Acknowledgments
Scanning was funded by separate MRC grants to KW and to PMM and AJ. HJB is supported by the Wellcome Trust and SS by the EPSRC. We are grateful to Saad Jbabdi for help with image analysis and to Matthew Robson and Clare Mackay for support with image acquisition.
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