Developmental stages and sex differences of white matter and behavioral development through adolescence: a longitudinal diffusion tensor imaging (DTI) study

Abstract

White matter (WM) continues to mature through adolescence in parallel with gains in cognitive ability. To date, developmental changes in human WM microstructure have been inferred using analyses of cross-sectional or two time-point follow-up studies, limiting our understanding of individual developmental trajectories. The aims of the present longitudinal study were to characterize the timing of WM growth and investigate how sex and behavior are associated with different developmental trajectories. We utilized diffusion tensor imaging (DTI) in 128 individuals aged 8-28, who received annual scans for up to 5 years and completed motor and cognitive tasks. Flexible nonlinear growth curves indicated a hierarchical pattern of WM development. By late childhood, posterior cortical-subcortical connections were similar to adults. During adolescence, WM microstructure reached adult levels, including frontocortical, frontosubcortical and cerebellar connections. Later to mature in adulthood were major corticolimbic association tracts and connections at terminal gray matter sites in cortical and basal ganglia regions. These patterns may reflect adolescent maturation of frontal connectivity supporting cognitive abilities, particularly the protracted refinement of corticolimbic connectivity underlying cognition-emotion interactions. Sex and behavior also played a large role. Males showed continuous WM growth from childhood through early adulthood, whereas females mainly showed growth during mid-adolescence. Further, earlier WM growth in adolescence was associated with faster and more efficient responding and better inhibitory control whereas later growth in adulthood was associated with poorer performance, suggesting that the timing of WM growth is important for cognitive development.

Keywords: Cingulum; Inhibition; Maturation; Prefrontal; Uncinate fasciculus; Variability.

Figure 1. Stages of significant growth and timing of maturation in white matter development

Figure is divided into three columns corresponding to FA, RD and AD, respectively. Developmental changes in FA were all increases, while those in RD and AD were mostly decreases. Each row is an ROI whose label abbreviation is explained in Table 1; rows are sorted by time of maturation in FA, which is defined as the time that the rate of change was no longer significantly different from the null (p=0.05, bootstrap corrected). Colors represent % change per year (red=increase, blue=decrease).

Figure 2. Sex differences in white matter development

Figure is divided into three columns corresponding to FA, RD and AD, respectively; it is further divided by sex (top=female, bottom=male). Differences were predominantly seen during childhood and late adolescence/early adulthood, representing greater change of FA and RD in males (no significant differences were seen for AD). Each row is an ROI whose label abbreviation is explained in Table 1; ROIs shown in the figure were significant for at least one of the three measures. Colors represent % change per year (red=increase, blue=decrease). Black rectangles indicate stages with significant sex differences.

Figure 3. Associations between VGS latency/variability and WM development

Heatmaps represent the association between the behavioral variables and (A) mean WM levels and (D) rates of change in WM development. These plots are divided into three columns corresponding to FA, RD and AD, respectively; they are further divided by behavioral variable (top=latency, bottom=variability). Each row is an ROI whose label abbreviation is explained in Table 1; included ROIs were significant for at least one of the three measures. RD was the only measure significantly associated with latency, while FA and RD were both related to variability. Colors represent magnitude of brain behavior correlation (red=positive, blue=negative). The scatterplots further illustrate these associations in a single region (cer.c) for the measure RD by showing individual subject brain and behavioral measures within significant stages of association; data points (single scans or scan-to-scan changes) were included if they fell within the stage (in some cases, subjects have multiple points plotted). For each stage, a simple linear fit is shown highlighting the direction of association (B: mean-level RD vs. latency; C: mean-level RD vs. variability; E: rate of change in RD vs. latency; F: rate of change in RD vs. variability). Colors in these plots represent different significant stages of association, with ages identified in the legends.

Figure 4. Associations between inhibitory errors, white matter development and hemispheric differences

Heatmaps represent the association between behavior and (A) mean WM levels and (C) rates of change in WM development. These plots are divided into three columns corresponding to FA, RD and AD, respectively; they are further divided by hemisphere (top=left, bottom=right). Each row is an ROI whose label abbreviation is explained in Table 1; included ROIs were significant for at least one of the three measures. Colors represent magnitude of brain behavior correlation (red=positive, blue=negative). Black rectangles indicate stages with significant hemispheric differences in brain-behavior associations. These differences predominantly reflect significant brain-behavior correlations in the left hemisphere, but not the right. The scatterplots further illustrate these associations in a single region (CIN.H) for the measure FA by showing individual subject brain and behavioral measures within significant stages of association; data points (single scans or scan-to-scan changes) were included if they fell within the stage (in some cases, subjects have multiple points plotted). For each stage, a simple linear fit highlighting the direction of association (B: mean-level FA vs. inhibitory errors; D: rate of change in FA vs. inhibitory errors). Colors in these plots represent different significant stages of association, with ages identified in the legends. Hemispheres are plotted separately (left=circles/solid line, right=triangles/dotted line).