White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms

Abstract

Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents.

Figure 1

(a) Top, sagittal and axial views: T-maps of comparisons between subthreshold bipolar (SBP) adolescents and controls superimposed on the average T1-weighted magnetic resonance imaging (MRI) of all IMAGEN database participants. Blue colour indicates white-matter tracts where fractional anisotropy (FA) is lower; red indicates tracts where radial diffusivity (RD) is higher (P<0.05 family-wise error corrected) in SBP adolescents; green indicates regions with lower gray-matter volume in SBP adolescents (P<0.001, uncorrected); white indicates white-matter skeleton. FA and RD images are displayed using the ‘tbss_fill' script, which allows better visualization of the regions with significant between-group differences. (b) Three-dimensional representation using the Anatomist software (http://brainvisa.info); statistical maps are projected onto a single IMAGEN participant brain mesh. The same color code as above is in use.

Figure 2

Plots of mean fractional anisotropy (FA) (top) and mean radial diffusivity (RD) (bottom) along the posterior to anterior y axis (mm) of the white-matter skeleton. Red dots indicate values in subthreshold bipolar adolescents; blue dots indicate values in the controls; green bars indicate P-values; and green horizontal line the P<0.05 statistical threshold. Boxes indicate zoomed plots between slices 56 and 72.