White matter aberrations and age-related trajectories in patients with schizophrenia and bipolar disorder revealed by diffusion tensor imaging

Abstract

Supported by histological and genetic evidence implicating myelin, neuroinflammation and oligodendrocyte dysfunction in schizophrenia spectrum disorders (SZ), diffusion tensor imaging (DTI) studies have consistently shown white matter (WM) abnormalities when compared to healthy controls (HC). The diagnostic specificity remains unclear, with bipolar disorders (BD) frequently conceptualized as a less severe clinical manifestation along a psychotic spectrum. Further, the age-related dynamics and possible sex differences of WM abnormalities in SZ and BD are currently understudied. Using tract-based spatial statistics (TBSS) we compared DTI-based microstructural indices between SZ (n = 128), BD (n = 61), and HC (n = 293). We tested for age-by-group and sex-by-group interactions, computed effect sizes within different age-bins and within genders. TBSS revealed global reductions in fractional anisotropy (FA) and increases in radial (RD) diffusivity in SZ compared to HC, with strongest effects in the body and splenium of the corpus callosum, and lower FA in SZ compared to BD in right inferior longitudinal fasciculus and right inferior fronto-occipital fasciculus, and no significant differences between BD and HC. The results were not strongly dependent on age or sex. Despite lack of significant group-by-age interactions, a sliding-window approach supported widespread WM involvement in SZ with most profound differences in FA from the late 20 s.

Figure 1

Colored voxels show significantly decreased (blue) and increased (red) DTI-indices in SZ patients relative to HC and BD. Group differences are thresholded at p < 0.05 (two-tailed) after permutation testing using threshold free cluster enhancement (TFCE). Note that the white matter skeleton has been slightly thickened to aid visualisation.

Figure 2

Plots (a–d) Mean skeleton DTI values plotted as a function of age and group (HC = healthy controls, BD = bipolar disorders, SZ = schizophrenia spectrum disorders). Plots (e–h) Violin plot depicting the fitted values for each group. Plots (i–l) Uncertainty estimates of the age within each group when maximum FA, minimum RD, MD and AD are reached from a bootstrap procedure with 10 000 resamples.

Figure 3

Mean of skeleton DTI metrics plotted across quality control subgroup analyses (A) and Cohens d for pairwise comparisons across quality control subgroup analyses. (B) The labels on the x-axes reflect the number of participants in each analysis. The error bars of part A represent the standard error of the mean.

Figure 4

Results from region of interest (ROI) analyses with mean difference and variance from pairwise comparisons plotted for each DTI metric. The error bars represent 95% confidence intervals. List of abbreviations: Genu of corpus callosum (GCC), Body of corpus callosum (BCC), Splenium of corpus callosum (SCC), Anterior thalamic radiation L (ATR L), Anterior thalamic radiation R (ATR R), Corticospinal tract L (CST L), Corticospinal tract R (CST R), Cingulum (cingulate gyrus) L (CGL), Cingulum (cingulate gyrus) R (CG R), Cingulum (hippocampus) L (CGH L), Cingulum (hippocampus) R (CGH R), Forceps major (FMJ), Forceps minor (FMI), Inferior fronto-occipital fasciculus L (IFO L), Inferior fronto-occipital fasciculus R (IFO R), Inferior longitudinal fasciculus L (ILF L), Inferior longitudinal fasciculus R (ILF R), Superior longitudinal fasciculus L (SLF L), Superior longitudinal fasciculus R (SLF R), Uncinate fasciculus L (UNC L), Uncinate fasciculus R (UNC R), Superior longitudinal fasciculus (temporal part) L (Temporal SLF L), Superior longitudinal fasciculus (temporal part) R(Temporal SLF R).