Microstructural abnormalities of white matter differentiate pediatric and adult onset bipolar disorder

Evidence for white matter abnormalities in bipolar disorder (BD) was first observed in deep white matter hyperintensities in T2-weighted anatomical magnetic resonance images (1, 2). Abnormal expression of genes involved in regulation of oligodendrocytes provides further evidence supporting the possibility of white matter abnormalities in bipolar disorder (3). Diffusion tensor imaging (DTI) is specifically suited to interrogate the integrity of white matter by capitalizing on structural components restricting the diffusion of water (4, 5). Neuronal membrane and myelin sheaths are cellular structures that restrict the diffusion of water. In white matter where neuronal membrane of axons form tubular shapes, water can diffuse down the longitudinal axis of axons more easily than in radial directions of axonal axis, in which direction diffusion is restricted by neuronal membrane and myelin sheaths. Because DTI measures are derived from Brownian motion of water, this technique takes advantage of axonal membrane shape to tap into integrity of structures within white matter. Fractional anisotropy (FA) reflects the proportion of diffusivity along the axial axis of fiber tracts relative to radial directions (4, 5). Alterations in FA may be due to change in diffusivity in either the axial or radial directions, and thus it can be fruitful to examine diffusion in these directions separately. Prior DTI studies of BD have had mixed findings. Studies that took a region-of-interest (ROI) approach have focused on prefrontal-limbic circuits theorized to underlie affective dysregulation in BD. In pediatric BD, these studies have found lower FA in the anterior corona radiata (6) and superior frontal white matter (7). In adult BD, findings are more mixed in both direction of findings and location of abnormality, with some reporting lower FA in the anterior cingulum (8) and frontal white matter (9), and others reporting higher FA in the genu of the corpus callosum (10) and frontal white matter (11) or no abnormality in these regions (12). Examinations of specific tracts within the prefrontal-limbic circuit in adults have also yielded mixed findings, with some reporting lower FA in the anterior thalamic radiation (13), which makes up a part of the anterior limb of the internal capsule (14), and others reporting no difference between adult BD and healthy controls in subgenual cingulate or the amygdalo-hippocampal complex (15). Studies that examined the entire brain using either voxel-based morphometry (VBM) or tract based spatial statistics (TBSS) have found white matter abnormalities in regions beyond the frontal-limbic circuit. In pediatric BD, these included lower FA in superior longitudinal fasciculus (16), posterior corona radiata (17), posterior cingulum (16, 17), corpus callosum (16, 17), fornix (17), and occipital white matter (18). Findings in adults are again more mixed, with some studies reporting lower FA in the corpus callosum (19, 20), posterior thalamic radiation (21), and arcuate fasciculus (21), while others reported higher FA in inferior parietal (22) and occipital white matter (22, 23). In sum, studies of pediatric BD have tended to find more consistently lower FA than studies of adult BD. The literature from healthy white matter development is a helpful context in which to consider this pattern of findings. Cross sectional studies of typically developing individuals have found higher FA with age in the corpus callosum, internal capsule, thalamic radiations, corona radiata, arcuate fasciculus, and frontal and temporal white matter (24–26). Lebel and colleagues (26) examined maturation rate across commissural, association, and projection fibers, and reported that callosal fibers and association fibers reach maturity by late childhood and adolescence respectively, while projection fibers continue to mature into early adulthood. To date, no one has examined how white matter microstructure deviates from a typical maturational trajectory in BD, and whether the inconsistencies in the BD literature may be partially explained by deviations from a normal neurodevelopmental trajectory. Based on the above, we sought to determine whether early onset BD is associated with greater or more consistent white matter alterations than BD with adult onset. We measured FA in medication free pediatric and adult onset BD during the first episode of illness and investigated FA differences in BD relative to healthy controls. Because each tract follows a different normal developmental trajectory, we first obtained the center of tracts (skeleton) for each participant, then applied tract masks and extracted mean FA within each tract skeleton to evaluate group, age, and interaction effects at the level of the tract. We specifically hypothesized that white matter tracts that connect prefrontal and limbic regions such as the anterior limb of internal capsule (ALIC), anterior corona radiata (ACR), and cingulum would have lower FA in the BD group (6, 27), and that these differences would be more evident in the pediatric onset BD patients.