Aberrant White Matter Microstructure in Youth at High Risk for Bipolar Disorder

Advances in neuroimaging of bipolar disorder (BD) have highlighted key structural and functional abnormalities in prefrontal-limbic circuits. Youth with a family history of BD often experience early onset of mood symptoms that may increase their risk for developing BD. However, the etiologic mechanisms underlying this risk remain poorly understood. We aimed to identify white matter connectivity abnormalities by comparing regional microstructure in high-risk youth and healthy control (HC) participants.

Youths with depression and/or anxiety (n = 108, mean age [SD] = 14.9 [1.6] years) with a family history of BD but no prior antidepressant exposure and matched HC youths (n = 45, age = 14.8 [1.6] years) were recruited at 2 sites. Automated fiber quantification using diffusion tensor imaging was used to calculate the diffusion properties of fiber tracks and identify microstructural abnormalities. Correlations between clinical ratings and diffusion properties that differed between groups were examined in high-risk youths.

The high-risk group showed higher fractional anisotropy in anterior thalamic radiation and corticospinal, higher axial diffusivity in anterior thalamic radiation, lower mean diffusivity in corticospinal, and lower radial diffusivity in corticospinal and callosum forceps minor compared with the HC group (familywise error-corrected p < .05). Significant positive correlations between regional microstructural metrics and both the Pediatric Anxiety Rating Scale and the Children's Global Assessment Scale were observed in high-risk youths (false discovery rate-corrected p < .05).

Compared with the HC group, youths at risk for BD had altered integrity in the white matter of the callosum forceps minor, anterior thalamic radiation, and corticospinal tracts. Damage to these tracts may be a structural basis for impaired emotional regulation in high-risk youth and a potential target for early intervention.