White matter predictors of worsening of subthreshold hypomania severity in non-bipolar young adults parallel abnormalities in individuals with bipolar disorder

Background Identifying neural predictors of worsening subthreshold hypomania severity can help identify risk of progression to BD. While diffusion Magnetic Resonance Imaging (dMRI) studies reported white matter microstructural abnormalities in tracts supporting emotional regulation in individuals with BD, it remains unknown whether similar patterns of white matter microstructure predict worsening of subthreshold hypomania severity in non-BD individuals. Methods dMRI data were collected in: 81 non-BD individuals recruited across a range of subthreshold depression and hypomania, and followed for six months; and independent samples of 75 BD and 58 healthy individuals. All individuals were assessed using standardized diagnostic assessments, mood and anxiety symptom rating scales. Global probabilistic tractography and a tract-profile approach examined fractional anisotropy (FA), a measure of fiber collinearity, in tracts supporting emotional regulation shown to have abnormalities in BD: forceps minor (FMIN), anterior thalamic radiation (ATR), cingulum bundle (CB), and uncinate fasciculus (UF). Results Lower FA in left CB (middle, β = −0.22, P = 0.022; posterior, β = −0.32, P < 0.001), right CB (anterior, β = −0.30, P = 0.003; posterior, β = −0.27, P = 0.005), and right UF (frontal, β = −0.29, P = 0.002; temporal, β = −0.40, P < 0.001) predicted worsening of subthreshold hypomania severity in non-BD individuals. BD versus healthy individuals showed lower FA in several of these segments: middle left CB (F = 8.7, P = 0.004), anterior right CB (F = 9.8, P = 0.002), and frontal right UF (F = 7.0, P = 0.009). Non-BD individuals with worsening 6-month hypomania had lower FA in these three segments versus HC and non-BD individuals without worsening hypomania, but similar FA to BD individuals. Limitations Relatively short follow-up. Conclusions White matter predictors of worsening subthreshold hypomania in non-BD individuals parallel abnormalities in BD individuals, and can guide early risk identification and interventions.