0001 Circadian Instability Impacts Brain White Matter and Predicts Future Mania Symptoms in At-Risk Youth

Abstract Introduction Adolescence and young adulthood are key periods for the emergence of bipolar disorder (BD). Instability in sleep and RAR increases BD risk, with recent evidence showing that its impact varies depending on pre-existing mania vulnerability. Yet it remains unclear whether this vulnerability extends to the brain. This question is critical because if pre-existing mania vulnerability heightens neural sensitivity to sleep and RAR instability, it could exacerbate disruptions in emotion-regulation circuits, a core process implicated in BD, and thereby increase susceptibility to its onset. White matter organization in fronto-limbic pathways, which supports emotion regulation and is sensitive to sleep/RAR disruption, offers a promising neural substrate for probing this vulnerability. Methods Participants (16–24y; N=112), recruited across a continuum of mania vulnerability (MOODS-SRL - Mania), completed 14 days of actigraphy and a neuroimaging session. Diffusion MRI was used to derive Neurite Orientation Dispersion and Density Imaging, focusing on the Orientation Dispersion Index (ODI) of emotion-regulation tracts (cingulum bundle, forceps minor, uncinate fasciculus). Clinician-rated mania and depression were assessed at baseline and six-months. Variability in sleep duration and sleep onset was calculated, along with the Circadian Function Index (CFI), a composite measure of circadian activity rhythm robustness. We tested whether associations between actigraphy-derived sleep/RAR metrics and ODI were moderated by mania vulnerability at baseline, and whether ODI metrics at baseline predicted 6-month mood symptoms. Results Lower CFI (greater circadian instability) was associated with higher ODI (greater white matter disorganization) in the uncinate fasciculus (β=-0.22, P=0.018) among individuals with higher mania vulnerability. Higher uncinate fasciculus ODI predicted greater mania symptoms at follow-up and fully mediated the CFI-mania association (β=-0.10,95%CI[-0.14,-0.02]). No effects emerged for depressive symptoms. Sleep duration and onset variability were not associated with ODI (P>0.05). Conclusion Our findings suggest that circadian instability specifically impacts the uncinate fasciculus in individuals at elevated risk for BD, and this microstructural vulnerability predicts future increases in mania but not depressive symptoms. These results highlight a potential pathway linking rhythm disruption to emerging mania and underscore circadian rhythm stabilization as a promising target for early intervention aimed at protecting white matter integrity and reducing BD risk. Support (if any) National Institute of Mental Health (R01MH124828; PI: Soehner).