White matter microstructure mediates the link between rest-activity rhythm instability and mania symptoms in...

Adolescence and young adulthood are critical periods for the emergence of bipolar disorder (BD). Instability in sleep and rest-activity rhythms is associated with elevated risk for BD, yet little is known about the neural correlates of this vulnerability. White matter organization in fronto-limbic pathways, which support mood regulation and show sensitivity to sleep/rest-activity rhythm disruption, offers a promising avenue for investigation. Participants (16-24y;N = 112) recruited across a spectrum of mania vulnerability (MOODS-SRL) completed 14 days of actigraphy followed by a neuroimaging assessment. Diffusion MRI was used to derive Neurite Orientation Dispersion and Density Imaging, focusing on the Orientation Dispersion Index (ODI) of the cingulum bundle, uncinate fasciculus, and forceps minor. Clinician-rated symptoms of mania and depression were assessed at baseline and 6-months follow-up. We evaluated whether the links between actigraphy-derived sleep duration variability, sleep onset variability, and Circadian Function Index (CFI; index of circadian rhythm robustness) and white matter ODI were moderated by baseline mania vulnerability, and tested whether baseline ODI predicted 6-month mood symptoms. At higher levels of mania vulnerability, lower CFI (greater rest-activity instability) associated with higher ODI (greater white matter disorganization) in the cingulum bundle (β=-0.22;P = 0.029) and uncinate fasciculus (β = -0.22;P = 0.020). Moreover, higher uncinate fasciculus ODI predicted greater mania symptoms at 6-month follow-up and fully mediated the CFI-mania symptom association (β = -0.10;95 %CI[-0.14,-0.02]). Rest-activity instability may disrupt fronto-limbic white matter, increasing risk to mania in those at elevated vulnerability for BD. Stabilizing rest-activity rhythms in at-risk individuals may help preserve white matter integrity and mitigate BD risk.