Sex-specific developmental pathways link brain networks, sensory sensitivity, and sleep to adolescent pain

Multisite pain during adolescence predicts chronic overlapping pain conditions in adulthood, with females disproportionately affected. Sex-related neurobiological mechanisms underlying multisite pain development, however, remain poorly understood. Leveraging four consecutive years of Adolescent Brain and Cognitive Development Study® data, associations between neural connectivity (ages 9-10) and youth-reported number of painful body regions (ages 12-13) are investigated, considering the intermediary roles of sensory sensitivity and subsequent sleep disturbances: Resting-state functional magnetic resonance imaging connectivity among the salience (SLN), sensorimotor (SMN), and default mode (DMN) networks, is assessed separately for males (N = 2760) and females (N = 2728) and are then used in sex-stratified serial mediation models to test sensory sensitivity and sleep disturbances as mediators of links to pain. At age 12-13, 37% of the sample (54% females) report pain. In females, DMN-SLN connectivity is directly related to multisite pain, independent of mediators (b = 3.82, CI = [0.95-6.69]). In males DMN-SMN connectivity is indirectly associated with pain through sensory hypersensitivity and subsequent sleep disturbances (b = 0.18, CI = [0.04–0.43]). Mid and posterior insula centrality predict pain with sex-specific lateralization patterns. In this cohort study, sex-related neurodevelopmental pain pathways are characterized, potentially identifying targets for early, tailored interventions. Developmental pathways highlight the sex-related links between brain networks and the emergence of adolescent multisite pain via increased sensory sensitivity and worsening sleep.