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The human cerebral cortex is connected by intricate inter-areal wiring at the macroscale. The cortical hierarchy from primary sensorimotor to higher-order association areas is a unifying organizational principle across various neurobiological properties; however, previous studies have not clarified whether the connections between cortical regions exhibit a similar hierarchical pattern. Here, we identify a connectional hierarchy indexed by inter-individual variability of functional connectivity edges, which continuously progresses along a hierarchical gradient from within-network connections to between-network edges connecting sensorimotor and association networks. We found that this connectional hierarchy of variability aligns with both hemodynamic and electromagnetic connectivity strength and is constrained by structural connectivity strength. Moreover, the patterning of connectional hierarchy is related to inter-regional similarity in transcriptional and neurotransmitter receptor profiles. Using the Neurosynth cognitive atlas and cortical vulnerability maps in 13 brain disorders, we found that the connectional hierarchy of variability is associated with similarity networks of cognitive relevance and that of disorder vulnerability. Finally, we found that the prominence of this hierarchical gradient of connectivity variability declines during youth. Together, our results reveal a novel hierarchal organizational principle at the connectional level that links multimodal and multiscale human connectomes to individual variability in functional connectivity.

SummaryBackgroundParent-child transmission of suicidal behaviors has been widely elucidated, while the three-generation family suicide risk paradigm remains to be explored. This longitudinal study aimed to examine the influences of family history of suicidality (FHoS) among two prior generations on offspring’s neurodevelopment.MethodsWe conducted a retrospective, longitudinal study using the Adolescent Brain Cognitive Development (ABCD) study data collected from 2016 to 2021. Participants were allocated into four groups according to their parents’ (Generation 1 [G1]) and grandparents’ (Generation 2 [G2]) history of suicidality (G1−G2−; G1+G2−; G1−/G2+; G1+/G2+). We estimated adjusted associations between FHoS and offspring’s suicide ideation (SI), psychopathology, impulsivity and brain cortical volumes while controlling for age, sex, parental education, household income and marital status.FindingsA total of 11,875 children aged 9-10 years were observed from baseline to 3-year follow-up. Compared to G1-G2-, higher odds of SI were observed for G1-G2+ (OR=1·99, 95% CI [1·54-2·56]) and G1+G2+ (2·25 [1·46-3·47]) by child-report. Higher odds of SI were also observed for G1+G2- (1·54 [1·12-2·12]), G1-G2+ (2·57 [1·89-3·48]) and G1+G2+ (2·70 [1·60-4·56]) by caregiver-report. Higher odds for psychopathology were also observed (1·47 [1·11-1·96]; 3·33 [2·57-4·33]; 5·44 [3·42-8·66]), while higher family suicide risk was associated with high impulsivity (B=1·32 [0·48-2·17]; 2·24 [1·32-3·15]; 2·26 [0·47-4·05]). Offspring in G1+G2-had higher cortical volumes in 12 brain regions, including the bilateral insula, temporal regions and occipital regions, which were also significantly associated with their lifetime SI.DiscussionA cumulative risk pattern of FHoS in two prior generations was found for offspring’s neurodevelopmental outcomes. Earlier preventive interventions are warranted to weaken the familial transmission of suicidal risk.