Age-related development in prefrontal-subcortical resting-state functional connectivity in nonhuman primates

IntroductionUnderstanding age-related changes in functional connectivity (FC) with regards to the maturation trajectories of cortical-subcortical circuits is critical for identifying biomarkers for disease vulnerability. The present study investigated resting-state FC in adolescent and adult nonhuman primates to characterize developmentally-sensitive functional brain circuits. MethodsResting-state fMRI data were acquired in adolescent (33.3{+/-}1.59 months; n=22) and adult (117.29{+/-}2.86 months; n=15) squirrel monkeys and FC was compared in seven prefrontal and ten subcortical regions-of-interest (ROIs). The effect of subject age on FC between each pair of ROIs was evaluated to identify nodes with the most age-sensitive connections (hubs) which were then used in seed-to-whole-brain FC analyses. A subset of adolescents (n=7) was also assessed over 3 longitudinal scans to track changes in hub connectivity throughout adolescence. ResultsA significant effect of age on ROI-ROI FC was found for adolescent (p<0.001), but not adult, subjects (p=0.8). Evaluation of parameter estimates ({beta}) for each ROI-ROI pair found three within-prefrontal (dorsolateral (dlPFC), dorsomedial (dmPFC), and medial orbitofrontal cortices), two within-subcortical (R amygdala and L hippocampus), and three between prefrontal-subcortical (dlPFC, dmPFC, L caudate) hubs with the highest number of age-related connections. Large-scale organizational differences were also observed between the adolescent and adult groups. Longitudinal scans found within-subject changes in FC consistent with group effect. ConclusionsThe relationship between changes in FC and age during adolescence indicates dynamic maturation of several prefrontal-subcortical circuits in nonhuman primates. These findings provide specificity in our understanding of the development of functional brain circuits during and into late adolescence. SignificanceAdolescence marks a period of rapid development in the brain, but also increased vulnerability to mental health disorders. Age-related prefrontal-subcortical resting-state functional connectivity was evaluated in awake adolescent and adult squirrel monkeys. Identification of functional connectivity differences highlight a network of hubs with a high number of connections evolving from early to late adolescence, indicating selectivity in maturation during different stages of aging. Compared to adults, adolescents also show several large-scale organizational differences in circuits originating from important seed regions-of-interest. Longitudinal analysis reveals functional connectivity trajectories emerging from early adolescence and maturing into adult-like patterns during late adolescence. These findings identify functional connections that change dramatically during adolescence suggesting specific circuits that could be at heightened sensitivity to disease vulnerability.