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

Introduction Understanding 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. Methods Resting-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. Results A 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 (β) 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. Conclusions The 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. Significance Adolescence 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.