Age‐ and Sex‐Specific Patterns in Adult Brain Network Segregation

The human brain is organized into several segregated associative and sensory functional networks, each responsible for various aspects of cognitive and sensory processing. These functional networks become less segregated over the adult lifespan, possibly contributing to cognitive decline that is observed during advanced age. To date, a comprehensive understanding of decreasing network segregation with age has been hampered by (1) small sample sizes, (2) lack of investigation at different spatial scales, (3) the limited age range of participants, and more importantly (4) an inadequate consideration of sex (biological females and males) differences. This study aimed to address these shortcomings. Resting-state functional magnetic resonance imaging data were collected from 357 cognitively intact participants (18.2-91.8 years; 49.9 ± 17.1 years; 27.70 ± 1.72 MoCA score, 203 [56.8%] females), and the segregation index (defined as one minus the ratio of between-network connectivity to within-network connectivity) was calculated at three spatial scales of brain networks: whole-brain network, intermediate sensory and associative networks, as well as core visual (VIS), sensorimotor (SMN), frontoparietal (FPN), ventral attention (VAN), dorsal attention (DAN), and default mode networks (DMN). Where applicable, secondary within-, between-, and pairwise connectivity analyses were also conducted to investigate the origin of any observed age and sex effects on network segregation. For any given functional metric, linear and quadratic age effects, sex effects, and respective age by sex interaction effects were assessed using backwards iterative linear regression modeling. Replicating previous work, brain networks were found to become less segregated across adulthood. Specifically, negative quadratic decreases in whole-brain network, intermediate associative network, VAN, and DMN segregation index were observed. Intermediate sensory networks, VIS, and SMN exhibited negative linear decreases in segregation index. Secondary analysis revealed that this process of age-related functional reorganization was preferential as functional connectivity was observed to increase either between anatomically adjacent associative networks (DMN-DAN, FPN-DAN) or between anterior associative and posterior sensory networks (VIS-DAN, VIS-DMN, VIS-FPN, SMN-DMN, and SMN-FPN). Inherent sex differences in network segregation index were also observed. Specifically, whole-brain, associative, DMN, VAN, and FPN segregation index was greater in females compared to males, irrespective of age. Secondary analysis found that females have reduced functional connectivity between associative networks (DAN-VAN, VAN-FPN) compared to males and independent of age. A notable linear age-related decrease in FPN SI was also only observed for females and not males. The observed findings support the notion that functional networks reorganize across the adult lifespan, becoming less segregated. This decline may reflect underlying neurocognitive aging mechanisms like neural dedifferentiation, inefficiency, and compensation. The aging trajectories and rates of decreasing network segregation, however, vary across associative and sensory networks. This study also provides preliminary evidence of inherent sex differences in network organization, where associative networks are more segregated in females than males. These inherent sex differences suggest that female functional networks may be more efficient and functionally specialized compared to males across adulthood. Given these findings, future studies should take a more focused approach to examining sex differences across the lifespan, incorporating multimodal methodologies.