Population-Level Age Effects on the White Matter Structure Subserving Cognitive Flexibility in the Human Brain

Cognitive flexibility, a mental process crucial for adaptive behavior, involves multiscale functioning across several neuronal organization levels. While its neural underpinnings have been studied for decades, limited knowledge exists about the structure and age-related differentiation of the white matter (WM) subserving brain regions implicated in cognitive flexibility. This study investigated the population-level relationship between cognitive flexibility and WM properties across two periods of human adulthood, aiming to discern how these associations vary over different life stages and brain tracts among men and women. We propose a novel framework to study age effects in brain structure-function associations. First, a meta-analysis was conducted to identify neural regions associated with cognitive flexibility. Next, projections of these neural regions were traced through the Human Connectome Project tractography template to identify the subserving WM associated with cognitive flexibility. Then, a cohort analysis was performed to characterize myelin-related macromolecular features using a subset of the UK Biobank magnetic resonance imaging (MRI) data, which has a companion functional/behavioral dataset. We found that (1) the wiring of cognitive flexibility is defined by a subset of brain tracts, which present undifferentiated features early in adulthood and significantly differentiated types in later life. (2) These MRI-derived properties are correlated with individual subprocesses of cognition closely related to cognitive flexibility. (3) In late life, homogeneity of specific WM tracts implicated in cognitive flexibility declines with age, a phenomenon not observed in early life. Our findings support the age-related differentiation of WM implicated in cognitive flexibility as a natural substrate of adaptive cognitive function.