Functional Alterations in Gray Matter Networks Mediated by White Matter During the Aging Process

BACKGROUND AND PURPOSE: Extensive research has been carried out to investigate changes in various gray matter (GM) regions during the aging process using resting-state functional MRI. However, the impact of aging on the functional connectivity (FC) between white matter (WM) and GM, particularly white matter-gray matter functional connectivity (WM-GM FC), remains largely unknown. This study proposes a novel method for constructing functional networks that integrate both WM and GM. METHODS: By utilizing data from a lifespan cohort of 439 healthy adults, we devised a covariance-based approach to establish a gray matter-white matter-gray matter (GM-WM-GM) mediated network. The FC between GM and WM was quantified using the Johns Hopkins University International Consortium of Brain Mapping-Diffusion Tensor Imaging-81 WM atlas in combination with the Automated Anatomical Labeling atlas. First, the WM-GM FC was calculated via Pearson correlation coefficients between WM and GM regions, followed by the standardization of the resulting matrix. The GM-WM-GM FC was then constructed using the covariance matrix. Furthermore, topological properties were calculated for GM-WM-GM networks. Finally, the age effect of GM-WM-GM and its topology were explored. RESULTS: Our findings reveal a significant age-related decline in intranetwork connectivity and global network efficiency, while internetwork connectivity followed an inverted U-shaped pattern, suggesting functional dedifferentiation in the aging brain. Despite relatively stable local efficiency, the observed reduction in global efficiency indicates a weakening of long-range neural connections. Additionally, a decrease in network modularity further supports this trend. CONCLUSION: These results offer novel insights into the age-associated reorganization of brain networks, enhancing our understanding of the neural mechanisms underlying normal aging.