System-level reconfiguration of the aging brain: Linking dynamics, morphology and micro-architectures.

Healthy aging involves complex neural reconfigurations across both structural and functional domains. While resting-state functional magnetic resonance imaging (rs-fMRI) has linked static functional connectivity alterations to aging, the whole-brain dynamics of functional activity and their covariance with structural changes remain poorly characterized. To address this gap, we integrated three data-driven approaches to profile functional dynamics in the aging brain and decode their association with structural atrophy. Using rs-fMRI data from 252 participants-145 young adults (22.7 ± 3.4 years) and 107 older adults (68.7 ± 6.5 years)-we made several key observations. First, normalized Shannon entropy revealed a significant reduction in spatiotemporal complexity among older individuals. Second, phase synchronization analysis of BOLD signals indicated enhanced global integration and metastability in older adults, particularly within the dorsal attention (DAN), ventral attention (VAN), and frontoparietal networks (FPN). Third, temporal asymmetry analysis demonstrated increased nonreversibility and a heightened functional hierarchy in the aging brain, again most evident in the FPN. Morphometric analyses confirmed widespread structural atrophy in older participants. Crucially, partial least squares (PLS) analysis uncovered significant covariance between morphometric patterns and dynamic functional metrics, underscoring a tight structure-dynamics coupling in aging. Furthermore, structural atrophy correlated significantly with variations in micro-architecture maps. Finally, we evaluated the behavioral relevance of these dynamics through correlations with cognitive performance. Our findings offer an integrative, multiscale perspective on neural decline in aging, emphasizing the interplay between dynamic functional reorganization and structural atrophy.