Abstract

Numerous studies have shown that aging has important effects on specific functional networks of the brain and leads to brain functional connectivity decline. However, no studies have addressed the effect of aging at the wholebrain level by studying both brain functional networks (i.e., within-network connectivity) and their interaction (i.e., between-network connectivity) as well as their joint changes. In this work, based on a large sample size of neuroimaging data including 6,300 healthy adults aged between 49 and 73 years from the UK Biobank project, we first use our previously proposed priori-driven independent component analysis (ICA) method, called NeuroMark, to extract the whole-brain functional networks (FNs) and the functional network connectivity (FNC) matrix. Next, we perform a two-level statistical analysis method to identify robust agingrelated changes in FNs and FNCs, respectively. Finally, we propose a combined approach to explore the synergistic and paradoxical changes between FNs and FNCs. Results showed that the enhanced FNCs mainly occur between different functional domains, involving the default mode and cognitive control networks, while the reduced FNCs come from not only between different domains but also within the same domain, primarily relating to the visual network, cognitive control network, and cerebellum. Aging also greatly affects the connectivity within FNs, and the increased within-network connectivity along with aging are mainly within the sensorimotor network, while the decreased within-network connectivity significantly involves the default mode network. More importantly, many significant joint changes between FNs and FNCs involve default mode and subcortical networks. Furthermore, most synergistic changes are present between the FNCs with reduced amplitude and their linked FNs, and most paradoxical changes are present in the FNCs with enhanced amplitude and their linked FNs. In summary, our study emphasizes the diversity of brain aging and provides new evidence via novel exploratory perspectives for non-pathological aging of the whole brain.