How do thalamocortical connections shape causal structure among resting state brain networks during aging?

Abstract

The human brain undergoes significant structural and functional changes across the lifespan. Our current understanding of the underlying causal relationships of dynamical changes in functional connectivity with age is limited. On average, functional connectivity within resting-state networks (RSNs) weakens in magnitude, while connections between RSNs tend to increase with age. Recent studies show that effective connectivity within and between large scale resting-state functional networks changes over the healthy lifespan. The vast majority of previous studies have focused primarily on characterizing cortical networks, with little work exploring the influence of subcortical nodes such as the thalamus on large-scale network interactions across the lifespan. Using directed connectivity and weighted net causal outflow measures applied to resting-state fMRI data, we examine the age-related changes in both cortical and thalamocortical causal interactions within and between RSNs. The three core neurocognitive networks from the triple network theory (default mode: DMN, salience: SN, and central executive: CEN) were identified independently using ICA and spatial matching of hub regions with these important RSNs previously reported in the literature. Multivariate granger causal analysis (GCA) was performed to test for directional connectivity and weighted causal outflow between selected nodes of RSNs accounting for thalamo-cortical interactions. Firstly, we observe that within-network causal connections become progressively weaker with age, and network dynamics are substantially reconfigured via strong thalamic drive particularly in the young group. Our findings manifest stronger between-network directional connectivity, which is further strongly mediated by the SN in flexible co-ordination with the CEN, and DMN in the old group compared with the young group. Hence, causal within- and between- triple network connectivity largely reflects age-associated effects of resting-state functional connectivity. Thalamo-cortical causality effects on the triple networks with age were next explored. We discovered that left and right thalamus exhibit substantial interactions with the triple networks and play a crucial role in the reconfiguration of directed connections and within network causal outflow. The SN displayed directed functional connectivity in strongly driving both the CEN and DMN to a greater extent in the older group. Notably, these results were largely replicated on an independent dataset of matched young and old individuals. Our findings based on directed functional connectivity and weighted causal outflow measures strengthen the hypothesis that balancing within and between network connectivity is perhaps critical for the preservation and flexibility of cognitive functioning with aging.