Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging

Abstract

The brain is not idle during rest. Functional MRI (fMRI) studies have identified several resting-state networks, including the default mode network (DMN), which contains a set of cortical regions that interact with a hippocampus (HC) subsystem. Age-related alterations in the functional architecture of the DMN and HC may influence memory functions and possibly constitute a sensitive biomarker of forthcoming memory deficits. However, the exact form of DMN-HC alterations in aging and concomitant memory deficits is largely unknown. Here, using both task and resting data from 339 participants (25-80 y old), we have demonstrated age-related decrements in resting-state functional connectivity across most parts of the DMN, except for the HC network for which age-related elevation of connectivity between left and right HC was found along with attenuated HC-cortical connectivity. Elevated HC connectivity at rest, which was partly accounted for by age-related decline in white matter integrity of the fornix, was associated with lower cross-sectional episodic memory performance and declining longitudinal memory performance over 20 y. Additionally, elevated HC connectivity at rest was associated with reduced HC neural recruitment and HC-cortical connectivity during active memory encoding, which suggests that strong HC connectivity restricts the degree to which the HC interacts with other brain regions during active memory processing revealed by task fMRI. Collectively, our findings suggest a model in which age-related disruption in cortico-hippocampal functional connectivity leads to a more functionally isolated HC at rest, which translates into aberrant hippocampal decoupling and deficits during mnemonic processing.

Keywords: DMN; aging; episodic memory; hippocampus; resting state.

Fig. 1.

Age-related alterations of the posterior (A) and anterior (B) DMN and the HC RSN (C) for three different ICA-driven measures (voxelwise connectivity, global connectivity, and amplitude) after post-ICA motion correction. For each network, scatter plots display global functional connectivity (based on the whole network) and amplitude as a function of chronological age (n = 339). The slice panels indicate brain regions (in yellow) exhibiting age-related decline (for DMNs) and age-related increase (green contour, for HC component; k = 375 voxels within the entire MTL; hippocampus proper: LHC: k = 47; RHC: k = 25) in voxelwise functional connectivity overlaid on the sample-specific template created using DARTEL. Hippocampus proper as segmented by Freesurfer (surfer.nmr.mgh.harvard.edu/fswiki/FreeSurferWiki) is shown in white contour. Note that regions in yellow and green are subregions of the whole network shown in red, and global functional connectivity was measured across the whole RSN network (in red). The unit for the global functional connectivity is percent signal changes (intensity normalization followed by no scaling; SI Text).

Fig. 2.

HC RSN coupling in relation to longitudinal memory changes (36). Individuals (n = 51 subjects) who showed age-related decline over 20 y exhibited greater HC RSN coupling than their age-matched individuals (n = 51 subjects) who maintained episodic memory (age, 68.8 ± 7.1 y). The slice panels indicate brain regions (in green contour; P < 0.05 for demonstration purposes) exhibiting greater bilateral HC RSN coupling in the decliner than in the maintainer group. The bar graph indicates greater global connectivity of the HC network (based on the whole HC RSN shown in red) in decliners than maintainers. Error bars reflect standard error.

Fig. 3.

HC RSN coupling in relation to hippocampus and memory-related networks during an encoding task. (A) The scatter plot displays amplitude (percent signal changes) of the left hippocampus (xyz = −28 −14 −16), which promoted episodic encoding as a function of HC RS amplitude. Amplitude was computed as a joint metric of the SD of the HC time course (TC) and the maximum value of the HC spatial map (SM; SI Text). Both TC and SM are in units of percent signal changes. (B) The scatter plot displays the strength of a large-scale network (measured by brain score) that promoted episodic encoding as a function of HC connectivity during rest. Brain score is a subject-specific measure at network level that indicates how strongly an individual recruits an encoding network (SI Text). Here, a brain score represents a level of activation across the entire network that facilitated EM performance during the fMRI task (figure 1 e and f and table 2 in ref. 35). Functional connectivity during rest was computed from subject-specific SMs of the HC network according to a suggestion by Glahn and colleagues (46) (SI Text). (C) The scatter plot displays the relation between the strength of a network functionally connected to LHC (xyz = −28 −14 −16), which promoted the episodic encoding task, and HC connectivity during rest. Here a brain score represents a connectivity index across the entire network that facilitated EM performance during the fMRI task (Fig. S7).

Fig. 4.

HC RSN in relation to memory-related network recruitment during encoding. Older participants (55 y and older; n = 212 subjects) were subdivided into two age-matched groups of high- and low-HC couplers according to a median-split analysis based on the degree of HC coupling during rest. (A) Regions (in red) functionally connected to left HC (xyz = −28 −14 −16) during episodic encoding in the low-coupler group (n = 106; 66.5 ± 7.41 y of age). (B) Regions (in green) functionally connected to left HC (xyz = −28 −14 −16) during episodic encoding in the high-coupler group (n = 106; 66.5 ± 7.41 y of age). Regions with p < 0.0001 (FDR-corrected) are shown in red and green. The glass brain demonstrates brain regions that exhibited greater functional connectivity to the left HC during the encoding task for the low couplers than for the high couplers (left fusiform: xyz = −26 −36 −18; right fusiform: xyz = 28 −44 −16; left hippocampus: xyz = −28 −30 −16; right hippocampus: xyz = 24 −36 4; left inferior frontal cortex: xyz = −46 32 −4).