The left frontal cortex supports reserve in aging by enhancing functional network efficiency

Abstract

Background: Recent evidence derived from functional magnetic resonance imaging (fMRI) studies suggests that functional hubs (i.e., highly connected brain regions) are important for mental health. We found recently that global connectivity of a hub in the left frontal cortex (LFC connectivity) is associated with relatively preserved memory abilities and higher levels of protective factors (education, IQ) in normal aging and Alzheimer's disease. These results suggest that LFC connectivity supports reserve capacity, alleviating memory decline. An open question, however, is why LFC connectivity is beneficial and supports memory function in the face of neurodegeneration. We hypothesized that higher LFC connectivity is associated with enhanced efficiency in connected major networks involved in episodic memory. We further hypothesized that higher LFC-related network efficiency predicts higher memory abilities.

Methods: We assessed fMRI during a face-name association learning task performed by 26 healthy, cognitively normal elderly participants. Using beta-series correlation analysis, we computed task-related LFC connectivity to key memory networks, including the default mode network (DMN) and dorsal attention network (DAN). Network efficiency within the DMN and DAN was estimated by the graph theoretical small-worldness statistic. We applied linear regression analyses to test the association between LFC connectivity with the DMN/DAN and small-worldness of these networks. Mediation analysis was applied to test LFC connectivity to the DMN and DAN as a mediator of the association between education and higher DMN and DAN small-worldness. Last, we tested network small-worldness as a predictor of memory performance.

Results: We found that higher LFC connectivity to the DMN and DAN during successful memory encoding and recognition was associated with higher small-worldness of those networks. Higher task-related LFC connectivity mediated the association between education and higher small-worldness in the DMN and DAN. Further, higher small-worldness of these networks predicted better performance in the memory task.

Conclusions: The present results suggest that higher education-related LFC connectivity to key memory networks during a memory task is associated with higher network efficiency and thus enhanced reserve of memory abilities in aging.

Keywords: Aging; Cognitive reserve; Frontoparietal control network; Memory task fMRI; Small-worldness.

Fig. 1

a Network partition of 264 functional ROIs as described previously [34]. The left frontal cortex ROI that was added to this parcellation is highlighted by a red circle. b Group average functional connectivity matrices for successful encoding and successful recognition. The networks of interest (i.e., default mode network [DMN] and dorsal attention network [DAN]) for the present study are highlighted in bold

Fig. 2

Scatterplots showing the associations between left frontal cortex (LFC) connectivity to the default mode network/dorsal attention network (DMN/DAN) and small-worldness within the respective network during episodes of successful encoding (left panels) and successful recognition (right panels). Standardized regression weights and p values are based on multiple regression models controlled for age, sex, gray matter volume, apolipoprotein E ε4 carrier status genotype, and task reaction time

Fig. 3

Scatterplots illustrating the associations between years of education and small-worldness within the default mode network/dorsal attention network (DMN/DAN) during episodes of successful encoding (left panels) and successful recognition (right panels). Standardized regression weights and p values are taken from multiple regression models controlled for age, sex, gray matter volume, apolipoprotein E ε4 carrier status, and task reaction time

Fig. 4

Path diagrams illustrating how left frontal cortex (LFC) connectivity to the dorsal attention network (DAN) (a and b) and the default mode network (DMN) (c and d) mediates the association between years of education and DMN/DAN small-worldness for successful encoding (a and c) and successful recognition (b and d). Shown for each path are standardized β-weights derived from linear regression (i.e., a = effect of education on LFC connectivity, b = effect of LFC connectivity on DMN/DAN small-worldness when education is included, c = effect of education on DMN/DAN small-worldness, c′ = effect of education on DMN/DAN small-worldness when LFC connectivity is included, ab = indirect effect of education on DMN/DAN small-worldness via LFC connectivity). All paths are controlled for age, sex, task reaction time, total gray matter volume, and apolipoprotein E ε4 carrier status. The significance of regression weights is indicated by asterisks (*p < 0.05, **p < 0.01, ***p < 0.001), where significance of indirect effects (i.e., ab) is based on bootstrapping

Fig. 5

Hypothetical working model of reserve. Education is associated with higher efficiency (i.e., small-worldness) of functional brain networks, which is in turn associated with better cognitive performance. The association between education and functional network efficiency is mediated by the left frontal cortex (LFC) hub region (yellow sphere) that modulates the efficiency of downstream networks