Memory encoding and dopamine in the aging brain: a psychopharmacological neuroimaging study

Abstract

Normal aging brings with it changes in dopaminergic and memory functions. However, little is known about how these 2 changes are related. In this study, we identify a link between dopamine, episodic memory networks, and aging, using pharmacological functional magnetic resonance imaging. Young and older adults received a D2-like agonist (Bromocriptine, 1.25 mg), a D2-like antagonist (Sulpiride, 400 mg), and Placebo, in a double-blind crossover procedure. We observed group differences, during memory encoding, in medial temporal, frontal, and striatal regions and moreover, these regions were differentially sensitive across groups to dopaminergic perturbation. These findings suggest that brain systems underlying memory show age-related changes and that dopaminergic function may be key in understanding these changes. That these changes have behavioral consequences was suggested by the observation that drug modulations were most pronounced in older subjects with poorer recognition memory. Our findings provide direct evidence linking ageing, memory, and dopaminergic change.

Figure 1.

Plots of behavioral data showing mean discrimination of old from new items (indexed by Pr) and mean response bias (indexed by Br) according to age group and drug condition. For details of measures, see Materials and Methods: Behavioral procedures. Error bars represent the standard errors of the mean.

Figure 2.

Cross-section images of group main effects under Placebo (green) and group × drug × Pr effects (red), with parameter estimate (R–F) plots, showing key regions in which both effects are present. The cross-sections shows significant clusters (at P < 0.001, uncorrected, cluster size ≥5), superimposed on the SPM5 canonical T₁ image (http://www.fil.ion.ucl.ac.uk/spm/software/spm5/). The plots shows the mean differences in the parameter estimates for the early covariate between remembered (R) and forgotten (F) items, across subjects for each age group and drug condition, at the peak voxel of the cluster indicated by the relevant white arrow. Error bars represent the standard error of this difference.

Figure 3.

Plots of parameter estimates (R–F) against memory performance (Pr) in regions showing an interaction of age group × drug × Pr. Point plots with fitted regression lines illustrate activity–performance relationships for peak voxels in MTL, left inferior PFC, and striatum. The x-axis shows Pr for each subject and drug condition; the y-axis shows the differences in the parameter estimates for the early covariate between remembered (R) and forgotten (F) items. The point plots were generated from individual values extracted from the peak voxels for each subject, and adjusted for confounding effects of Br using the regress function in MATLAB 6.5 (http://www.mathworks.com/), and plotted against Pr. The best fit lines to indicate the linear effects of drug at each voxel were computed separately, also using the regress function, and are plotted on the same axes.

Figure 4.

Cross-section image of age group × drug interaction in right PFC, with parameter estimate (R–F) plot. For details of sections and plots, see legend to Figure 2.