Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Sep 30;105(39):15106-11.
doi: 10.1073/pnas.0802127105. Epub 2008 Sep 15.

Age-related changes in midbrain dopaminergic regulation of the human reward system

Jean-Claude Dreher  1 , Andreas Meyer-Lindenberg, Philip Kohn, Karen Faith Berman
Affiliations

Age-related changes in midbrain dopaminergic regulation of the human reward system

Jean-Claude Dreher et al. Proc Natl Acad Sci U S A. .

Abstract

The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[(18)F]FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects, we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans, show that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging. Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Statistical t maps of the within-groups effects in the different phases of the reward paradigm (P < 0.005, uncorrected). (A) (Left) Main effect of anticipating reward in young subjects during the delay period, showing activation in the left intraparietal cortex, ventral striatum, caudate nucleus, and anterior cingulate cortex. (Right) Main effect of anticipating reward in older subjects during the delay period, showing activation in the left intraparietal cortex only. The glass brain and the coronal slice indicate that no ventral striatum activity was observed in older subjects. (B) (Left) Main effect of reward receipt in young subjects at the time of the rewarded outcome showing activation in a large bilateral prefronto-parietal network. (Right) Main effect of reward receipt in older subjects at the time of the rewarded outcome showing bilateral prefronto-parietal activation.
Fig. 2.
Fig. 2.
Statistical t maps showing between-group comparison of fMRI BOLD signal by task phase. (A) Between-group comparison during reward anticipation showing higher ventral striatum and anterior cingulate cortex activation in young subjects. The graphs show parameter estimates in these two brain regions in young and old subjects. The glass brain indicates that the ventral striatum and anterior cingulate cortex are the only two brain regions more activated in young subjects during reward anticipation. (B) Group-by-reward outcome interaction showing that young subjects activate the dorsolateral prefrontal and parietal cortices more robustly, whereas older subjects deactivated the medial PFC less than young subjects. Graphs show the parameter estimates in the right dorsolateral PFC and anterior medial PFC in young and old subjects.
Fig. 3.
Fig. 3.
Relationship between midbrain dopamine uptake (Ki) and lateral prefrontal BOLD signal in young and old adults during reward anticipation and at the time of reward delivery. Significant positive correlation of midbrain Ki with BOLD change during reward anticipation in young subjects (x, y, z = 42, 46, 19; Spearman's r = 0.71, P < 0.01; regression line with 95% confidence bands) (A) and significant negative correlation of midbrain Ki with BOLD change in older subjects (x, y, z = −23, 30, 15; r = −0.97, P < 0.0001) (B). Significant positive correlation of midbrain Ki with BOLD signal in lateral PFC at the time of rewarded outcome: in young subjects (x, y, z = 49, 27, 11; r = 0.75, P < 0.005) (C) and significant negative correlation of midbrain Ki with BOLD response in older subjects (x, y, z = −42, 34, 4; r = −0.93, P < 0.001) (D). Correlations were observed bilaterally in the prefrontal cortex in all comparisons (see Text), except during reward anticipation in young subjects, where right predominated.
Fig. 4.
Fig. 4.
Voxelwise comparisons between the correlation maps of F-DOPA Ki with BOLD signal in young versus older adults. (A) During reward anticipation, between-group voxelwise comparisons of the correlation maps revealed that the slopes of the correlations in young subjects were significantly greater than those in older subjects (in whom the correlations were negative; see Fig. 3) in the lateral PFC. (B) At the time of reward outcome, between-group voxelwise comparisons of the correlation maps showed that the slopes of the correlations in young subjects were significantly greater than the negative correlation in older subjects (see Fig. 3) in the bilateral PFC and left temporoparietal junction.
See this image and copyright information in PMC

Comment in

  • Is getting older all that rewarding?
    Wong DF. Wong DF. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14751-2. doi: 10.1073/pnas.0807850105. Epub 2008 Sep 23. Proc Natl Acad Sci U S A. 2008. PMID: 18812511 Free PMC article. No abstract available.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fiorillo CD, Tobler PN, Schultz W. Discrete coding of reward probability and uncertainty by dopamine neurons. Science. 2003;299(5614):1898–1902. - PubMed
    1. Grace AA, Floresco SB, Goto Y, Lodge DJ. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci. 2007;30(5):220–227. - PubMed
    1. Robbins TW. Chemical neuromodulation of frontal-executive functions in humans and other animals. Exp Brain Res. 2000;133(1):130–138. - PubMed
    1. Knutson B, et al. Amphetamine modulates human incentive processing. Neuron. 2004;43(2):261–269. - PubMed
    1. Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature. 2006;442(7106):1042–1045. - PMC - PubMed

Publication types