Dopamine D2/3 binding potential modulates neural signatures of working memory in a load-dependent fashion.

Dopamine (DA) modulates cortico-striatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA measured by PET and fMRI activations, whereas others have failed to observe such a relation. A possible reason for the discrepant findings is differences in task demands, such that a more demanding task, with greater prefrontal activations, may yield a stronger association with DA. Moreover, a potential DA-BOLD association might be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing subgroups) healthy older humans (43% females), who underwent fMRI scanning while performing a working memory (WM) n-back task, along with DA D2/3 assessment with [11 C]raclopride and PET. Using multivariate partial-least-squares analysis, we observed a significant network showing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo-striatal-cortical circuit, which supports WM functioning. Critically, DA-BOLD association in the normal, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back. Moreover, normal-performing individuals, with up-regulated BOLD in response to increasing task demands, showed a stronger DA-BOLD association during 3-back, whereas low-performing individuals showed a stronger association during 2-back. This pattern suggests a nonlinear DA-BOLD-performance association, with the strongest link at the maximum capacity level. Taken together, our results suggest that DA might have a stronger impact on functional brain integrity during more demanding cognitive tasks. SIGNIFICANCE STATEMENT Dopamine (DA) is a major neuromodulator in the central nervous system, and plays a key role in several cognitive processes via modulating the blood-oxygenation level-dependent (BOLD) signal. Some work has shown a link between DA and BOLD, whereas others have failed to observe such a relation. A possible reason for the discrepancy is differences in task demands, such that a more demanding task, with greater prefrontal activations, may yield a stronger association with DA. We examined the relation of DA to BOLD during working memory under three load conditions, and found that DA-BOLD association is expressed in a load-dependent fashion. These findings explain disproportionate impairment in effortful cognitive tasks in neurodegenerative diseases such as Parkinson, but also in normal aging.