Activation in the dorsolateral prefrontal cortex during working memory is associated with dopamine release capacity

Objectives The dorsolateral prefrontal cortex (DLFPC) is a key brain region for cognitive functions, such as working memory (WM). Functional magnetic resonance imaging (fMRI) studies consistently show DLPFC engagement during WM tasks in humans, whereas preclinical work demonstrates that WM is dependent on prefrontal dopamine function. This study assesses whether prefrontal dopamine release capacity and DLPFC activation during WM are related in humans.

Methods Dopamine release in the DLPFC was determined in14 healthy volunteers by using Positron Emission Tomography (PET) scans with [11C]FLB457 before and after an amphetamine challenge. Ninety min scans with arterial input function were obtained. PET data were analyzed with constrained two-tissue compartment modeling. The outcome measure was change in BPND between pre- and post-amphetamine scans. The same subjects performed a WM task while blood oxygenation level dependent (BOLD) scans were acquired on a 1.5T MRI scanner. The outcome measure was BOLD signal change in the DLPFC during WM. The DLPFC region of interest was manually drawn on a T1 MRI scan for each subject and was applied to both PET and fMRI data.

Results The subject sample included 7 men and 7 women (age 31.8 ± 9.1 years). Average change in DLPFC BPND was -8.0 % ± 12%. BOLD signal change during WM was 0.015% ± 0.06%. Change in DLPFC BPND negatively correlated with BOLD signal change (r = -0.563, p = 0.036), i.e. higher dopamine release in the DLPFC correlates with stronger DLPFC activation during WM.

Conclusions Dopamine release in the DLPFC is associated with stronger engagement of the DLPFC during WM. This suggests that DLPFC dopamine transmission is critical for WM performance in humans. Examining this relationship in psychiatric disorders with cognitive disturbances will be important to understand the role of dopaminergic dysfunction in these disorders and design targeted therapeutic interventions.

Research Support NIMH P50 MH086404-01. EVDG is supported by Rubicon grant 825.12.009 (Netherlands Organisation for Scientific Research).