Pramipexole modulates fronto-subthalamic pathway in sequential working memory

Abstract

Brain dopamine may regulate the ability to maintain and manipulate sequential information online. However, the precise role of dopamine remains unclear. This pharmacological fMRI study examined whether and how the dopamine D2/3 receptor agonist pramipexole modulates fronto-subthalamic or fronto-striatal pathways during sequential working memory. This study used a double-blind, randomized crossover design. Twenty-two healthy male volunteers completed a digit ordering task during fMRI scanning after receiving a single oral dose of 0.5-mg pramipexole or placebo. The pramipexole effects on task performance, regional activity, activity pattern similarity, and functional connectivity were analyzed. Pramipexole impaired task performance, leading to less accurate and slower responses in the digit ordering task. Also, it downregulated the maintenance-related subthalamic and dorsolateral prefrontal activity, increasing reaction times for maintaining sequences. In contrast, pramipexole upregulated the manipulation-related subthalamic and dorsolateral prefrontal activity, increasing reaction time costs for manipulating sequences. In addition, it altered the dorsolateral prefrontal activity pattern similarity and fronto-subthalamic functional connectivity. Finally, pramipexole reduced maintenance-related striatal activity, which did not affect the behavior. This study confirms the role of the fronto-subthalamic pathway in sequential working memory. Furthermore, it shows that D2 transmission can regulate sequential working memory by modulating the fronto-subthalamic pathway.

Fig. 1. Digit ordering task and pramipexole effects on task performance.

A Digit ordering task (translated from German). ORD ordered; RAN random. Individual data, group means and SEMs of (B) the accuracy and (C) reaction time (RT) for ORD and RAN trials under pramipexole (PPX) or placebo (PLC). Mean RTs and SEMs for different (D) serial positions or (E) experimental blocks.

Fig. 2. Pramipexole effects on regional activity.

A Manipulation-related regional activation (random versus ordered trials, RAN > ORD) under pramipexole (PPX) or placebo (PLC). The color bar indicates t values. Coordinates are in the MNI space. Mean FIR timecourses and SEMs of (B) the maintenance-related regional activity and (C) the manipulation-related regional activity. dlPFC dorsolateral prefrontal cortex, STN subthalamic nucleus, %sc percent signal change, asterisks, p < 0.05.

Fig. 3. Relationships between behavior and fronto-subthalamic pathway.

A The pramipexole-induced (PPX > PLC) maintenance-related regional activity change and pramipexole-induced manipulation-related regional activity change from the subthalamic nucleus (STN) of a representative subject (S21). Maximum activity changes (peaks) are marked. %sc, percent signal change. B Means and SEMs of the peak latency in the STN. Asterisks, p < 0.05. C Correlation between the pramipexole-induced reaction time (RT) change and maintenance-related STN activity change. D Correlation between the pramipexole-induced manipulation-related RT cost change and manipulation-related STN activity change. Solid lines, p < 0.05; dotted lines, 95% confidence intervals. E Prefrontal activity patterns of the representative subject (50/300 voxels). The color bar indicates beta values. Means and SEMs of (F) the prefrontal activity pattern similarity and (G) fronto-subthalamic functional connectivity.

Fig. 4. Non-linear relationships between STN and sequential working memory.

The non-linear relationship is presented as a quadratic function for simplicity. Other non-linear functions are possible [39]. STN subthalamic nucleus, PPX pramipexole.