A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward-driven behaviors, which can result in life-altering morbidity. The mesocorticolimbic dopamine network guides reward-motivated behavior; however, its role in this treatment-related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward-learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD-fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex-matched PD patients with (n 5 19) or without (n 5 18) ICB. An incentive-based task was administered to a subset of patients (n 5 20) to quantify positively or negatively reinforced learning. Whole-brain voxelwise analyses and region-of-interest-based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P 5 0.013), orbitofrontal cortex (P 5 0.034), insula (P 5 0.044), putamen (P 5 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala-to-midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum-to-subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment-avoidance learning. These data indicate that PD-ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward-based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509-521, 2018.

Objective: Impulsive decision-making is characterized by actions taken without considering consequences. Patients with Parkinson's disease (PD) who receive dopaminergic treatment, especially dopamine agonists, are at risk of developing impulsive-compulsive behaviors (ICBs). We assessed impulse-related changes across a large heterogeneous PD population using the Barratt impulsivity scale (BIS-11) by evaluating BIS-11 first-and second-order factors. Methods: We assessed a total of 204 subjects: 93 healthy controls (HCs), and 68 ICB-and 43 ICB + PD patients who completed the BIS-11. Using a general linear model and a least absolute shrinkage and selection operation regression, we compared BIS-11 scores between the HC, ICB-PD, and ICB + PD groups. Results: Patients with PD rated themselves as more impulsive than HCs in the BIS-11 total score, second-order attention domain, and first-order attention and selfcontrol domains. ICB + patients recorded higher total scores as well as higher scores in the second-order non-planning domain and in self-control and cognitive complexity than ICB-patients. Interpretation: These results indicate that the patients with PD show particular problems with attentional control, whereas ICB + patients show a distinct problem in cognitive control and complexity. Additionally, it appears that all patients with PD are more impulsive than their age-and sex-matched healthy peers. Increased impulsivity may be a result of the disease course, or attributed to dopaminergic medication use, but these results emphasize the importance of the cognitive components of impulsivity in patients with PD.

Parkinson's disease (PD) is characterized by dysfunction in frontal cortical and striatal networks that regulate action control. We investigated the pharmacological effect of dopamine agonist replacement therapy on frontal cortical activity and motor inhibition. Using Arterial Spin Labeling MRI, we examined 26 PD patients in the off-and on-dopamine agonist medication states to assess the effect of dopamine agonists on frontal cortical regional cerebral blood flow. Motor inhibition was measured by the Simon task in both medication states. We applied the dual process activation suppression model to dissociate fast response impulses from motor inhibition of incorrect responses. General linear regression model analyses determined the medication effect on regional cerebral blood flow and motor inhibition, and the relationship between regional cerebral blood flow and motor inhibitory proficiency. We show that dopamine agonist administration increases frontal cerebral blood flow, particularly in the pre-supplementary motor area (pre-SMA) and the dorsolateral prefrontal cortex (DLPFC). Higher regional blood flow in the pre-SMA, DLPFC and motor cortex was associated with better inhibitory control, suggesting that treatments which improve frontal cortical activity could ameliorate motor inhibition deficiency in PD patients.