Neural bases of set-shifting deficits in Parkinson's disease

Patients with Parkinson's disease (PD) exhibit impairments in several cognitive functions similar to those observed in patients with prefrontal cortex (PFC) lesions. The physiological origins of these cognitive deficits are not well documented. Two mechanisms have been proposed: disruptions in corticostriatal circuits or a deficiency in frontal dopamine. We previously used functional magnetic resonance imaging (fMRI) in young healthy subjects to separate patterns of PFC and striatum activity during distinct phases of performance of the Wisconsin Card Sorting Task, a set-shifting task that reveals deficits in patients with PD. Here, the same fMRI protocol was used in PD patients and matched controls. Decreased activation was observed in the PD group compared with the matched control group in the ventrolateral PFC when receiving negative feedback and the posterior PFC when matching after negative feedback. In controls, these prefrontal regions specifically coactivated with the striatum during those stages of task performance. In contrast, greater activation was found in the PD group compared with the matched control group in prefrontal regions, such as the posterior and the dorsolateral PFC when receiving positive or negative feedback, that were not coactivated with the striatum in controls. These results suggest that both nigrostriatal dopamine depletion and intracortical dopamine deficiency may play a role in cognitive deficits in PD, depending on the involvement of the striatum in the task at hand.