Compensatory fronto-parietal hyperactivation during set-shifting in unmedicated patients with Parkinson's disease

Patients with Parkinson's disease (PD) often suffer from impairments in executive functions, such as mental rigidity, which can be measured as impaired set-shifting. Previous studies have shown that set-shifting deficits in patients with PD result from hypo-excitation of the caudate nucleus and lateral prefrontal cortices. The results of these studies may have been influenced by the inclusion of patients on dopaminergic medication, and by choosing set-shifting paradigms in which performance also depends on other cognitive mechanisms, such as matching-to-sample. To circumvent these potential confounding factors, we tested patients with PD that were not on dopamine replacement therapy, and we developed a new feedback-based paradigm to measure the cognitive construct set-shifting more accurately. In this case-control study, 18 patients with PD and 35 well-matched healthy controls performed the set-shifting task, while task-related neural activation was recorded using functional magnetic resonance imaging. Behaviourally, PD patients, compared with healthy controls, made more errors during repeat trials, but not set-shift trials. The patients, compared with controls, showed increased task-related activation of the bilateral inferior parietal cortex, and the right superior frontal gyrus, and decreased activation of the right ventrolateral prefrontal cortex during set-shift trials. Our findings suggest that, despite decreased task-related activation of the right ventrolateral prefrontal cortex, these early-stage unmedicated patients with PD do not yet suffer from set-shifting deficits due to compensatory hyperactivation in the inferior parietal cortex and the superior frontal gyrus.