Attenuated neural response to gamble outcomes in drug-naive patients with Parkinson's disease

Parkinson's disease results from the degeneration of dopaminergic neurons in the substantia nigra, manifesting as a spectrum of motor, cognitive and affective deficits. Parkinson's disease also affects reward processing, but disease-related deficits in reinforcement learning are thought to emerge at a slower pace than motor symptoms as the degeneration progresses from dorsal to ventral striatum. Dysfunctions in reward processing are difficult to study in Parkinson's disease as most patients have been treated with dopaminergic drugs, which sensitize reward responses in the ventral striatum, commonly resulting in impulse control disorders. To circumvent this treatment confound, we assayed the neural basis of reward processing in a group of newly diagnosed patients with Parkinson's disease that had never been treated with dopaminergic drugs. Thirteen drug-naive patients with Parkinson's disease and 12 healthy age-matched control subjects underwent whole-brain functional magnetic resonance imaging while they performed a simple two-choice gambling task resulting in stochastic and parametrically variable monetary gains and losses. In patients with Parkinson's disease, the neural response to reward outcome (as reflected by the blood oxygen level-dependent signal) was attenuated in a large group of mesolimbic and mesocortical regions, comprising the ventral putamen, ventral tegmental area, thalamus and hippocampus. Although these regions showed a linear response to reward outcome in healthy individuals, this response was either markedly reduced or undetectable in drug-naive patients with Parkinson's disease. The results show that the core regions of the meso-cortico-limbic dopaminergic system, including the ventral tegmental area, ventral striatum, and medial orbitofrontal cortex, are already significantly compromised in the early stages of the disease and that these deficits cannot be attributed to the contaminating effect of dopaminergic treatment.