Mutations in the Parkin (PARK2) and PINK1 gene (PARK 6) can cause recessively inherited Parkinson's disease (PD). The presence of a single Parkin or PINK1 mutation is associated with a dopaminergic nigrostriatal dysfunction and conveys an increased risk to develop PD throughout lifetime. Therefore neuroimaging of non-manifesting individuals with a mutant Parkin or PINK1 allele opens up a window for the investigation of preclinical and very early phases of PD in vivo. Here we review how functional magnetic resonance imaging (fMRI) can be used to identify compensatory mechanisms that help to prevent development of overt disease. In two separate experiments, Parkin mutation carriers displayed stronger activation of rostral supplementary motor area (SMA) and right dorsal premotor cortex (PMd) during a simple motor sequence task and anterior cingulate motor area and left rostral PMd during internal movement selection as opposed to externally cued movements. The additional recruitment of the rostral SMA and right rostral PMd during the finger sequence task was also observed in a separate group of nonmanifesting mutation carriers with a single heterozygous PINK1 mutation. Because mutation carriers were not impaired at performing the task, the additional recruitment of motor cortical areas indicates a compensatory mechanism that effectively counteracts the nigrostriatal dysfunction. These first results warrant further studies that use these imaging genomics approach to tap into preclinical compensation of PD. Extensions of this line of research involve fMRI paradigms probing nonmotor brain functions. Additionally, the same fMRI paradigms should be applied to nonmanifesting mutation carriers in genes linked to autosomal dominant PD. This will help to determine how "generically" the human brain compensates for a preclinical dopaminergic dysfunction.

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.