Asymptomatic carriers of a single mutant Parkin allele show underactivity of the left rostral putamen in the context of a visuospatial response conflict

Objective: Asymptomatic carriers of a single heterozygous mutation in the Parkin gene show a latent nigrostriatal dopaminergic dysfunction. To examine how a latent dopaminergic nigrostriatal dysfunction impacts on basal ganglia function we performed functional magnetic resonance imaging (fMRI) during response selection. Asymptomatic carriers of a mutant Parkin allele carried out a Simon task during fMRI. This response selection task was chosen because it's known that patients with Parkinson's disease are impaired at performing this task (Praamstra & Plat, 2001).

Methods: Asymptomatic individuals carrying a single mutant Parkin allele (n=8) and 11 healthy age-matched controls performed a Simon task during fMRI at 3 T. The Simon task is a two-choice reaction time task in which responses are coded by two symbolic cues. The position of these cues is either spatially compatible or incompatible with the response instructed by the symbolic cue. Participants respond faster when relative spatial positions of stimulus and response match than when they do not match („Simon effect“). Mean reaction times (RT) and error rates (ER) during fMRI were analyzed using ANOVA. Task-related BOLD signal changes were analysed using SPM2 software. Only correct responses were included in the estimation of task-related BOLD signal changes. For both types of analyses, statistical threshold was set at P<0.05.

Results: Incompatible trials were associated with a higher error rate in both groups. Parkin mutation carriers made significantly more errors than healthy non-carriers in both, compatible and incompatible trials (P<0.001). No significant differences in RT were found between mutation carriers and non-carriers. Analysis of the fMRI data revealed a relative decrease in activation of the left anterior putamen during spatially incompatible trials in Parkin mutation carriers relative to non-mutation carriers (peak difference at x, y, z=-24,9,6mm; T=4,85; p=0.033 corrected at the cluster level). This hypoactivity was present with right hand and left hand responses. No differences between groups were found during spatially compatible trials.

Conclusions: The fMRI results indicate that a mutant Parkin allele is associated with a dysfunction of basal ganglia processing when conflicting response tendencies have to be integrated in a correct motor response.