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From the Department of Neurology (B.F.L.v.N., M.M.W., H.R.S.), Christian-Albrechts University, Kiel, Germany; Department of Neurology and Donders Centre for Neuroscience (B.F.L.v.N., B.R.B.), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Neurology (K.R., K.L., J.H., F.B., C.K.), University of Lübeck, Germany; NeuroImage-Nord (K.R., T.v.E., F.B., H.R.S.), Hamburg-Kiel-Lübeck, Germany; Toronto Western Hospital-Research Institute (T.v.E.), CAMH-PET Centre, University of Toronto, Canada; Department of Neurology (P.P.P.), Central Hospital and Institute of Genetic Medicine, Eurac-Research, Bolzano-Bozen, Italy; and Danish Research Centre for Magnetic Resonance (H.R.S.), Hvidovre University Hospital, Copenhagen, Denmark.
* To whom correspondence should be addressed. E-mail: hartwig.siebner{at}drcmr.dk.
Objective: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements.
Methods: Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.
Results: Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation.
Conclusion: Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.
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