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Previous studies have shown that persons with Parkinson’s disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-thalamo-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however, unsuccessfully. Finally, there were no differences between pwPD and controls in task modulation of the cortico-striato-thalamo-cerebellar network. However, a restricted nigral-striatal model showed that negative modulation of SN to putamen connection was larger in pwPD compared to controls during random trials, while no differences between the groups were found during sequence learning. We speculate that learning-specific SN recruitment leads to a relative increase in SN- > putamen connectivity, which returns to a pathological reduced state when no learning takes place

What mechanisms allow us to direct a precise saccade to a remembered target position in space? The cerebellum has been proposed to be involved not only in motor and oculomotor control, but also in perceptual and cognitive functions. We used functional MRI (Echoplanar imaging at 1.5 T) to investigate the role of the cerebellum in the control of externally triggered and internally generated saccadic eye movements of high and low memory impact, in six healthy volunteers. Memory‐guided saccades to remembered locations of 3 targets (triple‐step saccades) in contrast to either central fixation or to visually guided saccades activated the cerebellar hemispheres predominantly within lobuli VI‐crus I. The same areas were activated when an analogous visuospatial working memory task was contrasted to the triple‐step saccades. Visually guided saccades activated the posterior vermis and the triple‐step saccades, contrasted to the working memory task, activated predominantly the posterior vermis and paravermal regions. Our data confirm the primary involvement of the posterior vermis for visually‐triggered saccadic eye movements and present novel evidence for a role of the cerebellar hemispheres in the mnemonic and visuospatial control of memory‐guided saccades. Hum. Brain Mapp. 22:155–164, 2004. © 2004 Wiley‐Liss, Inc.