Functional imaging of sequence learning in Parkinson's disease.

Sequence learning, a cognitive task linked to cortico-striatal function, is impaired in Parkinson's disease (PD). We chose this task as a behavioral paradigm to study the functional architecture of PD in treated and untreated conditions. In our studies, participants were scanned with H(2)(15)O while performing a kinematically controlled motor sequence learning task and a matching motor baseline task. Experiments revealed that a specific sequence learning network predicts learning in normal subjects, and in independent cohorts of early and advanced PD patients. The analysis of the relationship of network activity to learning performance revealed diverging influences of dopaminergic therapy and deep brain stimulation (DBS). DBS of the internal GP and of STN increased network activity and task performance, while levodopa decreased both measures. In separate studies, we investigated the role of dopaminergic modulation on brain activation during sequence learning. In healthy subjects dopamine transporter (DAT) binding correlated with learning-related brain activation in prefrontal, premotor and cingulate cortices, and in the thalamus. By contrast, in PD most of these regional relationships were lost. Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic input. In a final set of studies, we found a significant decline in learning performance in early stage PD patients followed over the course of 2 years. Longitudinal declines in learning-related activation were found in parietal areas, while concomitant increases were localized to the left hippocampus. These observations support hypotheses on disease-stage and task-specific effects within the different cortico-striato-pallido-thalamocortical loops and the mesocortical system in PD.