The role of dopamine in cognitive sequence learning: evidence from Parkinson's disease.

Electrophysiological and computational studies suggest that nigro-striatal dopamine may play an important role in learning about sequences of environmentally important stimuli, particularly when this learning is based upon step-by-step associations between stimuli, such as in second-order conditioning. If so, one would predict that disruption of the midbrain dopamine system--such as occurs in Parkinson's disease--may lead to deficits on tasks that rely upon such learning processes. This hypothesis was tested using a "chaining" task, in which each additional link in a sequence of stimuli leading to reward is trained step-by-step, until a full sequence is learned. We further examined how medication (L-dopa) affects this type of learning. As predicted, we found that Parkinson's patients tested 'off' L-dopa performed as well as controls during the first phase of this task, when required to learn a simple stimulus-response association, but were impaired at learning the full sequence of stimuli. In contrast, we found that Parkinson's patients tested 'on' L-dopa performed better than those tested 'off', and no worse than controls, on all phases of the task. These findings suggest that the loss of dopamine that occurs in Parkinson's disease can lead to specific learning impairments that are predicted by electrophysiological and computational studies, and that enhancing dopamine levels with L-dopa alleviates this deficit. This last result raises questions regarding the mechanisms by which midbrain dopamine modulates learning in Parkinson's disease, and how L-dopa affects these processes.