The role of dopamine in the brain - lessons learned from Parkinson's disease.

Parkinson's disease causes a characteristic combination of motor symptoms due to progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta. The core impairment of dopaminergic neurotransmission has motivated the use of functional magnetic resonance imaging (fMRI) in patients with Parkinson's disease to elucidate the role of dopamine in motor control and cognition in humans. Here we review the main insights from functional brain imaging in Parkinson's disease. Task-related fMRI revealed many disease-related alterations in brain activation patterns. However, the interpretation of these findings is complicated by the fact that task-dependent activity is influenced by complex interactions between the amount of dopaminergic neurodegeneration in the task-relevant nuclei, the state of medication, genetic factors and performance. Despite these ambiguities, fMRI studies in Parkinson's disease demonstrated a central role of dopamine in the generation of movement vigour (bradykinesia) and the control of excessive movements (dyskinesia), involving changes of both activity and connectivity of the putamen, premotor and motor regions, and right inferior frontal gyrus (rIFG). The fMRI studies addressing cognitive flexibility provided convergent evidence for a non-linear, U-shaped, relationship between dopamine levels and performance. The amount of neurodegeneration in the task-relevant dopaminergic nuclei and pharmacological dopamine replacement can therefore move performance either away or towards the task-specific optimum. Dopamine levels also strongly affect processing of reward and punishment for optimal learning. However, further studies are needed for a detailed understanding of the mechanisms underlying these effects.