Rethinking the role of continuous dopaminergic stimulation in Parkinson disease therapy.

This Viewpoint will examine continuous dopaminergic stimulation (CDS), a concept that has long been invoked as the optimal treatment strategy for improving symptomatic control of Parkinson disease (PD) patients experiencing motor fluctuations. The appeal of CDS has always seemed intuitive and is based, in part, on preclinical investigations implicating pulsatile dopaminergic stimulation as causing motor fluctuations and dyskinesia from levodopa (LD) treatment. However, four large-scale randomized controlled clinical trials testing infused drug delivery have demonstrated only partial effectiveness of CDS at reducing daily OFF time. Other clinical trial data has offered evidence that a reduction in OFF time also can be accomplished from targeting sites in motor pathways downstream from the basal ganglia. Neural plasticity and a CNS calcium receptor signaling compound, ophthalmate, may also hold answers to the regulation of OFF time. Finally, insights derived from neural computational modeling of PD motor pathway pharmacology and the involved electrophysiological connections may guide future understanding of motor fluctuations in PD and their management.