Dopamine replacement therapy (DRT) is the standard and very effective symptomatic treatment for early to moderate Parkinson disease (PD). The most important DRT component is the Long Duration Response (LDR), a pharmacodynamic effect that builds up over the course of weeks. DRT actions are poorly understood and the basis of the LDR is unknown. As the LDR wanes in advancing disease, PD patients develop troublesome motor fluctuations and increasing disability. LDR kinetics suggest long-term plastic changes in striatal function. Studies of striatal dopamine actions indicate that striatal dopaminergic neurotransmission regulates ?vigor;? modulation of the velocity, amplitude, force, or frequency of movements. Vigor is closely allied with the concept that striatal dopaminergic neurotransmission mediates motivation; assessment of act utility and appropriate scaling of actions to perceived rewards. Recent theoretical and experimental results suggest that tonic striatal dopamine signaling is a key determinant of movement vigor. Convergent clinical pharmacologic and experimental data lead to a strong hypothesis that the LDR results from chronic DRT partially restoring movement vigor. This model of the LDR requires stable ?records? of action values. Recent non-human primate work on saccadic eye movement vigor indicates the existence of striatal dopaminergic neurotransmission stably encoding motor behavior values for prolonged periods ? a potential mechanism for the LDR. Prior experiments examining vigor in PD did not take the LDR into account, resulting in incomplete examinations of the role of vigor deficits in PD. Our long-term goal is to understand the clinically relevant actions of DRT. The primary objective of our proposal is to test the hypothesis that the LDR results from partial restoration of normal movement vigor-motivation. Our secondary objective is to evaluate a potential mechanism underlying the LDR. The rationale for these experiments is that better understanding of the LDR, a clinically crucial component of DRT action, will lead to improved symptomatic therapy. We will study recently diagnosed PD subjects. All subjects will undergo standard evaluations of clinical, cognitive, and motivational features. Subjects will perform incentive motivation tasks assessing movement vigor ? motivation coupling to assess our primary hypothesis. A task assessing saccadic eye movement vigor in response to stable value signals will be employed to evaluate our secondary hypothesis. They will perform all tasks before and after LDR induction in both the ?practical off? and post-acute treatment states. Validation of our hypotheses would have considerable impact by identifying the functional process underlying the LDR and providing information for uncovering the mechanisms of the LDR. This would facilitate research into LDR mechanisms, provide a rational basis for developing valid animal models of the LDR, and open a new path towards improved symptomatic management of PD.

Public Health Relevance

Dopamine replacement therapy is very effective in early Parkinson disease but its mechanisms of action are understood poorly. A long-acting component of dopamine replacement therapy, the long duration response, is particularly important and may result from partial restoration of normal coupling between the importance of an action goal and speed of action movement. We will determine if the long duration response in early Parkinson disease is associated with improved coupling of action goals and movement speed, which may lead to improved symptomatic treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Sieber, Beth-Anne
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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