Many important neurological and psychiatric illnesses involve abnormalities of dopamine function. Positron emission tomography (PET) has been used to quantify the regional sensitivity of the brain to activation of dopaminergic pathways. However, for repeated serial studies or in children, PET may be less appropriate. This R21 application proposes to implement a novel method using functional MRI to measure cerebral blood oxygen-level dependent (COLD) responses to the mixed dopamine agonist apomorphine in normal humans. Furthermore, we will validate this pharmacological challenge functional MRI (phMRI) method in the following ways: (1) Test with a single-blind protocol whether such responses are specifically related to drug; (2) test whether the phMRI method is sensitive to important functional differences, by comparing BOLD responses are neurologically relevant, by determining the magnitude and time course of clinical improvement in PD patients at similar apomorphine blood levels to those achieved in controls, and by measuring in all subjects the growth hormone response to apomorphine. At present there are no published data with dopamine agonist phMRI in humans to guide this pilot study. However, successful apomorphine challenge phMRI experiments in non-human species and apomorphine challenge PET studies in humans, together with our own recent successful development of levodopa challenge phMRI in humans, suggest that the proposed approach is feasible. If this translational research is successful, it will bring a method previously tested only in other species to a finished state in which it could be immediately applied to the study of human diseases. In this laboratory, exp3ected applications of this method would include longitudinal studies of treatment-induced side effects in Parkinson's disease, and pathophysiological studies in Tourette syndrome or dopa-related dystonia.
| Gordon, Mollie; Markham, Joanne; Hartlein, Johanna M et al. (2007) Intravenous levodopa administration in humans based on a two-compartment kinetic model. J Neurosci Methods 159:300-7 |
| Black, Kevin J; Carl, Juanita L; Hartlein, Johanna M et al. (2003) Rapid intravenous loading of levodopa for human research: clinical results. J Neurosci Methods 127:19-29 |
