This proposal, PET/MRI measurements of basal dopamine function in human subjects, will perform studies that translate a novel marker of basal D2 receptor occupancy from prior studies in non-human primates (NHP) to studies in human subjects, and then subsequently evaluate the role of persistent chronic pain in altering basal dopamine function. To date, the only existing method for evaluating basal neurotransmitter levels in living human brain has been PET studies in conjunction with depletion of neurotransmitter. In this method, dopamine depletion is accomplished over a period of days by repeated administration of an inhibitor of an enzyme that is required for dopamine synthesis. However, dopamine depletion produces motor dysfunction and a host of psychiatric symptoms and thus requires continuous observation of subjects over a period of days. A less noxious method of assessing basal dopamine function could significantly expand clinical utility. In this proposal, we will test a novel method that provides information similar to dopamine depletion studies, but this will be accomplished using infusion of targeted D2 ligands that transiently and incompletely displace dopamine from D2 receptors. Preliminary results in NHP demonstrate a coupling between D2 occupancy and induced function, supporting the hypothesis underlying this methodology. In order to establish an appropriate dose of D2 antagonist and to demonstrate the hypothesized relationship between occupancy and function in human subjects, first we will perform graded dose-response studies in human volunteers using methods similar to those in our prior NHP studies, except for the potential use of an FDA-approved antagonist to improve fMRI detection power, if we find that this method is required. Concurrently with these studies, we will evaluate the differential effects of antagonist on brain functional connectivity, and correlate changes in connectivity with the drug occupancy measured by PET. These studies will establish an optimal dose and define a relationship between dopamine blockade and changes in connectivity. Subsequently, we will perform a cross-sectional study of pain-free control subjects versus subjects with persistent chronic pain, under the hypothesis that reduced basal dopamine function is a marker for persistent chronic pain. Simultaneously, we will evaluate whether difference between patient populations are better assessed by functional connectivity or pharmacological challenge. Overall, these studies will translate a important new imaging marker to clinical investigations, investigate the relationship of D2 antagonist occupancy to both induced fMRI signal and altered brain functional connectivity, and compare the inferred levels of basal dopamine between chronic pain patients and normal control subjects.
This project proposes a novel method in order to study dopamine levels, and functional brain connections, in the basal ganglia of normal subjects and patients with persistent chronic pain. This exploratory study will investigate technical aspects of the methodology, the effects of blocking dopamine neurotransmission on neural communication, and the relative levels of dopamine and global neural connections in chronic pain patients versus subjects free from pain.
