  Pharmacological challenge imaging has mapped, but rarely quantified, the
sensitivity of a biological system to a given drug. We describe a novel method
called rapid quantitative pharmacodynamic imaging. This method combines
pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge
drug over a short time scale, and functional imaging to rapidly provide
quantitative estimates of drug sensitivity including EC50 (the concentration of
drug that produces half the maximum possible effect). We first test the method
with simulated data, assuming a typical sigmoidal dose-response curve and
assuming imperfect imaging that includes artifactual baseline signal drift and
random error. With these few assumptions, rapid quantitative pharmacodynamic
imaging reliably estimates EC50 from the simulated data, except when noise
overwhelms the drug effect or when the effect occurs only at high doses. In
preliminary fMRI studies of primate brain using a dopamine agonist, the
observed noise level is modest compared with observed drug effects, and a
quantitative EC50 can be obtained from some regional time-signal curves. Taken
together, these results suggest that research and clinical applications for
rapid quantitative pharmacodynamic imaging are realistic.
