Measurements of regional cerebral blood flow (rCBF) during cognitive activation, and the effect of drugs which modulatesynaptic function on the rCBF responses, can be used to examine synaptic integrity in the brain in health and disease. In healthy subjects performing an active working memory for faces task, rCBF effects of physostigmine, an inhibitor of acetylcholinesterase, were measured by positron emission tomography with 15O-water. Significant effects were demonstrated and were shown to become stable within 40 minutes after establishing a steady-state plasma concentration of physostigmine by controlled infusion, derived by experimentally determined pharmacokinetics (Ann Rep Z01 AG 00133-LN). No habituation with repeated testing was evident. Subjects performing the task had increased rCBF in occipitotemporal visual brain regions and in right prefrontal cortex. Physostigmine reduced rCBF increments in the right prefrontal cortex in relation to a decrease in reaction time during the working memory task, indicating that the right prefrontal cortex is involved in effort and subject to cholinergic modulation. Whereas young and old subjects showed differences in resting-state rCBF, consistent with an aging effect, while performing the working memory task during physostigmine infusion, both groups showed similar reductions in reaction time. Unlike the young subjects, the old subjects failed to activate frontal and posterior cingulate regions during the task.
