Many sedative/hypnotic drugs used in anesthesia are given specifically to ablate memory formation during unpleasant medical experiences. The production of this reversible memory impairment, with the avoidance of excessive sedation, is of key concern to both patients and clinicians on a daily basis. These drugs may impair memory solely by their sedative effects on arousal and attention systems in the brain, or additionally by specifically affecting memory processes. We have shown that one such drug, propofol, has memory effects independent of sedation during behavioral testing. We wish to delineate the physiologic basis for this finding. Recent functional neuroimaging studies have identified differing neuroanatomical regions mediating arousal, attention and memory processes in humans who have not had any drug. Thus, the separate memory and sedative effects of propofol could be mediated in different neuroanatomical regions. The main hypothesis tested in this research proposal is that there are differing neuroanatomical regions mediating drug-induced sedation and amnesia, and that these can be identified by specific changes in electrophysiology and more precisely by changes in regional cerebral blood flow (rCBF). If a physiologic basis for the separation of drug- induced memory from sedation effects can be shown, then it is possible that these can be manipulated separately, and that sensitive and specific measures of these functional effects can be developed. Even in the absence of explicit recall, poorly understood unconscious memory processes are still present during anesthesia. These are of clear concern to both patients receiving anesthesia and clinicians administering anesthetic drugs. The methods developed and used in this proposal will be applicable to the study of anesthetic effects, and possibly the study of memory enhancing drugs, on memory processes. Propofol and thiopental, models of anesthetic drugs with differing sedative and memory effects, will be studied over a wide dose range. Current measures of sedation are inadequate monitors over both sedative and anesthetic concentrations of drug. The first specific aim will determine the best electrophysiologic measure of sedation over all concentrations of the drugs studied, and locate generators of this measure in the brain with a low resolution technique. The sedation independent effect of propofol on memory will be delineated using this electrophysiologic parameter. The second specific aim will locate the neuroanatomical regions mediating the sedative/hypnotic and memory effects of propofol using a high resolution rCBF technique by separately manipulating memory versus sedative processes.
