The drug, physostigmine, when administered to people by infusion in laboratory tests, aids and improves performance of everyday working memory. Working memory is the process which temporarily holds information such as a phone number until a person gets to a phone to dial the number.
In a new laboratory study, conducted at the National Institute on Aging (NIA), researchers used positron emission tomography (PET) to find and monitor the areas of the human brain that are activated during working memory, and to determine how activity in those regions is modified by a working memory enhancing drug.
Physostigmine is a short-acting drug that enhances levels of a substance (acetylcholine) between neurons in the brain. The drug improves efficiency and reduces the effort needed to perform working memory tasks while altering the activity of some of the brain regions activated by this memory task. The results of this study are reported in the June 10, 1997 issue of the Proceedings of the National Academy of Sciences*.
NIA scientist and lead author of the study, Maura Furey, Ph.D., points out that during the brief period the investigators monitored brain activity, the volunteers' abilities to recognize faces they had just been shown was improved when given the test drug. Furey continues, "A better understanding of how working memory functions could give us valuable clues as to how our brains process and manipulate such information. It could also teach us about how drugs that alter some cognitive processes, such as working memory, influence the brain's response."
Tacrine, the first approved drug for treatment against Alzheimer's disease, acts on the acetylcholine system in a way similar to physostigmine. Dr. Furey believes that since physostigmine improved the brain's response to memory tasks (which are related to observed improvements in performance), similar drugs that enhance the cholinergic system might help relieve symptoms in Alzheimer's disease patients. For now however, tacrine is a more practical drug to use clinically to relieve the symptoms of Alzheimer's disease since it is longer-acting than this form of physostigmine.
To conduct their study, Dr. Furey and colleagues recruited volunteers to NIA laboratories for a series of ten PET scans. The volunteers were separated into control and experimental groups which were matched by age, education, and gender. The ten PET scans allowed researchers to identify the areas of the brain where activity was taking place. The scans alternated between resting and memory task assignments. During the task scans for each trial, volunteers were shown a picture of a person's face, followed by a brief delay period during which subjects had to retain the information, followed by a test condition where subjects had to select from two faces, one of which they had seen earlier. The faces were then changed for each subsequent trial. The control volunteers received only saline during their brain scans whereas the experimental volunteers received physostigmine. Drug levels were checked after each scan by taking blood samples. PET scan results were then evaluated to identify those areas of the brain that were active during working memory to determine how the two conditions differed, both with and without physostigmine.
The results of the trials showed that enhancing acetylcholine transmission with physostigmine resulted in improved working memory performance and altered neural activity in a cortical region known to be important to this memory task. Pietro Pietrini, M.D., NIA scientist and another author of the study, points out that the mechanisms by which physostigmine acts remain unclear. The drug may enhance efficiency during the processing of information by focusing attention on the task at hand or it could help minimize the effects of distracting stimuli. Either way, a more efficient working memory could be a great advantage for Alzheimer's disease patients and other memory-impaired people. Pietrini points out that the NIA is currently involved in a more in-depth analysis of working memory using a different imaging technique (functional MRI) that he hopes will lead us to an even better understanding of this intriguing aspect of brain function.
Working on this study along with Drs. Furey and Pietrini were G.E. Alexander, Ph.D., H.C. Lee, M.D., J. VanMeter, M.D., C.L. Grady, Ph.D., U. Shetty, Ph.D., S.I. Rapoport, M.D., M.B. Schapiro, M.D., and U. Freo, M.D., of the NIA and J.V. Haxby, Ph.D., now at the National Institute of Mental Health, another of the 18 institutes along with the NIA that make up the National Institutes of Health. The National Institute on Aging leads the Federal effort supporting basic, clinical, epidemiological and social research on aging, Alzheimer's disease, and the special needs of older people.
*ML Furey, P Pietrini, et al, Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory, PNAS, 94 (1997).
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For more information on the NIA and aging in general, please visit our web site at http://www.nih.gov/nia. General information is also available from our resource center by calling, toll-free, 1-800-222-2225. Information and brochures on Alzheimer's disease is available from the Alzheimer's Disease Education And Referral (ADEAR) Center at 1-800-438-4380.