Scientists from the National Institute of Mental Health (NIMH) have used functional
brain imaging to show how visual working memory may be affected by a class of
drugs that is used with modest effectiveness to improve cognitive functioning
in some patients with Alzheimer's Disease (AD). This class of drugs, cholinesterase
inhibitors, includes the only FDA-approved treatments for AD.
Research results from "Cholinergic Enhancement and Increased Selectivity
of Perceptual Processing during Working Memory," appear in the December
22 issue of Science magazine.
In this study researchers compared brain images as well as visual working
memory performance of seven normal, young subjects while on physostigmine to
when they were off the drug. Physostigmine is a cholinesterase inhibitor that
is not used to treat AD because it is cleared from the blood too fast for clinical
use. The researchers' findings suggest that when subjects were on physostigmine,
their working memory may have been more efficient. Brain images showed that
physostigmine had a selective effect on activity in visual processing areas
at the time when new memories were acquired.
Cholinesterase inhibitors like physostigmine prevent the breakdown of the
neurotransmitter acetylcholine, which is known to play an important role in
learning and memory, and is found to be significantly reduced in AD.
Working memory refers to short-term memory for information that is temporarily
maintained for immediate use, like remembering a telephone number until it is
dialed or the locations of cars that you see in the rearview mirror while driving.
In working memory, a widely distributed set of brain areas acquires new information
through perception (encoding), holds that information in an active representation
(maintenance), and uses the information to perform a task (recall).
In their experiment, Maura L. Furey, Ph.D., of the Laboratory of Brain and
Cognition, NIMH, and her colleagues used functional magnetic resonance imaging
(fMRI), which can measure changes in brain activity from second to second. Brain
activity during working memory was measured both during infusion of physostigmine
and during infusion of a placebo. The results showed that physostigmine may
have improved the efficiency of working memory. In the brain, physostigmine
had a selective effect on activity in visual processing areas during the perceptual
encoding of new information. Physostigmine had no effect on activity in these
same areas when subjects were looking at nonsense patterns during a control
task. These results indicate that the way that cholinesterase inhibitors may
improve memory is by enhancing the selectivity of perceptual processing of information
that is to be remembered. Enhanced perception may produce more vivid memories,
thus simplifying the processing demands for memory maintenance and retrieval.
The research suggests that the memory-enhancing effect of cholinesterase inhibitors
in patients with AD may be attributable to a clearer perception of newly acquired
"With functional brain imaging, we can dissect the brain activity underlying
a complex behavior like working memory into responses to task components that
are mediated by different brain structures at different times during task performance.
Here we have shown how a drug may influence neural activity in a complex neural
system to result in a change in a complex behavior," said principal investigator
Other researchers were James V. Haxby, Ph.D., Chief, Section on Functional
Brain Imaging, Laboratory of Brain and Cognition, NIMH, and Pietro Pietrini,
M.D., Ph.D., Department of Clinical Biochemistry, Medical School, University
of Pisa, Italy.