http://www.sciencemag.org/cgi/content/full/290/5500/2275
NEUROSCIENCE: Boosting Working Memory
Trevor W. Robbins, Mitul A. Mehta, Barbara J. Sahakian*
Many parts of the brain are involved in the formation and storage of
long- and short-term memory. Working memory--a form of short-term
memory that depends on different populations of brain neurons, in
particular those in the prefrontal cortex--serves to maintain
temporary, active representations of information that can be rapidly
recalled (1). Neurons in the prefrontal cortex and associated areas
receive input from cholinergic pathways comprising neurons that
release the neurotransmitter acetylcholine, which originate in the
reticular core of the brainstem and basal forebrain (see the
figure). This anatomical organization leads to an obvious strategy for
improving working memory: increasing the amount of acetylcholine in
synapses. That this strategy works is demonstrated by Furey et al. (2)
on page 2315 of this issue. Using functional magnetic resonance
imaging (fMRI), these authors show that enhancing cholinergic activity
with the drug physostigmine (which blocks the breakdown of
acetylcholine) improves the efficiency of working memory in humans.
Multitasking in the brain. The main ascending cholinergic and
monoaminergic pathways in the brain and their possible contributions
to working memory (2, 3, 11, 12). Different neurotransmitter
pathways--acetylcholine (ACh), dopamine (DA), norepinephrine
(NE)--modulate working memory through separate mechanisms. It remains
unclear whether the serotonin pathway (not shown) is involved in
working memory (12). For clarity, the back-projections from the
frontal cortex and the projections between the neurotransmitter groups
have been omitted. DLPFC, dorsolateral prefrontal cortex; VLPFC,
ventrolateral prefrontal cortex; VTA/SN, ventral tegmental
area/substantia nigra pars compacta; LC, locus coeruleus; NBM, nucleus
basalis of Meynert; BS-ACh, brainstem cholinergic neurons. The
projections depicted reflect possible modulatory influences on working
memory. Anatomically, the NBM and LC project to most of the cortical
mantle and the VTA/SN has fewer projections in more posterior regions
(13).
Brains of human subjects performing a visual recognition task were
imaged first during infusion of physostigmine, and then, on a
subsequent day, during infusion of a saline placebo (2). The visual
recognition task comprised three stages--3 seconds to visualize a
human face (encoding), a 9-second pause during which the face is
"held" in working memory (memory), and then presentation of the
original face and a new face, requiring that one face be recognized
(recognition). In the new work (2), and in two previous studies using
positron emission tomography (PET) (3), physostigmine accelerated the
subjects' ability to recognize visual stimuli (human faces). In the
PET studies, this improvement correlated with a decrease in brain
activity in the dorsolateral prefrontal cortex--a region of the brain
considered crucial for accurate working memory--and an increase in
brain activity in regions of the visual cortex. Because of the poorer
temporal resolution of PET compared with fMRI, the PET work did not
provide information on the parts of the brain that were activated at
each stage of the visual recognition task.
With fMRI, Furey et al. (2) now show that the increased activity in
the visual cortex after physostigmine treatment occurred during the
encoding of faces. Therefore, improved working memory performance may
be due, in part, to enhancement of the earliest stages of visual
processing in the cortex, possibly through an increase in the
signal-to-noise ratio of neuronal information processing
(4). Increased visual processing in response to physostigmine is
consistent with results from other work in which animals were infused
intracerebrally with selective cholinergic agents (5), but it is
unclear how the Furey results relate to other findings in experimental
animals. For example, Furey and colleagues suggest that, for certain
types of memory, boosting the input of visual information leads to
reduced activity in the prefrontal cortex. However, injection into the
rat prefrontal cortex of muscarinic or nicotinic receptor
antagonists--which prevent acetylcholine from binding to its
receptors--produces different profiles of impairment on two working
memory tasks; only the more demanding task was impaired by the
nicotinic receptor antagonist (6). This raises the possibility that
acetylcholine might have different effects depending on whether it
binds to muscarinic or nicotinic receptors. Consistent with this
notion, in both normal volunteers and patients with Alzheimer's
disease, nicotine improves performance on working memory tasks that
demand heightened attention (4).
The drug-induced changes seen by Furey and co-workers in the
prefrontal cortex during face recognition, unlike those in the
posterior regions of the brain, were not preferentially associated
with any particular stage of the task. The authors choose to explain
this finding in terms of the Petrides model of working memory
(7). This model assigns the more passive ("on-line") short-term
maintenance of information (8) and the more active ("executive")
processing of information held on-line to the ventral and dorsal
regions of the prefrontal cortex, respectively. The investigators
postulate that decreased dorsal prefrontal cortex activity reflects
reduced requirements for "executive" operations after increased
posterior cortical activity. But not all activity in the prefrontal
cortex was reduced during the face recognition task after
physostigmine infusion; increased activity was still observed in the
inferior prefrontal cortex. As the authors point out, it is unclear
whether the activity of this area subsumes the ventrolateral
prefrontal cortex. If this area is close to the ventrolateral
prefrontal cortex (area BA47), then this might reflect enhancement of
the entire network of "on-line" working memory (7). The precise
relationship between working memory and different regions within the
prefrontal cortex is currently the subject of intense debate (8). The
Furey et al. study can now be extended with different working memory
tasks that vary in their degree of "executive" and perceptual
requirements. Thus, the final interpretation of drug-related changes
in the prefrontal cortex will ultimately depend on exactly which parts
of the prefrontal cortex carry out each stage of working memory and on
the exact brain regions where drug-induced changes in activity occur.
Modulating the activity of monoaminergic neuronal pathways (that
release monoamine neurotransmitters such as dopamine and
norepinephrine) controls dynamic neural networks in the neocortex (9,
10). For example, methylphenidate (an indirect enhancer of dopamine
and norepinephrine) decreases the activity of a working memory
"circuit" that includes the dorsolateral prefrontal cortex and the
posterior parietal cortex, while improving overall performance on a
memory task (10). Together with the new Furey et al. findings, these
studies raise the exciting possibility that aspects of working memory
may be improved by drugs with selective actions on different
neurotransmitter systems, resulting in possible therapeutic benefits
for patients with cognitive disorders such as Alzheimer's disease.
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T. W. Robbins is in the Department of Experimental Psychology, University of
Cambridge, Cambridge CB2 3EB, UK. E-mail: twr2@cus.cam.ac.uk M. A. Mehta
is in the MRC Cyclotron Unit, Imperial College School of Medicine,
Hammersmith Hospital, London W12 0NN, UK. E-mail:
mitul.mehta2@csc.mrc.ac.uk B. J. Sahakian is in the Department of Psychiatry,
University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
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