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The Machinery of Thought - Working Memory Studies of the brains of monkeys and, more recently, of humans are=20 revealing the neural underpinnings of working memory, one of the mind's=20 most crucial functions by Tim Beardsley, staff writer _________________________________________________________________________= ____ In a darkened basement laboratory on the campus of the National=20 Institutes of Health in Bethesda, Md., volunteers earn $100 by lying for=20 two hours with their head inside a huge magnetic resonance imaging (MRI) machine while they gaze at a screen reflected in a mirror. The screen=20 periodically displays black-and-white pictures: some are faces, others=20 scrambled blocks of light and shade. When a face appears on the screen,=20 the subject signals by pressing buttons whether the face is a new one or=20 the same as one that was shown a few seconds earlier as a "target" to be=20 remembered.=20 As the test proceeds, the MRI machine bombards the volunteer's brain=20 with radio-frequency waves that excite hydrogen atoms in the=20 bloodstream, causing the atoms to emit signals of their own. Later, the=20 machine transforms the resulting electromagnetic cacophony into=20 color-coded maps of oxygen consumption levels throughout the subject's=20 brain. Because increased oxygen consumption results from heightened=20 neural activity, researchers can analyze these brain maps to learn what=20 parts of the brain work hardest when a person recognizes a face.=20 With experiments such as these, researchers are beginning to fathom the=20 neural processes underlying "working memory"--the limited, short-term=20 store of currently relevant information that we draw on when we=20 comprehend a sentence, follow a previously decided plan of action or=20 remember a telephone number. When we bring to mind the name of Russia's=20 president, for instance, that information is temporarily copied from=20 long-term memory into working memory.=20 Psychological studies have demonstrated that working memory is=20 fundamental to the human ability to reason and make judgments that rely=20 on remembered contextual information. There are compelling humanitarian=20 reasons for understanding working memory. Schizophrenia, one of the most=20 devastating mental illnesses, is believed to be caused in part by a=20 defect of this system. Studies of the molecular basis of working memory=20 "have implications for drug treatment in mental illness," says Patricia=20 Goldman-Rakic of Yale University, one of the most prominent=20 investigators of working memory.=20 An intensive research effort has started to produce detailed information=20 about the areas of the brain involved when we engage this vital=20 intellectual faculty and is illuminating the patterns of neural activity=20 that allow it to operate. The important role of specific brain chemicals in working memory is also becoming clear. Yet for all the progress,=20 researchers have still to agree on how working memory is controlled and=20 organized.=20 >From Electrodes to Fast MRI=20 The prototypical test for working memory involves what is called delayed=20 choice. An animal or a person signals where some specific cue was=20 previously seen, before an imposed period of waiting. Thus, a monkey=20 might be given a choice of two jars in separate positions and be=20 rewarded for pointing to the one in which it previously saw food placed.=20 The task provides no clue to the correct response at the time of=20 testing, so the monkey must rely on its recollection of the correct=20 location. A related challenge rewards an animal for remembering which of=20 several images it saw presented initially as a target. The NIH=20 volunteers who were recalling faces were engaged in a variant of this=20 test.=20 Technological advances have greatly enhanced researchers' ability to=20 probe the neural underpinnings of such capacities. Investigators began=20 studying cerebral activity in working memory some 40 years ago by=20 inserting electrodes into individual neurons within the brains of=20 monkeys. This method has its limits, however. Although monkey brains have clear anatomical similarities to human brains, the animals'=20 behavior is vastly simpler, making detailed comparisons with human=20 thinking problematic. Lacking language, the animals must be patiently=20 trained over a period of weeks to master tasks that a person would pick=20 up in a minute.=20 Electrode-recording techniques are also ethically unacceptable for use=20 on people. Researchers try to learn which parts of our species' brain do=20 what by studying the effects of damage caused by injury, disease or=20 therapeutic surgery. Yet patients have different medical histories--and=20 their brains vary in exact shape--so interpreting this clinical data is=20 tricky at best.=20 Earlier this decade, positron emission tomography, or PET scanning, made=20 enormous strides by showing which parts of the human brain are busiest=20 when performing different tasks, such as hearing words or speaking. But=20 PET requires exposing the human subjects to radioactive tracers, and to=20 keep radiation doses within acceptable levels, researchers have to use=20 techniques that can resolve brain areas only about a centimeter apart.=20 Also, during a delayed-choice task, PET scans are too slow to=20 distinguish between the neural activity pattern of a target being held=20 in mind and the pattern that follows a few seconds later when the target=20 is recognized.=20 The new technique used at NIH and elsewhere, called functional MRI, can=20 resolve the position of active neurons to about two millimeters and is=20 fast enough to study activity before and after the brain recognizes a=20 cue on a screen. The rapidly improving technique has over the past two=20 years become the state of the art for functional brain imaging.=20 Monkey Puzzle=20 Experiments involving electrodes implanted in monkeys still provide=20 crucial information, however, because they reveal in fine detail and on=20 a millisecond-by-millisecond timetable what happens as these primates=20 respond to cues and rewards. When animals perform such feats of working=20 memory, several brain regions can play a role, but as Joach=92n M. Fuster= =20 of the University of California at Los Angeles showed in the 1970s, one=20 area that is always involved is the prefrontal cortex.=20 The prefrontal cortex is a layer of tissue that lies just behind the=20 forehead. With neural connections to almost all the areas of the brain=20 that process sensory information, it is well situated to maintain a=20 flexible store of information relevant to any task at hand. It is also=20 the part of the brain that has grown the most in humans, as compared=20 with monkeys. Monkeys missing some parts of their prefrontal cortex=20 preserve their long-term memory but perform miserably on delayed-choice=20 tests. Humans similarly afflicted suffer a reduced attention span and=20 ability to plan.=20 Fuster and, separately, Kisou Kubota and Hiroaki Niki of the Kyoto=20 Primate Center made electrical recordings from a variety of neurons in=20 the monkey prefrontal cortex, including some that apparently were active=20 only while the animals were holding information in working memory.=20 Subsequently, Goldman-Rakic and her colleagues have explored working=20 memory in monkeys with more sophisticated tests. They established that=20 prefrontal neural activity during a delayed-choice task indeed=20 corresponds well to the functioning of working memory.=20 Goldman-Rakic and her associate Graham Williams have taken the analysis=20 all the way to the subcellular level, showing that receptors for the=20 neurotransmitter dopamine pivotally influence the responsiveness of=20 cells in the prefrontal cortex and their actions in working memory.=20 "There is no other example I know" of research that spans the gulf=20 between behavior and subcellular function, Goldman-Rakic notes. She and=20 her colleagues have recently shown that administering antischizophrenic=20 drugs to monkeys for six months leads to specific changes in the numbers=20 of two different types of dopamine receptors in that region, further=20 evidence that schizophrenia--or its treatment--alters normal function=20 there.=20 Research by other scientists supports the view that the prefrontal=20 cortex could sustain working memory. Robert Desimone of the National=20 Institute of Mental Health, along with Earl K. Miller, Cynthia Erickson=20 and others, has discovered in the monkey's prefrontal cortex neurons that fire at different rates during the delayed-choice task, depending=20 on the target the animal saw previously. Neurons in other parts of the=20 brain generally "forget" the target when a distracting stimulus=20 appears--their rate of firing changes. Prefrontal neurons detected by=20 Desimone and his colleagues, in contrast, maintain their rate of=20 activity during a delayed-choice task even after the animal is presented=20 with irrelevant, distracting stimuli.=20 Activity in some prefrontal neurons, then, appears to embody directly=20 the temporary working memory of the appearance of a target the animal is=20 seeking. Other researchers have found prefrontal neurons that seem to=20 maintain locations in working memory: Giuseppe Di Pellegrino of the=20 University of Bologna and Steven Wise of the National Institute of=20 Mental Health have found prefrontal neurons that are busiest when an=20 animal has to remember where it saw a cue. Stimuli fail to excite the=20 same frenzy unless they are in the location that is the current target=20 for the task.=20 Neurons in the prefrontal cortex could thus apparently control how=20 animals respond in a delayed-choice task. Fuster, one of the pioneers in=20 the field, says the prefrontal cortex "serves the overarching function=20 of the temporal organization of behavior" by driving networks that=20 maintain currently important information in an active state. And neurons=20 in the prefrontal cortex might exert their influence in more subtle=20 ways, too.=20 Besides controlling directly the responses in delayed-choice tests,=20 Desimone believes, the prefrontal cortex might tune the visual and=20 possibly other perceptual systems to the task at hand. "What's loaded=20 into working memory goes back to sensory processing," he suggests.=20 Hundreds of experiments with both animals and people have shown that=20 organisms are far more likely to perceive and react to cues relevant to=20 their current needs than to irrelevant stimuli. This effect explains why=20 we are more likely to notice the aroma wafting from a neighbor's grill=20 when we are hungry than just after eating. If Desimone is right, the=20 prefrontal cortex could be responsible for focusing an animal's=20 attention and thus possibly steering awareness.=20 Imaging studies with PET and functional MRI corroborate the evidence=20 from brain injuries that the human prefrontal cortex, like that of=20 monkeys, is central to working memory. Several research groups have now=20 imaged activity in the prefrontal cortex when people remember things=20 from moment to moment. Different tasks may also require various other=20 brain regions closer to the back of the head, but for primates in=20 general, the prefrontal cortex always seems to be busy when target=20 information is kept "in mind."=20 The Devil in the Details=20 Having shown that the prefrontal cortex is crucial to working memory,=20 investigators naturally want to understand its internal structure.=20 Goldman-Rakic and her associates at Yale have found evidence that when=20 an animal retains information about a spatial location, the prefrontal=20 activity is confined to a specific subregion. A separate area below it=20 is most active when an animal is remembering the appearance of an=20 object. These findings, together with observations of the anatomy of=20 neural pathways, led Goldman-Rakic to propose that the prefrontal cortex=20 is organized into regions that temporarily store information about=20 different sensory domains: one for the domain of spatial cues, one for=20 cues relating to an object's appearance and perhaps others for various=20 types of cues.=20 There are, moreover, some indications that the human prefrontal cortex=20 may be organized along similar domain-specific lines. A PET study=20 reported last year by Susan M. Courtney, Leslie G. Ungerleider and their=20 colleagues at the National Institute of Mental Health found that in=20 humans, as in the monkeys studied earlier by Goldman-Rakic, certain=20 brain areas are especially active during exercises that challenge=20 working memory for visual details and for locations. Moreover, the most=20 active brain regions lie in similar relative positions in both species.=20 Goldman-Rakic's proposal about the organization of the prefrontal cortex=20 argues against the standard view of the various components of working=20 memory. The British psychologist Alan Baddely proposed in 1974 that=20 working memory has a hierarchical structure, in which an "executive=20 system" in the prefrontal cortex allocates processing resources to=20 separate "slave" buffers for verbal and spatial information. The memory=20 buffers were supposed to be well behind the prefrontal cortex. But=20 Goldman-Rakic is unconvinced that the brain's executive processes are=20 confined to any particular location. Moreover, in the traditional model,=20 memories organized by domain would lie somewhere behind the prefrontal=20 cortex, not within it.=20 The high-speed imaging capability of functional MRI is now able to help=20 resolve the question. A study that Courtney and Ungerleider and their=20 colleagues published in April in Nature pinpoints the part of the brain=20 that is liveliest while working memory holds an image of a face. That=20 region--the middle part of the prefrontal cortex--has been fingered as=20 the crux of working memory in a variety of studies.=20 Yet the face-recognition task Courtney and company used does not involve=20 any obviously executive functions, Ungerleider notes. Their findings=20 thus contradict the view that only executive functions reside within the=20 prefrontal cortex, but they do fit with Goldman-Rakic's scheme.=20 Similarly, Jonathan D. Cohen of Carnegie Mellon University and his=20 co-workers found a region of the prefrontal cortex partly overlapping=20 the one identified by Courtney that is active while subjects remember=20 letters seen in a sequence. The more the subjects had to remember in the=20 Cohen experiment, the more active their prefrontal regions. So Cohen's=20 result also suggests that working memories are actually stored, in part,=20 in the prefrontal cortex. Domain-specific organization "is the dominant=20 view" of the prefrontal cortex, Wise says.=20 Wise himself does not subscribe to that dominant view, however. He=20 points, for example, to a study reported in Science in May by Miller and=20 his associates at the Massachusetts Institute of Technology. The=20 researchers recorded from neurons in the prefrontal cortex of monkeys=20 while they solved delayed-choice tasks that required them to remember=20 information about both the appearance and spatial locations of objects.=20 Over half the neurons from which Miller recorded were sensitive to both=20 attributes, a result not expected if domain-specific organization=20 prevails. "It argues against Goldman-Rakic's view that identity and=20 location are processed in different parts of the prefrontal cortex,"=20 Miller says.=20 Goldman-Rakic responds that she and her colleagues have recently found=20 hundreds of cells in part of the prefrontal cortex that respond=20 selectively even in untrained animals to objects or faces--further=20 evidence, she asserts, that the information in that area is organized in=20 part by sensory domain. "We do feel the evidence is overwhelming that=20 the functions of neurons in the prefrontal cortex are dictated in large=20 part by the neurons' sensory inputs," she says. Moreover, Goldman-Rakic=20 believes technical problems cast doubt on Miller's experiment. She=20 maintains the targets he used were too close to the center of the visual=20 field, which could produce spurious firings.=20 Keeping Self-Control=20 Michael Petrides of McGill University, another leading figure in the=20 field, has mounted a different challenge to the standard view.=20 Petrides's studies point to two distinct levels of processing, both=20 within the prefrontal cortex. In his view the levels are distinguished=20 primarily not by whether they maintain information about place or=20 objects, as Goldman-Rakic holds, but rather by the abstractness of the=20 processing they perform. The lower level in the hierarchy--physically=20 lower in the brain as well as conceptually lower--retrieves data from=20 long-term memory storage elsewhere. The higher "dorsolateral" level, in=20 contrast, monitors the brain's processes and enables it to keep track of=20 multiple events. This higher monitoring level is called on when subjects=20 are asked, for example, to articulate a random list of each number from=20 1 to 10, with no repetition: a subject has to remember each digit=20 already chosen.=20 Petrides finds that both humans and monkeys with lesions in the=20 dorsolateral part of the prefrontal cortex are crippled in their ability=20 to monitor their own mental processes: they perform badly on special=20 tests he has devised that require subjects to remember their earlier=20 responses during the test. He also cites PET studies of healthy humans=20 that find heightened activity in the same region when subjects are=20 performing the tasks he uses. The finding is the same whether the tasks=20 involve spatial cues or not. "The material does not seem to matter--the=20 process is crucial," Petrides says.=20 Other researchers have found evidence to support the notion that the=20 higher parts of the prefrontal cortex are key for self-monitoring. In an=20 experiment by Mark D'Esposito and his associates at the University of=20 Pennsylvania, volunteers performed either one or both of two tasks that,=20 separately, did not require working memory. One task required subjects=20 to say which words in a list read aloud were the names of vegetables,=20 whereas the other asked them to match a feature of a geometric figure=20 seen in different orientations. Functional MRI showed that the=20 dorsoventral prefrontal cortex became active only when subjects=20 attempted both tasks simultaneously. And in April at a meeting of the=20 Cognitive Neuroscience Society, D'Esposito presented a meta-analysis of=20 25 different neuroimaging studies. The analysis supported Petrides's=20 general notion that tasks involving more computation involve higher=20 regions of the prefrontal cortex. "It was amazing that this came out,"=20 D'Esposito says.=20 D'Esposito's analysis also confirmed earlier indications that humans,=20 far more than monkeys, represent different types of information in=20 different halves of the brain. The meta-analysis did not, however,=20 detect the upper/lower distinction between spatial and object working=20 memory that Goldman-Rakic espouses.=20 Asymmetry of the human hemispheres is becoming apparent to other=20 researchers as well. John D. E. Gabrieli and his colleagues at Stanford=20 University have used functional MRI to study the brains of volunteers=20 who were solving pictorial puzzles such as those often found on=20 intelligence tests. The puzzles were of three types. One group was=20 trivial, requiring the subject simply to select a symbol identical to a=20 sample. A second group was a little harder: people had to select a=20 figure with a combination of features that was absent from an array of=20 sample figures. The third group contained more taxing problems that=20 required analytical reasoning.=20 Gabrieli's study sheds some light on the debate over the organization of=20 the prefrontal cortex. When volunteers pondered the intermediate class=20 of tasks, which most resembled the tasks other investigators have used=20 when studying working memory, the right side of the higher part of the=20 prefrontal cortex was prominently active. Moreover, the activity was in=20 areas that other researchers have found to be used when cues about=20 spatial location are stored. This result fits Goldman-Rakic's idea that=20 working memory for spatial location is stored in the higher regions of=20 the prefrontal cortex, because these intermediate tasks all demanded=20 that subjects visualize features in different locations.=20 When the volunteers in Gabrieli's experiment worked on the hard=20 problems, however, the prefrontal cortices of the subjects became even=20 more active, on the left as well as the right side. The added complexity=20 produced a pattern of activation like that Petrides has found during his=20 tests of self-monitoring.=20 Gabrieli's data thus provide some support for Petrides's theory of a=20 higher executive level in the prefrontal cortex, as well as for=20 Goldman-Rakic's view that domain-specific regions exist there. "There=20 are definitely domain-specific places," Gabrieli says. "And there are=20 others that rise above that." In other words, both sides in the debate=20 over domain-specific organization of the prefrontal cortex may have a=20 point. Yet in June, Matthew F. S. Rushworth of the University of Oxford=20 and his colleagues reported in the Journal of Neuroscience that monkeys=20 with large lesions in their lower prefrontal cortex could still perform=20 well on delayed-choice tests. The finding casts new doubt on the theory=20 that object working memory resides there and seems to support Petrides.=20 It may take years before the outstanding questions about the prefrontal=20 cortex are settled and the operation of the brain's executive functions=20 are pinned down to everyone's satisfaction. "If you put a theory out,=20 people will attack it," Goldman-Rakic muses. "Everyone is contributing."=20 And the modus operandi of the brain's decision-making apparatus is=20 slowly becoming visible. "We are getting," Goldman-Rakic observes, "to=20 the point where we can understand the cellular basis of cognition."=20 ------------------------------------------------------------------------ Further Reading=20 "Cognitive Neuroscience." Special section in Science, Vol. 275, pages=20 1580-1610; March 15, 1997.=20 "Down-Regulation of the D1 and D5 Dopamine Receptors in the Primate=20 Prefrontal Cortex by Chronic Treatment with Antipsychotic Drugs."=20 Michael S. Lidow, John D. Elsworth and Patricia S. Goldman-Rakic in=20 Journal of Pharmacology and Experimental Therapeutics, Vol. 281, No. 1,=20 pages 597-603; April 1997.=20 Temporal Dynamics of Brain Activation during a Working Memory Task." J.=20 D. Cohen, W. M. Perlstein, T. S. Braver, L. E. Nystrom, D. C. Noll, J.=20 Jonides and E. E. Smith in Nature, Vol. 386, pages 604-608; April 10,=20 1997.=20 "Transient and Sustained Activity in a Distributed Neural System for=20 Human Working Memory." S. M. Courtney, L. G. Ungerleider, K. Keil and=20 James V. Haxby, ibid, pages 608-611.=20 "Integration of What and Where in the Primate Prefrontal Cortex." S.=20 Chenchal Rao, Gregor Rainer and Earl K. Miller in Science, Vol. 276,=20 pages 821-824; May 2, 1997.=20