THE DANA FOUNDATION’S BRAINWORK The Newsletter

Vol. 15 No. 4 July-August 2005

SPECIAL FOCUS: NEUROIMAGING Peering into the : News New Frontiers in Neural Imaging FROM THE FRONTIER BY BRENDA PATOINE

••• Vaccine boosts activity of ew technologies—and the the fast-emerging frontier of optical chemotherapy in brain cancer. Clinical innovative ways in which sci- imaging, or, more precisely, two-pho- trials show that patients with glioblas- Nentists have harnessed them— ton excitation microscopy combined toma multiforme, a particularly aggres- have driven advances in neural imaging with fluorescent dyes that label indi- sive brain cancer, survived longer if beyond what any expert predicted 10 vidual molecules in living tissue. Scien- they were treated with a vaccine fol- years ago. Ever more sophisticated tists are applying these tools to track lowed by chemotherapy than did those images from brain scans and new brain function in living animals in real patients treated with either the vaccine microscopy techniques are offering a time, right down to the level of synap- or chemotherapy alone. The finding strikingly clear glimpse of what’s going tic connections and beyond. continues recent progress in immune on underneath the bumpy surface of A recent meeting on neural imaging treatments for brain tumors (see “Brain our skulls. at Cold Spring Harbor Laboratory in Tumor Researchers Let Slip the Some of the greatest excitement in New York was testimony to the results Immune Cells of War,” May-June neural imaging right now surrounds possible using so-called “light 2005 BrainWork). microscopy” approaches. The vaccine appears to kill off A few dozen of the world’s chemotherapy-resistant cells, leaving leading experts in imaging behind a population of cells that can be gathered to compare notes, treated with chemotherapy, report John debate technical hurdles, and S. Yu, co-director of the Comprehensive share some of the most Brain Tumor Program at Cedars-Sinai remarkable video and still Medical Center in Los Angeles, and col- images of mammalian leagues in the August issue of Oncogene. in action. To make the vaccine, dendritic cells Two-photon microscopes were harvested from each patient’s use longer wavelengths of blood, grown in a dish that contained light, supplied by lasers, to proteins from glioblastoma tumors, and penetrate tissue more deeply then injected back into the patient’s and with less damage than bloodstream. The process generates other optical imaging modes. A critical advance that pushed (Continued on page 7) the field forward was the identification and cloning of Inside: the gene for green fluores- Economic Pathways Page 4 Green fluorescent protein, or GFP, is expressed in the cent protein (GFP), reported Alzheimer’s Detection Page 5 visual cortex of a transgenic mouse, as shown in this in a landmark Science paper in Sleep Signals Page 6 two-photon microscopy image. This type of imaging is 1994. GFP is a naturally advancing scientists’ understanding of the brain. (Continued on page 2)

BRAINWORK / July-August 2005 SPECIAL FOCUS: NEUROIMAGING

(NEURAL IMAGING, continued from page 1) “The genetics has gotten to the synaptic connections, Kleinfeld says occurring protein that essentially makes point where you can target cells pretty optical imaging now makes it possible cell tissue light up like a neon sign precisely with a fluorescent protein,” “to observe how different sensory and when viewed with light microscopy. says David Kleinfeld, a University of motor patterns sculpt and resculpt the Roger Tsien at the University of California, San Diego, neurophysicist connectivity.” California, San Diego, and others have who attended the meeting. “You can Some of the most cutting-edge developed a whole spectrum of GFP go back to the same cell every time and work with light microscopy involves variants, a broad pallet of colors that determine its functional identity. Does finding ways to identify neuronal func- worldwide are now using the cell report the same sensory features tion in a manner that is rational, quan- to characterize neuronal structure and time and time again, or does its role in tifiable, and reproducible. The ulti- activity to a degree never before possible. a circuit evolve with experience? You mate goal is to use different types of can now study the same animals over GFP-based indicators of neuronal ‘No Competition’ time, which is particularly critical when function in various types of in Among alternative methods, you’re studying brain development.” order to understand how they inter- “there’s no competition for optical connect and influence one another. imaging,” says Karel Svoboda of Cold Grappling with Circuits “What you’re really after is to record Spring Harbor, who co-chaired the These new methods are also making something that tells you about the meeting. “Using genetic tricks with a huge impact on systems neuro- state of the : is it sending an GFP and its dozens of variants, you can science, which seeks to construct output signal or not; what are its input now put into neurons fluorescent “wiring diagrams” that correlate brain signals like; what is its sense of histo- markers of structure, of specific mole- activity to specific behaviors. Much of ry?” says Kleinfeld. Each of these states cules, or of cellular function. This has the Cold Spring Harbor meeting can be understood by looking at specif- enabled a better understanding not focused on the challenge of under- ic physiological indicators that can now only of the structural biology of the standing neural circuits, Svoboda says. be visualized with optical imaging. brain at the level of synaptic circuits, “In the mammalian brain, you have Josh Sanes, a neurobiologist and but also has begun to help us learn a million upon millions of neurons,” head of Harvard’s new Center for Sys- about the function of populations of he says. “If you think of it from an tems Neuroscience, describes his neurons in the intact brain.” engineering standpoint, the brain is an dream scenario: “to label 10, 20, 30 electrical signaling device, and neurons different neuronal types with different are the signaling units. Any engineer colors, and do it such a way that when The Neuroscience Newsletter will tell you that if you want to under- the neuron fires it would change Editorial Advisory Board stand a circuit, you need to have a cir- color.” This would make it possible to Leslie L. Iversen, Ph.D. cuit diagram. You not only need a list track neural activity throughout the Kay Redfield Jamison, Ph.D. of components, but you also need to circuit, with different cell types and Pierre Magistretti, M.D., Ph.D know how neurons connect with one functional characteristics clearly Robert C. Malenka, M.D., Ph.D. Bruce McEwen, Ph.D. another and with what probability.” demarcated. Then, individual cells or Donald L. Price, M.D. There has been good progress on the even genes could be turned off or on Editor “parts list,” but understanding the to understand their roles in the circuit. Dan Gordon connection matrix is still at a “primi- Such studies are just beginning, and Design tive stage,” he says. many technical hurdles remain. Still, FTM Design Studio One reason: until now, the standard Svoboda says, “We’ve made remark- technique for constructing a diagram able progress.” For example, his group A PUBLICATION OF THE DANA PRESS of a neural circuit had changed little has pioneered in vivo imaging of neu- Jane Nevins, Editor in Chief since the late 1800s, when Spanish rons over long periods, even months at Walter Donway, Director anatomist Santiago Ramon e Cajal a time, something that was “just a pipe Editorial office: pioneered it. The technique essentially dream 10 years ago.” The Dana Center 900 15th Street, NW involves staining single neurons, iden- Washington, D.C. 20005 tifying where axons and dendrites Birth of Modern Imaging E-mail: [email protected] overlap, and marking those junctures Such advances were unimaginable DANA is a federally registered trademark. as synapses. back in the 1970s, when the advent of THE DANA FOUNDATION A problem with this approach, Svo- computerized tomography (CT) scan- 745 Fifth Avenue Suite 900 boda says, is that “there’s no function- ning marked the beginning of the mod- New York, NY 10151 al context. You don’t really know ern era of neural imaging. “CT was a For free subscription or change of address: whether or not and to what extent remarkable advance, because it was the [email protected], or fax to 202-408-5599. these neurons ‘synapse’ onto one first time you could look into the brain BrainWork on the Internet: www.dana.org another.” While electrical recording of a living person,” says Arthur Toga, © 2005 DANA PRESS studies can measure activity across who heads the Laboratory of Neuro

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Imaging at the University of California, “New Techniques Detect Alzheimer’s Imaging and Behavior: Los Angeles. Before Symptoms Develop,” this issue.) Reality Check Magnetic resonance imaging (MRI) and positron emission tomography Integration Is Key The visual appeal of imaging studies, (PET) followed CT. These powerful Toga encapsulates what he finds coupled with their relevance to things tools have enabled an unprecedented most exciting about the current state people care about, such as memory and emotion, can leave the work open to look not only at the brain’s anatomical of neuroimaging in one word: integra- less-than-critical interpretation. Experts structure, but also, in the case of PET tion. “We have made tremendous say findings on imaging and human and functional MRI (fMRI), at the progress in terms of the technological behavior come with a few caveats. patterns of brain activity that underlie advances to acquire images that of the Washington mental functions and pathological describe one part of the brain or anoth- University School of acknowl- states. Such “whole-brain” imaging er,” he says. Examples include diffusion edges that by the time discussions of modalities have transformed neuro- tensor imaging, which processes MRI what imaging can show enter the public science research and are increasingly scans in a way that enables researchers arena, brain function has begun to influencing the clinical practice of neu- to see the white tracts of neuronal sound overly localized. A good exam- rology, , and neurosurgery. axons, and new approaches to looking ple is the so-called fusiform face area in PET and fMRI are the elder states- at vascular architecture and blood flow the temporal lobe, considered by some researchers to be specialized for rec- men of neuroimaging. Not only have changes in the brain. ognizing faces and by others to be part they become indispensable for basic “What’s now occurring is the appli- of a complex distributed network. research, but their capacity to show cation of complex computational “By the time people read about this changes in oxygen and glucose metab- strategies that extract more informa- part of the brain, what they come away olism indicative of neural activity has tion out of the images that are with is that it’s the ‘face area,’” Raichle driven the burgeoning field of cogni- acquired, giving you a much more observes, but that may be an oversim- tive neuroscience, which seeks to comprehensive view of what’s happen- plification. understand higher-order brain func- ing in a normal brain and what’s going It’s also important to remember that tions and psychological states. wrong in pathological conditions,” imaging is correlational. Ed Smith, cog- At the same time, new PET imag- Toga says. “So now we can take that nitive at Columbia Uni- ing agents—the radioisotopes that data, ‘massage’ it, compare it against versity, explains: “By themselves, imag- ing studies don’t prove that a particular zero in on specific brain chemicals— statistical and imaging databases, and area is the source of a given mental have extended the uses of PET, mak- apply a variety of visualization algo- process, only that it’s active at the ing it possible to identify changes in rithms to look at it new ways.” same time.” To prove cause and effect, dopamine receptors in Parkinson’s Such progress would not have been scientists are increasingly backing up disease, for example. possible without the integration of results with studies of patients who In terms of clinical practice, neu- multiple disciplines, Toga says. “You have damage in the same area; a lesser roimaging has undoubtedly had the have mathematicians, computer scien- degree of activation in these patients greatest impact on neurosurgery. Brain tists, and related disciplines now work- adds weight to the argument that the scans are routinely used presurgically ing on these problems of imaging the region is necessary to the behavior in and, increasingly, during surgery to brain. That’s relatively new.” question. identify critical brain structures that Coupled with technological Smith also notes that time plays a role in imaging. Functional magnetic must be avoided in the operation and advances, this unprecedented collabo- resonance imaging, or fMRI, for exam- to guide the surgeon’s scalpel to a ration has spawned novel approaches ple, can distinguish events that occur a tumor or vascular occlusion. But imag- to neural imaging and allowed scien- minimum of two seconds apart. Most ing is also playing a greater role in neu- tists to look at age-old questions about of the mental tasks investigated in rology and psychiatry clinical practices. the human mind in a whole new way. imaging studies take far less time. For One sign of this progression is the “It’s the great quest,” Toga says. example, naming a picture involves government’s recent announcement “The brain is the only organ in the matching the picture to an internal that Medicare will cover the cost of body that makes us who we are, so we memory bank, retrieving its name, and PET scans in certain people suspected can’t help but want to see if we can pronouncing the word. The entire of having Alzheimer’s disease, a recog- get a handle on that.” process takes about half a second. nition of PET’s utility in differentiating More comprehensive views will take shape as whole-brain imaging studies, Alzheimer’s from other types of Brenda Patoine is a freelance science and such as fMRI, are joined to “faster” dementia. In October, the NIH medical writer based in LaGrangeville, N.Y. measurements and with cellular studies launched a five-year, 50-site study She can be reached at [email protected]. in animals, such as two-photon designed to identify biological markers microscopy. for Alzheimer’s through brain imaging, —Elizabeth Norton Lasley with the ultimate goal of improving early diagnosis and intervention. (See

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layer of the brain where “executive” 2005 BrainWork.) Cha-Ching! Neural processes like analysis and impulse One player, the investor, gave Processes Underlie control take place—specifically in a money to the other, the trustee; the structure called the medial prefrontal trustee could return some, all, or Economic Decisions cortex (mPFC). none. As reported in the April 1, “Someone whose mPFC is not well- 2005, Science, fMRI scans showed that BY ELIZABETH NORTON LASLEY developed might focus on the size of activity in the investor’s caudate grew the reward rather than its probability stronger when the trustee responded and make bad decisions, like gambling generously and the investor increased ince imaging technologies made or playing the lottery,” says Knutson. the subsequent payment. The signal their debut in the early 1990s, The striatum is involved in a less from the striatum also began to appear Sthey have gone from providing obvious type of reward known as altru- sooner as the investor gained confi- colored pictures of specific brain areas istic punishment, which Knutson likens dence in the trustee—in the final to yielding valuable information about to inching forward in traffic just to pre- rounds, even before the investor’s complex behavior. Such understanding vent the red sports car that’s been zip- decision was made—indicating that is of importance not only to clinicians ping along the shoulder from getting the caudate was building a model of and psychotherapists but, perhaps sur- back in. In a study reported in the the other player’s actions. prisingly, to economists. August 27, 2004, issue of Science, Ernst In this game the results of each The laws of economics have tradi- Fehr and colleagues at the University of round were known right away—the tionally discounted the brain, assigning Zurich asked subjects to play several trustee’s response appeared on the values to observed behavior and assum- rounds of a game in which one player investor’s computer screen. But ing that everyone will act in his or her entrusted another with money. The Camerer, one of the study’s authors, own best interest. “Economists have second player had the option of giving says the caudate may be able to build been happily ignorant of the brain and back half or keeping it all; if Player B an internal sense of what others will do psychology, and until recently that’s kept the money, Player A could assign even without immediate feedback. been fine because the brain processes a monetary punishment, though some- Camerer and California Institute of underlying behavior weren’t under- times at an additional cost, depending Technology economist Meghana Bhatt stood,” says Colin Camerer, an econo- on the rules of that round. devised a game in which one player mist at the California Institute of Tech- Positron emission tomography had to predict another’s choices from a nology. But humans are perplexing (PET) scans showed activity in the row of pictures on a computer screen. creatures who behave in irrational striatum when players accepted cost Activity in the caudate grew stronger as ways, and brain imaging is beginning penalties for the sake of giving stingy the player guessed correctly, even to offer some explanations. partners their comeuppance. More- though the player did not know the over, players with strongest activation results until the end of the game. The Circuitry of Satisfaction in the striatum were willing to incur The study, published online May 17, A central question in economics is the greatest cost to see justice done. 2005, in Games and Economic Behavior, why people want the things they want, “Altruistic punishment is probably a turned up another interesting finding: or, in neuroscience terms, how the brain key element in explaining the unprece- players with strong activation in a region processes reward. Imaging studies show dented level of cooperation in human known as the insula were less able to that in response to perceived reward, a societies,” the authors wrote, conclud- anticipate what others would do. Camer- brain region called the striatum is acti- ing that the anticipated satisfaction of er says the insula is likely to be “all about vated in remarkably specific ways. meting out punishment activates me,” and high activity in this area may The striatum comprises two tubular reward-related brain pathways. make it difficult to think strategically by structures in a V shape located behind putting oneself in another’s place. the eyes; its chief neurotransmitter is Model-building and the the well-known reward chemical, Caudate Nucleus Neuroscience for the dopamine. In a study published May A part of the striatum known as the Common Good 11, 2005, in the Journal of Neuro- caudate nucleus seems to be involved Some skeptics dismiss imaging for science, Brian Knutson and colleagues in predicting others’ behavior—an purposes like these as a high-tech form at Stanford University found that ability central to both cooperation and of phrenology, the 19th century parlor when a person considers the value of competition. In another game involv- science that involved interpreting the monetary gain, functional magnetic ing money exchange, a team headed bumps on a person’s scalp. Montague resonance imaging (fMRI) scans by P. Read Montague of the Baylor counters: “Even if fMRI did nothing showed activation in the striatum. But College of Medicine, Houston, noted more than provide a detailed atlas of when subjects weighed the likelihood increasing activity in the caudate as brain activity, it would be a huge of getting the reward, activity was players began to trust each other. (See contribution. But you can use it to strongest in the cortex, the outermost “News from the Frontier,” May-June (Continued on page 8)

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the future, it may also be used as a versity of Illinois at Chicago. “We are New Techniques diagnostic agent for AD. extensively evaluating some dual Detect Alzheimer’s Before the development of this brain agents in animal models, and comple- imaging technology, AD could be diag- tion of this project will allow us to Before Symptoms nosed with certainty only by examining identify a lead (preferred) compound brain tissue itself during an autopsy, that can potentially be used in human Develop Mathis says. PIB is a variation of one of subjects in the near future for both BY THOMAS S. MAY the tissue dyes used to positively diag- PET and SPECT studies.” nose AD after death, he explains. But Another amyloid-imaging technique he points out that, unlike the tissue that has recently been tested in animals dyes, PIB can enter the brain in living involves the use of magnetic resonance eing able to detect high blood humans, bind to the beta-amyloid imaging (MRI) equipment. In a study pressure can help doctors treat plaques, and be detected by PET. published in the April 2005 issue of Bthe condition before it causes a Nature Neuroscience, Makoto Higuchi stroke or other serious illness. Similar- Other Approaches and colleagues at the RIKEN Brain Sci- ly, the ability to measure blood sugar PET imaging with PIB has already ence Institute in Japan injected a group allows for the diagnosis and control of been used in more than 200 clinical of mice, specially bred with amyloid diabetes before it causes irreversible studies at 12 institutions worldwide, plaques in their brains, with a fluorine- damage to a patient’s blood vessels, Mathis says. He admits, however, that labeled, amyloid-binding compound. kidneys, or other organs. it is unlikely to become a general diag- Using a high-magnetic-field MRI Alzheimer’s disease (AD), however, nostic tool for at least another five machine, the researchers were able to is usually diagnosed only after clinical detect the amyloid plaques inside the symptoms, such as memory loss and living animals’ brains. “This work is confusion, become apparent—and the first to visualize brain amyloid by even then a diagnosis cannot be made fluorine-MRI, and it permits high- with complete certainty. In most cases, contrast imaging of the pathology these symptoms develop 10 to 20 with theoretically no background sig- years after plaques of beta-amyloid nals, because no fluorine atoms are peptide (Αβ) begin to accumulate present in the body,” Higuchi says. inside a person’s brain. Now, with the help of some recent- PET vs. SPECT vs. MRI ly developed neuroimaging tech- Magnetic resonance imaging has a niques, scientists can visualize Αβ Colored positron emission tomography higher resolution than PET, Higuchi inside the brain before the disease (PET) scans show differences in the brain adds, and there are other advantages to becomes debilitating. Using these new of a normal patient, left, and a patient MRI: “It does not require radioactivity techniques could help doctors predict with Alzheimer’s disease (AD). The scan from the tracer, and thus can circum- the course of the disease, gauge the of the patient with AD indicates reduced vent costly production and complex efficacy of various treatments, and one function and blood flow in both sides of the safety control of radioactive materials.” day possibly prevent or even reverse brain, which is common in Alzheimer’s. However, this technique cannot yet cognitive decline. be applied to humans. “We need to years. The main reason for the wait is inject the tracer at a considerably high Pittsburgh Compound-B that conducting PET studies requires dose, which might cause subacute or The first chemical that has been very expensive equipment. chronic toxicity,” Higuchi says. More- used successfully to detect the pres- In an attempt to make the detection over, the MRI scanners most hospitals ence of Αβ inside the brain of patients of early AD more widely available currently employ are not sensitive living with AD was developed by a using amyloid imaging, some of the enough to detect signals from amy- group of researchers lead by William same researchers who invented the loid-binding fluorine. Klunk and Chet Mathis of the Univer- PIB method are also developing a so- Most hospitals are also unable to sity of Pittsburgh. Named Pittsburgh called hybrid tracer—a chemical that use the amyloid-imaging technique Compound-B, or PIB for short, the could be used not only with PET but developed at the University of Pitts- chemical provides a tool to visualize with single-photon emission comput- burgh, using PET scanners and the beta-amyloid in the brain of living ed tomography (SPECT) as well. PIB compound, because of its high human subjects, with the help of “At present, SPECT is the key bio- cost. Nevertheless, this method is positron emission tomography (PET). medical imaging modality that is avail- already being utilized (in a few well- Mathis says the compound can help able in most nuclear medicine depart- equipped centers) in the evaluation of determine the efficacy of anti-amyloid ments around the world,” says lead some experimental treatments of AD. drug therapies in clinical trials, and in researcher Yanming Wang of the Uni- (Continued on page 8)

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then to the primary cortex, where the storing them more securely than if the An Eye on Shut-Eye signals are processed. To find out brain processed them only at the what happens when someone is sleep- moment they occurred. ing and hears a noise, Thomas Meanwhile, Eric Nofzinger and BY RABIYA S. TUMA Pollmächer, a lead investigator at the colleagues at the Western Psychiatric Max Planck Institute of Psychiatry in Institute and Clinic in Pittsburgh are Munich, and colleagues are using examining what regions of the brain unctional brain imaging is functional magnetic resonance imag- are active during sleep in healthy and thought to be one of the most ing, or fMRI, and EEG. depressed volunteers and are helping to Fimportant discoveries in sleep For these experiments, a volunteer explain why patients with depression research in the past 100 years. lies in the MRI scanner with electrodes have a hard time sleeping. Researchers are using it to look at on his or her head. When the volun- In these experiments, volunteers what happens in the whole brain dur- teer falls asleep, the researchers play a sleep in a normal bedroom setting, ing sleep, both in healthy individuals sound repeatedly. Significantly, the sci- with EEG electrodes attached and an and in people who suffer sleep distur- entists do not detect activation in the intravenous (IV) needle in their arms. bances such as depression, sleep apnea, thalamus or auditory cortex. The When volunteers reach a specified and insomnia. researchers interpret this lack of a stage of sleep, the scientists inject a Before brain imaging techniques strong signal to mean that the brain is solution of radioactive glucose developed, researchers relied on elec- actually trying to repress outside stim- through the IV. They then wake the troencephalograms, or EEGs, to learn uli, as if trying to maintain sleep and volunteers and put them in a positron about the different stages of sleep. prevent waking. emission tomography, or PET, scan- EEGs detect the electrical activity in During rapid-eye movement sleep, ner. Because the glucose goes to the the brain through electrodes placed on or REM, during which most dreaming cells that are most active, the team can a patient’s scalp. The technique mea- occurs, the group has observed a simi- see what regions of the brain were in use when they injected the solution. During REM sleep depressed patients have an overactive limbic sys- tem, which controls emotions. “It’s like they have a raw nerve, which is too easily overstimulated,” Nofzinger says. The team has started to look at what happens in patients who are depressed but receiving treatment. Nofzinger says they have preliminary results in these patients, and that although it is too In the past, traces from an electroencephalo- early to draw conclusions, there are gram, left, provided information about the undoubtedly differences between stages of sleep. That method has been upstaged untreated and treated patients. by functional magnetic resonance imaging, Sleep is key to restoring an individ- above, which provides a comparison of sensory processing during wakefulness, shown in the ual’s brain power. If scientists can find scan on the left, and light sleep. Sound signals out what healthy sleep looks like and are transmitted to the auditory cortex dur- what happens when it is disrupted—as ing wakefulness, as indicated by increased occurs in depression—they may be neural activity, but not during sleep. able to correct it. One striking observation, Pollmäch- er says, is what happens when his team sures general patterns of brain activity, lar pattern in which the auditory cor- uses EEG to see what is going on in a such as the speed of neural spikes, but tex is quiet. patient who complains about severe is not sensitive enough to distinguish “The brain functions in a closed sleep disturbances: “The EEGs are activity in different brain regions or in mode,” Pollmächer says. “It tries to almost non-remarkable. It could be the deeper structures of the brain, exclude external sensory information that by looking at deeper regions below the cortex. and reinforce internal signals.” [with imaging techniques] we will be Scientists know how sounds are That observation agrees with experi- able to understand why people per- processed in the brain when someone mental data showing that sleep is ceive their sleep is so bad.” hears something while they are awake, important for reinforcing memories. with neural signals passing from the While a person sleeps, the brain Rabiya S. Tuma is a science and med- auditory nerve to the thalamus and reviews the tasks or events of the day, ical writer in New York, N.Y.

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television static, the children with •••Controlling emotional feed- dyslexia required more contrast back is key to depression. People between the signal and background with anxiety disorders or depression before they could detect an image. complain not so much about the emo- News They had trouble seeing a pattern tion itself as its unceasing nature, says FROM THE FRONTIER regardless of whether the visual cues Daniel Weinberger of the National were processed by the M pathway or Institute of Mental Health. Now he (Continued from page 1) the P pathways, according to the and his colleagues may have found dendritic cells that display proteins to study, published in the July Nature why their experience is continuous, immune cells, instructing them to kill Neuroscience. according to work published in the other cells that have those proteins on The team concludes that the trouble June issue of Nature Neuroscience. their surfaces, including tumor cells. differentiating signals from noise affects Scientists know that the serotonin “What we show now is that one of more than one pathway, and may even transporter gene, which encodes a key the antigens being targeted by the involve other sensory systems. “Any- protein for in the vaccine is TRP-2 [tyrosinase-related thing we can do to jack up the vol- brain, comes in a long form and a protein-2],” Yu says. “When treated ume” on the important signals may short form. People who have the short with the vaccine, patients had much help children with dyslexia, Sperling form are susceptible to developing less antigen in their subsequent tumor concludes. depression or anxiety, though the than they did before treatment.” gene does not actually cause it. Tumors that had less TRP-2 were •••Blocking opiate receptors To find out how the short form more sensitive to chemotherapy than interferes with nicotine reward. affects emotional health, Weinberg- tumors with lots of TRP-2. The When a smoker lights up, nicotine in er’s team looked at 94 healthy indi- results suggest that targeting TRP-2 the cigarette turns on reward pathways viduals, some who have each form. is important in treating glioblastomas. in the brain, providing a sense of plea- Using brain imaging techniques, they sure. Researchers know how nicotine found that two regions involved in ••• Noise hides the signal in triggers the dopamine-responsive emotional responses, the amygdala dyslexia. Children with dyslexia have reward pathway, and now scientists at and the cingulate, were smaller in trouble recognizing the sounds that the University of Pennsylvania have people with the short gene. Also, the make up words, but it is not clear found how nicotine stimulates the opi- neural circuits connecting the amyg- why. One hypothesis is that dyslexic oid pathway. dala and the cingulate were weaker in readers are less able to perceive visual The team reports in the June 16 people with the short form than in cues that are processed by the magno- issue of Neuron that after conditioning, those with the long one. cellular, or M, pathway of the visual environmental cues were enough to That is important, says Weinberger, system. However, new research sug- trigger gene activity in the opioid path- because the amygdala controls a per- gests that the parvocellular, or P, way. When mice were given repeated son’s response to fearful situations, pathway also plays a role. nicotine injections in a cage distinct evaluating whether they should react The M pathway processes differences from their home cage, then placed in or not, and then the cingulate vets the in brightness and signals that change the injection cage but not given nico- amygdala’s response. If a fear signal rapidly in time, whereas the P pathway tine, the opioid pathway was activated. put out by the amygdala is not justi- handles signals that have a high spatial When given a choice, the mice pre- fied, the cingulate turns it off. But in frequency, such as narrow stripes. Anne ferred the injection cage. people with the short form of the Sperling, a postdoctoral fellow in neu- Significantly, both the nicotine- gene, the cingulate is not able to per- rology at Georgetown University Med- and environment-induced opioid form this editing function as effective- ical Center, and colleagues realized responses were blocked by pretreat- ly, so it is as if the amygdala is going that the past experiments testing chil- ment with an opioid inhibitor. After off all the time. dren’s ability to process M signals had this treatment, the mice lost interest “If you can’t shut off fear, it is used visual patterns displayed on a in the injection cage. much worse than just feeling it for “noisy” background, or displays where “We can block the molecular mech- the first time,” Weinberger says. The there was more going on than changes anisms and block the behavior,” says new evidence suggests that this phe- in the M signal. Sperling thought the lead author Julie Blendy, an assistant nomenon happens in people with the problem might not be the M pathway professor of pharmacology. That sug- short gene, which would explain why per se, but rather an inability to distin- gests opioid inhibitors might help peo- they are more prone to depression guish the signal from the noise. ple stop smoking by breaking the link and anxiety. The researchers found that if they between environmental triggers and —R.T. asked children to look for a pattern on reward sensations. a screen with a background resembling

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(ECONOMICS, continued from page 4) (ALZHEIMER’S, continued from page 5) understand how people think, and, in Although PET has a higher resolu- many cases, to predict what they’ll do.” tion than SPECT, it is very unlikely This idea may suggest some evil con- that medical insurance companies will glomerate peering into consumers’ pay for PET scans to diagnose AD in brains and exploiting their neural cir- the foreseeable future, Wang says. Suc- cuitry for profit. But the possibilities of cessful development of a hybrid tracer, imaging can be viewed the other way which could be used with either PET around. Aside from what Knutson cites or SPECT, “would bridge the gap as the obvious difficulty of getting the between the two imaging modalities,” consumer into the scanner, Camerer he argues, and the clinical application believes that with a better understanding of such a dual tracer “could be stream- of brain and behavior, economists can lined from the development stages in help people make better choices—both research laboratories directly to about immediate purchases and long- patients in clinics worldwide.” term financial planning. Such choices Thomas S. May is a science and medical might lower the estimated $5,000-per- writer based in Toronto, Canada. He can household credit card debt, or lower the be reached at [email protected]. number of personal bankruptcies from the 1.5 million filed in 2004. Finding ways to better integrate corti- cal and striatal areas might help people defer gratification and grasp the realities CREDITS: Pg. 1: Kasthuri and Lichtman, of compound interest. One day, insol- Harvard University; Pg. 5: Dr. Robert vency might even be a treatable disorder. Friedland / Photo Researchers, Inc.; Pg. 6: © Hannah Gal / Photo Researchers, Inc.; Elizabeth Norton Lasley is a freelance Pg. 6: Czisch et al., 2004. science writer in Woodbury, Conn.

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