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The Promise of Neuroscience

The demands of everyday life leave little time or reason to think about how we do what we do. Yet at any given moment innumerable and imperceptible transactions are occurring within the central nervous system—when we wake in the morning and shake off the impressions of a dream; when we go out for a walk, recognize a friend, and cross the street to say hello. The workings of the nervous system convey perceptions and states of mind that we can recognize and put a name to, and they make it possible for us to exchange signals—through language and in other forms—with other beings like ourselves. This same complex system even lets us screen out information, filtering our perceptions to highlight only what is different or noteworthy at the moment.

The brain is active throughout every day, even as we sleep, but we rarely, if ever, stop to consider that our thoughts, actions, and perceptions are the outcome of several trillion signals exchanged among nerve cells. The brain is such an efficient processor of information that most of the time we do not realize the magnitude of its task. Usually only a disruption of the nervous system—through disease or injury or inherited pre-disposition—calls our attention to the brain 's myriad functions.



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DISCOVERING THE BRAIN 1 The Promise of Neuroscience The demands of everyday life leave little time or reason to think about how we do what we do. Yet at any given moment innumerable and imperceptible transactions are occurring within the central nervous system—when we wake in the morning and shake off the impressions of a dream; when we go out for a walk, recognize a friend, and cross the street to say hello. The workings of the nervous system convey perceptions and states of mind that we can recognize and put a name to, and they make it possible for us to exchange signals—through language and in other forms—with other beings like ourselves. This same complex system even lets us screen out information, filtering our perceptions to highlight only what is different or noteworthy at the moment. The brain is active throughout every day, even as we sleep, but we rarely, if ever, stop to consider that our thoughts, actions, and perceptions are the outcome of several trillion signals exchanged among nerve cells. The brain is such an efficient processor of information that most of the time we do not realize the magnitude of its task. Usually only a disruption of the nervous system—through disease or injury or inherited pre-disposition—calls our attention to the brain 's myriad functions.

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DISCOVERING THE BRAIN For instance, what is the “movement center” in the brain that is thought to degenerate in Parkinson's disease? How can chemical compounds in brain cells influence the emotions we feel? Why does injury at a particular site on the head leave some patients unable to recognize an arm or a leg as part of their own body? Neuroscience is the field of study that endeavors to make sense of such diverse questions; at the same time, it points the way toward the effective treatment of dysfunctions. The exchange of information among a half-dozen branches of science and the clinical practice of mental health have shaped a new scientific approach to the study of the brain. The fruitfulness of this approach reaches far beyond the health care and research professions into most people's everyday lives. The research itself has a wide range of applications, from alleviating many hundreds of nervous and mental diseases to enriching the lives of the healthy. Key policymakers supported this research. The United States Congress in 1989 passed a resolution sponsored by Congressman Silvio Conte declaring the 1990s to be the Decade of the Brain. Following the official proclamation by President George Bush, the 1990 symposium on the Decade of the Brain attracted the participation of First Lady Barbara Bush, Secretary of Health and Human Services Louis W. Sullivan, Science Adviser to the President D. Allan Bromley, Congressman Conte, Senator Pete V. Domenici, and others. At the beginning of the 1990s, neuroscience combines mature theory, lively new possibilities for investigation, and technology that can yield information unheard of even a few years ago: the genetic markers for an inherited predisposition toward some mental disorder, or the intimate structure, down to the individual molecules, of a receptor in the brain for a particular chemical compound, or medical images that convey the flow of energy in different areas while the brain manages such tasks as reading and thinking. The end of the decade may see the picture more richly detailed in some areas and changed almost beyond recognition in others. In July 1990, a symposium brought scientists from all over the world to the National Academy of Sciences in Washington, D.C., to discuss the state of the field. Dominick Purpura, professor of neuroscience and vice president for medical affairs at Albert Einstein College of Medicine, Yeshiva University, ad-

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DISCOVERING THE BRAIN dressed the gathering on the subject of “the brain's new science.” He posed three basic questions: What is this endeavor known as the brain's new science? What makes it new? And what can it do for humankind? APPROACHING THE BRAIN FROM ALL ANGLES Neuroscience, in Purpura's thinking, is not a discipline—a statement that may come as a mild shock to some of its practitioners. Neuroscience is, rather, a way to approach specific questions about the structure and function of the human brain, whether in healthy development or when afflicted with injury or disease. Neuroscientific investigation may require the hands-on familiarity of neuroanatomy and physiology, the biochemical framework of neuroimmunology, or the specialized calculations of genetics; it may call for the bright scans of neural images that must be “ read” with an eye for subtle changes, or the observation of full-scale behavior, as studied in neuropsychology; it can involve the advanced mathematics of the computational sciences and the intricate cellular workings of molecular biology. Purpura imagines all these approaches to be like the colors of a rainbow, spread out by a prism. Neuroscience represents the sum of these approaches, the white light by which we can see and understand. Study of the brain can be more illuminating, of course, when it takes in the larger physical system of which it is a part. With all its intricate and powerful circuitry, the brain does not work in isolation. It shares in the circulation of the blood with the rest of the body; its cells require oxygen and nutrients and rely on the body's processes for fighting infection and for repair. Clearly, the physical state of the body can impinge on the brain in good health or in a great number of diseases or disorders that disrupt behavior or hobble the ability to think or feel. And everyone is familiar, if only by hearsay, with the “psychosomatic” headache or back pain that gives physical expression to something experienced in the mind; this is the brain-body influence working in the opposite direction. Enoch Gordis, director of the National Institute on Alcohol Abuse and Alcoholism, offers another example of this interrelationship. Understanding the role of the liver and kidneys in handling drugs

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DISCOVERING THE BRAIN and toxins may be crucial for treating substance abuse and addictions —among the most vexing problems in public health today. Over the years many nonscientists, too, have contributed to neuroscientific knowledge in the role of research subjects, whether in the clinical setting of the neurologist's office or as volunteers performing a cognitive task in the psychology laboratory. The two-way channel of information continues to expand: findings from the laboratory lead toward sharper criteria for diagnosing mental disorders and more effective methods for treating them, and in turn the clinician 's increasingly acute skills of diagnosis and observation supply the research scientist with more precise data for study in the lab. The data under examination in such laboratories often come in forms that would have been unimaginable a decade or two ago. But the research itself proceeds from the same basic ideas that guided the very first investigations in neuroscience. Essential to an understanding of the nervous system is the notion that the body experiences signals, or nerve impulses, both from the outside environment and from its own inner functioning; to keep these numerous signals from producing a chaos of sensation, the body organizes them into patterns. The nervous system, particularly the brain, carries out this task, not only organizing but also translating the signals into information the body can use—to activate a group of muscles, quicken the heartbeat, or recall the sight of a familiar face. More recently, scientists have come up with the idea of a chain of signals, each with its unique function in the series. First are the signals that pass from one whole nerve cell to another by means of electrical impulses or the chemical compounds known as neurotransmitters. Next come the “second messengers,” which broadcast a signal within one nerve cell; in response, a group of enzymes, the protein kinases, may convert another compound in the cell from its inactive state to an active one. The switched-on substance, in turn, acts in conjunction with a possible “third messenger,” a substrate that brings its own chemical factors into the formula. However long the chain of processes may appear, each link adds something necessary and irreplaceable—whether by fine-tuning the signal or by helping to spread it throughout a region.

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DISCOVERING THE BRAIN A scientific principle that has brought together some diverse findings in neuroscience is “parsimony in nature.” Simply put, this is the idea that natural processes or systems first observed in one context, for which they appear beautifully fitted, tend to turn up again in other contexts, sometimes filling other functions—to which they seem equally well suited. The neurotransmitters illustrate this notion: for instance, norepinephrine dilates the blood vessels in muscle tissue but causes the opposite effect, constriction, in the blood vessels of the skin. Thus it appears that nature has conserved the one transmitter and thriftily made it over to another use by having it interact with different receptor sites in the two contexts. Another striking instance of this principle is found in certain physical changes in the nervous system that accompany learning in very simple animals. In the marine snail Aplysia, a newly learned behavior is associated with the growth of signal-transmitting elements from its nerve cells. At the time of this new growth, the levels of cell-adhesion proteins drop briefly but significantly. This change in levels suggests to researchers that the proteins may actually serve to inhibit such extra growth much of the time, when learning is not taking place in the animal. By contrast, outside the brain, cell-adhesion proteins are much better known for their crucial role in the immune system, where they aid in the attachment of disease-fighting antibodies. In yet another context, cell-adhesion proteins may play a still different role in the development of a baby's brain, by guiding the migration of nerve cells to the six-layered cerebral cortex that covers most of the brain like the bark of a tree. “When neuroscience works well, it begins to unify data,” says Dominick Purpura. Such indeed was the effect of a recent feat in the research world: the mapping of the precise connections in the basal ganglia, deep inside the brain. In primates, this region was known in relatively little detail until recently. The basal ganglia are important for the control of movement, for which they receive signals from the cerebral cortex; electrical recordings show both these areas to be active a fraction of a second before a movement takes place. To map the pathways of these nerve signals has called for a solid foundation of anatomy, highly refined techniques for the selective staining of particular cells, and close studies of signal-carrying agents such as

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DISCOVERING THE BRAIN messenger RNA. With the pathways identified, both for nerve impulses that inhibit movement and for those that initiate it, researchers can begin to build new explanations of what goes wrong in neurological diseases that lead to disorders of movement, such as Parkinson's and early-stage Huntington's disease. They may be in a better position, too, to explain less well known diseases such as hemiballism, in which the patient involuntarily undergoes repeated, purposeless movements of the arm or leg that resemble jumping or throwing a ball. Stronger hypotheses about the mechanism of a disease can point the way toward more effective treatment and new possibilities for a cure. In highly complex disorders of the brain, in which many factors— genetic, environmental, epidemiological, even social and psychological —play a part, broadly based hypotheses are exceedingly useful. As Purpura says, “The problem here is to study how the system works, and that's what makes it neuroscience—not whether one is using molecular biology, electrophysiology, or any other particular aspect.” WHAT MAKES THIS SCIENCE NEW? Because neuroscience is so broadly based, drawing on research from many points across the scientific landscape, it is not easy to sort out the elements that make this science of the brain “new.” The fact is that neuroscience has not sprung from a revolutionary theory or a startling reversal of all that was known before; rather, the approach builds on a set of principles that, in scientific parlance, are unlikely to be proved untrue. (This cautious phrasing means that the principles have held up in rigorous testing so far, in a great variety of settings; but scientists stop short of guaranteeing them against future refinements or corrections, since a willingness to test—rather than to keep faith —is a hallmark of science.) One such principle is the current understanding that nerve cells can be excited by both electrical and chemical signals and that both types of signals act by altering the flow of ions (positively or negatively charged particles) into or out of the cell. Another principle holds that the development of the brain allows room for shaping by the environment (everything from nutrition and the family setting to incidence of disease) and that the two shaping forces, environ-

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DISCOVERING THE BRAIN mental and genetic, act on each other in an intricate weave, creating in every person's head a pattern of connections that is unique and yet recognizable within the standard form. Is there something special about the 1990s that makes this .the Decade of the Brain? Enoch Gordis answers this question with an emphatic “yes”: the research that is possible, or is already taking place, represents not just an extension of earlier efforts but a qualitative change. From a base of knowledge about the brain in general, neuroscience is now making the first exploratory inroads into the features that characterize us as human: the ability to create and to calculate, to empathize, to recall and plan, and perhaps even to develop illnesses that are uniquely human, such as schizophrenia or the problems of substance abuse. Advances in technology offer opportunities to examine the human brain not as inert anatomical matter but in its living, functional state. (For a survey of these methods, see Chapter 3 .) Using positron emission tomography (PET), researchers and clinicians can trace changes in activity from one region of the brain to another as the individual carries out a mental task (for instance, recognizing the written form of words and sorting them into categories). More than that: because the imaging computer receives and coordinates an enormous amount of information from a single scan, it is possible to produce a series of images—almost like a dissection—with each image representing a different layer of functioning in the brain. As a result, researchers can focus their studies, for instance, on the cognitive tasks that accompany reading, as distinct from the intricate processing of written words at the purely visual level. With these finer distinctions comes the ability to recognize interacting pathways of information in areas that had been blurred before and to address physiological problems that crop up at specific points along those pathways. Two forms of imaging work particularly well in the brain: PET, with its sensitivity to energy levels, and magnetic resonance imaging (MRI), with its precision of anatomical detail. Other imaging modes offer unique advantages as well: computed tomography, which can clearly distinguish gray and white matter; magnetic resonance spectroscopy, which can measure differing rates of energy metabolism in the course of a disease; magnetic source imaging, which

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DISCOVERING THE BRAIN has yielded some of the most precise information to date on the origin of epileptic seizures; and ultrasound imaging, favored for use with newborns. But the Decade of the Brain is more than a phase of new-and-improved technology; after all, technology is continually being improved. What is novel in the 1990s is the intriguing set of questions that are open to exploration—including some that could not even be framed, much less addressed, as recently as 15 years ago. For example, the role of genetics in several mental disorders was long suspected and is now gaining confirmation, as painstaking studies of heredity covering several generations of afflicted families reveal patterns of inheritance; at the same time, molecular biological studies are closing in on a physical explanation of how particular defects in the genes could ultimately lead to recognizable clinical symptoms. (For a fuller discussion, see Chapter 4 and Chapter 5 .) The magnificent plasticity of the brain—the great degree to which neuronal connections can be affected by environmental factors—is a topic that has also grown well beyond its origins in the study of the visual system. As will be shown in Chapter 6 , plasticity is considered an important principle for understanding the processes that form many other functional areas of the brain as well. Neuroscience also has its own version of parallel processing, which refers to the brain's ability to take in many kinds of perceptual signals through our five senses and to combine them in meaningful patterns (see Chapter 7 ). The increasing sophistication of computer technology, together with current work in artificial intelligence, finds application in neuroscientific studies of learning and cognition. And questions about the physical location of memory in the brain, which have puzzled scientists and philosophers since Aristotle, can be posed more precisely, thanks to cell-by-cell studies of how learning takes place in a variety of nervous systems, from some of the very simplest to the highly complex (as discussed in Chapter 8 ). A rush of technological innovation has recently converged with the momentum of many years of basic research, so that neuroscience is poised for great advances. Research on the brain has always been respected as a specialized line of inquiry within the life sciences; now it takes its place as a major

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DISCOVERING THE BRAIN scientific frontier for our times, bringing together many of the most engaging areas in the study of our own physical nature. A case in point is a specialized brain cell known as the pyramidal neuron. This neuron predominates in the cerebral cortex, the densely wrinkled sheet of “gray matter” that covers the human brain and regulates many of our sensations, thoughts, and characteristically human abilities. With their large cell bodies and their long axons for transmitting signals, pyramidal neurons are excellently suited to their task of bringing together information from one region of the enormously extensive cortex to another; Dominick Purpura only half-jokingly calls them “the acme of biological cellular evolution on earth.” These specialized cells not only transmit signals; they also incorporate into their structure a very effective pattern of sites for receiving signals. Some of the receptor sites are adapted to take up a specific neurotransmitter that inhibits further activity; other receptor sites (pore-like openings in the cell membrane) may respond specifically to calcium. Another part of the pyramidal neuron, the dendrites, branches outward from the main body of the cell; each dendrite sports a number of spines for receiving signals. These spines have become a feature of great interest in recent years because of growing evidence that they may take an active part in cellular processes that accompany learning. Moreover, it appears that structural and functional changes occur in the neurons that transmit the signals, as well as in those that receive them. Thus, the cellular mechanisms of learning may entail some restructuring throughout a region. To observe and explain these changes, neuroscientists call on several disciplines: biochemistry, molecular biology, and electrophysiology, to name a few. THE DEDICATION OF A DECADE What can “the brain's new science” do for humankind? Fortunately, the answers to this question are many. Purpura offers a few: Neuroscience can tell what the brain is made of— something that everyone alive probably wonders about occasionally—and how it takes shape to begin with; how the brain functions as a healthy system in adulthood, and what happens to it in injury or disease. Following from the last point, further

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DISCOVERING THE BRAIN study of the brain can direct researchers and health care professionals toward the prevention of many illnesses, bringing a halt to the ravages that such illnesses visit on millions of patients every year. Enoch Gordis adds another answer: The findings of neuroscience have been vital to recent gains in understanding the addictive disorders, from the genetic and environmental factors that figure into addictions to a clearer view of how drugs (including alcohol) act on the brain and how the injurious cycle of substance abuse can best be treated. Besides the direct application of its findings, neuroscience offers something that is of the greatest value in advanced research today: an overview. The broad perspective of neuroscience makes it possible to bring together disparate problems under a single unifying principle. Specific problems then fall into place as variations on the common principle, each with its appropriate context and function. An example is the action of lithium on brain cells—well established as an effective treatment for manic-depressive illness, but one whose mode of action is not yet completely understood. The strongest hypothesis at present is that lithium works by interfering with the brain's synthesis of a vitamin called inositol. This substance appears to act as part of a chain of chemical signals that affect mood; as a vitamin, though, it is also crucial in embryonic development, and its blockage during a pregnancy can lead to birth defects. Thus, an older observation —that lithium can be harmful during pregnancy—may be explained by the compound's interference with inositol. As another example, the level of calcium in cells can vary widely across regions of the brain and is often a major factor in healthy functioning. Many kinds of cells can take up calcium, but some are unable to remove it again (for example, the neurons of the hippocampus, a brain structure thought to be responsible for short-term memory). As a result, calcium accumulates and eventually destroys the cell. The inability to remove calcium may offer a clue to disorders that involve overactivity in certain brain regions, such as epilepsy, and to some degenerative disorders as well. In many other areas of brain research, too, neuroscience provides a unifying principle for tackling a problem from several angles at once: in the study of brain tumors, injuries of the brain and spinal cord, and dementias

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DISCOVERING THE BRAIN and other mental disorders that show evidence of some physical as well as psychological basis. In the opinion of many researchers, another challenge that awaits neuroscience is the examination of human nature itself and of the destructive strain that humankind seems to carry from one generation to the next like an inherited disease. Human history is dense with examples of aggression against our own and other species, for every imaginable reason and in every conceivable form. Perhaps this tendency is an inescapable part of our nature—or, indeed, of any animal nature. When coupled with the endless capabilities of human intelligence, however, it threatens destruction on a scale that would make any further research irrelevant. The challenge is to come to terms with human aggression before it reduces all our possibilities to silence. Neuroscience, with its theoretical, experimental, and clinical perspectives on the human brain and the human mind, can contribute significantly to meeting this challenge. As mentioned earlier, the Decade of the Brain was launched with a symposium. Under the sponsorship of the Institute of Medicine and the National Institute of Mental Health, many of the world's eminent neuroscientists gathered in July 1990 to discuss some of the exciting results from recent investigations and to plan research strategies for the future—strategies to make the most of the new prospects created by technology and by alliances between the public and private sectors (see Chapter 9 ). Maxwell Cowan, chief scientific officer of the Howard Hughes Medical Institute and chairman of the symposium's steering committee, listed three objectives for the event. First, it was a call to celebrate the great achievements in brain research, the years of painstaking work, at times without evident reward, and the advances—some small, some almost revolutionarily large—that have shaped the field during the second half of this century. Second, the symposium was to bring to the attention of policymakers the rich opportunities offered by neuroscience to address so many of the illnesses and disorders that threaten our country's public health, lower our productivity, and bring about great suffering for millions of Americans every year. Vigorous support for further research during the Decade of the Brain will be crucial if neuroscience is to extend today's experimental results into clinical practice

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DISCOVERING THE BRAIN and to make possible the results of tomorrow and the next 10 years. Third, the symposium was an event for the public: a chance for interested people in all fields to learn about the latest work and to share for a day or two in the heady sensation of surveying a scientific frontier together with some of the leading workers who are currently exploring it. The American public has been and continues to be the principal sponsor of scientific research; and in the study of the human brain, in particular, a great share of the field's excitement, as well as a clear presentation of its principles and methods, is owed to the public. This book aims to present both, with a minimum of jargon and with the optimum of interest and accessibility. Not only as sponsors of research, but as living, thinking exemplars of the infinitely varied creativity of the human brain, we are all entitled to share in the promise of neuroscience. ACKNOWLEDGMENTS Chapter 1 is based on presentations by Maxwell Cowan, Enoch Gordis, and Dominick Purpura.