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Testimony on Neuroscience Research at NIH by Zach W. Hall, Ph.D.
Director, National Institute of Neurological Disorders and Stroke
Carl Kupfer, M.D.
Director, National Eye Institute
Alan I. Leshner, Ph.D.
Director, National Institute on Drug Abuse

U.S. Department of Health and Human Services

Before the Senate Committee on Labor and Human Resources
March 6, 1996

Madam Chairman and members of the Committee, we are pleased to appear before you today to discuss our programs at the National Institutes of Health.

Neuroscience is a relatively new field of biological inquiry. With rare exceptions, the role of the brain in health and disease was not understood until the late nineteenth century. Silent and largely inaccessible except at autopsy,. the brain began to yield its secrets only when advances in surgery allowed scientists and clinicians to visualize it and intervene in its operations. In the last twenty years, advances in imaging, genetics, molecular biology and biophysics have propelled neuroscience into a "golden age" of intellectual discovery and rich practical rewards.

One measure of the pervasiveness of neuroscience can be found in a simple statistic: a recent inventory, of NIH funding documented the involvement of virtually every component for a total of almost $2 billion.. about 18 percent of the total NIH budget. Included in this diverse portfolio are extramural awards racing from investigator initiated studies to sophisticated clinical trials, projects in most components of the NIH intramural program, and research training programs to prepare young scientists for the rapidly, unfolding opportunities in future research.

The nervous system includes the brain and spinal cord, the sensory nerves that convey information to the brain about the internal and external world, and the motor nerves that cam, commands to act from the brain to the muscles and glands of the body. The brain interacts with ever important system of the body. It regulates our breathing, the beating of our heart, the movement and secretion of our gastrointestinal tract and, in cooperation with the endocrine system. maintains the constant internal environment of our bodies. It is also responsible for those features that make us most human: our language. our social interactions, our imagination, our ability to reason, our humor, and, most importantly, our sense of ourselves as individuals.

The brain has been called a three pound universe and the most intricate entity, on earth. Because the brain is so astonishingly complex, it is subject to many disorders including those of our senses. leading to blindness and deafness; cerebrovascular disease, resulting in death or disability; neurodegenerative diseases, mental illnesses, developmental defects. birth injuries, traumatic injury, brain tumors, sleep disorders, viral infections, seizures and autoimmune diseases. The nervous system is responsible for drug and alcohol addiction and it mediates pain, which is the most common of all complaints.

Brain disease strikes all, from the unborn to the elderly, and the success of modem medicine. which has extended life on both ends, has paradoxically created new challenges for brain research. The brains of the tiniest infants, kept alive through recent advances in prenatal medicine, are particularly susceptible to brain damage, and must be protected- at the other end of life. increased ace has put millions of Americans at higher risk of stroke, Alzheimer's disease and Parkinson's disease. Some brain disorders are among the most common of all diseases; others are so rare that a person is unlikely to have heard of them until a family member is affected. Although many brain diseases are lethal, more often they result in years of disability and chronic suffering.

During the last few years, the treatment of brain disease has been transformed by two developments. First, the extent and pervasiveness of brain disease has become more apparent, as the biological basis of such disorders as mental illnesses, alcohol abuse, and other drug addiction have been increasingly recognized. Second, we are entering a area of treatment of brain disease. Traditionally, medicine has had little to offer those suffering from a brain disorder. As we come to understand more about the brain, we are increasingly able to offer effective therapies for the prevention. treatment and rehabilitation of brain disease. The first ever useful treatments for acute stroke, spinal cord injury, amyotrophic lateral sclerosis (Lou Gehrig's Disease), multiple sclerosis and some forms of blindness and deafness have recently become available. A wide range of treatments for mental illnesses has greatly improved the lives of many people. As we learn more about how the brain works, we are better able to devise treatments based on rational understanding. Research on the brain offers the best hope for the tens of millions of Americans who will suffer during their lifetimes from a disorder of the brain.

Neuroscience at NIH

Just as the nervous system interacts with most systems of the body, most components of the NIH contribute to neuroscience research. The diversity of specialties required for neuroscience research the intimate and intricate relationships of the nervous system with other bodily systems. and the heterogeneity of nervous system disorders all make neuroscience research a cross-cutting activity at the NIH. Obviously the implications of many, basic research studies transcend the specific disease categories upon which the individual institutes are focused and many institutes support basic research in the neurosciences. Many diseases also bridge the missions of various combinations of institutes, for example, stroke is both an neurologic and vascular event. Several mechanisms foster cooperation among, institutes. Among these are joint efforts in large programs like the Human Brain Project, joint program announcements, cooperative sponsorship of workshops, less formal regular meetings on particular diseases (e.g. for Alzheimer's Disease), frequent communication among the directors and program staffs of the different institutes, and an intricate web of collaborative efforts among intramural researchers. Issues related to administration and organization of the NIH across institute boundaries are discussed in the report of the director of NIH and will be touched on only briefly, here.

We are here as representatives of all the Institutes, Centers. and Divisions at NIH whose missions include neuroscience research. Many ICDs have a primary focus in neuroscience. They include the National Institute of Neurological Disorders and Stroke, concerned with disorders of the brain, spinal cord, and the motor and sensory nerves; the National Institute of Mental Health. whose efforts are directed at mental disorders and the biological and psychosocial factors that determine human behavior and development; the National Eye Institute seeking to understand vision and its impairments; the National Institute on Deafness and Other Communication Disorders, concerned with hearing, balance. smell, taste, voice, speech, and language; the National Institute on Alcohol Abuse and Alcoholism, focusing on the physical and behavioral aspects of alcohol abuse; and the National Institute on Drug Abuse. seeking to understand the neural bases of drug abuse and dependence. Institutes such as the National Institute of Child Health and Human Development and the National Institute on Aging have research mandates that span many body systems. They have a special interest in neuroscience because of the important place of the brain in development and senescence and the many disorders that afflict the nervous system in early and late life. Examples include Alzheimer's disease, described by the chronic disease panel, and developmental disorders such as autism.

Another group of Institutes approaches neuroscience from a more limited, but deeply committed perspective. The National Institute of Dental Research supports substantial programs in research on pain and disorders of development. Genetics is important in all fields of research, but nowhere more so than in the nervous system; fruitful collaborations with the National Center for Human Genome Research are being pursued by almost every, component involved in neuroscience research. Disorders of the nervous system present special challenges for nursing care, opening up opportunities for joint ventures with the National Institute for Nursing Research.

Still more specific interactions occur among the neuroscience institutes and other Institutes whose missions include disorders that affect, or are influenced by, the nervous system. Thus the National Institute of Arthritis and Musculoskeletal and Skin Diseases has an interest in the pain of osteoporotic fractures and the neurological complications of systemic lupus erythematosus; the National Institute of Diabetes and Digestive and Kidney Diseases looks to neurological research for answers to problems of diabetic neuropathy; and the challenges of treating malignancies of the nervous system. and understanding the factors regulating nerve growth. engage the attention of the National Cancer Institute. Other panels will discuss some of these common interests in more detail. They include the interplay of nervous and cardiovascular systems in hypertension and stroke, as noted in the discussion of research sponsored by the National Heart, Lung, and Blood Institute; the interest of the National Institute of Environmental Health Sciences in the effects of toxins on the nervous system; and the neurological consequences of a host of infectious diseases within the purview of the National Institute of Allergy and Infectious Diseases.

Neuroscience research flourishes in part due to the efforts of other NIH components whose relationship to the brain may be less obvious. You will hear from another panel about the programs of the National Center for Research Resources and the National Library of Medicine. As imaging continues to bring the living brain within recall, and as information continues to come to light these resources will become even more available.

Also important are the research training activities of the National Institute of General Medical Sciences and the efforts of the Fogarty International Center in promoting international exchange and cooperation in neuroscience as in other fields. Understanding the nervous system and its disorders

The writer Italo Calvino imagined a series of conversations in which the great traveler Marco Polo described the cities he had seen to the emperor of China. Each city seemed different from all others but wonderful in its own way. Eventually the emperor realized that Marco Polo was describing the same city each time the emperor's capital) but from a different perspective. Similarly, NIH-supported scientists study the nervous system from many, different points of view, rancing from the behavioral to the molecular. and each continues to reveal new insights like the story, much of the excitement in neuroscience research arises because these views are coming together to explain how the nervous system works and how it breaks down. This overview of several unifying, themes and the promise the hold for the future reflects a convergence of research sponsored by several components of NIH.

Genetics: Genetics is a powerful unifying force and avenue for progress in the neurosciences as in all modem biology. Although genetics will be discussed in more detail by another panel the briefly note its importance here. The brain expresses nearly half of the scenes in the body, and about a third of all known genetic defects affect the nervous system. The genes for more than fifty nervous system diseases have already been discovered with hundreds remaining to be found. The identification of a gene provides new ideas and tools for further research. For some diseases, like Alzheimer's, amyyotrophic lateral sclerosis, and retinal degeneration, insights from less common inherited forms of a disorder point the way to understanding more common, non-inherited forms of the same disease. Ataxia-telangiectasia, on the other hand, is a rare disorder whose genetic basis provides fundamental clues to cellular signaling pathways important in many neurological and immunological diseases and in cancer. Areas of special promise are the molecular genetics of mental illness, alcohol and other drug addiction, hereditary blindness and deafness, and the genetics of complex traits.

Neurotransmitters and receptors: Nerve cells communicate with one another and with other body cells by releasing tiny amounts of chemical signaling molecules called neurotransmitters. A neurotransmitter may excite or inhibit a cell, making it more or less likely, to transmit a signal to the next cell. Some neurotransmitters act in more subtle ways to modulate activity, for example by making a cell more sensitive to other signals, exciting or inhibiting the cell directly.

Each neurotransmitter acts by binding briefly to specialized molecules on the cell surface, the receptors, which translate the binding event into a signal that affects the cell's behavior. Receptors determine the response of the cell to the neurotransmitter. The same neurotransmitter may either excite or inhibit a cell depending on the receptor involved.

For example, when the neurotransmitter acetylcholine released from motor nerves binds to the type of acetylcholine receptor on skeletal muscle it excites the muscle and causes it to contract. when the same acetylcholine released from nerves innervating the heart binds to a different type of receptor it slows the heart.

Understanding neurotransmitter systems has proved crucial to understanding many brain disorders. For example, in Alzheimer's disease cells that release the neurotransmitter acetylcholine are prominent among those which die; Parkinson's disease results when cells which use dopamine as a neurotransmitter die. The neurotransmitter dopamine also plays a key role in addiction, as all known addictions appear to increase the release of dopamine in a certain circuit of the brain. Very recently, there has been a surprising convergence of findings about the role of dopamine in addiction and Parkinson's disease. Although patients who are heavy smokers have been known to have a reduced risk for Parkinson's disease, the connection between the two has been baffling. Recent research has shown that an unidentified component of tobacco smoke inhibits an enzyme the destroys dopamine. These results suggest new approaches for the treatment of smoking and stimulate new thinking about why dopamine cells die in Parkinson's disease.

The central role of dopamine in cocaine addiction has recently been established by research showing that genetic alterations of mice to block dopamine removal yields animals resistant to cocaine that appear to be permanently high. Since cocaine is known to block dopamine removal, these findings suggest that the reward experienced by cocaine users is linked to the excess dopamine that results when its removal is blocked. Alcohol and THC (the active ingredient in marijuana) are also thought to act via specific receptors: alcohol interacts specifically with the neurotransmitter receptors for GABA, glutamate and sectioning; THC acts on a receptor that normally binds a newly-discovered signaling molecule in the brain called anandamide. The genes coding the receptors for each of the drugs of abuse have now been cloned, providing powerful tools for understanding and for treatment development.

One class of addicting drug, the opiates, is also important because of its role in the neural pathways that mediate pain. Pain, both chronic and acute. is a major medical problem. and the need is great for safe, effective pain medications. Opiates have been prescribed by physicians for centuries and are often still the most appropriate drugs for pain relief. Research workers have elucidated the neural pathways that control pain, and identified the sites at which the body regulates pain through the body's natural opiates, which are used as neurotransmitters. Recently a new compound has been found in brain that is opiate-like, but enhances, rather than reduces, pain: orphaning FQ. This discovery should open new lines of research into pain mechanisms, and lead to new treatments for pain.

Receptors are also critical to the most distinctive feature of the mammalian brain: its ability to learn and remember. Glutamate receptors play a vital role in the process by which signaling at synapses is altered by past experience. Recent research indicates that the same mechanisms responsible for learning and memory in the adult also play, a role in the development of the nervous system. Glutamate receptors are also important in understanding disease. Brain injury causes a massive release of glutamate which excites nerve cells. Through a mechanism of "excitotoxicity" resulting from the excessive inflow of calcium into nerve cells, brain cells that become over-excited by glutamate are injured and die. Many of the neurons that are injured after stroke or traumatic injury are thought to die from this secondary cause. One of the most promising lines of current investigation concerns ways in which excitotoxicity can be blocked, thus limiting the damage caused by lack of oxygen or by trauma.

Common mechanisms of nerve cell death: Many brain diseases arise from the death or injury of nerve cells. One of the most exciting opportunities in neuroscience research today comes from the increasing evidence that points to possible common mechanisms in disorders as diverse as stroke and acute injury; slow, degenerative diseases such as amyotrophic lateral sclerosis (Lou Gehrig's disease or ALS), Parkinson's disease, and Huntington's disease; and genetic disorders like ataxia telangiectasia and spinal muscular atrophy. These mechanisms may act alone or in combination to disable and kill nerve cells.

Recent research has shown that cells can regulate their own survival. During development, the nervous system produces more cells than it needs and then eliminates the excess cells. Interestingly these cells do not die by starvation or by being killed by their neighbors, but by a process of suicide or programmed cell death, in which specific death pathways are activated within the cell. These same pathways appear to operate in the adult in some cases of cell damage. Other pathways are known which act to protect cells from suicide. An important theme of current research in this area is to elucidate the pathways by which neurons and other cells regulate their own survival. The ultimate goal of such research is to develop treatments that would strengthen the "survival" pathways and inhibit the pathways leading to death. Experiments in animals have shown, for example. that stimulation of the "survival" pathways can limit cellular damage caused by experimental stroke.

One of the mechanisms by which cells ultimately die appears to be oxidative stress. When cells bum (oxidize) food to extract energy, certain dangerous, highly reactive molecules called free radicals are created as a by product. Much of the cumulative damage that occurs with aging, in all cells may be due to these molecules. There is now evidence that damage from accelerated oxidative stress plays a crucial role in a wide range of nervous system disorders, both acute and chronic. One type of ALS, for example, has recently been shown to arise from a defect in an enzyme that is part of the body's normal mechanisms for combating oxidative damage. The gas nitric oxide (not to be confused with the anesthetic nitrous oxide) provides another important example. Like glutamate, it has a dual personality. It is an important signaling molecule in the brain and vascular system, but under adverse circumstances can contribute to oxidative damage. The possible value of antioxidants for therapy is under investigation in animal models of several neurodegenerative diseases.

Development of the nervous system: For the nervous system to work it must develop properly. The complexity of the nervous system is far beyond the capacity of the genes to specify each detail. How the nervous system develops is one of the great mysteries of biology, a puzzle whose solution has profound implications for the treatment of disease, not limited to the explicitly developmental disorders. Understanding of how the nervous system develops is progressing rapidly on many fronts including understanding to the factors that control specialization of cells, the factors that guide the formation of appropriate connections and the mechanisms by which experience contributes to shaping the nervous system.

Nerve cells often migrate long distances from their place of birth in the developing nervous system, distances equivalent to a person traveling from New York to California. Cells also send their axons (the long electrically conductive fibers) over even greater distances to ultimately select and establish precise connections from among the billions of possibilities. Recently there has been substantial progress in understanding the molecules that guide these travels. They include both short-range (cell-to-cell contact) and long-range (diffusible) signals. In both cases the signals may act to attract or to repel. Progress in this as in many areas of neuroscience, has benefited greatly from the correspondence of findings in manuals with those in simpler systems that are much more accessible to experimental manipulation. Some families of molecules, for example guide neurons in similar ways in nematode worms, insects, and mammals, an evolutionary conservation that testifies to their fundamental importance.

Activity, is also crucial in refining the precision of the brain's wiring. The influence of activity brain wiring has been most carefully studied in the development of the higher brain areas responsible for visual processing where "critical periods" for the influence of experience have been demonstrated. The same glutamate receptor that is crucial for learning, also plays a key role in development. Recent findings have shown that activity can also regulate short-range guidance cues and that environmental stimulation can regulate programmed cell death.

The growth and survival of nerve cells during development depends on specific neurotrophic factors. Cells that do not establish an adequate supply of their growth factors usually supplied by the appropriate targets, undergo programmed cell death. Such factors continue to operate in the adult brain and their possible role in neurodegenerative orders is a subject of active investigation.

By understanding the normal agents and events that direct the development of the nervous system, researchers gain insight into the inherited disorders of the nervous system, developmental disorders such as cerebral palsy and autism, and the vulnerability of the developing brain to many types of insult. For example, in pregnant animals alcohol and cocaine have been shown to disrupt the migration of nerve cells and schizophrenia may be caused by disturbances in brain development before or shortly after birth. There is also the tantalizing prospect that the signals that control development can be harnessed to coax useful compensation following spinal cord injury or stroke, to slow or reverse neurodegenerative diseases, and to facilitate cell transplant and gene therapy strategies for nervous system diseases. Neurotrophic factors have already demonstrated their potential to save dying nerve cells in animal models of neurodegenerative diseases and some encouraging regrowth of damaged spinal cord nerve cells has been demonstrated in animals when growth inhibitors present in the spinal cord are neutralized and growth promoters are provided.

Pathways and functional organization of the brain: Understanding the brain requires more than knowing about molecules and cells. One must also understand how billions of cells interact in the complex neural circuits that form our brain. New techniques in computation. in imaging, and in behavioral studies give us new insight into how the brain is organized. Imaging offers us a non-invasive look at the working brain. Observing the activity of the brain during carefully designed perceptual and intellectual tasks is helping, to understand how the brain organizes the world and how its function is chanced by, disease, by drugs, and even in learning disabilities. For example researchers now can determine which parts of the brain are active while we move, while we see or hear, or even while we think. Neurotransmitter receptors and metabolism in different parts of the brain can be followed during normal and pathological function. Powerful new computer techniques are being, developed to mine the wealth of information these image's provide. Potential clinical applications include guiding surgeons treating epilepsies by mapping the location of critical functions near the epileptic focus.

The imaging studies complement research on animals using more invasive techniques for investigating the structure and function of the brain. These studies together have defined the pathways that underlie many aspects of behavior and disease in terms of anatomy, physiology, and the neurotransmitter systems that are involved. For example, real insights leave been gained in understanding the reward pathways that drive many addictions and how substances like cocaine act on those circuits. The peripheral, spinal cord and brain circuits controlling pain have been intensely studied. Circuits controlling sleep are becoming better understood with important clinical implications; for example, in some Sudden Infant Death Syndrome (SIDS) infants decreased neurotransmitter activity occurs in a relying of the brainstorm that controls breathing in response to elevated carbon dioxide during sleep. The complex circuitry controlling voluntary movements has also been a focus of attention. Understanding how the balance of pathways driving and inhibiting movement has been disturbed in Parkinson's disease has led to the development of a surgical procedure to restore that balance; preliminary results in patients have demonstrated very encouraging improvements in some cases and further evaluation of the procedure is continuing.

Any normal child can rapidly perceive and act on the visual environment better than the most advanced supercomputers. Much of the brain's computing power results because of its "parallel processing" design, a design in which the brain carries out different analytical functions simultaneously, rather than in succession like a computer. Much of our understanding of parallel processing in the brain comes from investigating how higher brain centers process visual information. The brain has not just one "map" of the visual world. but several, each optimized for different functions, such as detecting motion color, or recognizing an object. These insights, which are rapidly being tested in humans with imaging techniques, may help explain some of the highly specific Neurological deficits that may follow brain damage. such as disturbances in the ability to respond to colors and to faces.

The last few years have seen dramatic changes in our understanding of how much change the adult brain can undergo. Until recently circuits in the brain were assumed to be fixed once brain development was completed. Convincing evidence has now shown that the "maps" by which the auditory, somatosensory, and visual areas in the adult cerebral cortex represent the external world reorganize when the source of sensor, input is altered as with damage to the cochlea or to peripheral nerves easing signals from touch and pain sensors) or when patterns of activation chance. Similar changes have been found in the parts of the brain controlling movements and may participate in some types of motor learning. Such reorganization of brain circuits has recently been shown to underlie the phantom limb" sensation that persons with amputations often experience (and to suggest new treatment approaches); it can also contribute to the neuropathic pain that may follow stroke and may be responsible for some of the recovery of function that more fortunate stroke victims experience. Reorganization may also help explain why auditory perception in children with cochlear implants continues to improve for years after the initial implantation. Obviously learning more about the potential of the adult brain to reorganize--and how to facilitate useful reorganization--has far reaching ramifications

Treating and Preventing Nervous System Disorders

The ultimate aim of brain research is to discover effective means of treatment, rehabilitation and prevention for disorders of the nervous system. The development of new treatments requires years of painstaking research, as a new idea is brought from the laboratory. tested in animals, and. through a series of clinical trials of increasing size and complexity, its worth and safety established in humans. Research with human patients is one of the most difficult and demanding of all types of biomedical research, requiring rigorous design to yield reliable information and at the same time protect the interests of the patients. Although expensive and difficult, such research represents the ultimate payoff for our efforts. The complexity of the brain, the fact that it is shielded from the rest of the body by the blood-brain barrier. and the limited capacity of the brain to repair itself have meant that few treatments for brain disorders have been available for testing. Fortunately, that has begun to changed. At an ever-accelerating pace, progress in both basic and clinical research has provided new ideas, new techniques and new drugs for the treatment of brain disease.

The need for treatment is obviated when brain disease can be prevented. Often preventive measures are as simple as taking, a vitamin supplement; in other situations, surgery may be effective. Whatever the measure, proving that it is effective is only the first step; education of both the general public and physicians are essential to ensure that the fall benefits of prevention are realized. The key problem in implementing effective prevention is often to change the behavior of those who see no immediate risk. Thus research and education must go hand in hand. As we understand better the cause of disease, our ability to devise preventive measures is increased.

We cite several examples in which effective measures for treatment or prevention of brain diseases have become established. We believe that these examples provide but a taste of the future when examples of successful prevention and treatment of brain diseases will abound.

Mental disorders: Mental disorders have a devastating impact on individuals, families, and society. The suffering is compounded and treatment often obstructed by attitudes that fail to recognize the biological contribution to such disorders. Almost 5 million Americans suffer from the most severe forms of mental illnesses. Modem approaches to the treatment of mental illnesses have meant that for fully 80 percent of patients, their illness can be successfully treated or ameliorated. In fact. the focus of treatment research has shifted to developing treatments for those patients whose mental illnesses are resistant to treatment. or who suffer residual symptoms or unpleasant side effects from existing treatments.

Clinicians now have effective therapies for anxiety disorders which strike almost 27 million people sometime during, their lives and were once largely untreatable. Four of the most serious anxiety disorders are obsessing compulsive disorder (OCD), phobias, panic disorder. and post-traumatic stress disorder (PTSD). Although all share a central, primary symptom of intense anxiety, each anxiety disorder is thought to originate from distinctly different neuronal and psychological mechanisms. As one example, a new family of antidepressant medications, when combined with sophisticated behavioral therapy, reduces symptoms in 80 percent of those with OCD, a disease for which there was little hope only a few years ago. For treating panic disorder and post-traumatic stress disorder, recent research has underscored the therapeutic value of combining medication with behavior therapy. Investigators hope to extend these promising findings to develop combination treatments for other anxiety disorders.

Untreated, the manic episodes of manic depressive illness (bipolar disorder) are life-disrupting. In manic depressive illness, which affects 1.2 percent of the adult population, depressive episodes alternate intermittently with manic ones. Symptoms such as hyperactivity, explosive temper, impaired judgements, delusions, and insomnia severely handicap a person's capacities to interact with others and to pursue the normal activities of daily living. Although the mood stabilizer lithium is effective in treating the majority of persons with mania. a significant proportion of those with the illness--an estimated 20 to 30 percent--do not respond to, or tolerate, lithium. In a new randomized, double-blind, placebo- controlled trial, investigators showed that divalproex treats mania effectively in a significant number of lithium non-responders, providing a needed treatment option for patients with bipolar disorder.

Major clinical depression (unpopular depression) exists when persistent depressive thoughts and mood are accompanied by physiological disturbances in sleep, appetite, actitively low cost. can reduce antisocial behavior and head off more serious conduct problems in adolescence. Another research program, involving teachers and parents, is demonstrating that it may be possible to prevent many instances of child abuse and in the process, strengthen the bonds among family members.

Alcohol and drug addiction: Advances in the neurosciences have revolutionized our view of alcohol and other drug abuse. Convergent evidence has taught us that these are fundamentally brain disorders, but disorders that are expressed in behavioral ways in a social context. Progress in understanding has led to progress in treatment.

Naltrexone was recently approved by the FDA for the treatment of alcoholism. In clinical trials naltrexone was shown to be very effective in reducing both alcohol craving and alcohol consumption. Naltrexone is a medication that binds to the body's naturally occurring opiate receptors and its use in alcoholism treatment is a direct result of advances in our understanding of basic neuroscience. A variety of other promising compounds are also being, tested throughout the U.S.

Researchers have capitalized on the considerable body of information about brain opioids to develop medications for treating opiate addiction. For years, methadone and naltrexone were the only treatment medications available for physicians to prescribe for opiate addiction. The limitations of these drugs led to an intense search for other medications. The firtively low cost. can reduce antisocial behavior and head off more serious conduct problems in adolescence. Another research program, involving teachers and parents, is demonstrating that it may be possible to prevent many instances of child abuse and in the process, strengthen the bonds among family members.

Alcohol and drug addiction: Advances in the neurosciences have revolutionized our view of alcohol and other drug abuse. Convergent evidence has taught us that these are fundamentally brain disorders, but disorders that are expressed in behavioral ways in a social context. Progress in understanding has led to progress in treatment.

Naltrexone was recently approved by the FDA for the treatment of alcoholism. In clinical trials naltrexone was shown to be very effective in reducing both alcohol craving and alcohol consumption. Naltrexone is a medication that binds to the body's naturally occurring opiate receptors and its use in alcoholism treatment is a direct result of advances in our understanding of basic neuroscience. A variety of other promising compounds are also being, tested throughout the U.S.

Researchers have capitalized on the considerable body of information about brain opioids to develop medications for treating opiate addiction. For years, methadone and naltrexone were the only treatment medications available for physicians to prescribe for opiate addiction. The limitations of these drugs led to an intense search for other medications. The first result of that search. a drug called LAAM, was approved by the FDA in 199' ). It offers advantages over previous drug's, including dosage, and is intended to provide the treatment community with more options and improved treatment matching for patients. Buprenorphine, another new medication for heroin dependency, is now ready for review by the FDA.

Substantial progress is also being made toward the development of an anti-cocaine medication. Based on extensive basic research in how cocaine acts on the brain several potential anti-cocaine compounds have been identified and are currently being tested Most recently researchers have successfully immunized rats against the psychostimulant effects of cocaine and opened up the possibility of developing a vaccination against cocaine addiction.

Retinal disorders. Diabetic retinopathy, is a potentially blinding disease of the retinal blood vessels that affects half of the 14 million Americans with diabetes. Because the retina. as part of the central nervous system, has very limited capability for self- repair, the development of treatments that halt the progression of retinal disorders is particularly crucial. Research has now established laser surgery as a safe and effective treatment for diabetic retinopathy'. A recent study indicated that with timely laser surgery and appropriate follow-up care, even people with advanced diabetic retinopathy have a 90 percent chance of maintaining, vision. Other recent research has established that laser surgery can slow vision loss in some people with macular degeneration. This form of retinal degeneration. which affects about 100,000 Americans. was previously considered untreatable.

Stroke: Stroke is the third leading cause of death in the United States. About one third of the people who experience strokes suffer long-term disabilities, including about two million Americans today. An emergency program to treat the most common type of stroke within three hours has changed the outlook for and thinking about this disorder. In a clinical trial, the drug t-PA administered to dissolve the offending clot and restore blood flow increased the chances for a compete recovery by 30 percent. As the first convincing and effective treatment for acute stroke, this work initiates a new era in which stroke, for the first time, is considered a treatable disease. Just as important, the results of the t-PA study provide dramatic impetus to patient care systems to regard stroke as a treatable emergency with a critical window (a "brain attack") and offer real world models of how community care systems can organize to provide swift high quality care.

National programs of educating the public about stroke risk factors and hypertension control have contributed to a reduction of stroke deaths by 50 percent in the United States. A series of recent clinical trials demonstrated further progress in preventing the catastrophic effects of stroke in selected patient groups. A surgical procedure to remove blockage in the carotid artery leading to the brain can reduce the risk of stroke in people who have experienced a stroke or warning sign of a stroke, and is also effective in carefully selected individuals who have no outward sign of disease but are at risk for stroke because of severe narrowing of the artery. Another type of stroke, caused by a blood clot originating in the heart, occurs in older people with a heart arrhythmia called atrial fibrillation. Initial findings that two blood-thinning agents-- aspirin and warfarin-can reduce the risk of stroke was recently expanded to show that aspirin is just as effective as warfarin for many of these patients who do not have additional risk factors for stroke. This is good news for patients with a trial fibrillation since warfarin is significantly more expensive and must be monitored regularly. These studies complement findings demonstrating that cigarette smoke can quadruple the risk of stroke and cessation of smoking can remove the risk and that reducing high blood pressure at all ages, including old age reduces the risk of stroke.

Spinal cord injuries: About 200,000 Americans are permanently confined to wheelchairs because of spinal cord injuries. Each year, about 10,000 more people are injured, suffering paralysis and loss of sensation. About two thirds of these people are under 10. Surgical intervention may prevent further compression damage improvements in managing the devastating complications have reduced mortality rates; and specialized rehabilitation programs are now available. For the first time, a treatment to minimize damage has proven effective. High doses of the steroid drug methylprednisolone, given promptly, to persons with spinal cord injury, can significantly reduce the extent of neurological damage. In the laboratory encouraging studies have demonstrated that spinal cord nerve cells grow, contrary to previous belief. if the conditions are right.

Senson and motor disabilities: Neural prostheses are devices that connect with the nervous system electrodes to provide sensors input or stimulate muscle responses in persons with sensor, or motor problems. The development of practical prosthetics requires solving many problems of engineering, establishing long term compatibility with the body and understanding how the nervous system codes information. NIH has supported the continuing development of the cochlear implant for the hearing impaired, the first neural prosthesis to gain widespread clinical acceptance. The development of neural prosthetics for persons with spinal cord and other injuries also continues. Recently quadriplegic individuals have regained significant hand function using a neural prosthesis. Research on other functional neural stimulation prosthetics is continuing, including, for example, explorations of microstimulation as a means of enhancing the tactile sensation of persons with amputations and development of implanted stimulators for use in managing, the bowel and bladder function of persons with spinal cord injuries.

Multiple sclerosis and optic neuritis: Multiple sclerosis is a life-long, disorder that strikes young, adults, causing muscle weakness or rigidity, difficulty with balance, vision problems. and paralysis in about 300.000 Americans. Accumulating, data from research in humans and in animal models of multiple sclerosis has led to increasing understanding of the role of the immune system in this disease. The body's own immune system apparently contributes to the destruction of the insulating myelin sheaths that cover the long, projections of nerve cells. That destruction is the hallmark of the disease. NIH supported preliminary "pilot" clinical studies with immune modulators for the treatment of multiple sclerosis in the 1970's and 1980's. Several such drugs are now undergoing clinical trials supported by industry; one, interferon-beta, has received FDA approval and others are pending approval. Still more drugs are in experimental stages of development.

Over half of all people with first-time optic neuritis, a vision- impairing inflammation of the optic nerve that affects more than 25,000 Americans each year, will eventually develop multiple sclerosis. Based on data from two years of follow up of patients enrolled in the Optic Neuritis Treatment Trial, researchers found that treating first-time optic neuritis patients with a combination of intravenous and oral corticosteroids lowers their risk of developing multiple sclerosis. The results from this research offered the first scientific evidence that intravenous administration of corticosteroids helps to delay the progression of multiple sclerosis. It also suggests that this treatment may provide similar benefits for people that have other early symptoms of multiple sclerosis, as well as optic neuritis.

Birth defects and prematurity: Effective prevention of brain disease often starts before birth. Recent research has shown that vitamins taken by the mother can dramatically influence the risk that the nervous system of the growing fetus will develop improperly in utero. Research has shown. for example, that taking, the simple vitamin folic acid can sharply reduce defects in formation of the spinal cord, such as spina bifida. In contrast, too much vitamin A, well beyond the recommended daily allowance, can increase the risk of birth defects involving the face, head and brain.

The brains of babies who are born prematurely are at an early developmental stage, and are particulary susceptible to damage of the brain. Effective preventive measures, however, can limit their risk. Blindness due to retinopathy is particularly common in premature infants, but a recent studies has shown that it can be reduced over 50% by the simple technique of briefly freezing, the outer part of the retina. Savings to society of as much as $20 to $60 million could be realized as the result of this one finding. The brains of premature infants are especially prone to bleeding in the brain, known as intraventricular hemorrhage (IVH), often leading to severe neurodevelopmental problems. Researchers have found that this danger can be largely prevented by treatment of the babies with indomethacin.

Brain damage in premature infants often results in cerebral palsy, leading to a lifetime of disability. Some 30% of all cases of cerebral palsy are now thought to arise in this way. In a retrospective study researchers have found that treatment of the mother with magnesium sulfate (Epsom salts) is associated with a decreased incidence of cerebral palsy in very low--birth weight infants. NIH is currently examining the feasibility of a large. prospective clinical trial to evaluate this treatment as a preventive measure for premature infants at risk for cerebral palsy.

Fetal alcohol syndrome (FAS) is a serious disorder with physical and mental deficiencies that are costly to treat and rehabilitate and which often require long-term care. Prior to 1973 the cause of these defects was not known. NIH has supported a broad range of work aimed at preventing FAS and at understanding how alcohol affects the developing nervous system. Among other extensive efforts to inform the public about this preventable disorder, NIH has collaborated with the FDA to devise an appropriate warming label for alcoholic beverages.

Another important measure for preventing damage to the developing brain is to reduce the likelihood of low birthweight among newborns. Investigators have found that daily zinc supplementation, in appropriately selected pregnant women with relatively low concentrations of the mineral. is associated with increased infant birth weight and head circumference.

Finally, the importance of education and changing behavior in preventing disease is illustrated by the use of antenatal steroid treatment to reduce the risk of intracranial hemorrhage, respiratory distress syndrome or death in preterm infants. Although the effectiveness of antenatal steroid treatment has been well-established by clinical trials and epidemiological data, it has not achieved widespread acceptance among health care providers. To address this problem, NICHD, OMAR, NHLBI and NINR co-sponsored a Consensus Development Conference entitled, "The Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes". The conclusions of the conference were widely publicized. As a result, antenatal steroid treatment in one large test group was increased from 10 per cent before the conference to over 60 per cent following the conference. The continuing long-term impact is being further monitored.

Sudden Infant Death Syndrome: The impact of parental education as a preventive tool has been clearly demonstrated for Sudden Infant Death Syndrome (SIDS). SIDS is the leading cause of death in infants from one month to one year of age. Nearly 6,000 U.S. infants, more than one in 1,000 live births, die of SIDS each year. In 1992 the American Academy of Pediatrics recommended that infants be placed on their back or side to sleep to reduce the incidence of SIDS. NICHD led coalition of agencies aimed at getting this "Back to Sleep" message out to parents. The Institute reported in the fall of 1995 a national telephone survey of caretakers of infants born in the previous seven months that indicated infant sleeping practice has changed from 70 percent of infants being placed on their stomach to 70 percent being placed on their back or side to sleep. Basic research has also recently provided important clues about the causes of SIDS.

Neurodegenerative disorders: More than half a million older Americans have Parkinson's disease, a disorder that progressively impairs control of body movement, interferes with such abilities as walking and talking and often leads, over time, to rigid immobility. The disease results from the death of nerve cells using the transmitter dopamine in part of the brain. Treatment with the drug combination levodopa/carbidopa helps restore dopamine and can restore movement control early in the disease, but the treatment loses effectiveness as the disease progresses. A new drug called RO 40-7592 prolongs the effectiveness of the standard treatment by more than 60 percent by slowing the breakdown of dopamine and levodopa. The findings of this small study are being further tested. A surgical treatment has also shown promise in some patients and is now undergoing further trials. The procedure, called pallidotomy, attempts to restore the balance between brain pathways that activate and inhibit movement.

Errors in the diagnosis of individuals with various neurodegenerative disorders can have serious consequences. For example, progressive supranuclear palsy (PSP), a rare disease, is often misdiagnosed as the more prevalent Parkinson's disease because the two diseases share many motor symptoms and signs. Because PSP does not respond to medications for Parkinson s disease, the misdiagnosis can delay appropriate intervention. Research has revealed that testing of the sense of smell may be useful in the differential diagnosis of individuals in the early stages of PSP. Further, the application of contemporary imaging and molecular biologic techniques to biopsies of olfactory sensor tissue may prove useful in the early, diagnosis of brain diseases, such as Alzheimer's disease, in which the olfactor neurons are the only affected neural tissue that can be readily obtained from living patients.

We hope this statement conveys a sense of the challenges and opportunities in neurosclence research. Our citizens are already benefiting from advances in prevention and treatment. and there is every reason to expect that we will have even more exciting news to report at this committee's next review of NIH programs.

This concludes our remarks. We would be pleased to answer any questions you may have.

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