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Justification of Appropriation Estimates FY 2002

Authorizing Legislation: Sections 301 and 457 of the Public Health Service Act. Reauthorizing legislation will be submitted.

FY 2000 Actual
FTE: 597
BA: $1,029,783,000

FY 2001 Estimate
FTE: 625
BA: $1,177,020,000

FY 2002 Estimate
FTE: 637
BA: $1,316,448,000

Increase or Decrease
FTE: +12
BA: +$139,428,000

This document provides justification for the Fiscal Year 2002 activities of the National Institute of Neurological Disorders and Stroke. Description of NIH-wide Fiscal Year 2002 HIV/AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)."


The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to reduce the burden of neurological disease through research on the healthy and diseased brain, spinal cord, and nerves of the body. Trauma, infections, toxic exposure, birth defects, degenerative diseases, tumors, gene mutations, systemic illness, vascular events, nutritional deficiencies, adverse effects of essential treatments, and many other insults can disrupt the functions of the nervous system. Some neurological diseases, familiar to most Americans, are among the leading causes of death and disability-stroke, brain and spinal cord trauma, chronic pain, Alzheimer's disease, and epilepsy, to name a few. Others-literally hundreds-are unknown to most people, until a friend or relative is stricken. A few points illustrate the burden nervous system disorders impose on every age group and every segment of society:

  • Stroke is the third leading cause of death and a major cause of serious disability. New figures that better reflect the diversity of the U.S. population indicate that more than 700,000 people have strokes each year.
  • The Centers for Disease Control and Prevention estimates that 5.3 million Americans are living with disabilities from brain trauma, in addition to more than 50,000 deaths per year.
  • Numbers are difficult to come by, but pain is the leading reason people visit a physician, and chronic pain conditions are highly prevalent and difficult to treat.
  • Neurological disorders that begin in childhood impose burdens on children and families that are enormous when measured in years of disability or life lost. Epilepsy, which affects 2.5 million in the U.S., most often begins in young people. Cerebral palsy challenges 750,000 Americans from earliest years. Autism affects about 400,000 and may be increasing in incidence. Brain tumors are the second leading cause of cancer death for children under 15. Hundreds of inherited neurological disorders affect children and, though individually often rare, collectively cause great suffering.
  • Disorders that affect adults also cause many years of disability, lost life, and economic impact. Multiple sclerosis typically begins about age 30; two-thirds of spinal cord injuries occur in people younger than 30; and brain trauma is most common in young adults. With changing demographics, neurological diseases that affect older Americans are increasing. The incidence of Alzheimer's and other dementias, stroke, and Parkinson's disease increase substantially in persons over 60. Epilepsy and head trauma also show secondary peaks in the elderly.
  • Creutzfeldt-Jakob disease, and the related bovine spongiform encephalopathy ("mad cow disease"), serve as a reminder that rare disorders can have a disproportionate impact on public health concerns, such as the safety of the food and blood supplies.

[Note: Except where indicated, burden of illness figures in this document are from Disease-specific Estimates of Direct and Indirect Costs of Illness and NIH Support, 2000, DHHS, and Progress and Promise, 1992, Report of the National Advisory Neurological Disorders and Stroke Council.]

The intricacy of the brain is almost incomprehensible, and its mechanisms are elusive. The brain and spinal cord, encased in bone, surrounded by fluid, and isolated by the blood-brain barrier, are difficult to access, sensitive to intervention, and reluctant to regenerate following damage. For these reasons nervous system disorders have always been among the most difficult diseases to treat. Progress in treating neurological disorders often occurs in small steps, and, for most diseases, future improvements are likely to continue on an incremental course. Looking back over the last decade, however, remarkable advances are evident: the first acute treatments proven to improve outcome for stroke and spinal cord injury; drugs that ameliorate symptoms of multiple sclerosis and may slow disease progression; an increased range of drug and surgical options for treating epilepsy and for Parkinson's disease; electronic-mechanical devices that help compensate for sensory and motor disabilities; better diagnostics from molecular genetics and brain imaging; and progress in preventing strokes and neurological birth defects. What is more, an encouraging array of new treatments are under development to counteract symptoms, slow progression, or even undo damage to the brain. These include drugs, vaccines, electrical stimulation, cell transplantation, natural growth factors, neural prostheses, gene therapy, and behavioral intervention. For the first time the words "cure" and "repair" have entered the vocabulary of possibilities for many disorders of the nervous system.

Guided by extensive planning efforts, responding to developments in science, motivated by public health needs, and empowered by favorable funding, NINDS has accepted the challenge of more actively leading the scientific community toward the goal of reducing the burden of nervous system disorders. The following describes the scientific context, with some recent highlights of progress, and then describes actions the Institute is taking.


Understanding the nervous system and its diseases

Common themes in neurological diseases and fundamental neurosciences: One remarkable aspect of progress in neuroscience is the growing web of connections among research on different neurological disorders. Neurodegeneration-the death of cells in the nervous system-has usually been associated with classical neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS). Now scientists recognize that progressive cell death, often following similar mechanisms, occurs in many inherited childhood neurological disorders, epilepsy, multiple sclerosis, visual and hearing loss, in the wake of stroke and trauma, and even in psychiatric disorders such as chronic depression. For example, the neurotransmitter glutamate, which nerve cells use to excite one another, triggers "excitotoxicity" when excessive amounts accumulate. Excitotoxicity not only damages brain cells in injury and stroke, but also in ALS and Parkinson's and probably in many other diseases as well. Another common element of many diseases is apoptosis, or "cell suicide," a step-by-step program by which cells actively participate in their own death. Apoptosis helps shape brain circuits in normal development, but also comes into play in acute and chronic neurological disorders. Other recurring themes include "free radicals," signal transduction pathways (cells' biochemical command and control systems), immune-nervous system interactions, natural growth factors, plasticity, and gene expression. Confronted by hundreds of neurological disorders, it is encouraging that efforts against each will contribute to progress for others. Recent efforts to control cell death illustrate the trend.

Caspase inhibitors: In many neurological disorders nerve cells die by activating a process called apoptosis, or "cell suicide." Apoptosis is a step-by-step program though which cells actively disassemble themselves and die. A critical series of steps in that program involves a family of enzymes called caspases. Scientists have now demonstrated, through various pharmacological and genetic manipulations, that blocking caspases can reduce nerve cell death in animal models of stroke, trauma, and neurodegenerative diseases, including Huntington's and ALS. Efforts are underway to develop safe and effective means to block apoptosis in humans with neurological disorders.

Minimizing damage following spinal cord injury: Finding a cure for spinal cord injury is a dauntingly complex problem. One aspect is minimizing the "secondary damage" as cells continue to die in the hours and days following initial trauma. Several years ago NINDS supported trials proved that the steroid drug methylprednisolone can help in this respect, and this treatment is now standard practice for acute spinal cord injury. In separate efforts to improve on this strategy, scientists this year demonstrated in rats that injection, following spinal cord injury, of a natural growth factor FGF2 (basic fibroblast growth factor), of TTX (a toxin that blocks electrical activity), of DNQX (a drug that blocks certain actions of the neurotransmitter glutamate), or of interleukin-10 (an immune system signaling molecule) can reduce spinal cord damage following injury. Most scientists believe that a combination of approaches to minimize damage and to foster regeneration will be the best strategy for reducing the enormous burden imposed by spinal cord injury.

There is another sense in which themes are converging in neuroscience, and that is between fundamental neuroscience to understand the brain and research focused on specific diseases. It is tempting to think of a one-way path from basic neuroscience studies of how the brain works, through understanding of how disease disrupts this function, to development of treatments. In fact there has always been a mutually productive interchange between clinical and basic science, and these days the interaction is so intertwined that its often impossible to separate. To take one example, which carries a certain irony, studying the brain mechanisms of learning is a focus of fundamental brain science. Researchers are finding that the same components of the glutamate neurotransmitter signaling system that adjust synapse strength during learning are those that contribute to excitotoxicity when too much glutamate accumulates during various disorders. Another fulcrum of interaction arises from studies of inherited diseases that implicate defective genes whose normal function is unknown, or reveal added functions to known proteins, unlocking whole new areas of biology. The discovery of mutations in the protein dystrophin that cause Duchenne muscular dystrophy, and more recently parkin and synuclein in Parkinson's disease, huntingtin in Huntington's disease, and ataxin in spinocerebellar ataxia illustrate this aspect. Similarly the role of "prions" in the rare disorder Creutzfeldt-Jakob disease and in bovine spongiform encephalopathy ("mad cow disease") have opened new areas of biology. One of the least understood and most important aspects of all science is the "higher" functions of the brain, including complex emotions, thinking, and their development. Clinical human studies have always been particularly important sources of clues, and studies using brain imaging combined with psychological testing show how clinical studies are continuing to provide insights about normal brain functions.

Neural Circuitry of Emotion Regulation: After many years of relative neglect, neuroscientists are again embracing emotion as a legitimate research topic. New findings help to explain how the brain makes decisions and how emotions influence that process. These studies rely upon brain imaging to visualize areas of damage and to monitor brain activity coupled with cognitive and psychological testing. Among the findings arising from this work are demonstrations that damage to specific parts of a widely distributed brain "emotion" system may cause difficulties with tasks usually thought of as cognitive, such games of risk, or problems with acquisition of knowledge about accepted standards of moral behavior, despite apparently normal intellect. Previously well adapted individuals with damage to certain areas of the brain become unable to observe social conventions or to decide advantageously on matters pertaining to their own lives, despite well preserved learning, memory, language, attention and other intellectual functions. These findings have direct implications for understanding several psychopathologies, for serious consequences of brain injury in children and adults, and for insights into the biological mechanisms of normal cognition and emotion.

Genes and the nervous system: Perhaps it is obvious that this year's milestones in research on the human genome, and advances in molecular genetics generally, have many ramifications for neurological disorders. What may not be apparent is the extent to which genetics has become a unifying theme across all areas of neuroscience and the range of applications that genetic research brings to neurological diseases.

The most immediate connection of genetics to neurological disorders is in the realm of diseases caused by defects in single genes. More than half of human genes are expressed-that is, active-in the brain, so it's not surprising that many gene defects have consequences for brain function. In all, clinical scientists working together with molecular biologists have identified well over 200 single gene defects that are linked to neurological disorders. These include several forms of muscular dystrophy, ataxias, epilepsy, inherited forms of Parkinson's, ALS, and Alzheimer's, Huntington's disease, Tay-Sachs, Canavan, all forms of Batten disease, several leukodystrophies, spinal muscular atrophy, and many others. The December 1999 announcement that scientists had, for the first time, read the genetic code for a complete human chromosome (#22) illustrates the point. Scientists are still working to understand what it all means, but already genes on chromosome 22, the second shortest chromosome, have been implicated in a type of pediatric brain tumor, a variant of the movement disorder spinocerebellar ataxia, severe mental retardation, a type of epilepsy, neurofibromatosis type 2, meningioma (another form of brain tumor), and metachromatic leukodystrophy.

Although defects in single genes cause many neurological disorders, the contribution of genes to disease is usually not so simple. More often the combined influence from multiple interacting genes affects the susceptibility to and progression of nervous system disorders. Scientists are only beginning to understand these intricate interactions of genes and environment. Recent scientific advances in multiple sclerosis illustrate the complexities of the problem.

Unraveling the complex genetics of multiple sclerosis (MS): Physicians have recognized for many years that the susceptibility to multiple sclerosis may be inherited, but the genetics of this disorder are probably complex. The complexity may reflect several genes that act together in a given individual to confer susceptibility, perhaps different genes in different patients, and possibly more than one underlying cause. A few years ago a screen of all human genes identified 19 chromosomal regions that may harbor MS susceptibility genes. Scientists are examining each of these regions in detail in order to determine the exact location of the genes of interest. Most recently researchers focused on the HLA region, which includes the genetic code for certain proteins critical in immune responses. Results showed that there is an underlying genetic heterogeneity in MS, supporting inferences from studies of pathology, neuroimaging and immunology which suggest that MS may result from more than one underlying biologic process.

Finding a gene that is connected to a disorder, whether singly or in combination with others, is only a first step towards understanding a disease, but one that can provide essential clues. This is so whether or not the normal function of the gene is known. The path from gene discovery to practical applications is a difficult one, often with unexpected turns.

Ataxia telangiectasia and cancer: Ataxia telangiectasia is an inherited disorder that causes progressive ataxia (loss of movement coordination) beginning usually between ages 1 and 2. In addition to loss of certain brain cells, children with this disease often suffer immune deficiency, increased likelihood of cancer, and abnormally high sensitivity to radiation. Each year about 500 people inherit damaged copies of the relevant gene from both parents, and thus the disease ataxia telangiectasia. About 1% of the population -more than 2 million people- who carry one defective gene are spared most problems of this disorder but may have four times increased risk of cancer and increased sensitivity to radiation. About 5 years ago scientists identified the previously unknown ATM gene which, when defective, causes ataxia telangiectasia. Subsequent study has revealed that the normal ATM gene helps prevent a cell from becoming cancerous when its DNA is damaged. Most recently scientists discovered a link between the cellular functions of the ATM gene and the BRCA1 gene for inherited breast cancer. The normal BRCA1 gene helps cells repair DNA damage. The normal ATM gene alerts the BRCA1 gene that DNA damage has occurred. This may explain the increased risk for cancer among children with ataxia telangiectasia and carriers of one bad ATM gene. More generally, these findings are helping to elucidate how cells normally repair DNA damage and how compromise of this repair system contributes to cancer.

Understanding narcolepsy: Narcolepsy is a serious brain disorder that affects sleep in a dramatic way. Symptoms include sudden occurrences of daytime sleep, a frightening inability to move shortly after awakening or dozing off, and dramatic episodes of muscle weakness called cataplexy. In 1999 scientists discovered a defective gene that causes narcolepsy in dogs, one of the few animals that exhibit this disorder. The gene carries the instructions for making a receptor (detector molecule) by which nerve cells respond to a brain signaling chemical called hypocretin. Guided by the animal findings to examine the hypocretin system, clinical studies in people, reported in 2000, now show that most people with narcolepsy have defects in the hypocretin signal system. Rather than receptor loss, people have abnormally low levels of the hypocretin signal itself in the brain. Apparently the nerve cells that normally produce hypocretin either die or stop producing this substance. Supplying hypocretin, or drugs that mimic its actions, may help prevent or treat the disease.

For neurological disease the development of animal models of human disorders is one of the most important harvests from research in molecular genetics. In the past year genetic research has led to new or better models for Canavan disease, spinal muscular atrophy, neurofibromatosis, and neural tube defects, to name a few, adding to models for Huntington's disease, Batten disease, spinocerebellar ataxia, muscular dystrophies and others that were developed in recent years and are already in wide use. For diseases like ALS, Parkinson's and Alzheimer's that are inherited in about 10% of cases, mouse models based on the familial forms are proving essential for progress against the more common forms of these diseases as well. An important new trend is the advent of genetically engineered Drosophila (fruitfly) models of human neurological disorders, including epilepsy, Parkinson's disease, neurofibromatosis, and inherited ataxias. These simpler organisms offer substantial advantages over mammals for determining the biochemical processes that lead to disease. Mouse, fly and other animal models are crucial for understanding disease mechanisms, identifying genes that might modify the process, and developing treatment strategies.

With dramatic improvements in technology, studying gene expression is becoming an avenue for understanding many aspects of the normal and diseased nervous system. Because genes carry the blueprints for proteins, and proteins are the workhorses of cells, studying which genes a cell is using to make proteins, or "expressing," reveals many aspects of a cell's state and activity. The study of brain tumors is one illustration. Although most brain tumors are not inherited, brain tumors, like all cancers, are in a real sense gene disorders. The uncontrolled growth is caused by a succession of "hits" that damage genes, and the harmful activities of these cells reflect the subsequent expression of many other genes. For several years the NINDS Brain Tumor Genome Anatomy Project (BTGAP) has studied these phenomena in collaboration with the National Cancer Institute's Cancer Genome Anatomy Project (CGAP). One yield has been the discovery of more than 1000 previously unknown genes important in the brain, one of the richest sources of all for finding human genes. Clinical applications from molecular studies of brain tumors are also now beginning to emerge. Physicians treating patients with brain tumors are confronted with more than 100 different tumor types. Early studies, of just a few tumor types so far, show that characterizing gene expression will help doctors predict which therapies are best for a particular patient. In the future, following the leads from gene studies to find the causes of specific tumor types will produce better therapies. Recent scientific advances using gene expression to study early steps in neurodegeneration and to determine how the normal nervous system wires up properly help to illustrate the breadth of applications of this approach for the nervous system.

Understanding the early steps in neurodegeneration: Spinocerebellar ataxia-1 (SCA1) is an inherited disorder characterized by loss of movement coordination (ataxia), usually beginning in adulthood, reflecting the progressive death of nerve cells in the cerebellum, the spinal cord, and other parts of the brain. In 1993 researchers discovered that defects in a previously unknown gene, called ataxin-1, cause SCA1. Using this information scientists genetically engineered SCA1 mice that mimic the human disease, and studied how the ataxin-1 defect affected the expression of other genes using a very sensitive technique that highlights the differences between gene expression in diseased and normal animals. Six genes, all abundant in the cerebellum, are downregulated at a surprisingly early stage of the disease. Some of these genes produce proteins that regulate calcium within cells which is revealing because cells use calcium to control many critical internal processes, such as the release of neurotransmitters, and abnormal calcium levels have been previously linked to neurodegeneration in several disorders. The mouse version of a human gene called alpha-ACT-1 is also perturbed in SCA1 mice. This too suggests links to other disease because ACT-1 is affected in Alzheimer's and Huntington's diseases.

Assembling neural circuits: How precisely connected circuits of nerve cells form during development is one of the great mysteries of biology, a puzzle that has profound implications for understanding and treating many disorders. There is increasing evidence that transcription factors-signal molecules that turn genes on and off-control many aspects of neural development. However, to date transcription factors have been implicated in regulating very early, global events in development such as specification of the overall shape and pattern of brain structure, determination of specific nerve cell types, and selection of the early paths that axons grow, rather than in specifying the detailed connections among billions of nerve cells. Scientists have now discovered a transcription factor, called Er81, that appears to control the formation of specific connections in spinal cord circuits between sensory neurons, which grow into the spinal cord, and motor neurons, which lie within the cord. These findings are an important step in unraveling the signals that control the formation of nerve cell circuits. Understanding that process is important for progress against the many developmental disorders in which the nervous system becomes wired up improperly, including some forms of epilepsy and perhaps autism. Finding ways to stimulate the formation of appropriate connections is also becoming a limiting factor for promoting functional recovery in the injured spinal cord and brain, now that there has been significant progress in coaxing axons to regrow after damage.

Environment and the nervous system: It may seem paradoxical in this era of modern genetics, but one of the major themes in neuroscience is how the environment affects the brain in both children and adults. The "environment" here is all encompassing, not just external insults such as toxins, trauma and infections, but also nutrition, sensory stimulation, and exercise, the internal environment of the body during health and disease, and even the microenvironment that surrounds nerve cells in the brain.

There is also a growing appreciation for the many ways even the adult brain can change in response to external influences. One of the most dramatic examples of this is the finding that the adult human brain-even in 60 year old people-harbors neural stem cells, immature cells that can multiply and give rise to specialized types of cells that make up the brain. Studies from several laboratories, mostly in animals, show that the proliferation of adult neural stem cells is exquisitely sensitive to a wide variety of environmental factors, including stress hormones, trauma, environmental complexity, learning, and even physical exercise. Discovering what role these cells play in the brain, which signals control their behavior, how to encourage them to repair damage from disease, and, on a more negative note, to what extent they are the source of brain tumors, are major goals of ongoing research.

Isolation of adult neural stem cells: To study the capabilities of adult neural stem cells and the signals that control them, scientists must learn how to isolate, purify and multiply these cells. Therapeutic applications of adult stem cells may also require such methods. In the last year, researchers reached the goal of isolating and multiplying adult human stem cells using brain tissue removed during therapeutic surgery. The techniques rely upon a variety of genetic manipulations, labeling techniques, and cell culture methods developed in studies of mouse stem cells. Taken together these new findings suggest that the adult human brain harbors a complex population of stem cells that can give rise to nerve and glial (supporting) cells under appropriate culture conditions. However, to what extent adult stem cells can mimic the versatility of embryonic stem cells is not yet apparent. Embryonic stem cells multiply in unlimited numbers, produce all cell types of the nervous system, survive transplantation, migrate widely within the brain, and have already shown promising results in animal models of human disorders, so scientists are continuing to study all types of stem cells in animal models.

"Brain plasticity" refers to the ability of the brain to change. Understanding the cells and molecules that underlie learning and other forms of brain plasticity is one of the most exciting areas of neuroscience research. A moment's reflection will reveal the immense potential of encouraging adaptive brain plasticity. Following stroke and trauma, plasticity allows surviving areas of the brain to compensate, to some degree, for those lost. Why this occurs more completely in some people than others is poorly understood. The ultimate in plasticity would be to reconstruct lost brain circuits following damage, and finding ways to make that happen is another major area of research that is showing encouraging progress. However, brain plasticity is not always advantageous--maladaptive plasticity can contribute to brain disease. Some forms of dystonia, a painful disorder of movement control, may reflect such changes in the cerebral cortex; the distressing "phantom limb" pains that often bedevils amputees in a missing limb are another example; and many chronic pain syndromes may also reflect maladaptive changes in the circuits that carry pain signals to the brain. Understanding brain plasticity and learning to control it is a major theme of current neuroscience.

The brain and spinal cord are better protected from the external environment than most other organs, but hostile microbes can overcome the protective barriers, and all parts of the nervous system are subject to infectious diseases-poliomyelitis, meningitis, herpes zoster, encephalitis, rabies, HIV and the West Nile virus, to name a few. NINDS is continuing its long history of research on infections of the nervous system, with special efforts focusing on important public health issues such as HIV infection and on rare disorders, such as Creutzfeldt-Jakob disease, that have disproportionate public health implications, such as on the safety of the blood or food supply.

HIV infection causes significant neurological damage to the nervous tissues, and results in clinically apparent complications in a large percentage of persons with AIDS. The NINDS AIDS research program supports studies that investigate HIV entry and persistence in the nervous system, the mechanisms of viral direct and indirect factors injurious to the nervous system, and development of new treatments for the HIV CNS infection and related opportunistic infections and malignancies. It is important to note that most of the HAART (high activity anti?retroviral therapy) drugs do not cross the blood?brain barrier. Thus, there is concern that while patients may be free of detectable viral RNA traces, the brain may serve as a reservoir for HIV.

Basic research into HIV mechanisms and host cell responses have yielded some clues about the nervous system symptoms experienced by AIDS patients. Using special testing techniques, investigators are following the progression of HIV?associated neurological disease, and hope to be able to predict its course in individual patients.

In FY 02, increased AIDS funds will be directed at discovering drugs that would target the trafficking of HIV?1 into the central nervous system, identifying surrogate markers for measuring the extent of HIV?1in the nervous system utilizing advanced neuroimaging techniques, and developing sensitive laboratory assays for the detection of viral products in nervous system. Further emphasis will be placed on creating suitable non?human primate models for HIV?associated encephalopathy.

Refer to the Office of AIDS Research AIDS Congressional Justification for additional details.

Activation of the immune system, though normally helping protect from environmental insults, may contribute to the progress of slow neurodegenerative disorders such as Alzheimer's, to some types of epilepsy, such as Rasmussen's encephalitis, and to syndromes such as myasthenia gravis, Lambert-Eaton syndrome, lupus, Lyme disease, and multiple sclerosis. Following traumatic injury, immune cells invade the spinal cord and brain and secrete powerful regulatory molecules, with poorly understood consequences. Recent advances in MS research help illustrate how progress in immunology is being brought to bear on neurological problems.

Cytokines and multiple sclerosis: In MS a person's own immune cells cause inflammation in the brain and spinal cord, destroying the myelin that ensheathes nerve fibers and is essential for reliable conduction of high speed nerve impulses. Fundamental studies of the immune system provided tags that have enabled researchers to distinguish which of the many types of immune cells are the culprits in MS. In addition to the many cell types biologists have also found perhaps 100 different chemical signals that cells release to control critical steps in immune activity. Researchers have begun to determine which specific immune control chemicals are critical in MS. Studies implicate two messengers, called IP-10 and RANTES, that are members of a family of chemical signals called chemokines which attract immune cells to tissue and stimulate inflammation. Chemokines and their receptors, the cells' detectors of these signals, are especially good targets for developing potent and specific drugs, and chemokine system drugs are already under development for conditions such as HIV infection, transplant rejection, asthma and rheumatoid arthritis.

The environment is critical to nervous system function in another sense. Proper nerve cell function depends on stringent control of the microenvironment that bathes cells in the brain and spinal cord. Within the brain, non-neuronal cells called glia, which outnumber nerve cells by about ten to one, regulate ion concentrations, mop up excessive neurotransmitters, secure the blood-brain barrier, clear debris following damage, and monitor for infectious invaders. Glial cells called oligodendrocytes and Schwann cells also insulate nerve fibers to allow reliable and rapid electrical impulse traffic without crosstalk. Despite their generally supportive role, glia also give rise to "gliomas," the most common and devastating brain tumors. Although glia means simply "glue," there is increasing appreciation for the complexity of glial contributions to normal brain function and virtually all types of brain disorders, whether as a target of damage in diseases like multiple sclerosis and leukodystrophies, a source of problems in brain tumors, or as defensive players in trauma and infection.

Finally, the nervous system is intimately interconnected with every organ system in the body, and is both subject to influences from systemic diseases and a principal control for bodily systems. The adverse effects of diabetes on nerves of the body (diabetic neuropathy) is one prevalent example on which NINDS is focusing increased efforts. A recent scientific advance in Parkinson's disease highlights the interrelationship of the brain and body in another way.

Parkinson's disease affects many body systems: Parkinson's disease progressively robs people of their ability to control movement as nerve cells that produce the neurotransmitter dopamine die in a particular part of the brain. People coping with Parkinson's must also confront a wide range of symptoms beyond disruption of movement, including, for example, dementia, sleep disturbances, depression, swallowing problems, and sexual dysfunction. Cardiovascular disturbances include orthostatic hypotension, a loss of blood pressure upon standing. Symptoms suggest that some of these non?motor symptoms involve malfunction of the sympathetic nervous system, which is part of the body's "fight?or?flight" stress response network and relies upon the neurotransmitter norepinephrine, a chemical closely related to dopamine. Researchers using the imaging technique positron emission tomography (PET) have now discovered that most patients with Parkinson's disease lose sympathetic norepinephrine nerve terminals in the heart. Researchers are now investigating whether loss of sympathetic nerve terminals also occurs in other parts of the body and may contribute to other non?motor symptoms of Parkinson's disease.

Developing ways to diagnose, treat and prevent nervous system disorders

"Conventional" drugs, neurotrophic factors, cell transplantation, vaccines, enzyme replacement, immune modulation, neural prostheses, gene therapies, surgery, electrical stimulation, diet, behavioral regimens.......The variety of new treatments and preventive measures for neurological disorders on the horizon is startling to those familiar with the historical difficulty of treating these diseases. For the first time responsible researchers are even developing plausible approaches to repairing the brain and spinal cord following stroke or trauma. However, to go from an idea to a safe and practical reality for people requires a spectrum of efforts. Often whole new technologies must be perfected. From initial steps in translating basic research advances via cell culture, animal, and human clinical studies, potential therapies must proceed through testing in animal models, preliminary safety testing in humans, and, finally, clinical trials to evaluate effectiveness. NINDS must balance efforts on all of these fronts, and for a wide variety of diseases, to ensure that progress continues as quickly as possible.

"Translational research" is difficult to define, but generally bridges the gap from plausible ideas to the beginnings of useful therapies. Animal models of human diseases are an essential part of this process, whether created through genetic engineering, or more traditional pharmacological, surgical, immunological, or behavioral manipulations. A sampling of recent scientific advances illustrate how early studies in animal models of drugs, stem cells, and other approaches are paving the way for human studies.

A New Approach for Treating Menstrual Epilepsy: For over 100 years it has been known that women with epilepsy often experience a greater number of seizures at the time of menstruation - called "catamenial epilepsy." Researchers have found that the female reproductive hormone progesterone is converted in the brain to allopregnanolone, a natural steroid with protective activity against seizures. Just before menstruation there is a drop in the brain content of allopregnanolone, leading to an increase in seizure susceptibility. In animal studies, researchers found that a synthetic analog of allopregnanolone can reverse the increase in seizure susceptibility associated with a fall in brain allopregnanolone, which points the way toward treatments to prevent the menstrual seizures that impair the quality of life of many women with epilepsy.

New approaches to bone cancer pain: The most common symptom of bone cancer is pain. Scientists have developed a new approach to bone pain by trying to understand how an imbalance between the normal ongoing processes of bone formation and bone resorption (re-absorption, or dissolution), result in net bone destruction, which triggers pain. To test these ideas scientists first developed a mouse model of bone cancer, by injecting malignant bone cancer cells into mouse leg bones. Once a good animal model was established and found to mimic the human disease, researchers administered osteoprotegrin (OPG) to the bone cancer mice. OPG is a natural chemical signal that blocks the bone resorbing activity of osteoblasts. OPG not only blocked the bone destruction, but also substantially diminished pain-related behaviors, and prevented the spinal cord changes that underlie pain sensitization. If OPG itself, or a drug that mimics its effect, can block tumor induced bone destruction, bone pain, and spinal cord sensitization in people, safely and without serious side effects, it would enhance the quality of life for many people with bone cancer.

Stem cell therapy for spinal cord injury: Embryonic stem (ES) cells are unspecialized cells that multiply and give rise to all of the specialized cell types of the body. ES cell therapies have been proposed for many nervous system disorders because these cells have so many potentially useful capabilities-they can replace lost nerve cells or supporting cells, fill in structural gaps, and produce growth factors, to cite just a few possibilities. A research team has now developed an ES cell transplant method that improves the outcome from spinal cord injury in rats. The scientists used mouse ES cells that had been treated with retinoic acid, a natural signal from the developing nervous system that directs ES cells to specialize to form neural tissue. In behavioral tests, the hind limbs of the treated rats (but not controls) regained some coordinated movement and could partially support the body's weight, although the animals could not walk normally. Although several treatments for spinal cord injury have shown promise in animal models, this is the first that has worked when applied several days after, rather than immediately following, the injury. The scientists must now determine why relatively few transplanted cells survive, determine how the stem cells are helping, optimize the procedure, and ensure there are no long term harmful effects. All of this depends on continued progress in understanding the biology of stem cells.

Gene therapy strategy for Parkinson's disease: Parkinson's disease usually progresses slowly, reflecting the death of nerve cells in a brain region called the substantia nigra that produce the neurotransmitter dopamine. Several years ago scientists isolated a natural "neurotrophic factor" called GDNF (glial cell line derived neurotrophic factor) that promotes survival of dopamine cells. Short term experiments in animal models of Parkinson's disease reinforced the idea that GDNF might protect dopamine neurons, but this goal has been thwarted by the difficulties in providing sustained delivery of GDNF through the blood-brain barrier. A team of scientists has now adapted a type of virus, called a lentivirus, to carry into brain cells the gene for GDNF along with control signals that prompt cells to produce GDNF. In non?human primate models of Parkinson's disease the lentivirus gene therapy reduced degeneration of dopamine cells and improved movement control. From a broader perspective, these findings highlight the potential of gene therapy for neurological diseases, like most cases of Parkinson's, that are not caused by defective genes.

Many aspects of clinical research, besides testing of therapies, are essential for progress. Studies of epidemiology, the natural history of disease, and structure and function changes in disease are critical to lay the groundwork for better treatment. Clinical evaluation of people with neurological disorders is often the bottleneck in finding genes that influence neurological disorders. Finding ways to detect neurological disorders early is another critical need because for many neurodegenerative diseases very substantial damage in the brain has already occurred before the first symptoms are apparent. Blocking or slowing the death of nerve cells is likely to be much easier than repairing damage already done. Genetic studies are revealing important clues about what causes disease and who is susceptible, but a wide range of other approaches are essential, as illustrated by recent findings with brain imaging in Alzheimer's disease, behavioral tests to detect early indications of Huntington's, and biochemical measurements that may be promising to identify infants likely to develop autism.

With new treatment strategies emerging from studies in animals, clinical trials for neurological disorders are becoming increasingly important. A clinical trial, put simply, is a carefully designed investigation of the effects of an intervention on a group of patients. Usually, early trials test safety, and later, larger trials assess how well a therapy works. Although the concept of a clinical trial is simple, in practice carrying out a successful trial is difficult, with complex scientific, ethical and practical constraints. A series of pilot trials may be needed to assess proper dosages, help refine outcomes measures, or address other concerns before a large trial is undertaken. Many aspects of clinical trials can be especially difficult when dealing with brain disorders.

A successful clinical trial can change how medicine is practiced, with substantial benefits for patients. An inadequate, poorly designed or premature trial can set a field back, masking a potentially useful therapeutic approach and discouraging researchers in academia and industry. NINDS has a history of pathbreaking trials for neurological disorders, including the first treatments which reduce damage from stroke (t-PA) and spinal cord injury (methyprednisolone) and advances in prevention of birth defects (folic acid supplementation) and of stroke (though drugs or surgery). The Institute is making special efforts to enhance capabilities to foster clinical trials in the future. Already NINDS trials investigate interventions to treat or prevent neurological disorders, in infants, children and adults, through conventional drugs, hormones or other natural biological factors, diet, surgery, cell transplantation, hypothermia, immune based therapies, electrical or magnetic stimulation, enzyme therapies, and behavioral interventions. Among the targets of recent, ongoing and new trials are Huntington's disease, aneurysms, Duchenne muscular dystrophy, Parkinson's disease, progressive supranuclear palsy, Alzheimer's disease, dystonia, trauma, multiple sclerosis, epilepsy, Tourette syndrome, cerebral palsy, brain and spinal tumors, multiple sclerosis, pain, ALS, neurocysterosis, and the prevention, treatment and rehabilitation of stroke.

Enzyme replacement therapy for Fabry disease: Fabry disease typically first appears during childhood or adolescence with recurrent episodes of severe pain in the extremities, characteristic skin lesions, and effects on the cornea. Several years ago researchers determined that the disease is caused by insufficient activity of the enzyme a?galactosidase A which normally degrades a lipid (fatty substance) called globotriaosylceramide. Without adequate enzyme activity this lipid accumulates throughout the body, damaging the kidneys, heart, and blood vessels of the brain, causing death by the fourth or fifth decade. NINDS intramural scientists laboriously isolated the critical enzyme from placental tissue, injected it intravenously to Fabry patients, and showed that this procedure reduces the levels of globotriaosylceramide in the blood. However, lack of sufficient enzyme quantities hampered further tests. To overcome this limitation scientists developed a procedure to prepare the enzyme using DNA technology and human cells in culture. With adequate supplies of enzyme in hand, researchers conducted a phase I safety and dose?escalation clinical trial showing that enzyme therapy was safe and that it reduced globotriaosylceramide in the liver, blood, and urine. Moreover several of the patients were able to permanently discontinue the medications they were taking for the pains in their hands and feet. This trial provided the basis for a double?blind placebo?controlled phase II clinical efficacy trial of enzyme replacement therapy in Fabry disease that recently confirmed the reduction of pain in the hands and feet and also found improved kidney and heart function.


NINDS is accepting the challenge to lead neuroscience more actively than ever before. Our enthusiasm is guided by a strategic planning process, motivated by changes in science, technology, and public health needs, and enabled by the funding environment. NINDS acts through workshops, solicitations, training programs, information dissemination, providing essential research resources, selecting grants of unusual promise, and, by substance and example, through the intramural research program.

Planning: The NINDS strategic planning process engages the efforts of intramural and extramural scientists, Institute staff, and the public. Beginning in 1999 strategic planning panels organized around cross-cutting scientific themes have helped the Institute identify critical needs and opportunities that are the focus of Institute activities. NINDS distributed the strategic planning document "Neuroscience at the New Millenium" widely and revised the plans following extensive public comment. The Institute has also devised and disseminated a detailed plan of action for health disparities within its mission. To complement these broad efforts, NINDS has begun planning focused on specific diseases. A task force, including scientists and the public, helped formulate the Parkinson's Disease Research Agenda, which was submitted to Congress in March 2000. A Parkinson's Disease Implementation Committee is helping to track and guide the Institute in carrying out that agenda. Through extensive collaboration with the National Cancer Institute, a Progress Review Group conducted extensive review and planning for brain tumor research, reporting its findings in the fall of 2000. Follow up efforts will continue. The landmark conference "Curing epilepsy: focus on the future" launched planning efforts for that disorder, now well underway, and a steering committee is organizing a comprehensive planning effort focusing on stroke. NINDS will continue specific disease planning efforts alongside of continued attention to scientific, technology, and resource issues common to all neurological disorders.

The Institute is also continuing its efforts to develop the "Healthy Brain Project." As we continue to combat disease, we must also must also focus on promoting a healthy brain throughout life. We should not accept nervous system decline any more than we accept deteriorating cardiovascular health as the inevitable consequence of disease or of normal aging, and we must learn to apply insights about brain development to maximize cognitive and emotional function for all Americans. The Healthy Brain Project will develop plans for long term studies of cognitive health and risk factors that compromise brain function. These results, like similar studies of the heart, will ultimately lead to recommendations for interventions and life?style changes to improve cognitive and emotional health of the American public.

Workshops: Workshops and other scientific meetings are one mechanism through which NINDS tries to catalyze progress. Workshops can serve many purposes. Group discussions are integral to the planning process, and small, focused meetings can address matters arising from the more global interchange. For example, following recommendations from the Parkinson's planning effort, a meeting in October 2000 evaluated therapeutic opportunities for clinical testing in Parkinson's disease. Meetings can also foster collaborations among scientists from different disciplines to focus on a particular disease. An NINDS organized meeting on Parkinson's disease in 1995 brought together clinicians and molecular biologists and led directly to discovery of the first defective gene that can cause this disease. This year a conference brought together immunologists with specialists in spinal cord injury, who rarely interact with one another, to confront how immune reactions following trauma help and hinder recovery. Another use for conferences is to encourage young scientists to enter research on a particular disease. A major NINDS epilepsy conference made special efforts toward bringing new scientists into the field, including a follow-up grant program directed specifically to that purpose. Meetings can also help explore new technologies and what role NINDS should play in making them available to the research community. The April 2000 workshop exploring "high-throughput screening" for drug development brought together academic, government, and industry scientists toward that end.

Examples illustrate the scope of NINDS efforts through meetings, large and small. In the past year NINDS, often in cooperation with other components of NIH and with private groups, supported workshops on diseases including: Pelizaeus-Merzbacher disease and X-lined spastic paraplegia; Niemann Pick type-C; chronic pain; multiple sclerosis; restless legs syndrome, periodic limb movement disorders, and narcolepsy; Parkinson's disease; epilepsy, autism and pervasive developmental disorders; hereditary spastic paraplegias; amyotrophic lateral sclerosis and spinal muscular atrophy; Duchenne muscular dystrophy; FSH dystrophy; neurofibromatosis; traumatic brain injury; Hallovorden-Spatz syndrome; brain tumors; channelopathies; Rett and Kallman syndromes; and pediatric stroke. Meetings on technologies or scientific issues discussed: the role of dopamine in neurological disorders; high-throughput drug screening; neural prostheses; the genetic basis for brain development and dysfunction; computational neuroscience; nanotechnology; clinical trials issues; adaptive learning interventions for verbal and motor deficits; functional imaging in brain development; imaging as a surrogate disease marker in multiple sclerosis; optical imaging; and gene therapy for neurological disorders.

Workshops planned for the near future will focus on topics such as: neural prostheses; myoclonus, paroxysmal dyskinesias and related disorders; dystonias generally and blepharospasm specifically; cognitive neuroscience; quantitative tools for assessing movement impairment in children; risk factors for autism; outcomes in clinical neurological research; pain; glioma (brain tumor) cell biology; protein microassays in brain and nervous tissue; antiepileptic drug monotherapy; and specific aspects of spinal cord injury and repair.

Solicitations: Recent and continuing NINDS led solicitations focus on: developing tests for Creutzfeldt-Jakob disease to protect the blood supply; the role of microglia in normal and abnormal immune responses of the nervous system; exploratory grants in pediatric brain disorders; understanding nerve cell circuits in the spinal cord; the function of synaptic proteins in synapse loss and neurodegeneration; mitochondrial function and neurodegeneration; the role of parkin and related proteins in Parkinson's disease; pilot studies for re-establishing connectivity in spinal cord injury; innovations in translational epilepsy research for junior investigators; functional MRI and intervention for cognitive deficits after traumatic brain injury; and research on research integrity.

NINDS is also increasing the flexibility of its grant programs. Following a successful solicitation for exploratory (R21) grants for pediatric research, the Institute extended that program and is extending the use of this mechanism to encourage exploratory research in other fields. For the first time the Institute, along with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), has jointly funded grants with a voluntary organization, the Juvenile Diabetes Foundation. This program focused on neurological complications of diabetes, and may set an example for other public-private partnership efforts. To rapidly meet critical research needs with minimum disruption of research efforts, the Institute has also made use of supplements to current grantees. The enthusiastic response to a continuing infrastructure supplement program highlights the large unmet need for equipment to carry out day-to-day research more effectively. A special supplement program also enabled many researchers to gain access to new microarray technology for studying gene expression. Supplements to the Parkinson's Disease Research Centers enabled new projects in areas such as genetics of Parkinson's in minority populations and the use high throughput screening technology for screening potential Parkinson's drugs. An NINDS and the National Institute of Mental Health (NIMH) supplement to an existing brain bank facility also will provide for a critical need for tissue to study Autism.

Now, more than ever before, NINDS is interacting closely with other components of NIH. In addition to the traditional collaborations with Institutes such as NIMH, the National Institute of Child Health and Human Development (NICHD), the National Institute on Aging (NIA), and the National Center for Research Resources (NCRR), among others, on issues of common interest, the increasing integration of science is driving growing interaction with other Institutes such as NIDDK, as well as participation in large trans-NIH efforts in cross-cutting areas. A few examples of recent solicitations illustrate this trend. In genetics: gene expression profiling in the nervous system; mouse brain atlas for functional genomics; and efforts such as the mouse, rat and zebrafish genome projects, the Center for Inherited Disease Research, and ethical, legal, and social issues of human genetics and genomics research. In technology: bioengineering research partnerships; bioengineering nanotechnology program; national programs of excellence in biomedical computing. In critical clinical issues: hyper accelerated awards in immunomodulation trials; Rett syndrome; basic and translational research in emotion; self-management strategies across chronic diseases; pilot clinical trial grants for pharmacological interventions in pediatric traumatic brain injury; developmental pharmacology.

NINDS will issue solicitations focused on specific needs highlighted by the disease specific planning efforts in Parkinson's disease, brain tumor, epilepsy and stroke, and arising from workshops on topics such as gene therapy. For example, a recent program is designed to attract researchers from other disciplines to apply their insights to Parkinson's disease. In the near future solicitations will also target aspects of research on stem cells, deep brain stimulation, microarrays, muscular dystrophy, autism and childhood neglect, among others.

Training: NINDS continues its efforts to support training of scientists at all levels from graduate school, through post-doctoral study, and through career development awards. Following extensive review by a subcommittee of the NINDS Advisory Council, the Institute is revising programs to support training of clinical researchers, including adjustments of stipend levels, durations, and percentage time for various training awards to meet changing conditions in the academic medical environment. The Institute is also continuing special efforts to attract scientists to clinical problems, through grant programs, such as in epilepsy research, and through workshops, such as the November 2000 neurobiology of disease workshop focused on Parkinson's disease at the Society for Neuroscience annual meeting, and through extensive outreach efforts, especially directed towards minority students.

Intramural: The NINDS Intramural research program helps foster progress through the excellence of its research programs in many areas of neuroscience. Several research advances highlighted in this document, in areas including treatments for Fabry disease and clinical studies of Parkinson's disease, represent Intramural efforts. The Intramural program can also help lead by setting an example for how disciplines can be brought together in an integrated research effort necessary for progress in neuroscience. The progress in developing a National Neuroscience Center at the NIH, which will speed the translation of basic research finding toward effective therapies, can serve as a paradigm for the greater scientific community.

Health disparities: NINDS has prepared a five year plan for addressing health disparities within its mission, and the expanded NINDS Office of Special Programs in Neurosciences is coordinating implementation of the plan. This comprehensive program focuses on health issues related to stroke, HIV-associated neurological disorders, neurological complications of diabetes, epilepsy, injury to the developing brain, cognitive and emotional health, and chronic pain, as well as addressing concerns about training of minority scientists and information dissemination. In addition to a wide range of clinical and epidemiological research studies, workshops, public information, and training activities, the Institute is continuing to build its successful Specialized Neuroscience Research Program (SNRP) for minority institutions.

Organization and staffing: To take on a more active role in shaping research, NINDS has reorganized its extramural division in a flatter structure. The Institute is continuing its successful efforts to recruit highly qualified staff necessary to carry out and provide oversight for the Institute's activities. NINDS is also enhancing training opportunities for critical personnel. This year NINDS is making special efforts to reinforce its clinical trials capabilities through staff recruitments and other means. This will allow the Institute to work more closely with researchers to expedite well designed clinical trials for neurological interventions.

Other grant programs: The collective wisdom of the scientific community, honed by the vigorous marketplace of ideas, remains the greatest asset of neuroscience research. In noting that NINDS has become more active in leading neuroscience, it is important to emphasize that the Institute continues to rely for most of its research on the insight and ingenuity of scientists around the United States. Independent investigators recognize scientific opportunities and submit unsolicited grant proposals responsive to the mission of the Institute. A sampling of recent new grants shows projects that focus on disorders such as stroke, Alzheimer's, chronic pain, traumatic brain injury, spinal cord injury, multiple sclerosis, migraine, aneurysms, Lyme, autism, Parkinson's, Huntington's, ALS, spinal muscular atrophy, Canavan, dystonia, and attention deficit hyperactivity disorder; on therapies including drugs, surgery, radiation, cell transplantation, neural prostheses, and gene therapy; on technologies within the realm of bioengineering, biomaterials, and imaging; and on fundamental neuroscience such as brain development, apoptosis, regeneration, plasticity, glial cell biology, neurotrophic factors, and neural plasticity. NINDS will continue to encourage proposals in all scientific and clinical areas relevant to reducing the burden of neurological disorders.


Last Modified February 3, 2011