NIH 1998 Almanac/The Organization/NINDS/      

National Institute of Neurological Disorders and Stroke: Major Divisions

The institute is organized as five divisions: convulsive, infectious, and immune disorders; fundamental neuroscience and developmental disorders; stroke, trauma, and neurodegenerative disorders; and extramural activities for support and coordination. A division of intramural research conducts laboratory and clinical research in NIH laboratories.

Division of Convulsive, Infectious and Immune Disorders

The division stimulates and supports wide-ranging research on neurological illnesses, including infectious and immune disorders, epilepsy, neuromuscular disorders, and sleep.

The Epilepsy Branch encourages research to prevent epilepsy and improve its diagnosis and treatment. Research is supported on convulsive and paroxysmal disorders of the nervous system, including narcolepsy and other sleep disorders. The branch administers an extensive antiepileptic drug development and monitoring program.

Research on infectious diseases includes "slow virus" diseases, encephalitis, meningitis, and the neurological aspects of AIDS. Research emphasizing neuroendocrinology and the neurological basis of pain is also supported. Research on immunological diseases includes demyelinating disorders such as multiple sclerosis, and neuromuscular disorders such as myasthenia gravis and immune-mediated (Guillain-Barre) neuropathies. Research on other neuromuscular disorders includes studies of the muscular dystrophies and other myopathies, and the other major peripheral neuropathies.

Division of Fundamental Neuroscience and Developmental Disorders

The division supports research aimed at acquiring broad, fundamental new knowledge about the nervous system. Grant applications are accepted on fundamental cellular, molecular, and systems neuroscience including neural structure and function, and in basic disciplines such as neuronal cell biology, neuroanatomy, neurochemistry, neurophysiology, developmental neurobiology, and neurogenetics. The division also supports research on developmental disorders including cerebral palsy and other motor disorders, mental retardation and learning disorders, autism and behavioral disorders, and birth defects.

Division of Stroke and Trauma

The division supports basic and clinical research on stroke and cerebral ischemia, injury to the head and spinal cord, and a broad range of neurological disorders of adults and the aged. Alzheimer’s disease and other dementias, Huntington’s disease, and amyotrophic lateral sclerosis are division responsibilities, as are studies of migraine, brain tumor, and chronic back pain. Basic research includes such topics as regeneration, plasticity, cell death (apoptosis and necrosis), cell cycle regulation, and cell biology of neurons, glia, and cerebral endothelium. Clinical research includes development of neural prostheses to extend function in patients with spinal cord injury or other neurologic impairment, clinical trials of surgical and pharmacological interventions for cerebrovascular disease, the use of hypothermia to treat severe traumatic brain injury, and pharmacological and transplantation studies to treat Parkinson’s disease. Attention is given to new imaging techniques (PET, fMRI, NRS) that allow precise anatomic and functional study of the brain after stroke, trauma, or disease.

Stroke research encompasses all aspects of cerebrovascular disorders. Of high priority are investigations into causes and neurological consequences of embolic and hemorrhagic stroke, and mechanisms of secondary damage to nervous tissue. The division encourages research on injury to the head, spinal cord, and peripheral nerves. Major goals are to find ways to promote regeneration of damaged nerve tissue, and to restore function after injury.

Research activities in the neurodegenera-tive disorders include studies of the physiology, biochemistry, pharmacology, anatomy and cellular biology, pathology, genetics, and epidemiology of these diseases in humans and relevant animal models. Of particular interest are studies of neural plasticity, trophic factors that promote neuronal survival, biology of stem cells of the nervous system, and tissue implantation.

Tumor research focuses on the migratory and proliferative capacities of astrocytes and precursor cells, as well as unique molecular properties of glioma. Research on neural prostheses has yielded motor prostheses to restore hand and arm function in paralyzed individuals; in addition, devices to assist in standing and bowel and bladder control are under development.

Division of Extramural Activities

The division provides administrative support and coordination for the institute’s research grant, research training, and research contract activities including the SBIR (Small Business Innovation Research) and the STTR (Small Business Technology Transfer) programs. The division directs and carries out scientific and technical merit review of proposals for research contracts, program projects, clinical research centers, special research grants such as multi-institutional clinical trials, and career development and research training. Management services for research grants and contracts are provided.

The division coordinates training and career development of young investigators, including predoctoral fellowships for minority students and students with disabilities. Also offered are mentored research scientist development awards that foster the development of neurosciences research faculty at historically black colleges and universities.

Opportunities include institutional and individual training awards as well as support through research development awards, awards for reentry into the neurological sciences, an integrated clinical and research career development program for physicians that begins during residency, and research supplements for underrepresented minorities and individuals with disabilities. New career development awards focus on patient-oriented research for clinically trained individuals.

Division of Intramural Research

The division conducts basic and clinical research in neurological and related disciplines. Notable achievements have included drug therapies for debilitating neurological diseases such as parkinsonism and new techniques to help scientists better understand how the brain and nervous system function. Major research advances in neurovirology, neurochemistry and neuroimmunology have also come from the division.

NINDS scientists continue to explore central nervous system disorders such as Creutzfeldt-Jakob disease that appear to be slow infections caused by transmissible viruslike agents. These agents are unique in some respects, but in others exhibit classical viral properties. Research focuses on delineating the agents’ chemical, biological and genetic nature, and on learning the nature of disease pathogenesis.

Inherited disorders of lipid metabolism such as Gaucher’s, Niemann-Pick, Fabry’s, Krabbe’s, and Tay-Sachs are studied. This work includes biochemical and diagnostic studies, carrier identification, and genetic counseling. Studies on the molecular basis of the diseases have reached a new frontier; enzyme replacement therapy has been successfully developed for patients with Gaucher’s. Gene replacement is also being explored for patients with this and other metabolic disorders.

Many research projects in computed tomography advance the clinical applications of the technique as well as provide scientists with a wealth of valuable research data. In other imaging work, studies with the PET scanner have shown a relationship between glucose uptake and brain tumor growth. This scanning technique allows scientists to obtain axial transverse or coronal images of the brain. It also provides dynamic functional data such as rates of glucose consumption in different parts of the brain measurements of the storage, degradation, and turnover of radioactively tagged metabolites. Functional magnetic resonance imaging is a new technique being used to study brain activity.

In the Neuroimmunology Branch, the role of immunological mechanisms as they may relate to the cause of diseases such as multiple sclerosis is being studied. Immunological and genetic factors are being examined in families with multiple affected members or in twins in which either one or both twins have multiple sclerosis. The role of HTLV-I and other retroviruses as the cause of demyelinating disease is being assessed. Finally, new approaches to treatment of multiple sclerosis are being examined and MRI is being used as a tool to study the natural history of the disease and to assess the efficacy of experimental treatments.

In the Surgical Neurology Branch, NINDS scientists have undertaken intensive studies of brain tumors, pituitary tumors, neuronal implantation, gene therapy and immuno-toxins for brain tumors, and selected aspects of cerebrovascular disease and epilepsy.

The Medical Neurology Branch’s human motor control section focuses on how the brain controls voluntary movement and how these processes become deranged with different movement disorders. Recent advances have been made in understanding of focal dystonia and brain plasticity. The neuromuscular diseases section has made recent important observations on postpolio syndrome, neuromuscular disorders in AIDS, polymyositis, and neuropathies associated with paraproteinemia. The cognitive neuroscience section conducts innovative research on human cognitive processes such as planning, memory, and object recognition and investigates how these processes become impaired in the presence of neurological disease or trauma. A clinical neurogenetics unit has been formed.

The Epilepsy Research Branch investigates the pathophysiology of seizure disorders and cognitive function in individuals with epilepsy, as well as organization of language and memory function in normal controls using positron emission tomography studies of cerebral blood flow, metabolism, and neurotransmitters, intracerebral electrode recordings, and magnetic resonance imaging. Animal and cellular models are used to study excitatory and inhibitory mechanisms, the neuropharmacology of antiepileptic drugs, and potential novel therapeutic compounds.

The Stroke Branch explores the mechanisms by which stroke risk factors operate and analyzes mechanisms of neuronal ischemic damage at physiologic and molecular levels. The goal of these studies is to improve the prevention and treatment of human cerebrovascular disease. A clinical stroke research program is integrated with the basic stroke research program.

A major research goal of the Neuroepi-demiology Branch is to understand factors influencing the occurrence of neurological disorders in population groups. Using epidemiological methods, the branch carries out research that may resolve clinical problems related to the cause, prevention, and treatment of nervous system diseases. The branch is currently involved in research on cerebral palsy, pediatric migraine, and progressive supranuclear palsy.

Clinical Neuroscience Branch research focuses on amine neurotransmitter mechanisms in the brain and peripheral autonomic nervous system, and on neurotransmitter function and metabolism in various neurological disorders. In addition, the section studies how neurotransmitters and other factors regulate the synthesis of neurotrophic factors, as well as systems in which neurotransmitters, in particular neuropeptides, can function as neurotrophic factors.

Exploring the design, conduct, and analysis of experimental or observational studies of the nervous system is the work of the Biometry and Field Studies Branch. Branch scientists develop new methods to meet the institute’s needs for designing experiments and field studies, analyzing data, and devising statistical models of biological processes. The branch also acts as statistical coordinating center for several continuing or planned clinical trials and for longitudinal field studies involving U.S. and foreign scientists. In one cooperative international project, the goal is to determine whether electroencephalography can predict if a child who has had one seizure associated with fever will have another.

The Experimental Therapeutics Branch seeks to develop improved pharmacotherapies for neurologic diseases. At the molecular level, scientists are working to characterize central transmitter receptors and information transduction processes as well as to develop pharmaceutical approaches to the selective regulation of gene expression within the central nervous system. At the systems level, studies focus on basal ganglia function especially in relation to dopamine receptor mechanisms and the effect of drugs that influence motor behavior. At the clinical level, investigators attempt to elucidate pathophysiologic mechanisms and develop novel pharmaceutical interventions for neurodegenerative disorders that impair motor and cognitive function.

The Developmental and Metabolic Neurology Branch is concerned with inherited disorders of metabolism such as Gaucher’s disease, Niemann-Pick disease, Fabry’s disease, and Tay-Sachs disease. Investigations include the identification of enzymatic and molecular defects, devising diagnostic and carrier detection methods for genetic counseling, and development of enzyme and gene replacement therapy for patients with these disorders. The branch is also involved in the development of transgenic animals that mimic human metabolic disorders. The pathogenesis of heritable disorders for which the metabolic basis is unknown such as type C Niemann-Pick disease, is also under investigation through "reverse genetics" including chromosomal mapping and identification of the mutated genes and the normal gene products.

The Neuroimaging Branch focuses its research on brain tumors, movement disorders, and stroke. Research tools used are: 1) positron emission tomography to assess the rate of glucose utilization in brain tumors and cerebral blood flow in ischemia and 2) magnetic resonance imaging (MRI) and spectroscopy (MRS) to assess diffusion and perfusion (MRI) and levels of various metabolites (MRS) in brain tumors and cerebral ischemia, and brain iron distribution in normal controls, as well as in patients affected by movement disorders (primarily Parkinson’s disease and parkinsonism).

The Laboratory of Adaptive Systems studies molecular basis of associative memory. Laboratory observations have related the behavior of living animals to signal processing in neuronal networks and to subcellular molecular cascades. Data have implicated molecular and biophysical mechanisms that are conserved in molluscan and mammalian species, which could have relevance for human physiology. Cellular analyses of associative memory in the snail Hermissenda (Pavlovian conditioning), the rabbit (Pavlovian conditioning), and the rat (spatial maze learning, olfactory discrimination) revealed a sequential cascade of cellular and subcellular events during memory formation that includes the activation of the Ca2+ and GTP-binding protein calexcitin (cp20), and inactivation of voltage-dependent K+ channels.

Such conservation suggested that these associative memory mechanisms may provide targets of dysfunction in Alzheimer’s disease. In fact, recent studies revealed Alzheimer’s-specific defects of K+ channels and altered metabolism of calexcitin. Theoretical constructs based on these memory networks have also been mathematically described and are now being incorporated into computer-based artificial networks.

Laboratory of Central Nervous System Studies staff conducts research into the pathogenesis of human slow viral infections, including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler syndrome; and into the mechanisms of viral persistence and cellular damage in such disorders as subacute sclerosing panencephalitis, tropical spastic paraparesis, and AIDS encephalopathy/dementia complex. Widely varying experimental methods are used including in vivo and in vitro transmission studies; in situ hybridization techniques for localization of genetic material; immunofluorescent, immunoblotting, and immunoperoxidase techniques; and neuroepidemiologic studies and polymerase chain reactions, cloning, and sequencing.

Research also extends to other degenerative central nervous system disorders of undetermined etiology in humans and animals that have not yet been shown to be related to a transmissible agent or agents: Alzheimer’s, amyotrophic lateral sclerosis (ALS), the ALS-Parkinson-dementia disorders of the South Pacific, and Viliuisk encephalomyelitis among Siberian Iakut people. Recent work in Alzheimer’s disease has demonstrated that amyloid protein present in Alzheimer’s (and Down syndrome) plaques maps to chromosome 21.

Studies are being conducted to better delineate differential diagnosis of Guillain-Barré syndrome, acute flaccid paralysis, transverse myelitis, poliomyelitis, and acute axonal motor neuropathy and their etiologies.

The Laboratory of Developmental Neurogenetics applies genetic, molecular biological and transgenic technologies towards the discovery and functional analysis of genes relevant to the development and operation of the nervous system. The ultimate goal is to gain a detailed understanding of functional interactions among genes that determine growth, migration and differentiation of nerve cells. Towards this end, the laboratory has discovered a number of genes, most of which encode transcriptional regulators with roles in the nervous system. The focus is on genes regulating development and differentiation of myelin-forming glial cells whose malfunction may result in dysmyelinating or demyelinating disorders such as multiple sclerosis (section of developmental genetics), and of pigment cells whose malfunction may result in eye abnormalities or hearing loss (mammalian development section).

Research in the Laboratory of Molecular Biology is focused on in vitro and in vivo models to systematically perturb stem cell differentiation and the first steps in synapse activation. Use is made of transplantation and transgenic technology to obtain in vivo data validating models developed in tissue culture. Work is aimed at understanding the major control points in the developing nervous system. The results provide a systematic technical basis for new therapies targeting CNS disease.

The Laboratory of Molecular and Cellular Neurobiology consists of the myelin and brain development section and the membrane biochemistry section. Techniques of biochemistry, molecular biology, cell biology and immunology are utilized to investigate basic and clinically related questions about biological membranes.

Primary goals of research in the myelin and brain development section are to elucidate physiological and pathological roles of glycoproteins and glycolipids of myelin and myelin-forming cells. The basic research focuses on functions of the myelin-associated glycoprotein (MAG) and gangliosides in oligodendrocyte and Schwann cell differentiation and in myelin maintenance. The clinically related research concerns molecular pathogenesis of disorders of CNS myelin, such as leukodystrophies and multiple sclerosis, as well as the roles of antibodies to glycoconjugates in immune-mediated peripheral neuropathies.

The membrane biochemistry section focuses on cellular signaling and its regulation. The principal model under investigation is the adenylyl cyclase system which consists of receptors that bind hormones or neurotransmitters, hererotrimeric G proteins that transduce signals, and a catalyst that generates cyclic AMP which is the intracellular second messenger. Current research emphasizes molecular mechanisms by which different subtypes of beta-adrenergic receptors are regulated and the role of subunit dissociation in the interaction of G proteins with adenlyly cyclase.

Basic research in the Laboratory of Molecular Medicine and Neuroscience includes studies of the pathogenesis of human neurotropic virus infections during the course of clinical disease and establishment of biological models using neural cell cultures. Neurotropic viruses studied are the human polyomavirus, JCV, which causes a demyelinating disease in immune compromised individuals, termed progressive multifocal leukoencephalopathy (PML) and the human lentivirus HIV-1, which causes an encephalopathy/encephalitis as a significant complication in AIDS. A second project is to determine response of neural cells to viral gene expression at the molecular, transcriptional level to define not only cell susceptibility to infection but gain insight into normal cell functions. A third project is to apply the data and expertise gained from studies utilizing human neural cells and viral gene expression to development of cell and viral vectors for delivery of therapeutic molecules to the CNS.

Laboratory of Neurobiology investigators develop and apply innovative structural and analytical techniques to basic problems of cell, membrane, and molecular neurobiology in the central nervous system. Laboratory scientists are studying the secretory mechanism underlying synaptic transmission, the mechanism of organelle movement underlying axoplasmic transport, and the organization of neuronal cytoplasm. Also under study are distributions of regulatory chemical elements, especially calcium and phosphorus, within nerve cells as a function of neuronal activity, as well as hormonal regulation of dendritic spine development in pyramidal neurons.

The Laboratory of Neurochemistry is concerned with development, structure, and functional organization of the nervous system, with a special focus on molecular and physiological mechanisms that are involved in establishing and maintaining the neuronal phenotype. Many techniques ranging from the anatomic to the molecular, genetic, and invertebrate, as well as mammalian model biological systems, are employed to study various processes of neurogenesis, migration, differentiation and specification of neuronal phenotype during development and maintenance of diversity and plasticity in the mature nervous system.

The primary goal of scientists in the Laboratory of Neural Control is to understand the systems of central nervous system neurons that produce and control movement in human beings and other vertebrate animals. Much of the work is done on systems of neurons in the spinal cord and brainstem, where the input elements (sensory afferent supraspinal descending fibers) and output elements (the motoneurons that control specific muscle groups) have clear functional identities.

Given these functional landmarks, it is possible to work out the organization of interneurons that integrate descending motor command signals with afferent input before delivering control signals to the output motoneurons. Scientists often study neural systems that control rhythmic movements such as locomotion and breathing. An important reason for this is that patterned rhythmic activity in motoneurons can occur in isolated pieces of the spinal cord and brainstem. In many cases, this activity closely resembles that found in intact animals, supporting the assumption that the same basic neural circuits are responsible. These neural systems can be studied in much greater detail in educed preparations than is possible in the intact organism. Several investigators are also pursuing related mathematical and computational studies of the properties of individual nerve cells and of systems of interconnected neurons. These studies are done with close attention to experimental data and they are used to guide future experimental work.

The Laboratory of Neurophysiology has used model mammals (rats and mice) to improve the understanding of how brain tissue forms during embryogenesis in humans. During this complex process, several thousand cells begin to divide many times to generate the many millions of cells composing the adult CNS. Most of the research involves three regions of the brain: the spinal cord, hippocampus and cortex. Complementary strategies have been devised de novo or adapted to characterize physiological correlates of major stages in the development of these brain regions. These stages include cell division, death, migration, differentiation, circuit and network formation about which relatively little is yet known.

The experimental strategies include 1) fluorescence-activated cell analysis and sorting, which permits unparalleled perspective of physiological properties expressed

by live cells identified in different stages and 2) video microscopic imaging and high-fidelity electrical measurements of physiological properties in vitro expressed by cells sorted at different stages. Flow cytometry provides a complete and compelling account of developmentally relevant physiological properties expressed by all of the cells composing these (and other) brain regions, while experiments in vitro permit detailed investigations of their physiological roles in the context of tissue formation under controlled experimental conditions.

Using these strategies members of the Laboratory of Neurophysiology have found that the brains of rats (and mice) are generated in a quite stereotypical manner, which can be recognized for further study, even after completely dissociating it into a single-cell suspension. This may facilitate multi-disciplinary investigation of its physiological basis during different stages of development.


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