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.
