National Institute of Neurological Disorders and Stroke
The National Institute of Neurological Disorders and Stroke is a part of the U. S. National Institutes of Health, it conducts and funds research on brain and nervous system disorders and has a budget of just over US$1.5 billion. The mission of NINDS is "to reduce the burden of neurological disease—a burden borne by every age group, every segment of society, people all over the world". NINDS has established two major branches for research: an extramural branch that funds studies outside the NIH, an intramural branch that funds research inside the NIH. Most of NINDS' budget goes to fund extramural research. NINDS' basic science research focuses on studies of the fundamental biology of the brain and nervous system, neurodegeneration and memory, motor control, brain repair, synapses. NINDS funds clinical research related to diseases and disorders of the brain and nervous system, e.g. AIDS, Alzheimer disease, muscular dystrophy, multiple sclerosis, Parkinson disease, spinal cord injury and traumatic brain injury.
Established in 1950 by the U. S. Congress as the National Institute of Neurological Diseases and Blindness to help handle the casualties of World War II, NINDS grew along with the NIH. During the 1950s and 1960s, NINDS and the NIH had strong Congressional support and received significant appropriations. However, this funding declined in 1968; the NINDS was created in 1950 to study and treat the neurological and psychiatric casualties of World War II. Many service people had returned with serious brain injuries, nerve damage, psychic trauma. According to one estimate, "neurologically disabled veterans in the postwar years accounted for about 25 percent of the patients in general hospitals and 10 percent of those in psychiatric hospitals". In addition, 1.7 million American men had been rejected for military service due to a neuropsychiatric condition or learning disorder. NINDS was created as part of an effort to "revive the extinct neurological field". At the time and its focus on "emotional tensions due to interpersonal and cultural maladjustments" held sway in US medicine, while neurology, with its focus on the inner workings of the brain, had fallen out of favor.
During WWII, all of the administrative positions of the American Board of Psychiatry and Neurology held by the US armed services were filled by psychiatrists. After the war, a survey by the Veteran's Administration of the members of the American Board of Psychiatry and Neurology found that 48 were neurologists and 456 were psychiatrists. In 1948, Abe B. Baker, chair of neurology and psychiatry at the University of Minnesota, formed the American Academy of Neurology to give young neurologists a national organization to join. However, sustained research in neurology was not possible without a national institute. In the late 1940s and early 1950s, vocal American Neurological Association members testified before Congress, arguing that there needed to be such an institute, they articulated the arguments, made on a smaller scale by citizens' groups for diseases such as multiple sclerosis, cerebral palsy, muscular dystrophy and blindness. Members of the research grants committee of the National Institute of Mental Health, founded in 1949, contend that they helped provide an impetus for the new institute, as when reviewing grant applications they saw a significant number of neurological projects and proposed a separate institute for them.
The National Institute of Neurological Disorders and Blindness, the original name for the NINDS, was established on November 22, 1950, three months after President Harry Truman signed the Omnibus Medical Research Act on August 15, 1950. The legislation had been passed with the efforts of Senator Claude Pepper, responsible for helping the majority of the NIH institutes get their start, wealthy New York entrepreneur Mary Lasker, Fight for Sight founder Mildred Weisenfeld, who had retinitis pigmentosa. NINDB was not conceived of coherently at the beginning. For example, blindness was added because some concerned citizens raised the issue with Lasker who, in turn asked Congressman Andrew Biemiller to do so in Congress, he added it to the bill, being sympathetic with the cause since his mother was blind. NINDB was "responsible for conducting and supporting research and training in the 200 neurological and sensory disorders that affected 20 million individuals in the United States and were'the first cause of permanent crippling and the third cause of death.'"
Because the etiology of the most common neurological diseases was poorly understood, NINDB undertook both clinical and basic research on the disorders themselves and on treatments. In the beginning, the NINDB had an Advisory Council made of six medical professional and lay people, all appointed by the U. S. Surgeon General, they granted its funds. The NINDB's first annual budget was US$1.23 million. This came from the existing NIH budget, as Congress had not appropriated any new funds for the institute when it was created. Although the NINDB's budget was increased to $1.99 million in 1952, there was still no money for new research programs. Moreover, the institute had a lab; as Ingrid Farreras writes in her history, "The research conducted by the institute was still supported by the NIMH and the institute's survival was unclear."The NINDB's first director, Pearce Bailey, was appointed on October 3, 1951, came with experience from the Neuropsyc
Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are overactivated by glutamatergic storm. Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases and proteases such as calpain; these enzymes go on to damage cell structures such as components of the cytoskeleton, DNA. Excitotoxicity may be involved in spinal cord injury, traumatic brain injury, hearing loss, in neurodegenerative diseases of the central nervous system such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, alcoholism or alcohol withdrawal and over-rapid benzodiazepine withdrawal, Huntington's disease.
Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia. Blood sugars are the primary glutamate removal method from inter-synaptic spaces at the NMDA and AMPA receptor site. Persons in excitotoxic shock must never fall into hypoglycemia. Patients should be given 5% glucose IV drip during excitotoxic shock to avoid a dangerous build up of glutamate around NMDA and AMPA neurons; when 5% glucose IV drip is not available high levels of fructose are given orally. Treatment is administered during the acute stages of excitotoxic shock along with glutamate antagonists. Dehydration should be avoided as this contributes to the concentrations of glutamate in the inter-synaptic cleft and "status epilepticus can be triggered by a build up of glutamate around inter-synaptic neurons." The harmful effects of glutamate on the central nervous system were first observed in 1954 by T. Hayashi, a Japanese scientist who noted that direct application of glutamate to the CNS caused seizure activity, though this report went unnoticed for several years.
D. R. Lucas and J. P. Newhouse, after noting that "single doses of 20-30gm have... been administered intravenously without permanent ill-effects", observed in 1957 that a subcutaneous dose described as "a little less than lethal", destroyed the neurons in the inner layers of the retina in newborn mice. In 1969, John Olney discovered that the phenomenon was not restricted to the retina, but occurred throughout the brain, coined the term excitotoxicity, he assessed that cell death was restricted to postsynaptic neurons, that glutamate agonists were as neurotoxic as their efficiency to activate glutamate receptors, that glutamate antagonists could stop the neurotoxicity. Excitotoxicity can occur from substances produced within the body. Glutamate is a prime example of an excitotoxin in the brain, it is the major excitatory neurotransmitter in the mammalian CNS. During normal conditions, glutamate concentration can be increased up to 1mM in the synaptic cleft, decreased in the lapse of milliseconds.
When the glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by a process called apoptosis. This pathologic phenomenon can occur after brain injury and spinal cord injury. Within minutes after spinal cord injury, damaged neural cells within the lesion site spill glutamate into the extracellular space where glutamate can stimulate presynaptic glutamate receptors to enhance the release of additional glutamate. Brain trauma or stroke can cause ischemia. Ischemia is followed by accumulation of glutamate and aspartate in the extracellular fluid, causing cell death, aggravated by lack of oxygen and glucose; the biochemical cascade resulting from ischemia and involving excitotoxicity is called the ischemic cascade. Because of the events resulting from ischemia and glutamate receptor activation, a deep chemical coma may be induced in patients with brain injury to reduce the metabolic rate of the brain and save energy to be used to remove glutamate actively..
Increased extracellular glutamate levels leads to the activation of Ca2+ permeable NMDA receptors on myelin sheaths and oligodendrocytes, leaving oligodendrocytes susceptible to Ca2+ influxes and subsequent excitotoxicity. One of the damaging results of excess calcium in the cytosol is initiating apoptosis through cleaved caspase processing. Another damaging result of excess calcium in the cytosol is the opening of the mitochondrial permeability transition pore, a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release reactive oxygen species and other proteins that can lead to apoptosis; the pore can cause mitochondria to release more calcium. In addition, production of adenosine triphosphate may be stopped, ATP synthase may in fact begin hydrolysing ATP instead of producing it. Inadequate ATP production resulting from brain trauma can eliminate electrochemical gradients of certain ions. Glutamate transporters require the maintenance of these ion gradients to remove glutamate from the extracellular space.
The loss of ion gradients results in not only the halting of glutamate uptake, but in the reversal of the transporters. The Na+-glutamate transporters on ne