The NINDS is the leading supporter of stroke research in the United States and sponsors a wide range of experimental research studies, from investigations of basic biological mechanisms to studies with animal models and clinical trials.

Currently, NINDS researchers are studying the mechanisms of stroke risk factors and the process of brain damage that results from stroke. Some of this brain damage may be secondary to the initial death of brain cells caused by the lack of blood flow to the brain tissue. This secondary wave of brain injury is a result of a toxic reaction to the primary damage and mainly involves the excitatory neurochemical, glutamate. Glutamate in the normal brain functions as a chemical messenger between brain cells, allowing them to communicate. But an excess amount of glutamate in the brain causes too much activity and brain cells quickly "burn out" from too much excitement, releasing more toxic chemicals, such as ccfmases, cytokines, monocytes, and oxygen-free radicals. These substances poison the chemical environment of surrounding cells, initiating a cascade of degeneration and programmed cell death, called apoptosis. NINDS researchers are studying the mechanisms underlying this secondary insult, which consists mainly of inflammation, toxicity, and a breakdown of the blood vessels that provide blood to the brain. Researchers are also looking for ways to prevent secondary injury to the brain by providing different types of neuroprotection for salvagable cells that prevent inflammation and block some of the toxic chemicals created by dying brain cells. From this research, scientists hope to develop neuroprotective agents to prevent secondary damage. For more information on excitotoxicity, neuroprotection, and the ischemic cascade, please refer to the Appendix.

Another area of research involves experiments with vasodilators, medications that expand or dilate blood vessels and thus increase blood flow to the brain. Vasodilators have long been used to treat many disorders, including heart disease. Researchers hope that vasodilators may aid in the rehabilitation of stroke victims by increasing blood flow to the brain. So far, unfortunately, they have shown limited success, possibly because they have not been given soon enough after the onset of stroke.

Basic research has also focused on the genetics of stroke and stroke risk factors. One area of research involving genetics is gene therapy. Gene therapy involves putting a gene for a desired protein in certain cells of the body. The inserted gene will then "program" the cell to produce the desired protein. If enough cells in the right areas produce enough protein, then the protein could be therapeutic. Scientists must find ways to deliver the therapeutic DNA to the appropriate cells and must learn how to deliver enough DNA to enough cells so that the tissues produce a therapeutic amount of protein. Gene therapy is in the very early stages of development and there are many problems to overcome, including learning how to penetrate the highly impermeable blood-brain barrier and how to halt the host’s immune reaction to the virus that carries the gene to the cells. Some of the proteins used for stroke therapy could include neuroprotective proteins, anti-inflammatory proteins, and DNA/cellular repair proteins, among others.

The NINDS supports and conducts a wide variety of studies in animals, from genetics research on zebrafish to rehabilitation research on primates. Much of the Institute’s animal research involves rodents, specifically mice and rats. For example, one study of hypertension and stroke uses rats that have been bred to be hypertensive and therefore stroke-prone. By studying stroke in rats, scientists hope to get a better picture of what might be happening in human stroke patients. Scientists can also use animal models to test promising therapeutic interventions for stroke. If a therapy proves to be beneficial to animals, then scientists can consider testing the therapy in human subjects.

One promising area of stroke animal research involves hibernation. The dramatic decrease of blood flow to the brain in hibernating animals is extensive – extensive enough that it would kill a non-hibernating animal. During hibernation, an animal’s metabolism slows down, body temperature drops, and energy and oxygen requirements of brain cells decrease. If scientists can discover how animals hibernate without experiencing brain damage, then maybe they can discover ways to stop the brain damage associated with decreased blood flow in stroke patients. Other studies are looking at the role of hypothermia, or decreased body temperature, on metabolism and neuroprotection.

Both hibernation and hypothermia have a relationship to hypoxia and edema. Hypoxia, or anoxia, occurs when there is not enough oxygen available for brain cells to function properly. Since brain cells require large amounts of oxygen for energy requirements, they are especially vulnerable to hypoxia. Edema occurs when the chemical balance of brain tissue is disturbed and water or fluids flow into the brain cells, making them swell and burst, releasing their toxic contents into the surrounding tissues. Edema is one cause of general brain tissue swelling and contributes to the secondary injury associated with stroke.

The basic and animal studies discussed above do not involve people and fall under the category of preclinical research; clinical research involves people. One area of investigation that has made the transition from animal models to clinical research is the study of the mechanisms underlying brain plasticity and the neuronal rewiring that occurs after a stroke.

New advances in imaging and rehabilitation have shown that the brain can compensate for function lost as a result of stroke. When cells in an area of the brain responsible for a particular function die after a stroke, the patient becomes unable to perform that function. For example, a stroke patient with an infarct in the area of the brain responsible for facial recognition becomes unable to recognize faces, a syndrome called facial agnosia. But, in time, the person may come to recognize faces again, even though the area of the brain originally programmed to perform that function remains dead. The plasticity of the brain and the rewiring of the neural connections make it possible for one part of the brain to change functions and take up the more important functions of a disabled part. This rewiring of the brain and restoration of function, which the brain tries to do automatically, can be helped with therapy. Scientists are working to develop new and better ways to help the brain repair itself to restore important functions to the stroke patient.

One example of a therapy resulting from this research is the use of transcranial magnetic stimulation (TMS) in stroke rehabilitation. Some evidence suggests that TMS, in which a small magnetic current is delivered to an area of the brain, may possibly increase brain plasticity and speed up recovery of function after a stroke. The TMS device is a small coil which is held outside of the head, over the part of the brain needing stimulation. Currently, several studies at the NINDS are testing whether TMS has any value in increasing motor function and improving functional recovery.

Clinical Trials

Clinical research is usually conducted in a series of trials that become progressively larger. A phase I clinical trial is directly built upon the lessons learned from basic and animal research and is used to test the safety of therapy for a particular disease and to estimate possible efficacy in a few human subjects. A phase II clinical trial usually involves many subjects at several different centers and is used to test safety and possible efficacy on a broader scale, to test different dosing for medications or to perfect techniques for surgery, and to determine the best methodology and outcome measures for the bigger phase III clinical trial to come.

A phase III clinical trial is the largest endeavor in clinical research. This type of trial often involves many centers and many subjects. The trial usually has two patient groups who receive different treatments, but all other standard care is the same and represents the best care available. The trial may compare two treatments, or, if there is only one treatment to test, patients who do not receive the test therapy receive instead a placebo. The patients are told that the additional treatment they are receiving may be either the active treatment or a placebo. Many phase III trials are called double-blind, randomized clinical trials. Double-blind means that neither the subjects nor the doctors and nurses who are treating the subjects and determining the response to the therapy know which treatment a subject receives. Randomization refers to the placing of subjects into one of the treatment groups in a way that can’t be predicted by the patients or investigators. These clinical trials usually involve many investigators and take many years to complete. The hypothesis and methods of the trial are very precise and well thought out. Clinical trial designs, as well as the concepts of blinding and randomization, have developed over years of experimentation, trial, and error. At the present time, researchers are developing new designs to maximize the opportunity for all subjects to receive therapy.

Most treatments for general use come out of phase III clinical trials. After one or more phase III trials are finished, and if the results are positive for the treatment, the investigators can petition the FDA for government approval to use the drug or procedure to treat patients. Once the treatment is approved by the FDA, it can be used by qualified doctors throughout the country. The back packet of this brochure contains cards with information on some of the many stroke clinical trials the NINDS supports or has completed.

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Source: National Institute of Neurological Disorders and Stroke,
NIH Publication No. 99-2222