Stroke is a sudden loss of brain function caused by the interruption of blood flow to the brain, either due to ischemia (blood-vessel blockage) or hemorrhage (blood-vessel rupture). It is the fourth biggest killer and the leading cause of disability in Canada. Stroke survivors can suffer devastating and disabling effects ranging from paralysis, speech difficulties, memory loss, and even behavioural changes.
People who live to the age of 80 have a one-in-four chance of experiencing a stroke. And sadly, given Canada’s aging population, most of us will have to cope with stroke at some point in our lives—whether it hits us personally, or a member of our immediate family or our spouse’s family.
In Canada,the mortality rate from stroke is approximately 20%, but stroke research and patient care in Alberta have already made a difference. In Calgary the rate is down to about 10%. Stroke patients in the city spend less than 4 hours in the emergency ward as opposed to the 20 to 30 hours that used to be the norm. Significantly, this saves the health system about 45 beds, which would cost an extra $50 million each year.
The Calgary Stroke Program
The main reason for this success is the Calgary Stroke Program, directed by AHFMR Scientist Dr. Alastair Buchan. Built over the past eight years and staffed at present by a team of 50 people, this program provides acute, rehabilitative, and preventive care to stroke patients in a unique continuum spanning the range from experimental to clinical work. The program is conducting three research projects: One project looks at patients who have suffered an acute stroke, to determine who recovers well and who doesn’t; another examines susceptibility to stroke based on risk factors and on previous experience of a ministroke; and the third studies how stroke patients recover.“Every stroke is different,” says Dr. Buchan. “Some people have a stroke and recover; others are left devastated. These differences can be explained to some extent by the patient’s age, by the severity of the stroke, or by other risk factors such as diabetes or high blood pressure, but a lot of the variance is not explained. We want to know why these differences exist.”
Dr. Buchan explains that those who have a ministroke—a transient ischemic attack (TIA)—which causes tissue damage are probably more sensitive and more likely to have further stroke events. Those without tissue damage are more resistant. “We’re trying to determine if there are different gene patterns in those who are more susceptible to stroke versus those who are more tolerant.”
One of the program’s projects is a study called FASTER (Fast Assessment of Stroke and TIA to prevent Early Recurrent Events). Patients who suffer these TIAs are at high risk for a full-blown stroke. Whereas most stroke studies take 3 to 6 months to put TIA patients into a randomized trial—FASTER takes 3 to 6 hours. Getting this high-risk population into treatment immediately could dramatically reduce their chances of suffering a major stroke.
The Seaman Centre
Key to the Calgary Stroke Program’s unique ability to see stroke patients quickly are the scientists at the Seaman Family MR Research Centre at the Foothills Hospital. Using magnetic resonance imaging (MRI), researchers and clinicians are able to identify the TIA patients with a higher risk of experiencing a full stroke, and then treat those patients to prevent it.AHFMR Clinical Investigator Dr. Andrew Demchuk is a stroke neurologist who examines stroke patients using MRI, CT, and ultrasound techniques. He then tracks these patients for two years, in hopes of identifying features that will determine which ones are at high risk for a recurrence or a more serious incident. “We’ve done everything we can to set up an environment in which someone who has a stroke within a hundred miles of the Foothills Hospital gets in to us very quickly,” says Dr. Demchuk. “We have a team that deals with these patients very quickly and we do our imaging very quickly. It’s a unique set-up and it allows us to provide a very high level of care. It’s the reason I’m in Calgary.”
While Dr. Demchuk applies MRI techniques and makes them work for patients, AHFMR Scholar Dr. Richard Frayne is the MRI physicist who develops the techniques. Dr. Frayne also came to Calgary because of the opportunity offered by the Seaman MR Centre, arriving the same week the huge magnet became operational. He uses it in his study of blood flow, to take pictures of the shape of blood vessels to find blockages
Moving to a tissue window
Time is truly of the essence when it comes to stroke. The only treatment currently available for stroke patients is a clot-busting drug called tPA (tissue plasminogen activator), which can dissolve blockages causing stroke or heart attack. However, tPA has strict limitations, making only a fraction of patients eligible—it is only approved for patients within the first three hours of their stroke. After that time window, patients do not seem to benefit.
“We’re trying to move from a time window to a tissue window for treatment,” explains Dr. Frayne. “Using a combination of medical imaging techniques, we want to determine which patients would benefit from receiving tPA, even outside that three-hour window. We want to tailor the treatment to the individual.”
Dr. Frayne is also interested in using MR imaging for stroke prevention, to assess which patients are at greatest risk by looking at the blood vessels in the neck to spot regions that are partially blocked. He also studies new ways of treating stroke that involve MR imaging to assess the therapy and monitor the re-establishment of blood flow. “Someday this magnet could be used for stroke prevention, treatment, and follow-up,” he says.
Another cog in the wheel at the Seaman Centre is AHFMR Scholar Dr. Ross Mitchell. Dr. Mitchell does biomedical informatics—he uses mathematics and computers to analyze the MR imaging and to find better ways of producing those images. “We’re applying information technology techniques from fields like geophysics and astronomy, and applying them to solve medical problems,” he explains.
A unique group
Dr. Mitchell attributes much of the Centre’s success to the unique interdisciplinary group of researchers situated right in the hospital instead of in a separate department on the main campus. He encourages his students and post-docs to attend stroke rounds every week, in order to listen to clinical discussion about how to treat patients. “My rule of thumb is to be no more than 50 metres from where the patients are treated—that’s how we get a lot of our ideas for research.” He explains that one project got its start on the way back from stroke rounds because of a discussion between a stroke neurologist, a physicist, a computer scientist, and an electrical engineer about the patient they had just seen. “I don’t know of many places in Canada that have that kind of connection.”
Dr. Mitchell and his colleagues are building a computer model based on MR imaging to predict which brain tissue will live and which will die in stroke patients. Patients come back to be scanned 30 days later, and the prediction can be checked. “This kind of computer image would allow doctors to treat based on the patient’s individual physiology and not just based on that three-hour time frame,” he says. “It could revolutionize stroke treatment.”
MRI techniques
Edmonton also has a first-rate MRI set-up right next to an emergency ward in the University of Alberta NMR Centre. The facility allows scientists to study stroke using three MRI magnets dedicated solely to research. AHFMR Scholar Dr. Christian Beaulieu works in the Centre, developing new MRI techniques to evaluate and monitor brain injury after stroke.One of Dr. Beaulieu’s projects deals with non-invasive measurements of blood flow in the brain. The standard method of measurement involves the injection of a contrast agent which is then observed as it passes through the brain to get an idea of the blood flow. New techniques can measure blood flow without the contrast agent by using magnetic resonance to tag blood in the neck and watch where it goes in the brain—a less expensive method, which also allows the scan to be repeated. “We’re trying to optimize this method for the elderly population, the population most at risk for stroke,” says Dr. Beaulieu, explaining that the elderly tend to have slower blood flow in the brain. “We will then compare this method to that of the contrast agent, and see if it works as well to detect the areas of low blood flow in the brain that are causing the stroke.”
Another project examines white-matter degradation after a stroke. White matter can be thought of as the wiring that allows different parts of the brain to communicate with one another. “We’re interested in how the wiring changes after a stroke,” says Dr. Beaulieu. “How it degrades over time—how much and how fast.
“These and the other techniques we’re working on are all geared toward a better understanding of what is happening early on in acute stroke,” he continues. “The power of MRI is in its ability to take different types of pictures that give you critical information that otherwise would be unattainable with alternative imaging methods like x-ray and CT.”
Hypothermia
While MRI is undoubtedly a wonderfully diverse tool for stroke research, it is not the only means by which Heritage researchers in Alberta are tackling the disease. In a non-clinical research setting, Dr. Fred Colbourne looks for ways to reduce injury and promote recovery after a stroke. One of his primary interests is the study of how hypothermia can reduce cell and brain damage in stroke victims—an area he has been working in for over a decade. Scientists have known for many years that cooling can reduce the injury that an organ suffers. Recent cases like Baby Erika, the Edmonton toddler who survived several hours in sub-zero temperatures, have illustrated the effectiveness of cooling in preserving tissue. Dr. Colbourne explains that since cooling patients too much causes cardiac complications, his approach is to use a much milder level of hypothermia—33°C (normal body temperature is around 37°C).“We’ve studied this in a number of different stroke models and have learned that hypothermia can reduce injury if you prolong it. With a short period of hypothermia—a couple of hours or even half a day—the amount of protection is trivial. It may reduce cell death, but not permanently.”
The hippocampus (the part of the brain responsible for memory) is particularly sensitive to stroke. Because these cells don’t die immediately after the event but over a period of several days, the time between when the stroke occurs and when cell death occurs is an opportunity. “Hypothermia can reduce cell death if you intervene early enough within a window of about twelve hours,” says Dr. Colbourne, pointing out that there is only a three-hour window in which to use clot-busting drugs for stroke patients.
Dr. Colbourne also studies the effect of hypothermia on hemorrhagic stroke (when a blood vessel in the brain actually ruptures). Initially Dr. Colbourne thought that hypothermia did nothing for this type of stroke—until he realized he was trying it too early. “Intervening too early after a hemorrhagic stroke seems either to make matters worse or else brings no benefit,” he explains. “This is because there are some side effects to hypothermia. It is known to prolong bleeding time, for example, which isn’t a problem in uncomplicated ischemic stroke models, but aggravates bleeding in hemorrhagic stroke. Now our focus is on how to treat these side effects so we can intervene earlier.”
Recovery
AHFMR Senior Scholar Dr. Jeffrey Kleim is also interested in promoting recovery after stroke, but rather than focusing on trying to save the brain tissue that has been damaged, he focuses on the tissue that remains. He wants to understand how the brain recovers after stroke and use that information to guide the development of therapies for the clinic.Patients undergo motor rehabilitation to help them recover from movement difficulties impairment induced by stroke. Some people show good recovery rates, but others do not. Dr. Kleim wants to know what happens in the brains of patients who recover. “We want to figure out how the brain adapts to the fact that it’s missing a piece of tissue,” he says. “If we can understand the mechanisms, we might be able to come up with interventions that promote that process. So we’re doing experiments with drugs that might promote the recovery process, and we’re also trying to figure out the best kind of therapy to give and the best time to give it.”
The theory is that if you lose one part of your brain, other parts of the brain take over. For this to happen, some neurobiological change has to occur in those areas. Dr. Kleim uses a technique that allows him to map movement in the brain. He explains that different regions of the brain control different body parts. “The part that controls your wrist is right next to the part that controls your fingers so the brain is actually a map of your body. We make what are called motor maps, where we take a picture of the top of the brain—almost like an aerial photograph—then pass small amounts of current through different areas to see what movements are produced.”
After rehabilitation, the brain can be mapped again to see how the map has changed in response to both the damage and the therapy. The area which may have controlled your elbow before a stroke might now control your fingers, to compensate for lost tissue. “It’s quite remarkable that the brain has the capacity to do this and can adapt so quickly,” says Dr. Kleim. “We want to know what happens to the neurons within these brain areas that are undergoing change, and what it is about physical therapy that drives these changes.”
“There is some very exciting stroke research going on in Alberta,” summarizes Dr. Alastair Buchan. “But prevention is also key. It’s so important for people to choose a healthy diet and get regular exercise. We need to move beyond simply coping with this devastating illness after it happens.”
Credentials and publications
Dr. Alastair Buchan is a full professor in the University of Calgary Department of Clinical Neurosciences, and director of the Calgary Stroke Program. He is an AHFMR Scientist and also receives funding from the Heart and Stroke Foundation (both provincially and nationally), the Canadian Stroke Network, the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI), and Western Economic Diversification Canada.
Dr. Andrew Demchuk is an AHFMR Clinical Investigator and assistant professor in the University of Calgary Department of Clinical Neurosciences. He also receives funding from the Heart and Stroke Foundation of Canada, CIHR, and the National Institutes of Health (NIH) in the United States.
Dr. Richard Frayne is an AHFMR Scholar and an associate professor in the departments of Radiology and Clinical Neurosciences at the University of Calgary. He also receives funding from the Heart and Stroke Foundation of Canada and the Canada Research Chair program.
Dr. Ross Mitchell is an AHFMR Scholar and associate professor in the departments of Radiology and Clinical Neurosciences at the University of Calgary. He also receives funding from CIHR, the MS Society of Canada, and the Heart and Stroke Foundation of Canada.
Dr. Christian Beaulieu is an AHFMR Scholar and assistant professor in the Department of Biomedical Engineering at the University of Alberta. He also receives funding from CIHR, the Heart and Stroke Foundation of Canada, NSERC (Natural Sciences and Engineering Research Council of Canada), and the Whittaker Foundation.
Dr. Frederick Colbourne is an AHFMR Scholar and an associate professor in the University of Alberta Department of Psychology. He also receives funding from the Canadian Stroke Network, CIHR, NSERC, and the Heart and Stroke Foundation of Canada.
Dr. Jeffrey Kleim is an AHFMR Senior Scholar and an associate professor in the University of Lethbridge’s Department of Psychology and Neuroscience. He also receives funding from CIHR, NSERC, the Canadian Stroke Network, and the NIH.
Selected publications
Kennedy J, Ma C, Buchan AM. Organization of regional and local stroke resources: methods to expedite acute management of stroke. Current Neurology and Neuroscience Reports 2004 Jan;4(1):13-18.
Alexandrov AV, Demchuk AM, Burgin WS, Robinson DJ, Grotta JC; CLOTBUST Investigators. Ultrasound-enhanced thrombolysis for acute ischemic stroke: phase I. Findings of the CLOTBUST trial. Journal of Neuroimaging 2004 Apr;14(2):113-117.
Frayne R, Goodyear BG, Dickhoff P, Lauzon ML, Sevick RJ. Magnetic resonance imaging at 3.0 tesla: challenges and advantages in clinical neurological imaging. Investigative Radiology 2003 Jul;38(7):385-402.
Zhu H, Goodyear BG, Lauzon ML, Brown RA, Mayer GS, Law AG, Mansinha L, Mitchell JR. A new local multiscale Fourier analysis for medical imaging. Medical Physics 2003 Jun;30(6):1134-1141.
Beaulieu C, de Crespigny A, Tong DC, Moseley ME, Albers GW, Marks MP. Longitudinal magnetic resonance imaging study of perfusion and diffusion in stroke: evolution of lesion volume and correlation with clinical outcome. Annals of Neurology 1999 Oct;46(4):568-578.
MacLellan CL, Girgis J, Colbourne F. Delayed onset of prolonged hypothermia improves outcome after intracerebral hemorrhage in rats. Journal of Cerebral Blood Flow & Metabolism 2004 Apr;24(4):432-440.
Kleim JA, Bruneau R, VandenBerg P, MacDonald E, Mulrooney R, Pocock D. Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurological Research 2003 Dec;25(8):789-793.