Announcer: From the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health, welcome to another installment of NICHD Research Perspectives.
Dr. Michael Weinrich: Hello, I'm Michael Weinrich, Director of the National Center for Medical Rehabilitation Research here at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. I'm your host today. Thank you for joining us for another in our monthly series of podcasts. The National Center for Medical Rehabilitation Research, the NCMRR, supports research to enhance the health productivity, independence, and quality of life of people with physical disabilities. May is National Stroke Awareness Month, and we're here today to talk about the role of the National Center for Medical Rehabilitation Research in helping those who have experienced a stroke. The roles of the Institutes and Centers here at the National Institutes of Health often overlap. The primary agency for stroke research is the National Institute of Neurological Disorders and Stroke, or NINDS.
The National Center for Medical Rehabilitation Research collaborates with the NINDS and other NIH Institutes on supporting rehabilitation research activities. Our Center supports two main kinds of stroke-related research: to help people to regain their physical functioning after a stroke and to develop medical devices that help them function more effectively when it's not possible for them to regain their physical functioning. A stroke occurs when an area of the brain is suddenly deprived of blood. Blood carries both oxygen and nutrients to cells, and so brain cells deprived of blood soon die. There are two types of stroke. Ischemic stroke occurs when a blood vessel is blocked, often by a blood clot, and the blood supply is abruptly cut off. Hemorrhagic stroke occurs when a blood vessel in the brain breaks and bleeds into the surrounding brain tissue. Whenever possible, it's better to prevent a stroke from occurring than it is to treat a stroke after it happens.
Known risk factors for strokes include smoking, high blood pressure, atrial fibrillation, and irregular rhythm of the heartbeat, diabetes, and high cholesterol levels. If you smoke, you should quit. If you have any other of these risk factors, you should work with your doctor to get them under control. A stroke can sometimes occur suddenly. The warning signs of stroke include sudden numbness or weakness of the face, arm, or leg, especially on one side of the body; sudden confusion; trouble speaking or understanding speech; sudden trouble seeing in one or both eyes; sudden trouble walking; dizziness; loss of balance or coordination; sudden severe headache with no known cause. If you have any of these warning signs and you think you are having a stroke, call 9-1-1 immediately. The chances for successful treatment and recovery are greatest soon after a stroke begins, so it's very important not to delay. A person having a stroke may not realize what's happening to them. If you think someone is having a stroke, if that person suddenly loses the ability to speak, to move an arm or a leg on one side, or their face suddenly appears paralyzed on one side, call 9-1-1 immediately.
Ischemic strokes, the strokes that often result from a blood clot, are the most common. The clots causing them can be dissolved with a drug called TPA, tissue plasminogen activator. Again though, the chances of success are greatest if the stroke patient gets treated as soon as possible, preferably in the first few hours after the stroke occurs. The specific symptoms depend on the region of the brain affected and the extent of the tissue damage. Stroke occurs in the brain, but it can affect the entire body. Long-term effects range from mild to severe and may include paralysis; numbness; pain; and difficulty thinking, speaking, and comprehending problems; or emotional problems like anxiety, frustration, and depression.
With us from the National Center for Medical Rehabilitation Research are Ralph Nitkin and Theresa Hayes Cruz. Dr. Nitkin is also the deputy director for the National Center for Medical Rehabilitation Research. Today he'll tell us about the standard treatments used to rehabilitate people who have suffered a stroke and describe the NCMRR's role in stroke rehabilitation research and tell us some about the current research projects in this area. Dr. Cruz is a program officer in the NCMRR, and she manages the research portfolio in musculoskeletal and neurological rehabilitation, motor control, and assistive devices. Dr. Cruz will tell us about the development of new technologies to help stroke patients compensate for physical impairment or disabilities. With us on the phone are two NCMRR grantees, Dr. Randolph "Randy" Nudo and Dr. Amy Bastian. Randy is the director of the Landon Center on Aging and a professor of molecular and integrated physiology at the University of Kansas Medical Center in Kansas City. His research involves understanding how the brain reorganizes itself after a stroke with nearby unaffected areas taking over function of the damaged areas. Amy is the director of the Motion Analysis Laboratory at the Kennedy Krieger Institute in Baltimore. She's also a professor of neuroscience at the Johns Hopkins University School of Medicine. Amy is working to understand how damaged different regions of the brain, such as the cerebellum and cerebrum, affect movement like walking and reaching. Her research focuses heavily on studies of motor learning in order to understand what type of training might be optimal for rehabilitation.
Our first guest is Dr. Ralph Nitkin. Ralph, can you tell us about the role of the NIH in general and the NICHD in particular in deciphering what happens to the brain after a stroke and what we know about how the brain compensates for such injury?
Dr. Ralph Nitkin: Well, studies in animal models and clinical studies in humans have taught us a lot about the cascade of events that occur in the hours, days, and weeks after a stroke. Depending on the size and location of the stroke, some brain tissue is permanently damaged. In the surrounding regions, the brain makes other changes, both positive and negative, as it works to preserve, adapt, and compensate for this loss. The initial tissue loss and the resultant brain changes have functional implications such as paralysis, speech impairments, or cognitive or behavioral deficits. Now dramatic improvements often occur in the first few days as the brain circuitry recovers from the initial stroke damage. But targeted therapy can push these improvements even beyond this initial phase.
NIH research has provided a lot of good news about the importance of early and aggressive therapeutic intervention once the patient has been stabilized and damage has been assessed. So, early on, we can use functional tests and impressive brain imaging technologies to provide important prognostic information for the patient and their family about the extent of the stroke and potential therapeutic options. Research has demonstrated that targeted exercises can drive the brain to make remarkable functional gains after stroke. Basically, we're applying classic principles of learning and behavior to brain circuitry recovering from stroke damage. So, using these research approaches, trained therapists can work with the patient to treat the deficits in movement, speech, or even cognition behavior. The specific approaches also depend on the goals of the patient and the resources of their family and community.
The NICHD has worked with the National Institute of Neurological Disorders and Stroke to support major clinical trials on stroke rehabilitation—constrained use trials to improve hand and arm function and treadmill training and aboveground training to improve walking. So, constrained use trials involve carefully designed clinical packages to encourage more use of the partially paralyzed limb. And this is kind of a direct application of the use-it-or-lose-it principle. And while the treadmill training and aboveground training is designed to awaken spinal cord circuitry and enhance walking activity in patients that have paralysis of lower limbs, the bottom line is basically that our brain and nervous system is dynamic and has remarkable ability to adjust, compensate, and recover. But stroke rehab takes work, weeks of focus and repetition, and broader health and lifestyle adjustments also help recovery.
Dr. Weinrich: Ralph, what are some of the pressing questions that remain in this area? Can you tell us what some of our grantees are doing to address them?
Dr. Nitkin: Well, across the NIH we continue to support a lot of research on the dynamics of brain functions, how our brain adjusts to damage and disease, and how it responds to training and experience. But one key issue is how to optimize recovery for a given stroke patient. We're seeking even better ways to assess initial stroke damage and the remaining brain circuitry to build on. And during treatment, we need more sensitive means of monitoring brain plasticity, recovery, and the early functional gains. We need to fine-tune therapeutic treatments to better support the goals of the patient and their family. This includes optimizing the delivery of rehabilitation. So, what's the key active ingredient? How intense? How often? How long? And as we start to get improvements, how do we maintain and reinforce these functional gains?
Medical rehabilitation is also considering the use of other approaches to enhance therapeutic exercise. So, for example, there's some exciting research on the use of mild electrical or magnetic stimulation of the brain to stimulate specific brain circuitry and enhance recovery. We are also looking at the use of specific drugs to increase patient engagement and improve functional gains. I also alluded to the use of robotics and other mechanical devices to deliver therapy and support functional activities. Some of our researchers are focusing on the secondary changes in the spinal cord circuitry that result from stroke, especially in the context of partial paralysis and spasticity.
Treatments of the spinal cord and muscle level could provide an additional means of reducing some of these stroke impairments. This may include electrical stimulation of muscle and nerve and the use of other assistive devices. And some of our stroke researchers are also considering prevention of secondary conditions, such as falls and deconditioning, which can profoundly affect the health outcomes in stroke patients. So, a key finding from our clinical trials is that intensive therapy can improve function even in chronic stroke patients months or years after the initial stroke. And so the challenge is to provide the evidence to the health care system to justify a broader range of support for chronic stroke patients so that they can still continue to make functional gains even in the chronic phase.
Dr. Weinrich: Thank you, Ralph. Our next guest, Dr. Theresa Cruz, oversees much of our Center's research on the development of assistive devices—devices that help people to overcome a movement disorder or limitation. Theresa, this is a comparatively new field that's growing at an astonishing rate, isn't it? The development of the microprocessor has made all sorts of advances possible. Can you tell us about your program's recent highlights as well as some of the projects your grantees are working on now?
Dr. Theresa Cruz: Thanks, Mike. Assistive technology has certainly come a long way in recent years. Remember that an assistive device can be something as simple as a cane, a brace, or a wheelchair or as complex as a robot or an electrical stimulator. And NIH supports research across this wide range. For example, we're currently funding research in the area of functional electrical stimulation, or FES. This involves placing electrodes over paralyzed muscles or sometimes inserting them directly into the muscle under the skin to artificially assist contractions. This technique can be applied to many different parts of the body, including the upper and lower limbs, to increase function.
NIH is also supporting research in the area of rehabilitation robotics. These devices provide a controlled environment to practice many repetitions of a task. We're currently supporting research to look for the best ways to use these devices. Furthermore, many researchers are looking at ways to combine assistive therapies. So, Ralph talked about electrical stimulation of the brain. Can we use that combined with other therapies to produce an even greater outcome? How important and how do we use sensory feedback is also a major question. Finally, the ubiquitous nature of cell phones and particularly smartphones has opened up a new realm of mHealth technologies for assistive devices. Are there ways to use apps and information from cell phones to improve our rehab?
Dr. Weinrich: Theresa, are there technical issues or barriers that keep us from making full use of these technologies? What needs to be done to overcome these?
Dr. Cruz: On one level, there's the ease of use and cost as major considerations. The amount of improved function is also a consideration. It isn't enough to see a statistical significance. The therapy or the assistive device needs to contribute a meaningful improvement to the person's life to be worthwhile. So one way to address that is to include the consumer or the end user throughout the design process. On a deeper level, we need to understand which types of therapy are right for which type of patient. Ralph talked about this. So who are the responders and the non-responders to our therapies?
Dr. Weinrich: Thanks very much, Theresa. Now, our next guest, Dr. Randy Nudo of the University of Kansas, will tell us about his discoveries in how the brain compensates for a stroke-related injury. Randy, you are well known in the field for your work investigating these fundamental mechanisms of recovery in nonhuman primates. Can you briefly describe these studies for us?
Dr. Randy Nudo: Yes. These studies really are done in experimental animals so that we can get information about how the brain repairs itself really at this cellular and molecular level. And we found that exactly what has been described about use and physical therapy rehabilitation after stroke enhancing the recovery of stroke patients. We find this in our animal models as well, and that when a part of the brain is injured, those cells die, but there are other parts of the brain that can share that function, and through physical rehabilitation, those areas expand their functional control over the deprived muscles so that some functional recovery can occur. This is the brain's normal process of repair.
We know that there are treatments that can be given within a few hours after stroke to try to rescue any neurons that are vulnerable, but we now know quite a bit from these studies about how the brain immediately initiates the repair process and it tries to restructure circuitry; in fact sends out new pathways to other parts of the brain. So when there is a stroke, damage to a limited part of the brain—the post-stroke brain is not like a normal brain with a piece missing; it really is a completely rewired system. And so there is this phase over the course of days to weeks, perhaps even months, when the brain is undergoing that repair process. And so we're learning how to best enable the brain to repair itself using its own intrinsic mechanisms and then trying to enhance them in various ways.
Dr. Weinrich: So, Randy, what are some of the remaining barriers we need to overcome in the quest to help people recover from the effects of a stroke?
Dr. Nudo: Some of the barriers include the understanding when to intervene and understanding the molecular process that the brain goes through after stroke is actually allowing us to try to predict when those optimal periods would be. When new fibers grow in the brain, they occur during the initial weeks, and so we think that early time after stroke may be a particularly good window in which to intervene. Now, the challenges that we don't entirely know—how much and when to deliver these therapies, whether it's rehabilitation or drugs, and so we are trying to understand whether we can intervene extremely early, perhaps even in the first couple of days or weeks, or a couple of days, or the first week in order to initiate that process earlier, and enhance recovery to a greater extent.
The other great barrier is that really the therapies that have been available thus far are for those with mild to moderate injury and moderate impairments, but those that have the most severe types of strokes with severe paralysis, we're still struggling to try to adapt our new knowledge to that patient population. Now there is great hope in that area though because we're understanding that there are new drugs that target the molecular pathways that are involved in the brain's intrinsic growth processes and that we're now developing agents that will actually enhance that process. There is great hope that someday stem cells actually will be part of that process as well. And finally, there's an area that, much like with the kinds of the assistive devices that Dr. Cruz talked about, will enhance directly the brain's ability to repair itself.
Microtechnology is advancing at an incredibly fast pace, and in the not too distant future, we will see devices directly implanted into the brain, much like we have for Parkinson's patients with deep brain stimulation to reduce tremors, it's likely that we will have devices implanted in brains one day that will simulate the functions of the damaged parts of the brain and bypass damaged circuitry. There have been a few humans that have been implanted with these devices that have large strokes, and the results are very promising. But we're at a very early stage of that research, and we need to find, we need to have more information from additional patients, and so that will take some time to work out those issues.
Dr. Weinrich: Thanks so much, Randy. Our final guest is Dr. Amy Bastian, director of the Motion Analysis Laboratory at the Kennedy Krieger Institute. Amy, can you first explain to us the normal role of the cerebellum in orchestrating movements and what happens when it goes wrong?
Dr. Amy Bastian: Thank you. The cerebellum is Latin for little brain, and the cerebellum is a part of the brain that sits at the base. We think that the cerebellum is important for movement coordination, and by that I mean the ability to coordinate motions, for example, of the arms and the legs. So if you think about it, when you stand and move your arms, what happens is that not only are muscles active in the arms to control the movement, but you have to be activating muscles in the legs to keep you standing while those arm movements occur. If you don't have this, then what happens is that your movements become unstable and you may actually knock yourself off balance. Now we think that the cerebellum is doing this kind of job, this movement coordination, and we think that it does this by learning how to predict what the effects of movement are. An example of this is, when you see a little baby first learning to move, when they move their arms in the standing position, often they knock themselves over, and this is because they can't coordinate the legs, the muscles in the legs, for their arm movements.
Now an important point about the cerebellum is that it actually helps to keep movement calibrated by constantly learning movement. And so damage in the cerebellum causes incoordination of movement. People are still able to make movement, but what happens is their movements become disorganized, ataxic, where they have difficulty reaching for objects; they over- or undershoot them. Their walking becomes irregular. They veer and they may fall, and we think that this is all due to this loss of learning and coordination, which helps people to keep their movements well calibrated.
Dr. Weinrich: Amy, much of your work involves having people walk on treadmills and recording their movements and then analyzing the gaits of people with different brain injuries. Can you summarize for us what you've learned and how it's been applied to help patients?
Dr. Bastian: Sure, Dr. Weinrich. So I mentioned earlier that we think that the cerebellum is an important part of brain for learning movement control. What we found is that people with cerebellar damage have difficulty learning new kinds of movements, and one kind of movement we've been studying is walking. We use a split-belt treadmill. This is a special custom treadmill where we can make the legs move at different speeds, and using this device we can study how people learn new gait patterns. Now, what we found is that if you damage the cerebellum, you actually cannot learn new gait patterns very well. Now the interesting thing is that if the cerebellum is intact—as it is typically in a stroke because stroke more often affects other parts of the brain, the cerebrum for example—what happens is that the cerebellar learning mechanisms can be leveraged in order to help those patients. So as Randy mentioned earlier, we need to understand patient-specific rehabilitation, and so this is one example of that. If we have a patient with cerebral damage, a stroke like we've been talking about, but their cerebellum is intact, we can use that cerebellar learning to help them to acquire a new walking pattern on our split-belt treadmill. Now if you think about it, what we're actually doing is we're making people learn a new walking pattern in an unusual situation, and we effectively can train their limp out. So our recent studies suggest that this cerebellar learning mechanism can be used to help rehabilitate cerebral stroke patients.
Now the interesting thing is that now noninvasive brain stimulation is coming into play in our laboratory with our collaborators. And what we are finding is that not only by training the right patients on the right devices but also by stimulating parts of the brain that we think are important for the learning is benefiting these patients in terms of their ability to retain the new learned pattern. So we're very excited about the new kinds of mechanisms that we're uncovering to use one part of the brain to compensate for damage in another part of the brain. We think that these kinds of principles are very important for stroke rehabilitation, and we're also working towards understanding in our cerebellar patients if there are new learning mechanisms that we can use to help them recover. So I think the bottom line here is that the work that's going on right now is trying to focus on patient-specific rehabilitation, it's trying to leverage new learning mechanisms in order to understand how to optimally rehabilitate people, and, in doing so, we're actually understanding how different parts of the brain contribute to learning and control of movement.
Dr. Weinrich: Thank you, Dr. Bastian. The perspectives that you and Dr. Nudo provide are really very encouraging. I'd like to let our listeners know that the staff of our sister institute, the National Institute of Neurological Disorders and Stroke, has a stroke awareness page on their institute's website. The site contains useful information on stroke as well as publications and other materials that community groups can distribute to their members to help them reduce their stroke risk. You can access the site at stroke.nih.gov. That brings us to the end of our podcast. I'd like to thank Dr. Ralph Nitkin, Dr. Theresa Cruz, Dr. Randy Nudo, and Dr. Amy Bastian for talking with us today. I'd also like to thank our podcast listeners for joining us and for your interest in our work at NICHD.
For more information on any of today's topics and many related topics, visit www.nichd.nih.gov. That's www.nichd.nih.gov. I'm Michael Weinrich, and I hope you will join the staff of the NICHD for more podcasts as they are posted on our website each month.
Announcer: This has been NICHD Research Perspectives. To listen to previous installments, visit nichd.nih.gov/researchperspectives. If you have any questions or comments, please email NICHDInformationResourceCenter@mail.nih.gov.
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