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Waking up the brain after stroke

From the July-August ACP Observer, copyright 2007 by the American College of Physicians.

By Yasmine Iqbal

After years of researching and developing stroke rehabilitation techniques, Rafael H. Llinas, MD, assistant professor of neurology at the Johns Hopkins Bayview Medical Center, has concluded that "the brain is a very lazy organ."

He doesn't mean to be disparaging. Rather, his view signals a fundamental shift in how physicians and researchers now view the long-term consequences of stroke. For years, it was thought that stroke victims reached a plateau in their recovery within three to six months because vital neural connections had been lost forever. But the last decade has seen researchers embracing the idea of "neuroplasticity"—the concept that the brain can continue changing and rewiring if patients are challenged and stimulated in new ways.

Too often, however, the demands of managed care lengths-of-stay means that standard therapy has to focus on getting patients to work around motor impairments instead of trying to improve them, an approach that researchers now think lulls the brain into "laziness."

Virtual reality games get patients more involved in stroke rehabilitation after a stroke. The Hand-Wrist Assisting Robotic Device, or HOWARD, conveys motions from the patient's hand to the actions of a virtual hand.


Virtual reality games get patients more involved in stroke rehabilitation after a stroke. The Hand-Wrist Assisting Robotic Device, or HOWARD, conveys motions from the patient's hand to the actions of a virtual hand.



As a result, researchers now are working on ways to galvanize the brain and get it to reorganize, either by using existing pathways for new purposes or creating new pathways even years after a stroke occurs. Their methods run the gamut from physical therapy techniques, to electrical stimulation of the brain, to robotics, to medications generally used to treat other neurological disorders. Here's a look at some of the most promising developments.

New rehabilitative techniques

Constraint-induced movement therapy (CIMT) involves intensively exercising an impaired limb while restraining the unaffected one. Unlike conventional therapy, which might focus on getting patients to rely on their stronger side, CIMT forces them to develop the potential in their weaker areas.

"When we reinforce the notion of 'learned non-use,' by teaching patients to compensate, we squelch the potential of use," said Steven L. Wolf, PhD, professor of rehabilitation medicine at the Emory University School of Medicine in Atlanta.

Dr. Wolf was the principal investigator in the EXCITE (Extremity Constraint Induced Therapy Evaluation, published in the Nov. 1, 2006 Journal of the American Medical Association) clinical trial, which involved 222 patients who had experienced strokes three to nine months before enrolling in the study. All patients had experienced hemiparesis that resulted in diminished arm or hand movement. During the study, 106 patients wore an immobilizing mitt on their less-impaired hand or arm for 90% of their waking hours for 14 days. These patients received therapy, which included practicing repetitive movements and functional activities (such as eating and writing) for up to six hours a day. The remaining 116 patients received standard care.

In one year, the CIMT patients regained more function than control group patients. They were able to complete a task 52% faster, compared with 26% faster in control group patients, and they increased the proportion of tasks completed with their impaired limb more than 50% of the time by 24%, compared with a 13% increase in the control group.

The EXCITE trial was the first multi-center clinical trial of any rehabilitation method to improve motor function after a stroke. "The EXCITE trial really moved rehabilitation into the Phase 3 clinical trial arena," said Carolee J. Winstein, PhD, professor of biokinesiology and physical therapy at the University of Southern California, Los Angeles, the study's co-principal investigator. She noted that although it's clear that CIMT was successful, key questions about what intensity and duration of therapy are needed to make a difference remain unanswered. "We still need to understand what the ingredients are that made this work," she said.

Some researchers suspect that CIMT need not be so intense to be effective. Stephen J. Page, PhD, associate professor of physical medicine and rehabilitation at the University of Cincinnati, has developed a modified CIMT regimen that involves therapy sessions of 30 minutes a day, three times a week, for 10 weeks. The less-impaired limb is restrained for five hours a day, five days a week. In his studies, patients show clinically significant motor function gains, and fMRI scans show activity in previously dormant areas of the brain. "Modified CIMT is much less intensive, but compliance is much higher, and evidence suggests that it's just as effective as CIMT," he said.

Dr. Page has also been studying mental practice techniques—simply visualizing the performance of physical movements—which engages the same areas of the brain that would become active if the patient were actually performing the task. In an article published in the April 2007 issue of Stroke, Dr. Page and his colleagues demonstrated that patients who underwent 30-minute mental practice sessions directly after physical therapy significantly increased their arm motor function compared to a control group receiving only physical therapy.

"Athletes and musicians often use mental practice and visualization to help them perform," said Dr. Page. "Now we're finding that it's an easy, cost-effective strategy for stroke rehabilitation, as well."

Robot-assisted physical therapy

Experts agree that patients make the most progress when working one-on-one with a therapist. But sometimes, patients can experience even better results when their human therapists work in tandem with a robotic device. Examples of robot-assisted therapy include:

  • The Lokomat, manufactured by Hocoma, a Swiss-based company, assists with partial body-weight supported treadmill training to help patients with walking and gait problems. Patients are strapped into a modified parachute harness while the legs are guided through walking motions by two brace-like components. Traditional training of this type required two therapists to move the legs; with the Lokomat, patients can train for longer periods while the device precisely monitors their gait patterns.
  • The KineAssist, which is being developed at the Rehabilitation Institute of Chicago, is the first over-ground walking and balance exercise system. It's a wheeled device that follows and supports patients from behind, allowing them to walk, climb stairs and practice turning. It can even nudge patients slightly off balance, allowing them to practice catching themselves before they fall.
  • The Hand-Wrist Assisting Robotic Device, or HOWARD, developed at the University of California at Irvine, is a splint-like device that fits around the hand and monitors patients' ability to make gripping and grasping movements. If they can't complete the movement, HOWARD uses a pneumatic system to help them the rest of the way, allowing the brain to relearn the activity.

"Many patients don't have access to good rehabilitation programs," said Steven C. Cramer, MD, Co-Director of the University of California Irvine's Stroke and Cerebrovascular Center, who helped develop HOWARD. Although he admitted that it might be a while before robotic therapy is simple and cost-effective, he envisions a time when patients might supplement their outpatient rehabilitation with a therapy robot in the home.

HOWARD, lets a patient begin a motion, such as opening a hand, and then completes the full range of motion if the patient cannot. The patient then relearns how to complete such tasks.


HOWARD, lets a patient begin a motion, such as opening a hand, and then completes the full range of motion if the patient cannot. The patient then relearns how to complete such tasks.



But even the biggest proponents of robot-assisted therapy say that the technology has its limits. "Robots will never completely substitute for therapists," said Elliot J. Roth, MD, Senior Vice President for Medical Affairs at the Rehabilitation Institute of Chicago. "Their main advantages are that they make therapy more consistent, predictable and measurable."

And there's a danger in allowing patients to rely too much on robot-assisted movement, said George Hornby, PhD, a researcher at the Rehabilitation Institute of Chicago. He noted that some studies indicate that locomotion robots are best used only in the initial stages of therapy when patients are very weak. "Patients don't learn as well if they're getting continuous assistance," he said, noting that patients may not become attuned to subtle sensory and balance shifts while walking if a robot is doing much of the work to hold them up and move their limbs. "Robots are like training wheels," he said. "They can get you to a certain point, but after that, you have to learn to correct your own mistakes."

Electrical stimulation therapies

For years, researchers have been studying how low levels of electrical or magnetic stimulation can speed brain recovery. Although the exact mechanism for how this works isn't well understood, it's thought that the stimulation somehow enhances the brain's ability to form new neural connections. Therapies include:

Cortical stimulation involves applying targeted electrical stimulation directly to the cerebral cortex adjacent to the damaged areas of the brain. Seattle-based Northstar Neuroscience, Inc. currently has 21 sites enrolled in a trial of its Renova Cortical Stimulation System, which is comprised of an electrode patch that is placed on the brain and connected to an implantable pulse generator in the chest. The device is turned on only during therapy sessions and explanted after a number of weeks. Previous studies of cortical stimulation suggest that once the device induces neuroplasticity, motor function improvements are permanent, even after the hardware is removed.

Repetitive transcranial magnetic stimulation (rTMS) involves a less-invasive method that uses magnetic fields generated by passing electrical current through a conducting coil held close to the skull. The magnetic pulses can be used to slow activity on the undamaged side of the brain, forcing the damaged portion to work harder during therapy (a concept similar to CIMT). It can also be used to stimulate the damaged portion of the brain. Transcranial direct current stimulation (tDCS), which applies a weak direct current through the scalp, is also being studied for its potential to jump-start neural activity.

Finding new uses for common medications

Researchers are studying how medications used to treat other conditions can be used to relieve stroke symptoms. For example, antidepressants, such as selective serotonin reuptake inhibitors, might help relieve pain as well as depression; amphetamines might be used to increase cortical excitability; and Botox has been shown to help with spasticity. Investigators are also examining whether medications used to treat Parkinson's disease, including carbidopa-levodopa and ropinirole, might be used to improve motor function and aphasia. Modafinil, generally used to treat narcolepsy, has been used with some success to treat patients with brainstem strokes who suffer from sleep disorders and apathy.

All the newest therapies, technologies and drugs won't make any difference, experts say, if physicians, therapists, patients and patients' families don't commit to the idea that stroke rehabilitation is an ongoing process. But Richard D. Zorowitz, MD, visiting associate professor and chairman of the department of physical medicine and rehabilitation at Johns Hopkins Bayview Medical Center, noted that for most patients, the rehab period is shorter than ever. "Inpatient therapy has gradually shifted focus from getting patients to being functional to just getting them to be safe at home," he said. "And insurance companies continue to mandate that we send patients home earlier and earlier." Dr. Winstein added that "a big problem is that there's limited continuity between inpatient and outpatient programs."

Another challenge is getting therapists to try innovative but sometimes time-consuming strategies, such as CIMT. "People are dying to learn effective rehabilitation techniques, because conventional therapies often aren't effective," said Dr. Page. "But it takes a while for these things to trickle down to the average therapist in the field." Dr. Roth added that robotic technology might be a particularly tough sell. "Therapists are conditioned to work with their hands and rely on their interpersonal skills," he said. "They don't always accept that technology might help them."

"There are always going to be more 'techie' things in stroke rehabilitation," said Dr. Llinas. "But the most important development will be in how these advancements change our entire concept of care." He pointed out, for example, that the advent of tPA therapy, although it's not appropriate for every kind of stroke, helped people to understand that they needed to get treatment for stroke as soon as possible. Now that treatments for chronic stroke are proliferating, they will hopefully raise awareness that stroke rehabilitation can continue to be effective long after the actual event.

"It's great that all these advancements are putting more focus on the problem of stroke itself," said Dr. Llinas. "The more we learn about stroke and its effects, the more we realize that rehabilitation will almost always provide the potential for improvement."

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