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On a chilly Minnesota evening last December, 16-year-old Tiffany Cowan sat uncomplainingly in Room 242 of the University of Minnesota’s Masonic Memorial Building as two graduate students from the University’s Brain Plasticity Laboratory carefully attached a series of wires to her scalp and right arm.
Tiffany Cowan (Photo: Jim Bovin)
Cowan, with the consent of her parents, had volunteered to participate in one of the lab’s studies, which was examining the safety of using transcranial direct current stimulation (tDCS) as a treatment for children with congenital stroke. tDCS is a type of painless, noninvasive brain stimulation that delivers a low (battery-powered) and persistent current to specific areas of the brain through small electrodes. Experimental studies have suggested that it may help adult stroke victims regain some function of their limbs. This is among the first to investigate whether it may help children, too.
Tiffany, who suffered a stroke either before or during birth, has limited use of the right side of her body. Although the lithe, blonde teenager leads an active life, including playing the violin (like nearly all violinists, she bows with her right hand and does the more demanding finger work with her left), she’s eager to participate in research that might enable her to have more muscle control of her stroke-damaged hand.
She’d particularly like to write with that hand.
Lead researcher Bernadette Gillick, P.T., Ph.D., hovered maternally around Tiffany as the graduate students prepared the young woman for the tDCS stimulation. Gillick spoke to Tiffany constantly, putting her at ease as she explained everything the graduate students were doing.
“You’re my eleventh subject in this study,” she quipped. “That’s why your nickname is C-11.”
Eventually, all the electrodes were secured on the correct areas of Tiffany’s capped head, and the actual experiment began. The graduate students switched on the tDCS machine, being careful to hide the device’s controls from both Tiffany and Gillick. This was a double-blinded controlled study, which meant that half the children were being randomly assigned to a “control” group that received a pretend, or sham, treatment. To ensure the integrity of the study’s results, it was important that the children and Gillick, who would be interpreting the data, didn’t know which child was in which group.
“How do you feel?” Gillick asked.
Tiffany smiled again. “Fine,” she answered. “It just feels a bit like my hair is being pulled.”
(Photo: Jim Bovin)
Understanding how the brain reorganizes itself after a stroke or other brain injury is the overall mission of the Brain Plasticity Laboratory. Located in the Children’s Rehabilitation Center on the University’s East Bank campus, the decade-old lab is engaged in a variety of fascinating — and often unique — research using various brain stimulation, rehabilitation, and imaging techniques. Findings from this research are not only enabling scientists to gain deeper insight into how the injured brain restructures itself, but they are also pointing to promising new therapies that may help children and adults recover lost function after such an injury.
“There are only a couple of other labs that I’m aware of around the country that are doing some of the things that we’re doing here,” says James Carey, P.T., Ph.D., who codirects the lab with Gillick and Teresa Kimberley, P.T., Ph.D. In fact, he adds, the Brain Plasticity Laboratory may be the only one using a special dual type of brain-priming technique in its studies.
There’s urgency to this area of research. Stroke affects about 795,000 American adults each year, according to the U.S. Centers for Disease Control and Prevention. It’s the leading cause of serious long-term disability in the nation, and it costs the country an estimated $54 billion annually in health care services and lost productivity.
Focal dystonia, another major focus of the lab’s research, also has a devastating effect on many people’s quality of life. Tens of thousands of Americans have this neurological movement disorder, which causes specific sets of frequently used muscles, such as those in the hands, feet, or throat, to involuntarily contract and form unnatural positions. Current treatments are often short-lived and ineffective.
“If we could develop a reliable, effective intervention for these conditions,” says Kimberley, “we would have a profound effect on many people’s lives.”
Thanks in large part to advances in brain imaging technology, it’s now known that the brain is not a static organ after childhood. It is constantly creating and reorganizing new pathways among its 100 billion cells.
The term plasticity (which comes from the Greek word plaistikos, meaning “to form”) refers to the brain’s ability to change its structure and function as a result of new learning and experiences. Until the 1960s, scientists believed that after childhood the brain became a static organ, unable to create new pathways among its 100 billion cells, or neurons. But thanks in large part to advances in brain imaging technology, it’s now known that the brain is constantly reorganizing those pathways. In fact, the adult human brain is even capable of creating new neurons, a process called neurogenesis.
The knowledge that the brain can be retrained to regain lost function has led to the development of a wide range of plasticity-based behavioral therapies. Today, patients who have experienced a stroke or other brain injury are prescribed rigorous and repetitive physical exercises or tasks in order to “rewire” their damaged brain. For stroke patients, this rehabilitative therapy usually begins 24 to 48 hours after the stroke.
“Traditional therapies are effective,” says Carey. “They do help. But given the magnitude of the stroke lesions in some people, they may just not be enough.”
A newer idea, he explains, is to use tDCS or a similar technology called repetitive transcranial magnetic stimulation (rTMS) to “prime” the brain so it will be more receptive to the effects of behavioral therapy.
“If we can adjust the brain to be more responsive to behavioral therapy, we might get better results,” Carey says.
Other laboratories in the United States and elsewhere are also investigating the uses of brain stimulation as an adjunct to traditional stroke therapies, but the University’s Brain Plasticity Laboratory is taking that concept one step further.
“We’re doing priming of the priming,” explains Carey.
To understand how brain-stimulation priming helps stroke patients, you have to first understand how a stroke injures the brain and how, in a somewhat surprising way, the brain responds to that injury. The most common type of stroke damages the brain by interrupting blood flow to the neurons. Without oxygen in the blood, the cells in the immediate region of the stroke begin to die within a few minutes.
Strokes tend to occur on one side, or hemisphere, of the brain’s cerebrum, the largest part of the brain. Located in the top and front section of the skull, the cerebrum is responsible for movement, speech, thinking, memory, the regulation of emotions, and other functions. The hemispheres, which are connected by a thick band of nerve fibers called the corpus callosum, specialize in different functions. When it comes to movement, each hemisphere controls the muscles on the opposite side of the body.
The goal of all stroke rehabilitation therapy is to restore function to the weak side of the body. Achieving this outcome is challenging — and not only because of the damage in the stroke hemisphere. After a stroke, the cells in the nonstroke hemisphere respond in a way that compounds the problem: They become more “excitable.” This exaggerated excitability inhibits healthy cells in the stroke hemisphere from rewiring themselves to regain lost muscle function.
“It’s maladaptive,” explains Carey. “Some have called it a double disablement. As if the stroke weren’t bad enough, the patient gets a disablement from the extra inhibition coming from the other hemisphere.”
The University’s Brain Plasticity Laboratory, along with a handful of other labs around the world, has demonstrated in experimental studies that rTMS and tDCS brain stimulation can suppress the inhibitory behavior of the non-stroke side of the brain, thus “priming” the stroke side to be more receptive to behavioral therapies. The University’s lab is unique, however, in having also discovered that low-frequency (inhibitory) stimulation of the non-stroke hemisphere appears to work even better when it is preceded by high-frequency (excitatory) stimulation.
Currently, the Brain Plasticity Laboratory is the only research group in the United States to have received Food and Drug Administration approval to conduct studies involving this “priming of the priming” technique. Initial clinical trials completed by the lab have been promising, showing a distinct trend toward improved function in adult stroke patients who receive the double-priming treatment.
Recently, the lab has expanded its focus to include research on pediatric stroke. Although thought of mainly as an adult illness, stroke is a leading cause of death and disability in children as well. Each year, about 11 of every 100,000 U.S. children under the age of 19 — including about one of every 4,000 newborn babies — experience a stroke, according to the American Stroke Association. The major causes of stroke in children are congenital heart problems, infections, blood disorders (such as sickle cell anemia), and diseases of blood vessels in the brain.
Children show a tendency to advance faster than adults undergoing stroke rehabilitation therapies. Scientists believe children’s brains may have greater plasticity, enhancing their ability to create new neural pathways in response to injury. But 50 to 80 percent of children with a history of stroke enter adulthood with a permanent disability. The most common is total or partial hemiplegia — paralysis on one side of the body.
Last summer, the Brain Plasticity Laboratory completed a pediatric study that combined rTMS with behavioral therapy. For the study, which was conducted in conjunction with the Gillette Children’s Specialty Healthcare Hospital in St. Paul and funded by a $1 million challenge grant from the National Institutes of Health, the lab recruited 19 children ages 8 to 16. All had hemiplegia as a result of a stroke.
For 13 days the children received treatment, which alternated daily between rTMS stimulation of the nonstroke side of their brain and one-on-one sessions with an occupational therapist. Half of the children received real rTMS stimulation; the other half received sham treatment. (Neither the researchers nor the children knew which treatment the children were receiving until the study was completed.) Throughout the study the children wore a cast on their “good” arm to force them to use only their stroke-affected arm for everyday tasks as well as for the occupational therapy exercises.
Teresa Kimberely, P.T., Ph.D., Bernadette Gillick, P.T., Ph.D., and James Carey, P.T., Ph.D., codirect the University's Brain Plasticity Laboratory. (Photo: Brady Willette)
Both groups of children showed some functional improvement at the end of the study, but those who received the real rTMS stimulation performed significantly better than the other group — and those added gains came with no adverse effects.
“The big question is, can we translate the results that we observed here in our research laboratory to the clinical setting,” says Gillick. “Because that’s ultimately where this is supposed to go. The goal is to improve the lives of those who live with the consequences of stroke.”
Gillick’s current pediatric study — the one Tiffany joined — is using tDCS technology for brain stimulation. Although both technologies can alter brain-cell excitability in the cerebrum, tDCS is less expensive and more portable. That’s because tDCS delivers current directly to the brain, whereas rTMS uses magnetic fields to produce its low-dose electric currents.
“We have just completed the interim analysis and have been approved to continue the study to completion of 20 subjects,” says Gillick. If promising results are found — and she believes they will be — then the next step will be an intervention study combining tDCS with behavioral rehabilitation.
Gillick’s long-term goal is to determine whether this combination of brain stimulation and physical therapy would be even more effective when used soon after a child experiences a stroke. “If we could get closer to around the time of the actual event, we might have a greater impact,” she says.
Children tend to advance faster than adults undergoing stroke rehabilitation therapies. scientists believe children’s brains may have greater plasticity, enhancing their ability to create new neural pathways in response to injury.
A week after her initial participation in the tDCS safety study, Tiffany Cowan returned to the Masonic Memorial Building to be hooked up to the brain stimulation machine for a second and final time.
First, though, she asked if she could have a moment to talk with Gillick.
“She literally sat me down,” recalls Gillick, “and said, ‘OK. You’re going to have another study, right? And you’re going to be actually treating people in that study, right? I want to participate in that study, so sign me up.’”
That conversation underlines the importance of the Brain Plasticity Laboratory’s research, says Gillick — and the great need for more effective treatments for people who have experienced a stroke or other brain injury.
“Tiffany returned for her follow-up excited about the next phase of the study,” Gillick says. “I’m excited, too.”