Stroke is one of humanity’s most feared medical misfortunes. In the United States alone, it afflicts 800,000 people every year, has left 6.5 million survivors, and is the leading cause of disability.
Triggered by ruptures or blockages of blood vessels in the brain, stroke kills brain cells and leaves a multitude of long-lasting effects that include weakness in limbs, dizziness and imbalance, and the loss of vision and speech. It kills about 140,000 people annually in the United States.
Because stroke primarily hits older people, some think of it as an inevitable and impossible-to-treat consequence of aging. But not biomedical engineer Bin He, Ph.D., physical therapist James Carey, Ph.D., P.T., neurosurgeon Andrew Grande, M.D., or neurologist Mustapha Ezzeddine, M.D., at the University of Minnesota. Their collective research holds the potential for limiting the permanent damage that stroke leaves behind.
He, for instance, has long been fascinated by the teamworking potential of brains and computers. He and his colleagues have developed technologies to help people with paralysis from spinal cord injuries. In their research, subjects have learned how to remotely move and manipulate robotic objects with the help of skull caps that detect electroencephalogram (EEG) brain waves and a brain-to-computer communications interface (BCI) that translates the EEG signals into commands for the robotic devices.
Recently, He and his team have tried their technology with stroke patients, a transition sparked by the experiences of one of He’s colleagues who had a stroke.
“That was a shock to me, and it made me think about how BCIs can help treat stroke,” says He, who directs the U’s Institute for Engineering in Medicine and Center for Neuroengineering and holds the Medtronic-Bakken Chair for Engineering in Medicine.
Based on the motor-imagination abilities intact in many patients, merely thinking about moving a paralyzed limb could generate useful EEG signals. “We developed a virtual hand, and we trained the subjects to control that virtual- reality hand to grasp a virtual cup,” He says. “They saw that their brain makes them able to do that.”His team began by training patients to think in a way that generates EEG signals that direct a computer to move a cursor on a screen. With that goal achieved, the next step was even more challenging, a project designed for stroke patients without muscular control of their hand.
Using this technology, he says, it might be possible to stimulate and reactivate injured brain tissue to restore function. He hopes it will one day become standard treatment for stroke patients.
Strengthening through inhibition
Carey, a professor in the Medical School’s Program in Physical Therapy, is involved in yet another innovative approach to treating stroke. Carey and his colleagues, which include He and Grande, are investigating the perhaps counterintuitive idea that an effective way to strengthen the areas of the brain injured by stroke is to temporarily inhibit the healthy parts.
The researchers inhibit the healthy brain hemisphere using repetitive transcranial magnetic stimulation (rTMS), a noninvasive and painless technology that applies a weak magnetic pulse directly to a person’s head.
Because the healthy side can have a suppressive effect on the stroke-affected side, inhibiting the healthy hemisphere can ultimately excite surviving neurons in the stroke-affected hemisphere. This can help certain patients gain better use of their stroke-affected hand.
After the patient’s exposure to rTMS, “we ask the subject to do a task, such as moving a cursor on a computer screen and using their stroke-affected hand to follow a target over and over,” explains Carey, who has researched this approach since 2006. “The patient benefits from the rTMS stimulation and the motor learning training at the same time,” he continues, a combination that may be more effective than either approach separately.
This technique appears to help some types of stroke patients. “The location of the stroke is one factor, and the age of the subject is another,” Carey says. “It will take more time and studies to determine what are the other absolute factors. Perhaps genetics and life habits are factors that need to be ferreted out.”
A cell transformation
Grande, an assistant professor of neurosurgery and codirector of the University’s Earl Grande Stroke and Stem Cell Laboratory, is also active in basic science research that approaches stroke recovery from a different direction.
“People have functional impairments after stroke because brain neurons have died in the area of the stroke,” he says. “Our approach is to regenerate neurons that have been lost, and to have those new neurons establish connection with existing brain circuits to lead to a recovery of function.”
Since human stem cells were discovered in the 1990s, neuroscientists have known that stem cells from skin or other sources can regenerate over time to replace damaged cells of many types. More recently, researchers have tried transplanting stem cells into the brain to replace damaged neurons. But these transplants rarely survive, as they can be rejected or form tumors, making them less than ideal.
Grande’s team achieves that transformation using genetic reprogramming to alter the glial cells so they become immature neurons. From there, the hope is that the immature neurons grow into mature neurons that can connect with already extant neurons. So Grande’s lab is trying a new approach.
“What we’ve done,” he says, “is to try to change a cell already in the brain into a neuron. We’ve taken glial cells [nonneuronal cells that provide support for neurons in the nervous system] already in the area of the stroke damage, and converted them into neurons.”
“It’s like taking an apple and turning it into an orange,” he says of the transformation from glial cell to neuron. “Ultimately, it could provide the means for a recovery of function after stroke.”
In current stroke treatment, patients generally achieve only limited recovery after a critical window of time has passed, Grande notes. “After that, what can you do? That’s where reprogramming for regeneration can help,” he says.
The breadth and depth of stroke research at the U isn’t going unnoticed. The University was named one of 25 large medical centers collaborating in StrokeNet, a research network formed in 2014 by the National Institutes of Health in an effort to gain efficiency by creating a national infrastructure that focuses on stroke prevention, recovery, and rehabilitation. StrokeNet partners conduct multiple trials for the network, contribute their own ideas for new trials, create regional research centers, and train the next generation of stroke researchers.
Along with the Neurological Emergencies Treatment Trials (NETT) Network, to which the University also belongs, StrokeNet fosters repeat teams of researchers and administrators, which brings “a much greater degree of efficiency than if every trial had to bring together new physicians, coordinators, and regulatory people,” says Ezzeddine, the medical director of stroke services at University of Minnesota Medical Center and the U’s principal investigator for StrokeNet.
With that efficiency and the innovative approaches University investigators are taking to improve recovery after a stroke, the future looks brighter. Yet much more is possible.
“It is amazing what we can accomplish when there is an intense research focus on a problem,” Grande says. “Look what we’ve done with Ebola and HIV. We need a similar focus on stroke.”