Since Hippocrates, the father of medicine, first described a stroke, scientists have made great strides in understanding both the causes of strokes and how to treat them. But plenty of questions remain unanswered, especially regarding helping the brain and body recover faster and more completely. 

For example, what’s the best way to personalize care? What technologies would help patients recover more completely? And perhaps the most elusive question: Can we find a magic drug to recuperate lost brain function? Tufts researchers are pressing toward the answers to those questions, from a variety of different angles.

Miranda Good, an assistant professor at Tufts University School of Medicine and neurovascular physiologist at Tufts Medical Center’s Molecular Cardiology Research Institute, is investigating how to salvage damaged brain tissue. Mary Teena Joy, an assistant professor of neuroscience at the Graduate School of Biomedical Sciences, focuses on understanding brain circuit changes after stroke at the Joy Lab, which is based at the Jackson Laboratory (JAX) in Bar Harbor, Maine. Lester Y. Leung, an associate professor at the School of Medicine who’s also a vascular neurologist and director of the Comprehensive Stroke Center at Tufts Medical Center, regularly treats patients recovering from stroke. And, Gabriele Moriello, a physical therapist and associate professor at the School of Medicine, has used new technology to help patients with recovery.

They all recently spoke with Tufts Now to share insight into the frontiers of stroke research.

Salvaging Brain Tissue

There are two types of strokes: ischemic, which occur when a blood vessel in the brain is blocked, and hemorrhagic, which occur when there is bleeding in the brain. In the case of an ischemic stroke, blockage of a blood vessel cuts off blood supply from a part of the brain. As brain cells lose oxygen, they die. Once they’re dead, they can’t be brought back to life. 

However, after a stroke, some cells on the perimeter of the initial stroke injury may still be salvageable. Physicians refer to this injured but salvageable tissue as the penumbra. 

Medications and surgeries exist to remove blockages from the blood vessels in the brain in the case of a stroke. But no medicine currently exists that targets the penumbra. “Right now, the only thing we can do is try to minimize the initial injury,” Good said. “There’s nothing at the moment to limit the expansion of that injury.”

Good’s research aims to develop drugs that target those penumbra cells. “We want to protect the cells that are debating, “should I die, or should I live?’” she said.

Good investigates how to protect those cells via two pathways: returning blood flow to the part of the brain that is not receiving enough oxygen and reducing inflammation in the penumbra. The faster and further blood flow returns into damaged tissue, the more of it can be salvaged. And inflammation from the brain’s response to the stroke injury can further damage brain tissue in the penumbra that may be salvageable.

To target both pathways, Good studies a protein in the brain called pannexin1. Blocking pannexin1 helps blood vessels in the brain to relax, increasing blood flow.

Blocking pannexin1 also helps limit inflammation by reducing the amount of white blood cells—immune system cells that cause inflammation—entering the brain from the bloodstream. Preclinical studies in mice from Good’s research group have shown that blocking pannexin1 reduces inflammation in the brain and reduces the stroke injury. Preclinical studies like these are needed to identify new therapeutic interventions, she said. 

Personalizing Care

Strokes seem to affect male and female humans differently, too, which is an active area of research for stroke experts. For example, said Good, women who have recently completed menopause are suddenly at a much higher risk of stroke and other vascular events, but scientists aren’t entirely sure if the underlying mechanisms that cause that change in women are the same as mechanisms that worsen stroke outcome in men. Digging deeper into that question could eventually identify hormonal or non-hormonal pathways that may trigger strokes in women and aid the creation of drugs that target those pathways. 

“We’re extremely far behind in understanding the mechanisms that are regulating diseases in women, including stroke,” Good said.

Another big question is how to personalize stroke care based on variables beyond sex. The type of stroke, where in the brain it occurred, and which brain signaling pathways it affected should all play a role in designing a treatment and recovery plan, Leung said. Current recovery plans tend to be “cookie-cutter,” with a limited set of possibilities for rehabilitation therapy type and duration. 

“There’s a lot more opportunity to use our knowledge and expertise, like brain scans, for example, to get a sense for what types of therapies will really help one specific person,” Leung said. 

Leung used the example of a person who has lost their ability to speak due to a very severe stroke on the left side of their brain. Standard speech therapy may not work very well for them, since much of their language-processing brain tissue has been damaged. The knowledge of where the stroke occurred, gained via brain scans, might indicate that music therapy—which harnesses the abilities of the right side of the brain—could work very well for them. 

Personalizing care could also mean finding new ways to anticipate late complications after stroke, or LCAS, which include seizures, persistent fatigue, depression, anxiety, cognitive impairment, sleep disorders, severe headaches, and chronic pain that occurs weeks to months after a stroke. Scientists could create predictive models that estimate the likelihood of such complications based on a patient’s unique brain injury and demographic information, Leung said. Currently, “that level of personalization doesn’t exist,” but it is one goal of Leung’s research with stroke survivors.

Refining Recovery

Researchers are also working to understand how the brain recovers. Brains that have been damaged by a stroke initially lose certain functions. But the brain is able to adapt to changing circumstances through its life—an ability scientists call “plasticity.” 

“It’s really a question about how we harness that plasticity,” Joy said.

Joy’s research involves imaging brain activity in mouse models to pinpoint how specific neural circuits in the brain reorganize after a stroke. She hopes the research will ultimately help scientists better understand how brain plasticity can improve a patient’s motor skills, like holding a glass of water, combing their hair, or picking up a fork, for example. 

Plasticity isn’t always beneficial, either. When a stroke patient loses some of their motor function, they may compensate for that loss of function with movements that hinder their recovery or lead to pain in overused joints. As one example, a stroke patient who has lost some ability to reach with their upper limbs might compensate by hyperextending other body parts, which may cause injury over time.

Joy’s research aims to understand how the brain’s reorganization after a stroke causes that compensation. “We want to understand what in the brain is causing that, and how we can discourage that maladaptive plasticity and encourage beneficial plasticity in the brain.”

Signaling pathways in the brain that have to do with learning may also be involved in stroke recovery. Joy’s previous work as a postdoctoral researcher identified a protein on the surface of different brain cells including neurons, called chemokine receptor type 5 or CCR5, that “puts the brakes” on brain plasticity. When cellular signaling via that protein is deactivated, the brain can learn better and build new neural pathways. Now, in her work at Tufts-JAX, Joy is investigating what types of drug therapies can best target pathways that engage CCR5 in the brain and looking for other molecular and neural targets in the brain that control learning.

“Scientists are still in the quest of whether we can come up with a magic drug for stroke that can significantly improve function,” Joy said. “Even a 20% increase in motor function means a meaningful change in the life of a stroke patient.”

Stem cells—human cells that have not yet differentiated into specific body system cells such as blood cells, skin cells, immune cells, and more—could be that magic drug. Much more research is needed, Leung said. But there’s a potential that stem cells could rebuild brain tissue from the ground up, bypassing the problem of salvaging damaged tissue.

Technological Advances

Some of the most exciting advances in the stroke world are in the technology space, Leung said.

For example, physical therapists who work with those who have had a stroke have begun to incorporate exoskeletons—mechanical frames that can support a person while they move—into their therapies, Moriello said. Having the support of an exoskeleton helps a patient repeat certain movements that may not otherwise be possible, like walking, in the hopes that the brain will adapt.

Implants in the brain or spinal cord can also help neurological signals bypass damaged tissue. The technologies “essentially enhance or amplify the signal from the brain to a part of the body, so the body is able to hear that signal better,” Leung said. Recently, the U.S. Food and Drug Administration approved a medical device that stimulates the vagus nerve with electrical impulses to help stroke survivors with arm paralysis improve their motor skill recovery. Stroke researchers are working to understand how such devices and similar technologies can help stroke patients with a variety of neurological impairments.