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Why our bodies, and brains, bounce back

Yale Medicine Magazine, 2014 - Autumn


How regeneration happens and how it might be exploited are the subjects of intense investigation.

On January 22, 2013, Helen Bolan sat down to dinner with her husband, Chris, and their 10-year-old daughter, Sarah, at their home in Trumbull, Conn. Helen was about to comment on the ocean of hot sauce that Chris was pouring onto his stew, but the words wouldn’t come out. As she struggled to speak, it became clear that something was seriously wrong. Chris dialed 911, and an ambulance rushed Helen to the hospital.

While frightening, the episode was only a warning—an event known as a transient ischemic attack, or TIA. Often called mini-strokes, TIAs are temporary blockages of the arteries that feed the brain, causing stroke-like symptoms that last no more than 24 hours. Exactly two weeks later, almost down to the minute, Helen had another TIA. Sarah called an ambulance, and Helen watched her reflection in the mirror as paralysis overtook her right side. Helen’s doctors didn’t see anything on her initial brain scans to explain the attacks, but Helen had a history of migraines, and the intense headaches are known to present with TIA-like symptoms. After her second TIA, she started taking a migraine medication, and Chris and Helen hoped that her neurological woes were behind them. Helen went a full four months without another TIA. Then, on June 14, she had a stroke.

“Outstanding programming”

The body is a battlefield. It deals with insults and injuries every day, from the sting of a paper cut to the massive damage that can occur during a stroke. Immune cells fight off infection, torn muscles recover, and broken bones mend. Even an organ as fragile as the brain can recover. Speech and motor function may return even after large swaths of brain cells perish during a stroke. “Almost all the people who have strokes recover some function between one week and six months,” said Stephen M. Strittmatter, M.D., Ph.D., the Vincent Coates Professor of Neurology, professor of neurobiology, and co-director of Yale’s Program in Cellular Neuroscience, Neurodegeneration and Repair.

The human body and brain are designed to bounce back from injury. “Part of that robustness comes from the fact that the cells in our bodies have outstanding programming, and they can repair and reconstitute tissue and organ function even after an insult,” said Laura E. Niklason, M.D., Ph.D., professor of anesthesiology and of biomedical engineering. To a large extent, the body heals on its own, but those natural healing mechanisms can falter or fail. Researchers at Yale are looking for ways to bolster the body’s ability to bounce back by studying the human body where it is most vulnerable—and where it is most resilient (see sidebar).

“Different tissues and organs have different degrees of resilience,” said Ruslan M. Medzhitov, Ph.D., the David W. Wallace Professor of Immunobiology and a Howard Hughes Medical Institute investigator at Yale. “What makes us really sick, and what can kill an organism, animal, or human, is when the most vulnerable aspect of our physiology—the organs or tissues or processes that have least resilience—are affected enough to push them over the edge.”

The brain is especially sensitive, and so the body has developed a host of defenses to protect it from insults. A hard skull shields it from mechanical blows, and internal mechanisms maintain the supply of glucose and oxygen to the brain even at the expense of other tissues. “These mechanisms ultimately increase the resilience of the entire organism because they protect the weakest links in the system,” said Medzhitov.

None of those mechanisms can protect the brain from a stroke, but neurologist David M. Greer, M.D., Ph.D., hopes that a new application of an old technique can help to buffer the brain from stroke-induced injury.

Greer, the Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli Professor of Neurology and and professor of neurosurgery, is Yale’s principal investigator of a nationwide Phase II/III clinical trial to study the effects of induced hypothermia in limiting brain damage during the acute phase of stroke. Induced hypothermia—lowering a patient’s body temperature to 91 degrees Fahrenheit—has been used for years in the operating room and, more recently, following cardiac arrest. The precise mechanism is unclear, but therapeutic hypothermia appears to allow the body—and the brain—to get by with less oxygen. Greer and his co-investigators believe cooling could prevent stroke-related damage in a number of ways: hypothermia slows the metabolic rate of cells, stabilizes cell membranes, halts the release of harmful neurochemicals and enzymes, and reduces inflammation. The investigators plan to test the technique in combination with tissue plasminogen activator (tPA), a naturally occurring protein administered during a stroke to dissolve blood clots in blocked vessels.

If the stroke team can prevent too much damage from occurring, the brain will take over its own healing. But often stroke victims don’t arrive at the hospital in time to receive such acute treatments as this one, according to Greer. Helen Bolan didn’t.

After an insult, the brain rearranges

Bolan didn’t know she’d had a stroke until four days following the event, during a regularly scheduled appointment with her doctors at Bridgeport Hospital. To Helen, the stroke was unlike her TIAs: she was groggy but fully mobile, and her trouble with words came on gradually rather than all at once. Her husband was out of town. There was no one to notice anything amiss. By the time she saw Greer, a lot of damage had been done. Her speech was significantly impaired—she knew what she wanted to say but words escaped her—and her right side was weak and sore.

In August 2013, Greer diagnosed Helen with Moyamoya syndrome—an uncommon disease that causes the constriction of arteries in the brain. Looking at her brain scans, Chris and Helen could see the tissue that had been lost, and they saw the dark line of her carotid artery collapse as it curved into the left side of her brain. “It was quite startling,” said Chris. “[Her] brain was starving.”

To preserve her undamaged brain tissue, surgeons rerouted an artery to supply more blood and oxygen to her left hemisphere. After the surgery and months of rehab, Helen slowly recovered the functions she’d lost. But she’s not quite her old self. “I’m not as talkative as I used to be,” she said.

“There is a significant amount of recovery that happens naturally,” said Strittmatter. The brain doesn’t regenerate; it rearranges. One region of the brain can take on functions like speech and movement that were previously the province of regions now damaged by stroke or trauma. “So the function is moving,” said Strittmatter.

How this reconfiguration happens is something of a mystery, according to Strittmatter, though animal studies indicate that it’s likely to be some combination of changes in the wiring and biochemistry of synapses, the conjunctions between nerve cells. While it is unlikely that the brain can make new nerve cells to replace those lost during a stroke, it can make new connections. Scientists can see this process unfold in mice. Using two-photon excitation microscopy to look inside the brains of living animals, they can watch single nerve fibers and their synapses change over time. After a stroke, new pathways and bridges around the damage can emerge from surviving axons. “Those new connections may make up for a dead neuron that was lost in a stroke or trauma,” said Strittmatter. But only up to a point; the more damage that is done, the fewer brain cells we have in reserve.

Dissolving the neural glue

“The ability to make new connections and rearrange connectivity drops as the brain develops,” said Strittmatter. As we enter adulthood, the brain starts making molecules that inhibit rearrangements, locking synapses into place like neural glue. Strittmatter’s lab is looking for ways to dissolve that glue selectively. Over two decades of research, his group has identified neurite outgrowth inhibitor, or Nogo, a molecule that inhibits the sprouting of new synapses, and has characterized the receptor protein by which Nogo transmits its instructions. They have also found molecules that block that transmission by trapping Nogo and preventing access to the receptor. Testing in rats has identified compounds that enhance recovery from stroke without side effects. Strittmatter co-founded Axerion Therapeutics to develop medications based on these findings, though he says it will be 18 to 24 months before any drug candidates are ready for clinical trials. Such drugs would hold promise for patients like Helen, who don’t reach the hospital in time to receive the clot-busting agents that must be given no more than three to four hours after symptoms appear. By blocking Nogo’s inhibitory effects, the drugs could allow patients to make more neural connections and experience faster and more complete recovery not just from stroke but from any traumatic neural injury.

Even without drugs to enhance the plasticity of her brain, Helen regained nearly all of the function she had lost. The first sign that she had recovered came almost eight months after the stroke. “After the surgery, Helen got bored,” said Chris. Once her rehab assignments weren’t challenging enough to keep her engaged, she knew it was time to go back to work, and in April she returned to her job as an accountant. She still has trouble finding the right word sometimes, and her right side feels sore on occasion. “I know it could have been a lot worse,” said Helen. “I was very lucky in a lot of ways.” /yale medicine

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