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Physicians Update


Physicians Update

Summer 2006: Neuroscience

How the Brain Rewires After Stroke

Recent advances have provided vital clues that shed light on how the brain repairs and rewires itself, facilitating recovery from stroke. "We're beginning to understand exactly how the brain repairs itself after stroke," says S. Thomas Carmichael, M.D., UCLA neurologist. "We are identifying time windows in which certain repair processes are active.

Dr. Carmichael and researchers in his lab are studying the molecular and cellular mechanisms of axonal sprouting and stem cell responses to brain injury, and how these two processes of neuronal regeneration lead to repair of damaged brain circuits.

Using imaging techniques, researchers have determined that most of the recovery after stroke occurs in the tissues that border the nerve cells that die due to lack of blood supply and oxygen. In addition, researchers discovered which gene systems mediate the axonal sprouting. These findings offer two important clues about the biology of stroke recovery.

The brain operates as a set of circuits that control movement, thinking, emotion and behavior. A stroke interrupts or kills off certain circuits, causing debilitating paralysis as well as speech and cognitive problems and behavioral and emotional changes. Some spontaneous recovery does occur, however. For example, a patient may be unable to move his or her left side at all immediately following a stroke. Over time, usually about six months, some function returns. The circuits nearest the area damaged by the stroke naturally form new connections, routing around the damage and resulting in this recovery. "What is happening is the brain is remapping and reorganizing itself, and that is where recovery is occurring," Dr. Carmichael explains. "What we're trying to determine is if we can improve and enhance that recovery."

His research team found that nervous system injury induces expression of both growth-promoting and growth-inhibitory genes that together determine the location and degree of axonal sprouting. In the past, the extent of a patient's recovery depended upon the severity of the stroke. But new therapeutics may be able to boost the axonal sprouting process, allowing for the formation of more connections.

The brain could reroute its processes around the dead cells to restore more function. Children who suffer from stroke recover fully because their brains are still developing and are in a more plastic state, better able to make the circuit connections needed for repair. As humans grow and develop into adults, their brains solidify and lose that ability.
For years, researchers debated whether the adult brain could remap itself the way younger brains do. After researchers proved this did happen in adults, the second critical step was to find out how. As it turns out, the gene expression associated with axonal sprouting in the adult brain after stroke is unique, not like the axonal sprouting found in the peripheral or developing nervous systems. "This may give us clues as to why the adult brain is not as successful at rewiring itself as the peripheral and developing nervous system is," Dr. Carmichael says. "Obviously, most adult stroke patients don't recover well enough after stroke to resume normal function, yet children do. The fact that there is a unique growth program in the adult brain suggests that there may be unique targets at which we can aim new therapeutics."

Dr. Carmichael and his researchers are working to identify molecular targets to promote a neuronal growth program and induce increased axonal sprouting after stroke. Patients are taken through therapies that force them to walk more, use their arms more, or challenge their language function more completely. However, there are no drugs now that can be used to induce improved recovery after stroke.

"There needs to be a combination approach," Dr. Carmichael says. "If we were to develop a drug that enhanced sprouting, we could use that drug in combination with physical therapies that are the traditional mainstay of stroke rehabilitation."

The long-term goal is to move neurological rehabilitation closer to the acute stroke and marry the treatment of recovery to the treatment of the stroke itself.

"Epidemiological evidence has shown that most motor and sensory recovery is finished by the six-month mark," Dr. Carmichael says. "The goal of the molecular studies in stroke rehabilitation is to move the start of neural repair closer to the acute stroke itself, and to extend this limited time window for recovery well beyond six months."

Recommended Reading
Carmichael ST (2006) Cellular and molecular mechanisms of neural repair after stroke: making waves. Annal Neurol. 59:725-742.

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