Rewiring Brains: Rehabilitation, Plasticity and Transplants

Each day we listen to new predictions about how the events of today or the future will cause the world to implode.  But, let’s assume we will once again navigate our way through these disastrous mine fields.  As we enter the second decade of the new millennium will we not only be traveling to new destinations in space, but also repairing and rewiring human brains?  These are exciting times for patients with disabilities, as we perform experiments using stem cells and engineered nervous system cells.   Will we cure currently incurable diseases?  Will patients walk again?  Time will tell.

Most people have a basic understanding of how a fractured bone “knits” itself back together or a cut finger heals leaving only a small scar.   But, the healing that takes place after a stroke, brain or spinal cord injury is much more complex.

THE PLASTIC BRAIN
The first thing that comes to mind is the “visible” man or woman that we could buy as a child and watch as the blue or red food coloring flowed in their blood vessels.  But, here “plastic” has a different meaning.  After any injury or stroke there is the potential for the brain to reorganize and repair itself; attempting to compensate for the cells that have been damaged or lost.  Once again we face the basic question:“Is it nature or nurture?”  Does the brain do all this by itself or can we influence how this reorganization takes place?  If we perform different types of physical, occupational or speech therapies on patients are we enhancing or hindering the brain’s recovery process?  The same is true for various drugs that we administer to patients at different times during their recovery. Some studies have suggested that amphetamines promote brain healing while benzodiazepines like diazepam will hinder it.

H.L. Menken, the journalist and curmudgeon, said that, “For every complex problem there is a simple solution that does not work.” Just look at what goes on inside the brain after it has been damaged and you will see why repairing the brain, rehabilitation, is so complicated and difficult.

  • Brain cells may still be marginally functioning in an environment of inadequate blood or oxygen that needs to be corrected.
  • Like a swollen bruise, the brain may improve as its swelling and edema resolve.
  • After an injury or stroke there may be increased electrical activity in alternate pathways and areas of the brain that have been partially spared. Areas that may be able to assume new functions.
  • The brain may recruit “parallel” pathways and networks that perform similar functions. For example a part of the brain that controls shoulder movement may start to take over movement of the hand muscles.
  • Reorganization of both structural and chemical pathways may take place, much like rerouting a train away from a washed out rail bed. If the message can’t get through the old way, it may seek a new path.
  • For the most part we are an adaptable species and will naturally seek out behavioral strategies to compensate for what we have lost. For example, as we become more forgetful we may make more lists.

WHAT REHAB DOES ACCOMPLISH

The key is to look at the various mechanisms of recovery and to figure out how rehabilitation can positively influence each one.  The recovery process clearly has a component of natural biological recovery, for we know that people will improve to some degree without rehabilitation. Like school, rehabilitation brings to the table new learning and exercises that take people to a higher functional level. Children who never go to school learn some skills while those with education develop much more sophisticated skills.

We have learned that exercise is more than just strengthening and keeping muscles moving.  Experimental evidence suggests that active functional therapies can recruit and open up new pathways in the brain.  In one study a group of normal people were taught to play a one handed piano exercise for five days, while another group was never shown the exercise.  Brain activity was measured at the beginning of the study and five days later.  Increased brain activity could be measured over the part of the brain that controlled the hand in those patients who performed the five days of exercises as compared to those who did not.

Much more elaborate experiments have been performed in primates.  A discrete stroke was created by closing off small vessels in the brain that resulted in weakness of one of the monkey’s hands. One half of the monkeys received exercises with food rewards while the other half did not. The half that received “therapy” improved more rapidly, but more importantly, these studies suggested that the brain was truly “plastic.” The part of the brain that previously controlled shoulder movement had now taken over movement of the hand.  The brain had reorganized itself and done so more efficiently in those who received “monkey therapy.”  Research like this supports the notion that therapies can facilitate the opening of new pathways and “turn on” brain cells that previously were not primarily responsible for the movement of a particular part of the body.

Another study reported that animals placed in an “enriched environment” after a brain injury did better. They were given more “toys” and activity.  Repetitive use of an extremity enhanced recovery, as did increased cage size, companions, stimulation and increased activities. Physiological studies suggested that those animal receiving “rehab” were better able to reorganize the structures in their brains. Rehab made a difference!

These types of studies raise some interesting questions.  Should we primarily teach patients how to compensate for their deficits or should we focus our strategies on paralyzed muscles for prolonged periods of time? How long will it take to open up a new pathway and what is the best way to do it? If we bypass the usual movement patterns and substitute new methods of movement will we prevent the opening of parallel or collateral pathways?  How long do you have to work with a paralyzed muscle to turn on a collateral network or neuron and can it be done routinely in humans?

In our current health care environment we may never know the answers to many of these questions, for we are asked to discharge a patient from rehabilitation as soon as possible.  Clearly therapy should not go on for years, but it may be that we are writing off some patients too soon and sacrificing some potential gains.

Dr. Mary Dombovy, a stroke researcher summarized the problem –
“It takes years of practice to become an accomplished pianist or a skilled craftsman or athlete and one gains facility by practicing the piano not the flute.  Clinical observations indicate that determination and prolonged practice also underlie the higher level of recovery seen in some patients. Unfortunately, most neurologically impaired patients receive only a few weeks or at most a few months of rehabilitation, much of which may not be specific to their deficits.”

THE HIGHTECH FUTURE
We know that after an injury there are early aborted attempts by the neurons and axons in the brain to regenerate and repair themselves.  The key is to create the proper environment so that these nerve cells and their connections will not only grow, but will also travel to the right place and make the proper connection.  If they do grow and make a wrong correction, there is not just the risk of an arm that will not move, but also that it will have an adverse effect such as spasticity.

Research laboratories have been actively looking for ways to facilitate the healing process.  Here are few of the more promising methods.

Peripheral Nerve Bridges.  This is just what it sounds like-a splice between two separated nerves, much like we would splice together a television cable. These are more useful in spinal cord injury where long white matter tracts are interrupted.  For example, a spinal cord injury may interrupt the axons in the neck that carry movement and sensation down to the legs.   In rats with experimental spinal cord injuries, researchers have successfully taken pieces of large peripheral nerves from an extremity and used them to bridge this gap, restoring movements in the hind limbs.  Not only does this bridge provide a pathway for growth, but it may also release growth factors that assist in the survival of the surrounding nerve cells.

FETAL CELL TRANSPLANTS. Tissue taken from a fetus can be transplanted into a laboratory animal or human and it will continue to produce chemicals such as neurotransmitters.  The best known use is that of fetal tissue transplants in Parkinson’s patients, where the fetal cells produce dopamine in the brain and the patient’s function improves.  The problems with this approach are many. The clinical benefit is modest and the amount of fetal tissue available is limited.  New methods of acquiring stem cells that are less controversial will greatly enhance future research.

GENETICALLY ENGINEERED TRANSPLANTS. The controversy over the use of fetal cells led to the use of genetically engineered cells.  Neural cells lines have been developed from human tumor lines by treating the tumor cells so that they will  no longer divide and one does not have to worry about causing cancer.  When transplanted into the Central Nervous System they send out axons and acquire other characteristics of neurons.

Within this group of cells are embryonic precursor cells.   These cells have the potential to become a variety of different cells when exposed to trophic growth factors. One of the problems is how to guide the regenerating axons into the right place.  In frogs and rats there appear to be “guidance cues” in the local environment where the cells are implanted that instruct the axons and neurons on how to make the right connection.   It was cells like these that were used in the first human motor neuron transplant.

THE MAKING OF HISTORY
One high tech bioengineering company has created neurons for transplantation.  The cells were isolated from a 22 year old man’s testicular tumor that had spread to his lung.  The cells were treated so that they would not divide or multiply and were then grown in cultures.  Multiple studies were performed where the cells were implanted into rats, mice and primates–in no cases were there any signs of tumor formation or viruses.  Called LBS-Neurons, they were then injected into the brains of animals that had been given a stroke. They consistently demonstrated reproducible improvements in function and learning.

The University Of Pittsburgh School Of Medicine performed a clinical trial in human stroke survivors who are between the ages of 18 and 75 years with a completed stroke of 6-24 months duration.  Two to six million cells were injected by direct stereotactic injection into and around the area of the stroke.  The goal was for these cells to integrate within the patient’s brain and send out axonal processes, release neurotransmitters and restore motor function.

Even though this group of patients did not demonstrate significant benefit, they were able to demonstrate the feasibility of neuronal implantation. It is clear that new exciting therapies are not just on the horizon, but may be here already.

The rehabilitation of patients with disabilities will continue to be a combination of high touch and high tech therapies.

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