The Injured Brain
When an injury or disease of the Brain begins to kill Neurons, a cascade of events takes place, disturbing the fine balance of Neuronal functioning.
Although the damage may be limited to only a small region of Brain tissue, the effects are quite widespread so that eventually, the whole Brain participates in the repair process that in turn, may continue for months or even years after the initial injury.
What happens when a normal, healthy Brain is suddenly and tramatically injured, by a blow to the skull, or by a stroke? In the first place, there is a dramatic change in the anatomy and physiology of the Brain - especially in the area of the injury.
One of the first changes occurs in the Blood-Brain Barrier (BBB). The mechanisms by which this barrier works are not completely understood, but we do know that the BBB is unique to the Brain.
In a healthy individual, the BBB protects the Brain from potentially harmful substances that may circulate in the blood, such as AntiBodies that cause inflammation, or blood itself, which is actually toxic to Neurons.
In the Brain, as in the rest of the body, the blood vessels branch into finer and finer sections called Capillaries, which are somewhat different in the Brain than in other parts of the body.
The cells that make up the walls of the Brain Capillaries, called Endothelial Cells, have a special chemistry and are so tightly joined together that they prevent most substances dissolved or carried in the blood from passing through them.
The selective filtering of substances into the Brain is what is meant by the Blood-Brain Barrier. This filtering process helps to ensure that the chemistry of the Brain remains in proper balance, or equilibrium.
Having said this, we also know that certain kinds of substances must pass into the Brain cells, to nurish them and to make NeuroTransmitters. To permit the passage of selected molecules, the Brain has evolved a network of very selective transport systems.
The walls of blood vessels are made of layers of proteins and fats that permit sugar, which fuels Neurons, some precursors of NeuroTransmitters, and some types of steroid Hormones to pass through.
Most of the Brain is protected by the BBB, but there is an area deep inside, around the Pituitary Gland, which allows specialized molecules to pass through rather easily.
The BBB's semipermeability enables the Brain to keep informed, about the internal state of the organism.
For example: the level of stress Hormones, like Adrenaline or NorEpinephine; Immune Cell funtions; nutritional state; etc.; and follow the effects of actions, initiated in the Brain, for the rest of the body.
When the BBB is disrupted by injury, blood cells (necessary for life, but toxic to Neurons, when they make contact), proteins, and other toxic substances can pour into the cellular spaces containing Neurons and Glia.
The extra unwanted fluids build up rapidly, and cause swelling (Edema). Glia Cells try to absorb the unwanted chemicals and fluids, in order to protect Neurons from harm and in the process, they swell up too.
Glia Cells act as sponges and scavengers of toxic by-products, caused by the injury; but when they become overloaded, they die and then re-release the toxic chemicals back into Cerebral circulation, where they kill additional Neurons.
In the earliest phase of the lesion, the injured, dying, and tramatized cells are in a state of shock and release all of their stores of Amino Acid NeuroTransmitters (Asparate and Glutamate, among others), and the Calcium Ions needed to activate them.
The extremely high levels of these substances are sufficient to kill vulnerable and weakened Neurons, by damaging their membranes or by exciting them to a point where they *burn out* and die.
Also, excitatory Neurons can become overstimulated and release Glutamate, excessive Glutamate introduces a massive amount of Calcium into Neurons, activating enzymes that kill the Neuron from within. This is called ExcitoToxicity.
Blood-borne and injury-produced charged particles of Oxygen and Iron (Free Radicals), are also highly toxic to injured Neurons, so the assault on Brain stability becomes even more deadly over time.
The rupture of blood vessels causes a drop in levels of Oxygen and sugar - the elements all cells need to survive. If the drop in proper transport of the critical elements is not quickly restored, further death of affected Neurons will occur, resulting in greater and greater functional disturbances.
At the injury site and in nearby tissue, there is biological chaos, as the Brain tries to adjust and fight the consequences of trauma. Within the first 24 hours after initial injury, Neurons and Glia continue degenerating and die off.
The dying cells give off chemicals that activate Macrophages, which move from the bloodstream into the injury area, to absorb and eliminate debris.
Up to this point, all the changes caused by the injury are localized emergency responses to the initial death of Neurons. But, a tramatic Brain injury is like a major accident, involving a lot of people.
Some are killed instantly, whereas others are badly wounded and may die a short time later. Still others suffer from long-term shock and never function quite right as long as they live, and some escape all harm and function very well.
The same thing happens to Neurons. Some, located in the immediate trauma area, do not die right away but begin to degenerate, during the first 24 hours after injury.
This process is called Secondary Degeneration and it can go on for weeks or months after Brain damage. Some cells look normal and do not die, but remain weakened and more vulnerable to stress and dysfunction throughout their life.
Although biochemical stability begins returning to the Brain, the cleanup process will continue for a long time. At the injury site or lesion, debris is eventually removed and a cavity is formed.
Glia cells and their helpers, which have gathered at the site to clean it up, now begin to form the scar tissue that will remain a part of the Brain's new architecture.
Sometimes, the Glial barriers prevent healthy, remaining Neurons from restoring Axonal connections.
In other cases, nerve terminals cannot pass the scar, and abnormal activity is then generated that can lead to Epileptic Seizures.
But what happens to the large number of Neurons that are only *wounded* - that receive only partial injury to one or more of their processes (Dendrites or Axons)?
The survival of the Neuron depends on the integrity of its membrane boundary. The Axon of a Neuron is like the principal root of a shrub (with the Dendrites being its branches) that has a number of rootlets.
It is possible to cut some, or even most of the rootlets, and the shrub will survive. The same is true for Neurons.
If most of the terminal buttons of an Axon are cut, there is still a good possibility that the cell itself will survive to make new buttons.
But if too much of the Axon is severed, the remaining part will begin to degenerate back towards the cell body, in a process called Retrograde Degeneration.
Eventually, the process will kill the entire Neuron, if nothing is done to stop it. The degenerative changes are caused by the injury-induced interruption of the flow of support substances up and down the Axon.
In particular, the loss of Trophic Factors which are normally taken up by the Synaptic buttons and transported back to the cell nucleus.
The reaction of the Neuron to the cutting of it's Axon (Axotomy) was first described by a German doctor, Franz Nissl, in 1894.
He used the term Chromatolysis (loss of color) to describe the process, because he was using a purple dye to stain normal and injured tissue.
The dying cells lost their coloration, because the microstructures taking up the stain had broken up or disappeared, in comparison to healthy Neurons; but the process is relatively gradual.
The Neuron will struggle to repair itself and extend a new set of Axon terminals. During the effort, there is a big increase in the cell's output of Nucleic Acid, the essential building blocks of biosynthesis.
New proteins and membrane components will be transported, to the growing Axon tips. This is the time during which the Neuron will need, the support of Trophic Factors and membrane repair materials, provided by Glia and adjacent healthy Neurons.
Many variables contribute to the Neuron's ability to block degeneration, among them:
- The age of the injured person (old Neurons do not do as well as young ones)
- The type of cell sustaining the damage (cells with short Axons are more vulnerable to degeneration than Neurons with longer Axons)
- The distance of the lesion from the cell body (the further away the cut is from the cell body, the better the chance of complete recovery)
- How many Axon branches there are (the more branches that remain intact, the better the chance of survival)
- The presence of Trophic Factors provided by healthy, neighboring cells
There are also instances of degeneration in Neurons that are NOT directly affected by the injury.
There may be no apparent lesion of the cell body, the Axon looks perfectly normal, but yet the cells begin the process of Chromatolysis and eventually die.
This type of Neuronal death is called TransNeuronal Degeneration because the death of one set of Neurons causes the loss of another set with which it has contact.
You have to remember that the vast majority of Neurons do not actually grow into one another; there is always a synaptic space between the terminal buttons of one cell and the Dendrites, Soma, or Axon of another.
Because there are these spaces, damage to one cell doesn't mean that the next should necessarily die.
Sometimes, TransNeuronal Degeneration can be seen in Neurons that are two, three, or more steps (Synapses) removed from the zone of injury, and no one can really say why this occurs.
We do know, however that if a PostSynaptic Neuron has a lot of inputs from other cells, the loss of any one input is not likely to kill it. Nonetheless, it is inaccurate to assume that lesion effects are relatively localized.
Injuries may produce more widespread and subtle TransNeuronal damage than can be seen by noninvasive, diagnostic imaging techniques like MRI.
When a Neuron loses some or all of its inputs through injury or disease, it is called DeAfferentation. For example, if nerve input from the hand to the Brain is lost, this is called DeAfferentation.
Conversely, if the Brain is damaged first and that causes Axons to the hand to die, this is called DeEfferentation. Although DeAfferentation may kill a PostSynaptic Neuron, it does not happen without a fight.
In order to keep going, the DeAfferented Neuron (as well as other kinds of cells) will first try to increase its sensitivity to a large number of chemical agents that can affect its activity.
For example: when a muscle fiber is DeAfferented (when its nerve connections are cut), the muscle fibers initially show contractions, caused by the release of AcetylCholine, that are much weaker than normal.
In the absence of input from Neurons, the sensitivity to AcetylCholine will increase dramatically, by 1,000 times its normal levels. How does this happen? Not because of an abundance of AcetylCholine.
If anything, the removal of the nerve's terminal buttons, near the muscle causes a drop in the actual amount of NeuroTransmitter being released. The *supersensitivity* is due to changes in the muscle fiber itself.
What happens is that the loss of Neural input, signals the muscle fiber to increase the number of receptors and receptor molecule sites along the muscle's surface.
To compensate for the injury, more receptors are formed, and the more there are, the easier it is to capture molecules of AcetylCholine in the muscle.
This means that normally ineffective, smaller amounts of NeuroTransmiter can still cause the PostSynaptic cells to generate impulses and action potentials or, in this case, the contraction of the muscle.
A similar process occurs in the CNS itself and has been studied in the area implicated in Parkinson's Disease.
Researchers have developed toxic chemicals that can selectively kill Neurons - simulating a Brain injury - in the NigroStriatal Pathway.
This pathway links the Substantia Nigra (meaning *black substance*, because these Neurons appear dark under the microscope) to the Striatum (the large *striped* Brain structure just under the Cortex.
It appears striped because many bundles of Axons, going to and from the Cortex, pass through it).
The Neurons in the Substantia Niagra make the NeuroTransmitter Dopamine, which activates the Neurons in the Striatum enabling voluntary movements.
However, if a selective poison is injected into the Niagra, on one side of the Brain, it kills many, but not all, of the cells and deprives the Striatum of its Dopamine.
This causes Stiatum Neurons to become supersensitive to the remaining Dopamine levels. That is, the cells in the Striatum form more receptors to capture any Dopamine.
Because the Neurons of the injured, DeAfferented Striatum have made so many more receptors to increase sensitivity, injection of a Dopamine stimulant - creates a bigger transmitter imbalance and will make an animal run in circles.
When the drug wears off, the animals appear quite normal. Researchers have also verified that the Dopamine supersensitivity and the circling behavior do not occur until at least 90% of Axons from the Nigra are destroyed.
This means that the *compensation* for the loss of input does not begin until a critical number of Axons have been lost. In fact, more recent research has shown that supersensitivity occur even without the loss of Neurons.
It turns out that any treatment or injury that blocks the release of NeuroTransmitters and NeuroHormones, or that blocks the attachment (binding) of these agents to their PostSynaptic receptors, will cause supersensitivity.
When damaged Axon terminals regenerate and restore the normal complement of contacts with the PostSynaptic membrane, the hypersensitivity disappears and normal activity returns.
Although more research would need to be done to prove the point, it may be that *psychotic episodes*, extreme irritability or hallucination, and delusions in some people could be the result of temporary blockage of normal Neuronal transmission.
Supersensitivity of the PostSynaptic cells could be responsible for the abnormal behaviors. Certain street drugs that block the junctions between Neurons and their target cells could also produce this effect.
We have just scratched the surface in reviewing the events that play a role in normal Brain functioning and in describing the relief efforts that take place, when trauma or disease disrupts this tightly orchestrated symphony.
The struggle to repair the damage and to adapt to the radically different circumstances that are produced by, and that follow, Brain injury is indeed a fascinating story.
Regeneration Repair & Reorganization
The art and science of Neurology is based on the physician's ability to name and diagnose diseases of the Nervous System.
These specialists now employ a highly sophisticated battery of both classic and new technologies that can be used to identify the problem (CAT, MRI, and PET scans, the EEG, among others).
Despite all this elegant and expensive machinery, the Neurologist must still be able to recognize the sometimes very dramatic and sometimes quite subtle changes in sensory, motor, and behavioral functions that can be caused by disease or injury to the Brain.
Once a diagnosis has been reached, what then? With all the high-tech machinery available, there are still no miraculous cures or treatments for Brain injuries or diseases.
In fact, the options for effective medical treatment of Brain injury and degenerative disorders, such as Parkingson's or Alzheimer's Disease, are very limited. That may be one reason why Neurologists are often guarded or downright pessimistic in their prognoses.
In all but the most experimental clinical treatments for Brain injuries, there is rarely an effort made to repair damaged Neurons directly.
Once the patient is out of immediate danger, the task of rehabilitation is usually handed over to specialized rehabilitation centers that employ teams of Physiatrists (medical doctors specialized in rehabilitation), physical and occupational therapists, and psychologists.
Although the number of such centers has increased dramatically over the last ten years, many physicians and NeuroSurgeons remain unconvinced, repair of damaged Brain tissue itself is a distinct, clinical possibility.
Their pessimism is reinforced by the fact that there is not much clinical research on recovery from Brain damage currently available. Lack of good communications between practitioners and researchers is also a problem, in bringing new information to physicians.
The scientific journals reporting positive experimental findings in laboratory animals are not often read by those in clinical practice. In turn, most laboratory scientists (except those who are also trained as physicians) do not typically read the clinical literature.
Which, many regard as too *soft* to be taken seriously, and they rarely ever see patients, so they do not understand the problems faced by clinicians.
To give an recent example, at a recent international conference on the use of fetal Brain-tissue transplants to treat Brain injury, a group of laboratory researchers met to propose using grafts for patients with Alzheimer's Disease.
Alzheimer's Disease causes the complete mental and physical deterioration of the patient and has a complex and as yet unknown etiology. Of the 60 scientists taking part in the meeting, only 4 had ever seen or had any contact with Alzheimer's patients.
Regardless of what doctors may or may not believe, there are many patients who suffer disabling head injuries who then go on to show remarkable recovery.
Often, the recovery requires a very long period of time; more time, perhaps, than doctors and our health-care system are willing to provide, to follow a patient's progress.
Over the last few years, there have been more clinical publications presenting cases of functional recovery after Cerebral injury and disease than at any time before.
Unfortunately, while they may carefully describe behavior, such papers often do not provide an accurate account of the physiological mechanisms responsible for the patient's improvement in locomotion or cognitive and sensory functions.
Rather than provide any false hopes, doctors may hesitate to tell victims of Brain damage that they will improve once blood clots are removed or Brain edema is reduced by surgery or pharmacologic treatments.
When patients continue to improve over time, they often want to know and understand what is going on in their heads. Unfortunately, the explanations they sometimes get are patronizing and can amount to a rehash of popular misconceptions about Brain functions.
For example, one *explanation* frequently given is that humans only use about 10% of the Brain (although where this particular number comes from is anybody's guess).
The idea probably goes back to the Nineteenth-Century localization of function doctrine; remember that all parts of the Cortex were parceled into discrete units.
So if the *thinking zone* occupied only 10% of the total Brain mass, and if some areas were not mapped (like just about everything underneath the Cortex), we might assume that much of the uncharted *virgin territory* could take over the functions of the damaged *thinking* area.
In a more elegant and scientific-sounding variation on this theme, the process of *taking over the functions* of damaged tissue is called Vicariance. The root of the word is the same as *Vicar*, the person in the Catholic Church who can be called on to replace a priest, who is unable to fulfill his duties.
Vicariance implies that different areas of the Brain have the potential to take over and mediate the specific functions of damaged Neurons.
This means, for example, that the Visual System might also be able to handle Motor functions or participate in Hearing - if it were required to do so as a result of injury to the other specialized areas of the Brain.
The technical term for the ability of healthy, individual Neurons to take over the functions of their damaged companions is called EquiPotentiality. But vicariance is only part of the story, and may in fact not be what is going on at all.
Another popular conception of how recovery might occur is based on the notion that the Brain has evolved *Backup* or *fail-safe systems* in case something goes wrong. This is like having backup computers in aircraft or second braking systems in cars.
Here, when one system breaks down, the secondary system immediately becomes operational and takes over for the damaged system.
In Neurology as in Engineering, the property of this system is called Redundancy. Another form of redundancy can be *Unmasked* in certain types of physiological experiments.
In the 1970s, Patrick Wall and his colleagues in London showed that previously silent Axon pathways in the BrainStem could become immediately active when the Primary Sensory Axons in the Spinal Cord were cut.
Since the appearance of activity occurred so soon after injury, Wall proposed that the new pathways were there all the time, but that their activity was masked or inhibited by the Primary Sensory Axons. Redundancy, or unmasking, in the Nervous System is often used to explain how a patient is able to retain function after suffering major Brain trauma.
An alternative explanation for recovery can be thought of as a type of reprogramming: a portion of the Brain not normally associated with a certain function can be *reprogrammed* to take charge of the functions of the damaged area.
In rehabilitation this is called Functional Substitution, recovery is explained not so much by having normal behavior return; but rather, by the development of alternative behaviors that permit patients to achieve certain goals in everyday life.
Even though the alternatives might not be as efficient as the original. A clear example of substitution is the person who losses the ability to speak, but who then communicates by typing on a computer.
Many paralyzed people can still drive cars because they have substituted hand controls for foot pedals. In the same way, Cognitive strategies or tactics can be substituted for more efficient behaviors that were irredeemably lost by injury.
Paul Bach-y-Rita, a specialist in rehabilitation medicine at the University of Wisconsin, has been a pioneer, in the study of substitution of function after Brain injury. He developed a type of video camera system that can be worn by blind people to help them see.
The camera was designed to translate visual images into a series of tactile impulses, which are sent to a patch-like unit taped to the patient's back. The hundreds of tiny impulses are delivered continuously to the patch in a specific pattern representing the image recorded by the camera.
The patients interpret the pattern, to represent the visual image, and thus can *see* the object in the environment. Here the patients are able to substitute information based on touch, for visual information.
And, use this tactile input to form an image of the world around them. To some extent most people are capable of forming visual images, using touch or other senses.
For example, if you close your eyes and someone puts a key in your hand, you can form a visual image of it. Perhaps blind people who are forced to depend on other sensory modalities, can perform such sensory substitution more efficiently than sighted people, because they are accustomed to depending on other senses to learn about the environment.
In this conceptual model of repair, the behavioral substitution is accompanied by some kind of structural reorganization of the Nervous System itself. In other words, the Left Frontal Cortex reorganizes itself to take over the functions of the damaged Right Frontal Cortex.
This idea is plausible, but it is rarely explained how a given Brain structure can *reorganize* itself to take on the work of another area, while still doing its own job as well.
It is as if a company lays off certain skilled workers in one part of the plant and then requires others to learn new tasks, while doing their own full-time work simultaneously.
Unless there are a lot of bored workers just hanging around waiting to be reorganized into new shifts, employee stress and eventual burnout might be a likely result of asking the same person to do two different things at the same time.
Is there something similar going on when such substitution of functions take place in the Brain? To the best of our knowledge, there is very little research yet being done to answer this question. One of the oldest explanations for recovery of function has been receiving renewed attention from researchers.
At the beginning of this century, the Swiss Neurologist Constantin von Monakow coined the term Diaschisis to describe how Brain injury could produce behavioral deficits that are followed by eventual recovery.
As a practicing Neurologist, von Monakow had many opportunities to observe patients with Brain damage who made relatively quick recoveries as well as those who never seemed to get better.
von Monakow believed that the normal Brain exists in a state of very delicate functional balance among its different parts. When a part is disturbed by injury or disease, that trauma can affect other parts quite a distance from the site of the original damage.
Diaschisis was thought to be a temporary block of function (or inhibition) produced by the shock of damage or irritation to Brain tissue. He believed that if an injury was not too severe, functional behaviors would return once the diaschisis wore off.
Later on, von Monakow suggested that some types of severe injury could result in a permanent state of diaschisis that would completely prevent any recovery of function.
Recent work with PET scans at UCLA has provided some evidence to show that after injury, certain Brain areas at a distance from the actual damage do become depressed (less blood flow and less Glucose utilization) but may recover their normal levels of activity over time.
On the other hand, each of the five *recovery* explanations we have discussed so far:
- The notion that we only use a small part of our Brains anyway, so we don't need it all
- Vicariance - other Brain tissue can take over the functions of damaged parts
- Redundancy - we have evolved backup, fail-safe systems that kick in when a part of the Brain is injured
- Substitution - we learn to switch behavioral tactics or strategies to accomplish the same goals
- Diaschisis - the shock of the injury must dissipate before we get better
All of these have a certain common sense logic when taken at face value, and all seem to be supported by recent clinical and experimental studies.
On the other hand, careful attention to the arguments reveal that they are all circular and do not explain what the Neurological mechanisms of recovery really are.
For example, it is said that behavioral recovery takes place when there is functional substitution between two Brain structures, but the observation of behavioral recovery is used to infer that functional substitution has taken place.
How do we get around this problem and come up with some experimental tests to determine what is actually happening? Recent research using PET suggests that there may be something to all of the explanations and that they all have a common link.
In the past few years, clinical investigators have looked at changes in patterns of Cerebral blood flow that occur in patients with Stroke or Brain injury. The blood flow measures are supposed to be indirect measures of Neural activity.
By using radioactive labels attached to Glucose analogs carried in the blood, we have seen how it is possible to create computer images, of the pattern of blood flow throughout the Brain. The scanning studies show a rather complex set of events.
First of all, tramatic injury causes a suppression of Neural activity indicated by decreases in blood flow, and this supports von Monakow's notion of Cerebral diaschisis.
Second, the studies show that the changes in the Brain are quite widespread, again supporting von Monakow's idea that the effects of even a localized injury are not all that local.
Blood-flow studies indicate that both sides of the Brain show changes in Neural activity - even though the lesion or injury may be limited to one side.
Third, both Cortical and SubCortical structures undergo dramatic changes in the pattern of blood flow and Neural activity, even though structures that do not appear to be directly or primarily connected with the zone of injury.
SubCortical structures are those located beneath the surface of the Cortex. For example, the Thalamus, Striatum, and BrainStem are important anatomical landmarks that are, by definition, SubCortical.
We think that these data can be interpreted to mean that the entire Brain, not just the region around the area of damage, reorganizes in response to Brain injury.
There is one reason that helps us to understand why, until very recently, people have used concepts based solely on conceptual and behavioral descriptions of recovery rather than looking for physiological explanations:
The long-held belief that in the adult Nervous System regeneration, anatomical reorganization, and renewal of Nervous tissue are simply impossible.
It was about sixty years ago that the famous Spanish anatomist and Nobel laureate Ramon y Cajal wrote:
"Once development is complete, the sources of growth and regeneration of Axons and Dendrites are irrevocably lost. In the adult Brain, Nervous Pathways are fixed and immutably; everything may die, nothing may be regenerated."
Ramon j Cajal and his students arrived at this pessimistic conclusion after having conducted years of studies on microscopic sections of the Brain and Spinal tissue taken from animals and human cadavers.
Sometimes they did observe abortive attempts at regeneration by certain Neurons in the Spinal Cord. But, for some reason, after growth over just a short distance, the Neurons either died or retracted their growing tips.
After a decade of research trying to find regeneration in animals with injuries to the CNS, Cajal concluded the majority of regenerative processes described in man are ephemeral, abortive and incapable, of completely and definitively repairing the damaged pathways.
Ramon j Cajal's students and many other researchers following in his footsteps continued to promote the concept of a Brain, incapable of any real regenerative phenomena. This became established dogma.
So that researchers, who might have reported seeing regeneration after injury were persuaded that their observations were false, and the anatomical changes they saw were artifacts, caused by their laboratory ineptitude.
If the best Neurologists asserted there could be no repair in the CNS, would it make much sense for clinicians to try developing treatments promoting something that could not happen?
This is one of the reasons for the general pessimism of clinical prognoses following Cerebral injury or disease.
The lack of research prevented progress and understanding, which, in turn resulted in the belief that regeneration, repair, and recovery after Brain and Spinal Cord injury were not possible.
It has taken almost sixty years for the scientific revolution we needed to develop the proper climate for research on how to promote and enhance Nerve regeneration in the damaged Brain of adult patients.
Recent work over the last decade indicates that different kinds of growth and regeneration, can take place in the damaged Brain.
However, such adaptive processes are not always spontaneous, and may require assistance to become evident.
First of all, to apply the right methods and know what we are looking for, we have to know what we mean by regrowth or regeneration.
Will the newly generated fibers grow back to form the right connections? Will they form abnormal connections?
When a damaged Neuron grows new terminals or new branches, that is considered an example of true regeneration.
This type of growth does occur in the Peripheral Nervous System. Can CNS Neurons do the same thing and re-establish connections?
There is still quite a lot of debate on this question, but it is becoming increasingly clear that, under just the right conditions, Neurons can be stimulated to regenerate - even in the Brains of adult subjects.
Some of the most interesting work on regeneration in the adult Brain, is concerned with the question of why Neurons have difficulty regrowing their Axons over relatively long distances.
Is the inability inherent to CNS Axons, or is the regenerative efforts blocked by chemical factors generally found in Brain tissue or produced by the lesion?
Under the right conditions it has been shown that Spinal Cord Neurons do have the inherent ability to regenerate. Sometimes Neuronal regeneration can be robust, but not necessarily beneficial to the organism.
This is why it is important to provide proper *guidance* to growing cells so that they enter into the appropriate target(s).
If we hope to learn whether Neuronal *plasticity* is good or bad for the patient, only long-term behavioral research will provide us with answers.
Scientists have tempered their enthusiasm and have not announced that a cure for Spinal Cord injury is just around the corner, because of the nature of the research until now.
After all, many of the scientists working on Nerve regeneration rarely examine the behavior of intact experimental animals; that is, they do not examine the reorganization to determine whether some measurable improvement in performance has taken place.
Researchers generally work with preparations that consist of cell cultures or isolated sections of nerves, grown in special environmental chambers.
As our understanding of Neuronal plasticity in the CNS continues to grow, we are learning there is no one physical mechanism that can explain all aspects of regeneration and recovery.
Although considerable research effort continues to focus on regeneration, there is another type of growth, stimulated by injury, that might play an important role in producing or blocking recovery in the damaged Brain.
The other form of injury-induced plasticity called, Collateral Growth or Sprouting has some interesting properties that play a part in the complex puzzle of recovery.
This far we have learned that the Brain and Spinal Cord are made up of Neurons working together both in local circuits and in long-distance ones.
Some Neurons receive information (input) from many different parts of the body, as well as from other areas within the CNS.
Indeed, it has been estimated that in some cases, a single Neuron can have as many as 10 million contacts with other Neurons throughout the Brain!
When the Axons projecting to a particular target are cut, that target is said to be DeNervated or DeAfferented. Depending on the extent of the injury, a cellular target might lose all of its inputs (afferent Axons) or just a few.
When the injury is not total, some of the undamaged Axons react to the disappearance of their companions, by increasing the size and number of their terminal buttons.
In effect, the undamaged Neurons grow (sprout) collateral branches on their Axons, which then occupy the synaptic spaces that were vacated by the death of damaged Neurons.
Usually, these Axons are part of the same system that normally innervates the target area, but in some cases, even *foreign* Axons will sprout new terminals to replace those that have been lost.
*Foreign* Axons simply pass through a region, without synapsing on (making contact) Neurons in the area.
Somehow, if these Axons of passage *learn* that the region has lost some of its connections, they will grow new terminals and form synapses that they ordinarily would not.
These are called anomalous projections, because they don't belong in the damaged region. It would seem that nature abhors a vacuum: If there is a vacated space, fill it up!
In fact, researchers have found that Axons actually compete with one another to occupy the denervated synapses, and there has been much speculation about which cells will win and which will lose in this competition.
Sometimes, although no one yet knows why, the anomalous projections get there before the Axons from the same functional system, and these may not be the ones needed to restore function.
In fact, the successful growth of the anomalous Axons can prevent functional recovery, because it often happens that the Axons that lose the competition pay the price by receding or even dying.
It might be that the cell bodies outside the immediate zone of injury and shock compete more effectively for synaptic space because they don't have to devote their metabolic resources to mere survival.
One of the first people to convince the scientific community that competitive sprouting could occur in the adult Brain was Geoffrey Raisman of Oxford University in England.
Raisman looked at the Septum (Septal Nucleus), in the inner Brain; because it receives inputs from two distinctly different Brain areas.
The Medial Forebrain Bundle (MFB), which comes from the BranStem and the Hippocampus, an area towards the top of the Brain linking Cortical and SubCortical structures.
Raisman was able to show, Axons coming from the Hippocampus, have their terminals on the Dendrites of the Septal Neurons, while those from the MFB end up mostly on the cell body itself.
After Raisman mapped these normal paths, he used other groups of adult rats and made lesions in either the Hippocampus or the MFB; he then waited several months to see what sprouting did occur.
The lapsed time also allowed the Brain to eliminate by-products of the initial injury. The next step was to make a lesion in the remaining pathways - if the MFB was injured first, then a lesion was made in Hippocampus, and vise versa.
The results showed that when either system had a lesion, the other system would sprout Axons into the vacated zone, to replace the terminals that were lost.
What was interesting here was that the two systems used different NeuroTransmitters, so when the replacement took place, the Septal cells were not getting their normal NeuroTransmitter inputs.
Although this landmark study opened the field for further study, it did not provide any behavioral data - not surprising as Raisman was an electron microscopist.
A short time later, Oswald Sreward, and collaborators at the University of Virginia began to attack the problem of collateral sprouting, looking at both physiological changes and behavioral effects.
They chose to see how sprouting may affect deficits in learning and memory caused by Hippocampus lesions.
Many animal studies and clinical reports in patients have shown, damage or removal of the Hippocampus or its related structures, will provoke a loss of short-term memory.
That is, things that were learned long before the injury can be recalled, but recently learned events do not seem to be stored without great effort and intensive training.
Because learning deficits caused by Hippocampus lesions are obvious, profound, and its anatomical pathways are well known, it was an excellent system to use in determining whether new sprouting could lead to functional recovery.
After recovery from the surgery, the rats were required to learn a spatial alteration task. Normal rats can always figure out how to get a food reward; but after the surgery, they required about two weeks to reach this point. The study showed:
First, that most of the connections had disappeared within a very short time after the injury.
Second, they noticed some very interesting changes in the Brain circuitry of those rats that had been kept alive for longer periods.
In these rats, Axons from the intact Cortex on the other side of the Brain had grown new branches to cross over into the damaged Hemisphere and replace the Synaptic contacts destroyed by the lesion.
Electron microscope analysis showed they were, in all respects, identical to normal Synaptic organization.
Another important observation was the time period needed for restoration of behavior - about two weeks - was about the time needed for the Axons to cross over and form new Synaptic connections in the damaged Hemisphere.
These findings certainly suggested that the sprouting from the healthy Neurons could play a role in behavioral recovery after Brain injury.
Other scientists picked up and extended Steward's ElectroPhysiological studies. They implanted electrodes next to Hippocampus Neurons that received terminals from the sprouting Axons.
The investigators knew exactly where to go; because maps had been developed through the anatomical work.
With the recording electrodes in place, the rats were tested in spatial learning tasks; while the electrical activity of their Neurons was recorded and compared to normal animals, who also had electrodes implanted that touched the same cells.
The electrical activity of the Hippocampal Neurons showed itself to be comparable to that seen in normal Brain tissue.
This finding was taken as direct proof, the Synapses formed by Axons coming from the other side of the Brain, functioned much the same as normal Axons.
The time course for the appearance of the ElectroPhysiological activity, closely paralleled the time course for the growth and behavioral recovery.
Not all of the conditions necessary for promoting functional growth are known, however. In certain cases, sprouting could even be the basis for making matters worse, for creating functional deficits.
In a provacative experiment, Gerald Schneider of the Massachusetts Institute of Technology, has seen a case of maladaptive sprouting in, the Syrian hampster.
For the hampster to locate a visual stimulus, it relies on Optic Nerve projections from the Retina to the Superior Colliculus, one of the SubCortical structures that helps us distinguish brightness and elemental form.
If the Superior Colliculus on one side of the Brain is removed at birth, the Brain reacts by undergoing considerable sprouting of the type we have just discussed - except that sprouting can sometimes take an abnormal turn.
In that abnormal case, the growing nerve terminals seek to establish their normal connections by growing across the Brain's MidLine to the opposite Superior Colliculus.
If the structure has been removed by surgery, the Axons cannot find their appropriate targets. Thus, they turn around, recross the MidLine, and compete for Synaptic space with normal cells - leading to maladaptive behavior.
Normally, a hungry hampster will immediately direct itself to food and grab it. The Brain injured hampsters, with anomalous growth, do just the opposite.
If the food is presented on the animal's left side, it turns to the right, as that is where it *sees* the food; because the abnormally crossed projections, results in maladaptive behavior.
The best proof that there is a causal link between maladaptive behavior and the anomalous growth is provided by the results of a second operation. When the crossed Axons were removed, the hampster stopped turning to the wrong side.
The animals still had trouble locating food, because they did have a blind spot, but at least they didn't turn completely away and were able to focus their search in the food's general direction.
Another example of anomalous sprouting with potentially maladaptive consequences comes from a report by MRIganak Sur, Preston Garraghty, and Anna Roe who used newborn ferrets in their experiments.
They began by asking the question: "What is intrinsically *visual* about the Visual Thalamus and Visual Cortex?"
What they meant to address by this question is the fact most people think that the Visual System is what we would call *hard-wired*.
That is during development, Axons from the eye are destined only to grow into the part of the Brain designated for the *Visual System*. But is this always the case?
Can Visual Axons be tricked into growing or sprouting into a different, nonvisual part of the Brain? Would such connections have any useful function? How can this be studied?
First of all, the investigators damaged the Visual Cortex and the Superior Colliculus on one side of the Brain.
In other animals they removed the Inferior Colliculus, which receives Axons from the ear and sends Axons to the Auditory Cortex.
The last operation was done to ensure the Medial Geniculate would lose its normal complement of Auditory Axons and provide an opportunity for the Visual System's Axons to grow in without competition.
The animals were allowed to reach maturity and then recording electrodes were placed in the Auditory Cortex or the Medial Geniculate.
And, stimulating electrodes were placed in the Optic Nerve to examine whether any kind of functional activity was likely to occur - if Axons from the eye, would grow into Brain structures concerned with hearing.
The authors showed, anomalous Axons from the Retina, would grow into the Auditory regions.
And, that cells in the Medial Geniculate and Auditory Cortex would produce electrophysical responses to Visual System stimulation.
"Visual cells in the Auditory Cortex had large receptive fields [meaning areas that responded to the stimulation of the Optic Nerve] and preferred slowly flashing or moving large spots or bars".
Sur and colleagues also injected horseradish peroxidase, which was carried back to the eye by the Axons. This enabled them to track the Axons' point of origin, in the Thalamus and Cortex.
The researchers went on to suggest that, at least in early development, the functions of the Thalamus and Cerebral Cortex can be altered or specified by the kinds of inputs the area receive.
Thus, they suggest that instead of Cerebral areas determining what the *inputs* are and how they respond.
It is the inputs that determine what the modality of a given region will be. In other words, what functions the area will have.
Because there is so little work available in humans or adult subjects, it is difficult to know whether the same kind of anomalous growth also takes place in humans.
However, indirect evidence does show that in people who have had their limbs amputated, there is a remarkable reorganization of areas that would normally respond to touch stimulation.
For example, some people who have lost a limb feel sensations on their faces when the area of the limb just above the amputation is stimulated.
This could represent massive reorganization of Neurons or anomalous growth. Until much more research is done on this question, we cannot say for sure which is the best explanation.
After many years of research and many similar studies, no one in the research community any longer questions whether sprouting can occur in the damaged adult Brain.
The big problem to be solved is whether or not the growth has beneficial or detrimental effects, and whether the new growth is needed to sustain the recovery, once it has actually occurred.
We know that it is vitally important to have anatomical and eletrophysiological proof that Neural growth can take place in response to injury, but such studies do not provide proof that such reorganization is necessarily good.
We now have a much better idea of what we mean by *reorganization*, *compensation*, or simply *response to Cerebral injury*.
And yet, we are still far from having all the answers we need, to develop an informed opinion about the proper therapeutic strategies to use with Brain-injured patients.
We know that regeneration and repair are possible in damaged nerve tissue. Scientists are now looking for the keys that will unlock the inherent plasticity in Brain tissue.
The puzzle is not just to find those keys, but to figure out how they work, to determine their risks and benefits to patients.