Neural Basis Of Recovery Of Function Research Paper

Such recovery is not common with an injury to the nervous system. One of the most important goals in the field of neuroscience is the issue of recovery of function following nerve, spinal cord, and brain injury. It is an unfortunate fact that injuries of the nervous system can produce profound deficits in the quality of life. Sometimes these deficits are obvious, as when an injured nerve affects motor or sensory functioning. Sometimes there are profound deficits without obvious signs of injury, as when someone suffers from memory loss from injury or developmental aging effects, for example, autism or Alzheimer’s disease. In either case we would like to be able to restore functioning.

Sometimes, however, there are instances of considerable recovery of function following brain injury. Stroke patients who initially have profound language disorders, for example, may in the long term have considerable restoration of function. Until recently, in the animal experimental literature, there has been difficulty in localizing neural correlates of functioning because the effects of damage were only temporarily observed with significant amounts of recovery of function over time. Ideally, if we had enough understanding of the nervous system then we might be able to promote recovery of function. The study of brain-behavior relationships, of localization of function, and of recovery of function, are intimately associated themes.

1. Theories

The four major theories that account for instances of recovery of function following brain injury are examined in this research paper. No one theory fully accounts for the spectrum of observed recovery, nor are the theories mutually exclusive—more than one factor may be involved in recovery. To a certain extent, these theories provide a heuristic outline of the factors that affect recovery. It is the hope that a better understanding of these factors will lead to more effective treatment of the injured.

1.1 Vicariation

Vicariation means second-handed. Recovery by vicariation occurs when an injury damages the part of the nervous system that is actually responsible for a function, and a second neural structure that had never been involved in that function now takes over for the injured structure and performs that previously lost function. A key feature of vicariation is that the structure that takes over the function was never involved in the original behavior. This distinction is lost in some treatments.

The best example of vicariation is the observation that injuries in young individuals are said to be less deleterious than similar damage when it occurs in adults. For example, damage to the left hemisphere in a stroke can cause profound loss of language functions in the adult. Children with left hemisphere damage, however, often do not show severe language deficits. This observation fits our concept of the plasticity of the developing organism.

This concept—that youngsters are less affected by brain injury—has been applied to laboratory experiments where it has generally been found that damage is less intrusive in young individuals. For example, damage to the frontal lobes does not produce delayed response deficits in monkeys, and damage to the septal region does not produce social cohesiveness in rats. However, it is not always true that an early lesion is beneficial. In these two examples, when the individual becomes an adult then delayed response deficits and increased social cohesiveness appear. Thus, the effects of the damage may not be obvious until the individual matures.

Of all the theories of recovery of function, the theory of vicariation is the least likely one to be true. This is because much of the recovery that has been attributed to vicariation is actually due to a region that already has some functioning. As a result, the following theories are more likely explanations, and thus more likely to cause recovery.

1.2 Diaschesis

Diaschesis refers to the effects of shock. Recovery by diaschesis occurs when a nervous system injury does not actually damage the tissue that is responsible for the lost function, but rather that the injury causes a shock effect which indirectly and deleteriously affects normal functioning, and function returns when the shock subsides. Shock can occur when there is temporary loss of the blood supply (loss of nutrients including glucose and oxygen, or loss of functions to remove waste metabolic products) or temporary loss of necessary modulating neural activity. The key feature is that when functioning returns it is mediated by the very same tissue that was responsible for the function in the first place, so that the recovered behavior is exactly the same as the original one. Thus, the idea of sparing is essential in the context of diaschesis.

Time appears to be the major manipulation to effect diaschesis. However, time itself is not a very profound or necessarily a helpful explanation. The real question is what happens that takes time to dissipate the effects of shock, or more to the point, what can be done to diminish the effects of shock. Steroid drugs have been given to prevent the effects of swelling, for example, and have some effect in mitigating loss of function from some spinal cord injuries. To be effective the treatment must occur soon after the injury. Since the brain and spinal cord are enclosed within the cranium and spinal column, respectively, any swelling of the nervous system in these confined spaces can cause substantial damage that is secondary to the original injury. Thus, besides indirect effects of shock any injury can cause additional damage.

One example of diaschesis from the laboratory is known as the Sprague effect. Damage to one superior colliculus in cats causes a visual neglect in the opposite visual field; that is, objects are ignored if they are presented in that visual field. Subsequent damage to the visual cortex on the same side as the visual neglect immediately restores reactions in the affected visual field. This example represents diaschesis by loss of normal neural modulatory influences. Here subcortical visual regions in the tectal area receive three visual inputs, one from the eye through the optic nerve to the superior colliculus, one from the opposite superior collicus, and the other through the visual cortex. By damaging the superior colliculus there is an imbalance in the surviving tectal region. By subsequently damaging the visual cortex on the same side as the visual neglect, the balance in the surviving tectal region is restored. This illustrates one of the major ways of thinking about diaschesis, which is to think of it as a balance of modulation of neural sources.

Another example from the laboratory is the loss of a simple visual discrimination for brightness. Rats trained on a black–white discrimination will appear to have lost that memory when their visual cortices are removed. With subsequent training the rats reacquire the ability to discriminate black from white. Since it takes about as many trials to relearn as it did to originally learn, this appears to be a case of vicariation where another part of the brain (presumably the remaining cortex) takes over functioning. If that is the case, however, that subsequent training is creating a new memory, then it should not matter whether training after the brain injury is made with the black or white stimulus as the correct choice. But reversing the correct choice profoundly interferes with subsequent training. This shows that although it appears that the brain injury has removed the original memory that in fact the memory remains to interfere with reversal training.

A number of manipulations have been found to affect recovery through diaschesis, each associated with diminishing the effects of shock and enhancing the expression of the spared tissue: extensive preoperative training, interoperative retraining (serial lesions), extensive postoperative retraining, cross-modal training on similar problems (i.e., training using other sensory modalities), drugs that diminish shock (e.g., steroids), drugs that enhance access to the spared tissue. As with strategies to improve performance on exams, a practical strategy to lessen the effects of future brain injury or the inevitable effects of aging would be to overlearn with multiple cues and learning methods.

Parkinson’s disease provides an example from the clinical literature where the diminishing effects of diaschesis prevents the initial appearance of symptoms. Parkinson’s disease is a movement and thought disorder caused by progressive degeneration of cells in the substantia nigra that project dopamine to the basal ganglia. Its symptoms only appear when so many nigra cells die that only about 20 percent of the normal amount of dopamine remains in the basal ganglia. Until that point, it appears that the basal ganglia can compensate for the loss of dopamine (see below). It is only when the dopamine projection to the basal ganglia falls below a critical point that the symptoms of Parkinson’s show themselves. Presumably, slow progressive disorder does not produce the effects of shock that would be seen with one larger lesion.

Of the factors that account for recovery of function from brain injury, diaschesis is one of the most important.

1.3 Neural Reorganization

Neural reorganization generally refers to the body’s own mechanisms for recognizing loss and for healing itself. However, man-made interventions can also be classified as reorganization. By far, neural reorganization receives the most attention of the four theories, although its practical usefulness has yet to be realized. Several means of effecting neural reorganization have been described. Importantly, these mechanisms are adaptations of means that the nervous system has for normal development and growth rather than specialized adaptations that might have evolved solely for the purpose of a complex brain being able to repair itself. That is, one questionable idea about brain organization in general is the idea that more complex brains, being more susceptible to injury of its delicate mechanisms, somehow developed a new method of dealing with brain injury. That seems not to be the case. Here the known mechanisms of reorganization are reviewed.

1.3.1 Reactive Synaptogenesis. Synaptogenesis refers to new synapse formation. This mechanism is essential developmentally for correctly hooking up the nervous system (along with overproduction and selective cell death, as in programmed cell death or apoptosis). Reactive refers to an action in response to injury. New connections can be made by a number of activities, including new axonal growth (sprouting), new pre-and post-synaptic growth and terminal and dendrite formation, new receptor formation and/or distribution, for example. Furthermore, injury to the visual cortex causes degeneration of its projections to subcortical visual areas which leaves vacated synaptic space that is filled by sprouting of the optic nerve. In the example above (see Sect. 1.2) where rats were trained on a black–white discrimination, sprouting in subcortical visual areas could account for the recovery of function. It is generally thought that sprouting should be beneficial and attempts have been made to promote sprouting. However, in the case of brightness discrimination this idea is questionable since subsequent damage to the areas of sprouting has no permanent effect in preventing learning differences in brightness. In general, since rats with visual cortical damage do not recover perceptions of form and pattern, neural reorganization is not a significant factor for those functions.

Two examples illustrate where sprouting is actually less than helpful. First, spinal cord injuries cause sprouting that is accompanied by tremors. The tremors are alleviated when the sprouted connections are destroyed. Second, injury of one superior colliculus in hamsters causes sprouting to the opposite superior colliculus. The result is that the animals visually orient to the side away from the visual stimulus. Cutting the sprouted optic nerve to the remaining superior colliculus resolves the problem. Thus, in these two examples, blindly enhancing sprouting by generally giving nerve growth factors, for example, may not be such a good idea. The problem with sprouting is to have control over where and what type of new growth takes place.

1.3.2 Neurogenesis. We learn that we are born with the total number of neurons that we are ever going to have, and that we continually lose neurons as we grow older. The one celebrated exception to this rule is that certain birds which learn a new song each mating season show cell division and new neuron development as adults. Adult rats and recently adult humans have been shown to create new neurons in the hippocampus, a limbic system structure associated with certain kinds of memories. It remains to be determined whether there are sufficient numbers of new neurons and whether there are functional connections of these newly available neurons. Similarly, it is unknown whether these neurons have a role in repairing brain injury. However, on the face of it, this is an exciting development.

1.3.3 Transplants. Related to the idea of natural neural replacement (neurogenesis) is the idea that we can purposely implant neurons to replace the damaged ones. Transplants have been tried most often in the case of patients with Parkinson’s disease, where the transplant donor is either the patient (dopamine producing cells from the patient’s own adrenal glands) or an aborted fetus (dopamine producing cells from the substantia nigra; this source is controversial). Initial results of such operations were mixed at best, with more recent limited successes. The ameliorating effects may not be due to the effects of dopamine or to neural connections formed by the implant, however. Nerve growth factors that are secreted by the implant are more likely candidates. Transplants themselves have been recently overshadowed by a return to surgical intervention, a procedure known as a pallidotomy which is a lesion of the globus pallidus.

1.3.4 Supersensitivity. Synapses that are deprived of their normal expected amount of input activity can become supersensitive whereby the synaptic transmission becomes unusually sensitive to small amounts of neurotransmitter. In Parkinson’s disease the deleterious symptoms are delayed presumably because of the compensating supersensitivity of cells in the basal ganglia that are deprived of their usual amount of dopamine from degenerating neurons in the substantia nigra. It is only when there is too much loss of dopamine that the basal ganglia neurons cannot compensate and symptoms of Parkinson’s appear. The actual mechanism of supersensitivity can involve increased sensitivity of the postsynaptic receptors, increased reactivity of postsynaptic receptors, increased number of postsynaptic receptors, changes in dendritic spines that reduce impedance (i.e., enhance trasmission), increased transmitter release, and changes in intracellular events that enhance the signal.

1.3.5 Prostheses. Man–machine implants may be used to overcome deficits. For sensory loss, these involve a transduction device to convert an external stimulus into a neural-like signal with a neural stimulator. Currently, auditory implants into the cochlear nerve or nuclei are being tried to restore hearing. Visual implants using a primitive camera and stimulation of visual cortex have a history of limited success in effecting primitive sensations. Not all prostheses are surgically placed into the brain. One alternative for visual problems is to place the pattern of visual stimuli onto a skin surface where the visual stimulus is now interpreted as a tactile stimulus. Other approaches have not involved sensory transduction but rather replace the damaged element responsible for higher level processing. In this regard a recent attempt has been made to implement functioning in a silicon chip that is used to replace a damaged hippocampus. For motor loss, electrodes have been implanted to stimulate muscles, coordinated by a computer, to effect walking. This requires sensors for proprioception and balance.

1.3.6 Unmasking. It is now well appreciated that the nervous system has multiple representations for each of the senses and motor functions. Moreover, it is becoming clear that representations may overlap each other, and that under normal circumstances some of the underlying representations may be suppressed. When a part of the main representation is damaged the underlying map may now express itself, either preventing any deficit or causing an apparent recovery. Unmasking is generally found in instances where the recovery occurs too quickly for sprouting or other types of reorganization to have been made.

1.3.7 Regeneration. Certain amphibians and lizards will grow a new limb to replace one that has been lost to a preditor. Amphibians and lizards also have the ability to re-establish connections when a nerve is severed. This regeneration is also seen to varying degrees in the peripheral nervous system of mammals, aided by the supporting Schwann cells which guide the reconnection. Although the capacity for regeneration persists in the central nervous system of mammals, regeneration is not a significant factor in recovery of function because central glial cells create scar tissue which becomes a significant barrier to reconnection.

1.4 Substitution

Substitution refers to using an alternative means to achieve the same goal. If damage has actually removed that part of the brain that is responsible for a function (as opposed to Diaschesis, above, for example) then substitution is the most likely means of recovery. Within the animal literature one needs to be cognizant of factors like substitution because otherwise false conclusions can be made about the nature of the recovery. Yet substitution is often ignored because it does not involve surgical or chemical intervention. There are three significant means of substitution. Recovery by substitution occurs when another sense, motor act or strategy can be used.

1.4.1 Sensory. A sensory stimulus or property of a stimulus can be used as a substitute for the original sensation. Damage to visual cortex in rats makes them blind to form and pattern perception yet they are still capable of detecting primitive visual experiences such as brightness and contour. As a result, such rats appear to be able to solve discriminations for orientation (e. g., horizontal vs. vertical black and white stripes) because they can make use of local brightness and contour cues to solve the problem. In extreme conditions where the rats are prevented from using these local cues, they can no longer ‘solve’ the orientation problem, and thus they are blind. The goal for a therapist would be to design conditions where a problem can be solved in multiple ways. For example, persons who are red–green color blind can learn to drive by noting the position of the active light on a traffic signal.

1.4.2 Motor. One motor act can substitute for the original motor act. Cats with dorsal rhizotomies (denervation of the sensory roots of the spinal cord) for the hind limb initially have difficulty walking a thin railing. After a period of time, however, the cats negotiate the task very well and appear to be completely normal. However, upon close examination with high-speed photography, it has been shown that these cats adopt a motor strategy of shifting their weight to properly place the hind foot. Clearly, functional recovery does not imply neural recovery.

Another example from the older literature would be the instance where a rat has been trained to run a maze. The same rat that has been trained to run can solve the very same maze when it is flooded and it has to swim. The same idea applies to conditions where brain damage prevents the original behavior.

1.4.3 Strategy. After ruling out that the senses and motor functions are not affected, it might be found that there may be a problem with the implementation of a sequence of perceptions and actions. This higher order activity can be referred to as a strategy. For example, a woman with global (diffuse) brain damage got easily distracted, so much so that a telephone ring would be enough of an interruption that she would forget she was cooking. Or she would spend her whole day watching TV. Her strategy to overcome this deficit was to write a list of things to do, checking them off as she did them, and to have a timer set to go off every 15 mins. At every alarm she would check her list to see what it was she was supposed to be doing.

From the animal literature comes another example. Rats with hippocampal brain damage have difficulty in alternately pressing one of two bars for a food reward. This task requires that the animals remember which bar was pressed last so that they can press the other bar the next time. Some clever rats figure out that if they hold onto the bar that they just pressed then they immediately know to press the other bar the next time.

2. Factors

The discussion above identifies the major theories that can account for instances of recovery of function. Within this discussion we have identified a number of factors that can be used clinically and within the laboratory to promote recovery of function. It is reasonable at this time to simply list those factors, because although they were discussed in terms of theories above in truth many of these factors apply to more than one theory. Here is a listing of some factors that might enhance recovery of function: age at time of the injury, reduction in secondary effects of the injury (shock), the proficiency of preinjury training, training on alternative stimuli or strategies or acts, training between injuries (serial lesion effect), time after injury, amount of postinjury training on the same or similar tasks, substitutions. It would be misleading to suggest that any or all of these factors will lead to recovery in all instances. It is a sad fact that injuries to the nervous system produce profound and lasting deficits. The hope for further research is to find new applications of these factors and to develop new methods of treatment.

3. Implications

Clinically the importance of finding methods that enhance recovery of function is obvious. What is not so obvious is that the clinical and experimental literature about brain injury also give insight into the fundamental organization and operation of the brain and our mental life. The mind–body problem—the relationship of our physical being with our mental experience—continues to be a fundamental interest in psychology. Both the clinical and experimental literature make fundamental contributions to each other. Newer methods for imaging the brain during cognitive activity (f MRI, PET, neuromagnetic methods, along with the old standby EEG) have confirmed much of our understanding of the organization of the brain and what happens during injury, on the one hand, and given insights and further directions, on the other. The optimism of our times holds out great promise for sophisticated advances that may someday allow us to repair the damaged mind.

Importantly, we learn from the field of recovery of function the following lessons. First, localization of function is the norm in the nervous system. Second, there is a hierarchical organization to the nervous system, with basic functions organized at low levels. Third, even low levels of the nervous system are capable of seemingly sophisticated functions like learning and memory. Fourth, any one function is probably represented in only one place in the nervous system. However, fifth, similar functions can often accomplish the same goals.

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