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Neuronal Plasticity after Cortical Damage
Neuronal Plasticity after Cortical Damage
727
Neuronal Plasticity after Cortical Damage B Kolb, University of Lethbridge, Lethbridge, AB, Canada ã 2009 Elsevier Ltd. All rights reserved.
Measuring Brain Plasticity Although brain plasticity is presumed to reflect changes in the synaptic organization of the brain, it can be inferred from the measurement of change at many levels of analysis. Perhaps the most obvious level is behavior. If an organism’s behavior is altered, such as when a new habit or bit of information is learned, we can infer that there must be some persistent change in the nervous system that represents the habit or information. The identification of this plastic change may be seen by utilizing a range of techniques that run from global to molecular analyses of brain organization. One of the most global measures is the analysis of brain maps that can be demonstrated either by recording electrical activity of the cortex in response to external stimulation (e.g., sound, touch, visual patterns), by stimulating the cortex to elicit movements or perceptions, or less invasively by using in vivo imaging techniques such as functional magnetic resonance imaging (fMRI). For example, it has been known for over 50 years that stimulation of the cerebral cortex of humans or lab animals with a mild electric current will elicit movements of different body parts such that a map (in humans known as an homonculus) can be identified. Stimulation of specific points will elicit movements of the digits, leg, face, etc. As animals learn new motor skills, the details of the maps change, thus representing the newly learned skill. Thus, if a person learns to play a musical instrument, we can expect that the representation of the digits will expand to reflect the newly learned ability to make fine and rapid digit movements. Changes in the maps must reflect changes in the synaptic organization of the underlying cerebral tissue. Such synaptic changes can be shown by using specific stains to identify the structure of the neurons in the region of interest. One procedure, known as a Golgi stain, allows the dendritic fields of the neurons to be visualized and measured. Because most synapses are found on the dendrites and because space on dendrites is inevitably filled with synapses, we can measure the amount of dendritic space and infer synapse number. This is much like estimating the number of leaves on a tree by measuring branch length and the typical distance between the leaves. Simple arithmetic would allow an estimate of the total number of leaves. A similar logic allows synapse number to be estimated
on the dendrites visualized in Golgi stains. As animals learn new tasks, there are changes in dendritic organization that reflect the experience-dependent behavioral changes. But this method only allows an inference about synaptic change. In order to confirm that synapses really have changed, one must use electron microscopic (EM) techniques. EM analyses make it possible to visualize individual synapses, to identify synaptic type (excitatory vs. inhibitory), and to count the number of each type of synapse. Such analyses are laborious and time consuming, however, and not practical for most behavioral studies. If new synapses are formed in response to some experience, there must be some molecular mechanism that underlies the change. Thus, if new synapses are formed, proteins must be manufactured by cells, and the instructions for this manufacture will ultimately be controlled by genes. It is possible to measure both protein and gene expression in brain by using molecular probes, which provide yet another measure of brain plasticity. Finally, although thought to be relatively uncommon, brain plasticity can also result from the production of new neurons (known as neurogenesis) that become integrated into the host brain. Specific markers can be used to identify the birth of such new cells. The best studied region for these new cells is the hippocampus, although they may occur in small numbers elsewhere in the human brain. In sum, brain plasticity can be measured at many levels. Although the ultimate measures of plasticity are molecular, it is not realistic to begin there. The place to begin is with detailed analysis of behavior followed by global measures such as topographic maps, where relevant, and measures of synaptic change by using stains for pre- or postsynaptic processes.
Behavioral Change after Brain Injury We can identify at least three outcomes that could occur after brain injury. First, there may be compensation resulting from an adaptation to the lost function. Compensation could reflect a change in strategy or it may represent a substitution of a new behavior for the lost one. For example, a person who has a deficit in moving the eyes can be expected to have difficulty in reading. This difficulty can be solved, however, by moving the head, which allows restitution of function (reading) by substitution of one behavior for another. There are unlikely to be many plastic changes in the cortex to produce this behavioral change because the needed circuits are presumably already present. Similarly, if, following a stroke, a person can walk only with the aid of a cane, the
728 Neuronal Plasticity after Cortical Damage
ability to walk has returned but the original walking ability has not returned, just an adaptation to the behavioral difficulty. A second outcome might be partial restitution of the original behavior. This could reflect recovery from some sort of nonspecific effect of the injury, such as swelling, or it may reflect plastic changes that allow the brain to partly restore the disturbed behavior. Such plastic changes are most clearly seen in people with motor disturbances. Individuals may be unable to make movements of the digits or to organize their movements into purposeful sequences, but over time the capacity partially returns. Mapping studies using in vivo imaging have shown that the partial return of function is related to an expansion of the remaining motor cortical regions, as well as the recruitment of more distal regions (especially in the intact hemisphere) to control the movements. Animal studies have shown correlated changes in dendritic organization that presumably underlie the changes in map topography. Third, there is the possibility that there could be a complete restitution of the original behavior. Although it is at least theoretically possible for lost functions to completely return in a plastic brain, careful behavioral analysis shows that this is rarely, if ever, the case in either adult laboratory animals or human patients. In principle, however, it ought to be possible to reorganize the brain to allow at least some functions to completely recover. This process is most likely in the developing brain, and it has been documented for over 100 years that children with damage to language areas can show almost complete recovery of lost language functions.
Neuronal Adaptations to Brain Injury When the brain is damaged, there is a loss of neurons in the injured area, but, in addition, many neurons that are not directly injured lose their normal synaptic inputs. The immediate effect of this synaptic loss is (1) neuronal death, (2) atrophy of the dendritic and/or axonal fields that have lost their connections, and/or (3) subsequent reorganization of the connections. In principle, there are three ways that the brain could make changes that might support recovery. First, there could be changes in the organization of the remaining intact circuits in the brain. The general idea is that the brain could reorganize in some way to do ‘more with less.’ It is unlikely that a complexly integrated structure like the cerebral cortex could undergo a wholesale reorganization of cortical connectivity, but rather, recovery from cortical injury would be most likely to result from a change in the intrinsic organization of local cortical circuits in regions directly or indirectly disrupted by
the cortical injury. Although it might be possible to produce significant reorganization of cortical connections in the young brain, the overwhelming evidence in experimental animals is that this is rare and it is just as likely to be associated with abnormal functioning as with recovery. Second, there could be a generation of new circuitry. Cerebral reorganization can be stimulated either by some sort of behavioral therapy or the application of some sort of pharmacological treatment. In either event, the stimulus could influence reparative processes in the remaining brain or could enhance the production of new circuitry. Once again, it seems most likely that the induced neuronal changes would be in the intrinsic organization of the cortex. One might predict that induced neuronal changes might be more extensive than in the case of endogenous change, in part because the treatment can act upon the whole brain rather than just on affected regions. Third, there could be a generation of new neurons and glia to replace at least some lost cells. Stem cells that give rise to the neurons and glia of the brain remain active in the brain throughout life. It is thus possible that neurogenesis could be stimulated after injury, especially during development, and that these new neurons could replace those lost to injury or disease. All three of these possibilities for cerebral plasticity do occur, but the likelihood of each type of change varies with age at injury.
Plasticity after Adult Brain Injury The hippocampal formation of adult rats provided one of the first models to study synaptic replacement. When input to the hippocampus is reduced by damage to the major input pathway via the entorhinal cortex, there is a massive denervation of the hippocampal formation, which leads to atrophy of the dendritic fields of the hippocampal cells in the week after injury. Beginning at about 7–10 days after the injury, there is a slow regrowth of the dendritic fields, although the pattern of regrowth is different than the original pattern. This regrowth reflects a reorganization of the circuitry and it is correlated with a partial recovery of cognitive functions. The restructuring of the synaptic organization of the hippocampus occurs primarily because the remaining inputs to the hippocampus expand to occupy the regions of lost inputs. An analogous process appears to occur after restricted neocortical injury in adulthood. Frontal lesions in rats lead to atrophy of neurons in adjacent cortical regions, but by 30 days postinjury the atrophy begins to reverse, and by 3 months the affected neurons actually have more synaptic space than
Neuronal Plasticity after Cortical Damage
normal. Again, the dendritic change is correlated with partial recovery of cognitive tasks associated with the frontal injury. More recently, there has been much research on the effect of unilateral motor cortex injury on adjacent motor regions, contralateral motor regions, and the striatum. The general finding is that there is an initial atrophy of affected regions on the ipsilateral hemisphere, followed by a compensatory reorganization of neural networks that can be seen in dendritic organization in both the cortex and striatum. Some studies have shown increased dendritic fields in the motor regions of the intact hemisphere as well, which might be predicted from the in vivo imaging studies in humans. One unexpected finding of the studies is that lesion etiology appears to interact with the synaptic plasticity. It appears that the way the cortical tissue is killed may somehow affect the molecular cascade that subsequently leads to the synaptic reorganization. Little is known about the changes in gene or protein expression that give rise to the synaptic changes after cortical injury but there are large changes in the expression of various growth factors, such as fibroblast growth factor-2 (FGF-2), that likely play some role in stimulating the synaptic remodeling.
Plasticity after Infant Brain Injury Much more is known about plasticity following injury to the developing brain. Damage to various cortical areas in the second week of life in rats has been shown to lead to good functional recovery in adulthood, and this recovery is correlated with expansion of dendritic fields across the cortical mantle. This dendritic expansion takes several weeks to develop, however, and as the dendritic fields reorganize, there is an associated improvement in a variety of behavioral measures. In contrast, damage to cortical regions in the first week of life in rats produces atrophy of cortical neurons and this atrophy does not recover, nor does the lost behavior. Infant animals show changes not only in local cortical circuits but also in more distant cortical connectivity. Perhaps the most extensive studies of changes in cortical connectivity are those showing that after unilateral motor cortex lesions in infant rats or cats there is a major expansion of the ipsilateral corticospinal pathway from the undamaged hemisphere, which is correlated with partial recovery of skilled forelimb use. These expanded connections typically do not reflect the growth of new pathways, however; rather, they reflect the failure of superfluous pathways to die off during development. That is, normally in development, there is a period during which many pathways are eliminated, but after some types of brain injury these pathways are maintained. The presence
729
of these abnormal pathways may support some types of functional recovery, but it may also interfere with the normal functioning of remaining cortical functions. This possibility has been termed ‘crowding’ to reflect the idea that the normal functions of a cortical region can be crowded out by the development of abnormal connections. Thus, there may be recovery of some types of behaviors, such as motor functions, at the expense of other functions. This appears to be especially likely if the injury occurs during the period of neuronal migration and unlikely if it occurs during the period of maximal synaptogenesis. As noted earlier, synaptic change may also occur after injury because the brain generates new neurons. Although this is likely to be rare in the adult, it does occur during development, but the generation of these neurons varies with precise embryonic age and location of injury. If the brain is damaged prenatally during the time of neuronal generation, the brain can compensate by generating rather large numbers of new cells that appear to support at least partial restitution of function. If the developing brain is damaged postnatally, there can also be extensive neurogenesis, although it appears largely limited to injury during the second week of life and is most extensive when the injury is to the certain regions of the midline telecephalon, namely, the olfactory bulb or midline cortex. The newly generated tissue is functional and animals regain at least partial function. As in adult injury, little is known about the changes in gene or protein expression that give rise to the synaptic changes after cortical injury in infancy. There are increases in FGF-2 that correlate with functional outcome, but the exact role of the growth factors in synaptic reorganization and neurogenesis is poorly understood.
Factors Influencing Recovery and Plasticity after Cortical Injury in Adulthood Given that a wide range of factors can stimulate synaptic plasticity in the normal brain, it is not surprising that brain plasticity and behavior after cortical injury can be modified by many factors. The most powerful influence appears to be complex housing. Studies have shown consistently that placing experimental animals in complex environments in which there are conspecifics to interact with, novel objects to explore and interact with, and an opportunity for motor activity in complex terrain produces widespread changes in dendritic organization, endogenous growth factor production, and gene expression. Animals with cerebral injuries clearly benefit behaviorally from such experience, and there is a
730 Neuronal Plasticity after Cortical Damage
correlated reorganization of neuronal networks. A key feature of complex housing is that such experience produces extensive changes in the brain of laboratory animals; but what is the equivalent treatment in humans? The best guess is some type of multidisciplinary rehabilitation program that is relatively intense and thus lasts several hours a day. Such treatments may not be practical for many patients who may tire easily or have other ailments that make the intensity difficult. Other treatments thus may provide more viable options. The most common option is rehabilitation training, which is probably the most common treatment in human patients. Experimental studies in lab animals have shown functional improvement correlated with shifts in the organization of cortical motor maps with rehabilitation training, but rehabilitation training is generally only effective with fairly restricted brain injuries. One type of treatment that has been tried is the use of psychomotor stimulants such as amphetamine and nicotine. These stimulants produce large changes in synaptic organization in the normal frontal cortex, the effects being more widespread with nicotine. The administration of stimulants after brain injury is presumed to stimulate synaptic plasticity that can be co-opted by the damaged brain to facilitate recovery. Because stimulants also increase the endogenous production of neurotrophic factors such as FGF-2, it might be expected that neurotrophic factors might also facilitate reactive synaptic plasticity after brain injury and that is the case. Both FGF-2 and nerve growth factor (NGF) stimulate synaptic plasticity and functional recovery after cortical injury. There are a few studies looking at other types of factors including (1) inosine, which is a compound that enhances the production of connections from the injured hemisphere across to the damaged one, and (2) antibodies to a protein known as NoGo, which untreated acts to prevent synaptic plasticity. Both treatments are correlated with increased synapse formation in the remaining brain.
Factors Influencing Recovery and Plasticity after Cortical Injury in Infancy It is generally assumed that the developing brain will show more plasticity after injury than the adult brain and, similarly, that plasticity in the injured developing brain should be influenced more by factors than the adult brain. This is generally true, although the precise age at the time that the treatments are initiated does interact with the extent of observed plasticity. As a general rule of thumb, the sooner the treatments are
initiated, the larger the plastic changes (and correlated recovery) will be. As in adults, complex housing has a very large effect on both synaptic organization and behavior. Another treatment that is nearly as effective is tactile stimulation with a soft brush, typically lasting about 15 min several times a day. As little as 2 weeks of such stimulation after perinatal injury facilitates recovery measured in adulthood and produces large increases in synapse numbers relative to control animals. One reason for this large effect appears to be related to the stimulation of FGF-2 in the skin. This FGF-2 travels through the bloodstream to the brain and acts to enhance plasticity. Direct administration of FGF-2 can act in a similar fashion and under some circumstances can stimulate neurogenesis and the partial regeneration of injured cortical tissue. But not all treatments are beneficial after early injury. Prenatal stress or prenatal selective serotonin reuptake inhibitors (SSRIs) can interfere with reactive plasticity after perinatal injury and animals show severe behavioral impairments in adulthood. The fact that prenatal experiences can alter later brain plasticity suggests that the experiences alter gene expression, which later interacts with the brain’s capacity to generate plastic changes to facilitate functional recovery.
Summary In summary, the brain is capable of significant synaptic reorganization in response to a wide range of experiences, including injury. Plasticity can be measured at many levels ranging from behavior to genes. As methods of analysis are refined, we can anticipate that the mechanisms underlying brain plasticity and recovery of function after injury will become better understood and will allow the development of better treatments for brain injury throughout the life span. See also: Adult Cortical Plasticity; Cell Replacement Therapy: Mechanisms of Functional Recovery; Neurogenesis in the Intact Adult Brain; Neurogenesis and Neural Precursors, Progenitors, and Stem Cells in the Adult Brain; Spinal Cord Regeneration and Functional Recovery: Strategies; Synaptic Plasticity: Neuronogenesis and Stem Cells in Normal Brain Aging; Synaptic Plasticity: Neuronal Sprouting.
Further Reading Grossman AW, Churchill JD, Bates KE, Kleim JA, and Greenough WT (2002) A brain adaptation view of plasticity: Is synaptic plasticity an overly limited concept? Progress in Brain Research 138: 91–108. Hensch TK (2004) Critical period regulation. Annual Review of Neuroscience 27: 549–579.
Neuronal Plasticity after Cortical Damage Horn G (2004) Pathways of the past: The imprint of memory. Nature Reviews Neuroscience 5: 108–120. Johnston MV (2003) Brain plasticity in paediatric neurology. European Journal of Paediatric Neurology 7: 105–113. Kolb B (1995) Brain Plasticity and Behavior. Mahwah, NJ: Lawrence Erlbaum Associates. Kolb B and Whishaw IQ (1998) Brain plasticity and behavior. Annual Review of Psychology 49: 43–64. Neville H and Bavelier D (2002) Human brain plasticity: Evidence from sensory deprivation and altered language experience. Progress in Brain Research 138: 177–188. Nudo RJ (2003) Adaptive plasticity in motor cortex: Implications for rehabilitation after brain injury. Journal of Rehabilitation Medicine 41: 7–10.
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Payne BR and Lomber SG (2001) Reconstructing functional systems after lesions of cerebral cortex. Nature Reviews Neuroscience 2: 911–919. Shaw CA and McEachern JC (2003) Toward a Theory of Neuroplasticity. New York: Elsevier. Van der Kooy D and Weiss S (2000) Why stem cells? Science 287: 1439–1441. Wolf ME, Sun X, Mangiavacchi S, and Chao SZ (2004) Psychomotor stimulants and neuronal plasticity. Neuropharmacology 47: 61–79. Woo NH and Lu B (2006) Regulation of cortical interneurons by neurotrophins: From development to cognitive disorders. Neuroscientist 12: 43–46.
727
Neuronal Plasticity after Cortical Damage B Kolb, University of Lethbridge, Lethbridge, AB, Canada ã 2009 Elsevier Ltd. All rights reserved.
Measuring Brain Plasticity Although brain plasticity is presumed to reflect changes in the synaptic organization of the brain, it can be inferred from the measurement of change at many levels of analysis. Perhaps the most obvious level is behavior. If an organism’s behavior is altered, such as when a new habit or bit of information is learned, we can infer that there must be some persistent change in the nervous system that represents the habit or information. The identification of this plastic change may be seen by utilizing a range of techniques that run from global to molecular analyses of brain organization. One of the most global measures is the analysis of brain maps that can be demonstrated either by recording electrical activity of the cortex in response to external stimulation (e.g., sound, touch, visual patterns), by stimulating the cortex to elicit movements or perceptions, or less invasively by using in vivo imaging techniques such as functional magnetic resonance imaging (fMRI). For example, it has been known for over 50 years that stimulation of the cerebral cortex of humans or lab animals with a mild electric current will elicit movements of different body parts such that a map (in humans known as an homonculus) can be identified. Stimulation of specific points will elicit movements of the digits, leg, face, etc. As animals learn new motor skills, the details of the maps change, thus representing the newly learned skill. Thus, if a person learns to play a musical instrument, we can expect that the representation of the digits will expand to reflect the newly learned ability to make fine and rapid digit movements. Changes in the maps must reflect changes in the synaptic organization of the underlying cerebral tissue. Such synaptic changes can be shown by using specific stains to identify the structure of the neurons in the region of interest. One procedure, known as a Golgi stain, allows the dendritic fields of the neurons to be visualized and measured. Because most synapses are found on the dendrites and because space on dendrites is inevitably filled with synapses, we can measure the amount of dendritic space and infer synapse number. This is much like estimating the number of leaves on a tree by measuring branch length and the typical distance between the leaves. Simple arithmetic would allow an estimate of the total number of leaves. A similar logic allows synapse number to be estimated
on the dendrites visualized in Golgi stains. As animals learn new tasks, there are changes in dendritic organization that reflect the experience-dependent behavioral changes. But this method only allows an inference about synaptic change. In order to confirm that synapses really have changed, one must use electron microscopic (EM) techniques. EM analyses make it possible to visualize individual synapses, to identify synaptic type (excitatory vs. inhibitory), and to count the number of each type of synapse. Such analyses are laborious and time consuming, however, and not practical for most behavioral studies. If new synapses are formed in response to some experience, there must be some molecular mechanism that underlies the change. Thus, if new synapses are formed, proteins must be manufactured by cells, and the instructions for this manufacture will ultimately be controlled by genes. It is possible to measure both protein and gene expression in brain by using molecular probes, which provide yet another measure of brain plasticity. Finally, although thought to be relatively uncommon, brain plasticity can also result from the production of new neurons (known as neurogenesis) that become integrated into the host brain. Specific markers can be used to identify the birth of such new cells. The best studied region for these new cells is the hippocampus, although they may occur in small numbers elsewhere in the human brain. In sum, brain plasticity can be measured at many levels. Although the ultimate measures of plasticity are molecular, it is not realistic to begin there. The place to begin is with detailed analysis of behavior followed by global measures such as topographic maps, where relevant, and measures of synaptic change by using stains for pre- or postsynaptic processes.
Behavioral Change after Brain Injury We can identify at least three outcomes that could occur after brain injury. First, there may be compensation resulting from an adaptation to the lost function. Compensation could reflect a change in strategy or it may represent a substitution of a new behavior for the lost one. For example, a person who has a deficit in moving the eyes can be expected to have difficulty in reading. This difficulty can be solved, however, by moving the head, which allows restitution of function (reading) by substitution of one behavior for another. There are unlikely to be many plastic changes in the cortex to produce this behavioral change because the needed circuits are presumably already present. Similarly, if, following a stroke, a person can walk only with the aid of a cane, the
728 Neuronal Plasticity after Cortical Damage
ability to walk has returned but the original walking ability has not returned, just an adaptation to the behavioral difficulty. A second outcome might be partial restitution of the original behavior. This could reflect recovery from some sort of nonspecific effect of the injury, such as swelling, or it may reflect plastic changes that allow the brain to partly restore the disturbed behavior. Such plastic changes are most clearly seen in people with motor disturbances. Individuals may be unable to make movements of the digits or to organize their movements into purposeful sequences, but over time the capacity partially returns. Mapping studies using in vivo imaging have shown that the partial return of function is related to an expansion of the remaining motor cortical regions, as well as the recruitment of more distal regions (especially in the intact hemisphere) to control the movements. Animal studies have shown correlated changes in dendritic organization that presumably underlie the changes in map topography. Third, there is the possibility that there could be a complete restitution of the original behavior. Although it is at least theoretically possible for lost functions to completely return in a plastic brain, careful behavioral analysis shows that this is rarely, if ever, the case in either adult laboratory animals or human patients. In principle, however, it ought to be possible to reorganize the brain to allow at least some functions to completely recover. This process is most likely in the developing brain, and it has been documented for over 100 years that children with damage to language areas can show almost complete recovery of lost language functions.
Neuronal Adaptations to Brain Injury When the brain is damaged, there is a loss of neurons in the injured area, but, in addition, many neurons that are not directly injured lose their normal synaptic inputs. The immediate effect of this synaptic loss is (1) neuronal death, (2) atrophy of the dendritic and/or axonal fields that have lost their connections, and/or (3) subsequent reorganization of the connections. In principle, there are three ways that the brain could make changes that might support recovery. First, there could be changes in the organization of the remaining intact circuits in the brain. The general idea is that the brain could reorganize in some way to do ‘more with less.’ It is unlikely that a complexly integrated structure like the cerebral cortex could undergo a wholesale reorganization of cortical connectivity, but rather, recovery from cortical injury would be most likely to result from a change in the intrinsic organization of local cortical circuits in regions directly or indirectly disrupted by
the cortical injury. Although it might be possible to produce significant reorganization of cortical connections in the young brain, the overwhelming evidence in experimental animals is that this is rare and it is just as likely to be associated with abnormal functioning as with recovery. Second, there could be a generation of new circuitry. Cerebral reorganization can be stimulated either by some sort of behavioral therapy or the application of some sort of pharmacological treatment. In either event, the stimulus could influence reparative processes in the remaining brain or could enhance the production of new circuitry. Once again, it seems most likely that the induced neuronal changes would be in the intrinsic organization of the cortex. One might predict that induced neuronal changes might be more extensive than in the case of endogenous change, in part because the treatment can act upon the whole brain rather than just on affected regions. Third, there could be a generation of new neurons and glia to replace at least some lost cells. Stem cells that give rise to the neurons and glia of the brain remain active in the brain throughout life. It is thus possible that neurogenesis could be stimulated after injury, especially during development, and that these new neurons could replace those lost to injury or disease. All three of these possibilities for cerebral plasticity do occur, but the likelihood of each type of change varies with age at injury.
Plasticity after Adult Brain Injury The hippocampal formation of adult rats provided one of the first models to study synaptic replacement. When input to the hippocampus is reduced by damage to the major input pathway via the entorhinal cortex, there is a massive denervation of the hippocampal formation, which leads to atrophy of the dendritic fields of the hippocampal cells in the week after injury. Beginning at about 7–10 days after the injury, there is a slow regrowth of the dendritic fields, although the pattern of regrowth is different than the original pattern. This regrowth reflects a reorganization of the circuitry and it is correlated with a partial recovery of cognitive functions. The restructuring of the synaptic organization of the hippocampus occurs primarily because the remaining inputs to the hippocampus expand to occupy the regions of lost inputs. An analogous process appears to occur after restricted neocortical injury in adulthood. Frontal lesions in rats lead to atrophy of neurons in adjacent cortical regions, but by 30 days postinjury the atrophy begins to reverse, and by 3 months the affected neurons actually have more synaptic space than
Neuronal Plasticity after Cortical Damage
normal. Again, the dendritic change is correlated with partial recovery of cognitive tasks associated with the frontal injury. More recently, there has been much research on the effect of unilateral motor cortex injury on adjacent motor regions, contralateral motor regions, and the striatum. The general finding is that there is an initial atrophy of affected regions on the ipsilateral hemisphere, followed by a compensatory reorganization of neural networks that can be seen in dendritic organization in both the cortex and striatum. Some studies have shown increased dendritic fields in the motor regions of the intact hemisphere as well, which might be predicted from the in vivo imaging studies in humans. One unexpected finding of the studies is that lesion etiology appears to interact with the synaptic plasticity. It appears that the way the cortical tissue is killed may somehow affect the molecular cascade that subsequently leads to the synaptic reorganization. Little is known about the changes in gene or protein expression that give rise to the synaptic changes after cortical injury but there are large changes in the expression of various growth factors, such as fibroblast growth factor-2 (FGF-2), that likely play some role in stimulating the synaptic remodeling.
Plasticity after Infant Brain Injury Much more is known about plasticity following injury to the developing brain. Damage to various cortical areas in the second week of life in rats has been shown to lead to good functional recovery in adulthood, and this recovery is correlated with expansion of dendritic fields across the cortical mantle. This dendritic expansion takes several weeks to develop, however, and as the dendritic fields reorganize, there is an associated improvement in a variety of behavioral measures. In contrast, damage to cortical regions in the first week of life in rats produces atrophy of cortical neurons and this atrophy does not recover, nor does the lost behavior. Infant animals show changes not only in local cortical circuits but also in more distant cortical connectivity. Perhaps the most extensive studies of changes in cortical connectivity are those showing that after unilateral motor cortex lesions in infant rats or cats there is a major expansion of the ipsilateral corticospinal pathway from the undamaged hemisphere, which is correlated with partial recovery of skilled forelimb use. These expanded connections typically do not reflect the growth of new pathways, however; rather, they reflect the failure of superfluous pathways to die off during development. That is, normally in development, there is a period during which many pathways are eliminated, but after some types of brain injury these pathways are maintained. The presence
729
of these abnormal pathways may support some types of functional recovery, but it may also interfere with the normal functioning of remaining cortical functions. This possibility has been termed ‘crowding’ to reflect the idea that the normal functions of a cortical region can be crowded out by the development of abnormal connections. Thus, there may be recovery of some types of behaviors, such as motor functions, at the expense of other functions. This appears to be especially likely if the injury occurs during the period of neuronal migration and unlikely if it occurs during the period of maximal synaptogenesis. As noted earlier, synaptic change may also occur after injury because the brain generates new neurons. Although this is likely to be rare in the adult, it does occur during development, but the generation of these neurons varies with precise embryonic age and location of injury. If the brain is damaged prenatally during the time of neuronal generation, the brain can compensate by generating rather large numbers of new cells that appear to support at least partial restitution of function. If the developing brain is damaged postnatally, there can also be extensive neurogenesis, although it appears largely limited to injury during the second week of life and is most extensive when the injury is to the certain regions of the midline telecephalon, namely, the olfactory bulb or midline cortex. The newly generated tissue is functional and animals regain at least partial function. As in adult injury, little is known about the changes in gene or protein expression that give rise to the synaptic changes after cortical injury in infancy. There are increases in FGF-2 that correlate with functional outcome, but the exact role of the growth factors in synaptic reorganization and neurogenesis is poorly understood.
Factors Influencing Recovery and Plasticity after Cortical Injury in Adulthood Given that a wide range of factors can stimulate synaptic plasticity in the normal brain, it is not surprising that brain plasticity and behavior after cortical injury can be modified by many factors. The most powerful influence appears to be complex housing. Studies have shown consistently that placing experimental animals in complex environments in which there are conspecifics to interact with, novel objects to explore and interact with, and an opportunity for motor activity in complex terrain produces widespread changes in dendritic organization, endogenous growth factor production, and gene expression. Animals with cerebral injuries clearly benefit behaviorally from such experience, and there is a
730 Neuronal Plasticity after Cortical Damage
correlated reorganization of neuronal networks. A key feature of complex housing is that such experience produces extensive changes in the brain of laboratory animals; but what is the equivalent treatment in humans? The best guess is some type of multidisciplinary rehabilitation program that is relatively intense and thus lasts several hours a day. Such treatments may not be practical for many patients who may tire easily or have other ailments that make the intensity difficult. Other treatments thus may provide more viable options. The most common option is rehabilitation training, which is probably the most common treatment in human patients. Experimental studies in lab animals have shown functional improvement correlated with shifts in the organization of cortical motor maps with rehabilitation training, but rehabilitation training is generally only effective with fairly restricted brain injuries. One type of treatment that has been tried is the use of psychomotor stimulants such as amphetamine and nicotine. These stimulants produce large changes in synaptic organization in the normal frontal cortex, the effects being more widespread with nicotine. The administration of stimulants after brain injury is presumed to stimulate synaptic plasticity that can be co-opted by the damaged brain to facilitate recovery. Because stimulants also increase the endogenous production of neurotrophic factors such as FGF-2, it might be expected that neurotrophic factors might also facilitate reactive synaptic plasticity after brain injury and that is the case. Both FGF-2 and nerve growth factor (NGF) stimulate synaptic plasticity and functional recovery after cortical injury. There are a few studies looking at other types of factors including (1) inosine, which is a compound that enhances the production of connections from the injured hemisphere across to the damaged one, and (2) antibodies to a protein known as NoGo, which untreated acts to prevent synaptic plasticity. Both treatments are correlated with increased synapse formation in the remaining brain.
Factors Influencing Recovery and Plasticity after Cortical Injury in Infancy It is generally assumed that the developing brain will show more plasticity after injury than the adult brain and, similarly, that plasticity in the injured developing brain should be influenced more by factors than the adult brain. This is generally true, although the precise age at the time that the treatments are initiated does interact with the extent of observed plasticity. As a general rule of thumb, the sooner the treatments are
initiated, the larger the plastic changes (and correlated recovery) will be. As in adults, complex housing has a very large effect on both synaptic organization and behavior. Another treatment that is nearly as effective is tactile stimulation with a soft brush, typically lasting about 15 min several times a day. As little as 2 weeks of such stimulation after perinatal injury facilitates recovery measured in adulthood and produces large increases in synapse numbers relative to control animals. One reason for this large effect appears to be related to the stimulation of FGF-2 in the skin. This FGF-2 travels through the bloodstream to the brain and acts to enhance plasticity. Direct administration of FGF-2 can act in a similar fashion and under some circumstances can stimulate neurogenesis and the partial regeneration of injured cortical tissue. But not all treatments are beneficial after early injury. Prenatal stress or prenatal selective serotonin reuptake inhibitors (SSRIs) can interfere with reactive plasticity after perinatal injury and animals show severe behavioral impairments in adulthood. The fact that prenatal experiences can alter later brain plasticity suggests that the experiences alter gene expression, which later interacts with the brain’s capacity to generate plastic changes to facilitate functional recovery.
Summary In summary, the brain is capable of significant synaptic reorganization in response to a wide range of experiences, including injury. Plasticity can be measured at many levels ranging from behavior to genes. As methods of analysis are refined, we can anticipate that the mechanisms underlying brain plasticity and recovery of function after injury will become better understood and will allow the development of better treatments for brain injury throughout the life span. See also: Adult Cortical Plasticity; Cell Replacement Therapy: Mechanisms of Functional Recovery; Neurogenesis in the Intact Adult Brain; Neurogenesis and Neural Precursors, Progenitors, and Stem Cells in the Adult Brain; Spinal Cord Regeneration and Functional Recovery: Strategies; Synaptic Plasticity: Neuronogenesis and Stem Cells in Normal Brain Aging; Synaptic Plasticity: Neuronal Sprouting.
Further Reading Grossman AW, Churchill JD, Bates KE, Kleim JA, and Greenough WT (2002) A brain adaptation view of plasticity: Is synaptic plasticity an overly limited concept? Progress in Brain Research 138: 91–108. Hensch TK (2004) Critical period regulation. Annual Review of Neuroscience 27: 549–579.
Neuronal Plasticity after Cortical Damage Horn G (2004) Pathways of the past: The imprint of memory. Nature Reviews Neuroscience 5: 108–120. Johnston MV (2003) Brain plasticity in paediatric neurology. European Journal of Paediatric Neurology 7: 105–113. Kolb B (1995) Brain Plasticity and Behavior. Mahwah, NJ: Lawrence Erlbaum Associates. Kolb B and Whishaw IQ (1998) Brain plasticity and behavior. Annual Review of Psychology 49: 43–64. Neville H and Bavelier D (2002) Human brain plasticity: Evidence from sensory deprivation and altered language experience. Progress in Brain Research 138: 177–188. Nudo RJ (2003) Adaptive plasticity in motor cortex: Implications for rehabilitation after brain injury. Journal of Rehabilitation Medicine 41: 7–10.
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Payne BR and Lomber SG (2001) Reconstructing functional systems after lesions of cerebral cortex. Nature Reviews Neuroscience 2: 911–919. Shaw CA and McEachern JC (2003) Toward a Theory of Neuroplasticity. New York: Elsevier. Van der Kooy D and Weiss S (2000) Why stem cells? Science 287: 1439–1441. Wolf ME, Sun X, Mangiavacchi S, and Chao SZ (2004) Psychomotor stimulants and neuronal plasticity. Neuropharmacology 47: 61–79. Woo NH and Lu B (2006) Regulation of cortical interneurons by neurotrophins: From development to cognitive disorders. Neuroscientist 12: 43–46.