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Mechanisms for recovery of motor function following cortical damage
Mechanisms for recovery of motor function following cortical damage Randolph J Nudo Recent studies of focal injury to the cerebral cortex have demonstrated that the remaining, intact tissue undergoes structural and functional changes that could play a substantial role in neurological recovery. New information regarding the molecular and cellular environment in the adjacent, intact tissue has suggested that waves of growth promotion and inhibition modulate the self-repair processes of the brain. Furthermore, recent studies have documented widespread neurophysiological and neuroanatomical changes in regions remote from a focal cortical injury, suggesting that entire cortical networks participate in the recovery process. Addresses University of Kansas Medical Center, Landon Center on Aging, MS 1005 3901 Rainbow Boulevard, Kansas City, KS 66160 USA Corresponding author: Nudo, Randolph J ([email protected])
Current Opinion in Neurobiology 2006, 16:638–644 This review comes from a themed issue on Motor systems Edited by Eve Marder and Peter L Strick Available online 3rd November 2006 0959-4388/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.conb.2006.10.004
Introduction The cerebral cortex adapts to changing environmental demands throughout an individual’s life. Dendrites and spines branch and proliferate, synapses form and degenerate, and the efficacy of synaptic contacts is modulated within a complex intracortical network. Thus, it is not surprising that after an injury to the cerebral cortex, the structure and function of sensory and motor regions is drastically altered. Limited motor recovery can occur spontaneously after injury to the motor cortex; therefore, it will be interesting to determine which neural mechanisms underlie such recovery. Post-injury plasticity has been documented not only at the molecular, synaptic, cellular, network and systems levels in experimental animals but also many of these plasticity events have been correlated with alterations in cortical function using neuroimaging and stimulation techniques in humans. Basic phenomenology is now giving way to specific hypotheses regarding the mechanisms by which motor function is re-acquired after injury. In this review, we summarize some of the important new findings in this evolving field. Current Opinion in Neurobiology 2006, 16:638–644
Early demonstrations of post-injury plasticity Direct evidence that adjacent regions of the cortex are functionally altered after cortical injury can be traced to surface stimulation studies by Glees and Cole [1] in the early 1950s. After a focal injury to the primary motor cortex (M1) thumb representation, the damaged representation reappeared in the adjacent cortical territory. Studies in the somatosensory cortex by Jenkins et al. [2] seemed to parallel these results. However, using intracortical microstimulation (ICMS) techniques, somewhat different findings were observed in motor cortex by Nudo et al. in the 1990s [3,4]. Small, subtotal lesions were made in a portion of the M1 distal forelimb representation (DFL) in squirrel monkeys, and the animals were allowed to recover spontaneously (i.e. without the benefit of rehabilitative training) for several weeks. In contrast to earlier findings, the remaining DFL was reduced in size, giving way to expanded proximal representations [3]. Importantly, in animals that underwent rehabilitative training with the impaired limb, the DFL was preserved [4]. These results, in addition to others since then, have led to the conclusion that behavioral experience is a potent modulator of post-injury cortical plasticity.
New insights into the cellular and molecular mechanisms underlying local reorganization Although studies of representational maps in motor cortex are largely phenomenological, it is now clear that focal cortical injury results in specific neurophysiological and neuroanatomical changes in both adjacent and remote cortical tissue. Structural alterations occur in adult mammalian cortex as a consequence of experience [5]. Not surprisingly, focal cortical injury results in local neuroanatomical changes. Between three and 14 days after cortical infarction, rats demonstrate increased growthassociated protein 43 (GAP-43) immunoreactivity, suggesting neurite outgrowth in the peri-infarct region [6,7]. Between 14 and 60 days post-infarct, synaptophysin staining is significantly elevated, signifying increased synaptogenesis [6]. Although these studies used somewhat indirect measures, axonal sprouting has been demonstrated definitively in peri-infarct tissue in the rat barrel cortex using tract-tracing methods [8]. Local, surviving neurons become hyperexcitable, with associated upregulation of N-methyl D-aspartate (NMDA) receptors and downregulation of g-aminobutyric acid subtype A (GABAa) receptors [9]. Recent data in rodent models have now demonstrated that perilesional neurons (neurons in the intact cortical tissue adjacent to a focal injury) respond to injury with the www.sciencedirect.com
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expression of a specific and highly coordinated set of genes [10]. In a landmark study, Carmichael and coworkers [11] defined spatial and temporal patterns of expression profiles of growth-associated genes in the rat barrel field infarct model. They found that a focal infarct induces sequential waves of expression of growth-promoting genes throughout the period of axonal sprouting. Spatially, a growth-promoting region was distinguished in which growth-promoting proteins are increased, and growth-inhibitory proteins are decreased. This region corresponds to the zone of axonal sprouting found previously, and is distinct from the glial scar immediately adjacent to the infarct. It now appears that such neuronal growth programs are turned on early after focal infarct and might underlie the brain’s self-repair processes. A more recent study suggests that such growth programs are turned on even in aged brains, but demonstrate a unique temporal profile [12]. Exploiting this new understanding of cellular and molecular events following injury might provide new treatment approaches for recovery after CNS injury [13].
the M1 DFL and cutaneous inputs in the caudal portion [24]. Subtotal lesions of the rostral versus caudal sectors of the M1 DFL result in dissociable deficits related to the nature of the somatosensory inputs [25]. Thus, lesions in M1 do more than disrupt motor output pathways through corticofugal tracts. Such lesions effectively disconnect motor cortex from the somatosensory system.
Recent studies in human stroke survivors suggest that the intact, peri-infarct cortex plays a role in neurological recovery [14–16]. In an functional magnetic resonance imaging (fMRI) study, Cramer et al. [17] demonstrated that stroke survivors with good recovery show activity in the peri-infarct rim, although this activity is diminished compared with that in controls. In addition, after larger infarcts and in patients with poor behavioral outcome there appears to be a shift in activity towards the nonstroke hemisphere [18]. Furthermore, after several weeks of rehabilitation, motor representations in the injured hemisphere are enlarged relative to the initial post-injury map [19,20]. Also, constraint-induced movement therapy, in which goal-directed movement with the impaired hand is encouraged, produces a significant enlargement of the representation of the paretic limb in the injured hemisphere [21], closely paralleling results in non-human primates. Thus, a more normal fMRI pattern, in which the majority of neuronal activation is located in the hemisphere contralateral to the impaired hand (i.e., the injured hemisphere), seems to be associated with better recovery [22].
Although local axonal sprouting and synaptogenesis have been found in the peri-infarct cortex, until recently relatively little was known regarding changes in longrange intracortical networks after focal injury. We recently examined the intracortical connections of the reorganized PMv DFL after an MI DFL injury [29]. Quantitative examinations of the terminal fields of PMv intracortical fibers demonstrated little change, with the exception of one cortical area. Each animal that had sustained an injury to the M1 DFL displayed a remarkably consistent, dense cluster of PMv terminal boutons within the primary somatosensory cortex (S1) hand representation. This projection from PMv to S1 was sparse to non-existent prior to the lesion, and thus represents a novel intracortical connection between frontal and parietal cortex that was induced by the lesion. It has been known for some time that after cortical lesions in rats, corticostriatal fibers, which primarily connect various motor areas with the ipsilateral striatum, sprout from the intact (contralesional) cortex and terminate in the contralateral striatum, that is, on the side of the lesion [30]. Under certain conditions, the intact cortex can send novel projections to denervated portions of the red nucleus and spinal cord as well [31]. This recent study in nonhuman primates represents the first evidence of a major alteration of intracortical wiring patterns among different cortical fields (see Figure 1).
Plastic events remote from the cortical injury Mammalian brains are endowed with a rich intracortical network that enables reciprocal communication among the various sensory and motor areas. Injury to motor cortex causes potent disruption of integrated sensorimotor networks, resulting in loss of fine motor control [23]. For example, M1 normally receives substantial input from somatosensory cortex, conveying proprioceptive and cutaneous information that is presumably integrated with motor output commands in M1. These somatosensory inputs terminate in M1 in a segregated fashion, with proprioceptive inputs primarily in the rostral portion of www.sciencedirect.com
Even when the motor cortex is left intact after middle cerebral artery occlusion (MCAo), motor maps as defined by ICMS are disrupted, as recently demonstrated in rats by Gharbawie et al. [26]. The excitability of areas remote from the site of infarct is altered for significant periods of time after injury. Upregulation of NMDA receptors and downregulation of GABAa receptors has been observed in both the ipsilesional and the contralesional hemisphere [27]. Reorganization of motor maps also occurs in remote motor areas interconnected with the injured territory. For example, examination several months after a near-total lesion in the M1 DFL in squirrel monkeys shows that the ventral premotor cortex (PMv) DFL has expanded [28].
Sprouting of axons after cortical injury appears to be activity-dependent. After a focal ischemic infarct in rats, synchronous neuronal activity is a signal for post-infarct axonal sprouting to be initiated from the intact cortical hemisphere to peri-infarct cortex and the contralateral dorsal striatum [32]. It follows that differences in postinfarct behavioral experience will influence which areas Current Opinion in Neurobiology 2006, 16:638–644
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Figure 1
Schematic illustration of the effects of a unilateral cortical lesion (red circle) on spared cortical tissue as depicted in a nonhuman primate brain. Time-dependent neurophysiological and neuroanatomical alterations occur in the peri-infarct region (pink region surrounding lesion) and remote cortical areas. These include alteration in neurophysiological maps of motor representations, neurotransmitter receptor regulation, dendritic sprouting (not shown), local and remote axonal sprouting (short and long green arrows, respectively) and synaptogenesis (small black dots). These changes are accompanied by waves of growth-promoting and growth-inhibiting proteins (large white and black circles, respectively) that might trigger axonal sprouting and provide guidance to regenerating axons. Similar changes have been documented in the contralesional (undamaged) cortex, and are thought to be related to behavioral compensation in the ipsilesional forelimb, and possibly recovery of function by the contralesional forelimb. Recent studies suggest that lesion size is an important factor in determining the role of remote cortical plasticity. Concentric circles in PM denote expanded motor representations. Abbreviations: M1, primary motor cortex; PM, premotor cortex; S1, primary somatosensory cortex.
of cortex become targets for sprouting axons by differentially activating task-specific cortical areas. Unilateral damage to motor cortex in rats results in timedependent changes in the contralateral motor cortex [33]. Dendritic arborization occurs within about two weeks post-lesion, followed by an increase in synaptogenesis in layer V by about one month post-lesion. These changes are thought to be associated with behavioral compensation of the ipsilesional (less-affected) limb (Figure 1). Luke et al. [34] have demonstrated that after a unilateral lesion in the sensorimotor cortex, rats actually performed better with the ipsilesional limb than sham-operated controls, demonstrating this hyper-reliance, or extreme tendency to use the ipsilesional limb for balance, support, grasping and grooming. These rats also demonstrated increased synapses per neuron in layer V of motor cortex, and alterations in the morphology of synaptic boutons. Bury and Jones [35] provided evidence that compensatory hyper-reliance is related to denervation-induced changes rather than to increased forelimb use. Current Opinion in Neurobiology 2006, 16:638–644
In contrast to hyper-reliance and improved behavioral capacity with the ipsilesional limb demonstrated in rats, a growing number of studies in human stroke survivors with unilateral lesions has demonstrated impaired motor control of the ipsilesional distal forelimb [36–38]. Whether ipsilesional impairments result from disruption of callosal connections, ipsilateral corticospinal pathways, or pathways at some other level of the neuraxis is as yet unclear. Finally, although it is widely known that CNS injury increases neurogenesis, the role of neural stem cells and progenitor cells in recovery after injury has been unclear [39]. However, Zhang et al. [40] have demonstrated that after stroke in adult rats, immature neurons in the subventricular zone (SVZ) migrate in a chain-like structure towards the ischemic border in the striatum. Similar results were found by Komitova et al. [41]. Importantly, the results of Komitova et al. demonstrate that post-infarct environmental enrichment results in increased numbers of neural stem and/or progenitor cells and neurogenesis in the SVZ. Finally, using laser-capture microdissection, Liu et al. www.sciencedirect.com
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[42] analyzed gene expression profiles of endogenous SVZ progenitor cells in adult mice after MCAo. They found that SVZ cells after stroke expressed many genes involved in neurogenesis during embryonic development that are not present in normal SVZ cells. Thus, the notion that the ontogenetic environment is recapitulated after CNS injury is gaining support. Whether neural stem cells or progenitor cells become incorporated into cortical networks, or function as reservoirs for growth-promoting and growth-inhibiting proteins after stroke, is an important question for future research. Nonetheless, evidence for endogenous neurogenesis in the adult brain after injury, and the role of post-injury behavioral experience on this process, has prompted guarded optimism for proceeding with cellular therapies for neurological disorders, such as stroke [43].
tex lesion in rats was lessened by larger infarcts. One possible interpretation of these data is that if lesions are small, recovery of function can be accomplished largely by ipsilesional plasticity mechanisms. In that case, contralesional plasticity is more involved with increasing compensatory behaviors of the ipsilesional limb. By contrast, when lesions are large, ipsilesional plasticity mechanisms are limited, and contralesional plasticity is more involved with recovery of function of the contralesional limb. The current data are thus in accordance with previous studies suggesting that lesion size is a major factor involved in the initiation of the vicarious processes that purportedly plays a role in recovery from CNS lesions.
Re-emergence of the mass action principle
One of the most crucial questions that must be addressed by basic research is whether there is a period of time after cortical injury in which the remaining, intact system is more amenable to rehabilitative interventions, through drugs [49–51], electrical stimulation [52–54], behavior (physiotherapy) or some combination of treatments. The time-dependent cascade of events in peri-infarct and remote areas would suggest that neuroplasticity mechanisms have a long time course, although effects might diminish with time. Recent studies on animal models have begun to confirm that behavioral training after focal injury is most effective for restoring baseline behavioral performance, peri-infarct neurophysiological maps and enhanced neuroanatomical changes in the contralesional hemisphere when introduced within the first week after injury. In a rat MCAo model, Biernaskie [55] found that functional outcome and dendritic branching patterns in the contralesional hemisphere were attenuated when rehabilitation was initiated at 14 or 30 days post-infarct. After a focal cortical infarct in rats, Hsu and Jones [56] showed that delaying reach training for 25 days resulted in poorer behavioral recovery compared with that after training initiated at 4 days post-injury, but no differences in synaptic morphology in the contralesional hemisphere. In a nonhuman primate model of focal ischemia in the M1 DFL, Barbay et al. [57] showed that delayed training resulted in attenuated maintenance of the spared M1 DFL. However, previous studies demonstrated an exaggerated lesion after early excessive use of the impaired forelimb (by casting the unimpaired limb) in rats [58]. It is thought that such excessive use can exacerbate NMDA-mediated excitotoxicity, because the peri-infarct region is hyperexcitable after injury [59,60]. However, as these recent studies demonstrate, at least in conditions of moderate post-injury use, the early exaggeration of the lesion is not observed.
More than 75 years ago, Lashley [44,45] postulated his classic theories regarding the relationship between cerebral mass and behavioral change. According to his hypothesis, lesion volume is generally assumed to be associated with the severity of deficits, whereas lesion location is related to the specificity of deficits. Frost et al. [28] recently demonstrated that the PMv DFL expands linearly with respect to the size of the M1 injury. An interpretation formed on the basis of Lashley’s principles would suggest that after small M1 lesions, the surviving M1 tissue could potentially subserve the recovery of function. For example, after a small, subtotal lesion in the M1 DFL, the adjacent, intact DFL might be able to accommodate some degree of functional recovery, and thus, this local region might be the focus of reorganization of motor maps. After larger lesions, reorganization of the adjacent tissue might not suffice. As more and more of the M1 DFL is destroyed, there might no longer be sufficient distal representations (and associated descending fibers) to enable recovery to occur by this process. More distant forelimb motor representations, perhaps those in premotor cortical areas, or even the contralateral hemisphere, might then be engaged. Biernaskie et al. [46] have recently examined the effects of lesion size after MCAo on responses in the contralesional hemisphere. Following recovery, the role of the contralesional (undamaged) cortex in recovery was examined by microinjecting lidocaine to deactivate it. If the original deficits were reinstated, it would infer that the contralateral cortex participated in recovery. Reinstatement of behavioral deficits in the lesion-affected limb was only seen in animals with large infarcts. Smaller infarcts followed by lidocaine disruption didn’t seem to cause any effects, and the subjects behaved no differently than controls. Similar findings were found by Shanina et al. [47] using small photothrombotic lesions followed by a second lesion on the contralateral side. Finally, Hsu and Jones [48] recently demonstrated that the paradoxical hyperfunctionality of the ipsilesional forelimb after unilateral sensorimotor corwww.sciencedirect.com
Is there a sensitive period for post-injury plasticity and recovery potential?
Conclusions Injury to the motor cortex results in a potent disruption of coordinated networks and their underlying emergent properties, resulting in loss of fine motor control, and Current Opinion in Neurobiology 2006, 16:638–644
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the employment of compensatory movement strategies. It now appears that such a disruption to the cortical motor network triggers a major reassembly of inter- and intraareal cortical networks. Post-injury behavioral experience appears to be crucial to the reassembly of adaptive modules. Recent data suggest that the basic intracortical wiring plan is substantially altered. Waves of growthpromoting and growth-inhibiting proteins are expressed in the peri-infarct tissue and might initiate and guide novel axonal connections. This new information provides both a challenge and an opportunity to understand the inherent restorative mechanisms of the brain after stroke. If the brain possesses mechanisms for vicarious of function, we might be able to exploit such mechanisms to maximize recovery.
Update Although several recent studies have demonstrated that SVZ progenitor cells migrate to the site of injury, substantial growth of new neural tissue has not been observed. However, in a new study in rats, Kolb et al. [61] found that following cortical injury and subsequent therapeutic treatment, the injury cavity became filled with cells that stain positively for neuronal antigens. These events were correlated with significantly improved behavioral recovery. This study is remarkable as it validates the therapeutic potential for treatments that induce regeneration of new tissue after injury.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest
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proliferation and neurogenesis in the subventricular zone of stroke-lesioned adult rats. Stroke 2005, 36:1278-1282. The authors demonstrate that after MCAo, rats display neural progenitor cells, putative neural stem cells and neural precursors in the SVZ. Environmental enrichment resulted in increased numbers of putative neural stem cells and neuroblasts that migrated in chain-like structures towards the infarct. 42. Liu XS, Zhang ZG, Zhang RL, Gregg S, Morris DC, Wang Y, Chopp M: Stroke induces gene profile changes associated with neurogenesis and angiogenesis in adult subventricular zone progenitor cells. J Cereb Blood Flow Metab 2006, In press, DOI:10.1038/sj.jcbfm.9600371. This study examined gene expression profiles of SVZ cells in the adult mouse after MCAo. Stroke SVZ cells expressed many genes thought to be involved in neurogenesis, and normally expressed during embryonic development. 43. Lindvall O, Kokaia Z: Stem cells for the treatment of neurological disorders. Nature 2006, 441:1094-1096. 44. Lashley K: Brain Mechanisms and Intelligence: A Quantitative Study of Injuries to the BrainUniversity of Chicago Press; 1929. 45. Lashley KS: Basic neural mechanisms in behavior. Psychol Rev 1930, 37:1-24. 46. Biernaskie J, Szymanska A, Windle V, Corbett D: Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats. Eur J Neurosci 2005, 21:989-999. After MCAo in rats, the authors tracked recovery of forelimb function for four weeks. Then lidocaine was microinjected over the contralesional motor cortex to determine if the original deficits would be reinstated. Reinstatement of deficits occurred only with large lesions. 47. Shanina EV, Schallert T, Witte OW, Redecker C: Behavioral recovery from unilateral photothrombotic infarcts of the forelimb sensorimotor cortex in rats: role of the contralateral cortex. Neuroscience 2006, 139:1495-1506. After a unilateral photothrombotic lesion in the rat sensorimotor cortex, a second lesion was made in the contralateral cortex at 2, 7 or 10 days after the first infarct. The second lesion only affected the forelimb contralateral to the second lesion, and did not reinstate the original deficit. 48. Hsu JE, Jones TA: Contralesional neural plasticity and functional changes in the less-affected forelimb after large and small cortical infarcts in rats. Exp Neurol 2006, 201:471-494. After small or large unilateral sensorimotor cortex lesions in rats, enhanced motor skill learning was found in the ipsilesional forelimb, and was accompanied by neuroplastic changes in the contralesional cortex. However, neuroplastic changes were muted after large lesions. Performance was best in rats with small lesions. 49. Barbay S, Zoubina EV, Dancause N, Frost SB, Eisner-Janowicz I, Stowe AM, Plautz EJ, Nudo RJ: A single injection of d-amphetamine facilitates improvements in motor training following a focal cortical infarct in squirrel monkeys. Neurorehabil Neural Repair 2006, in press. 50. Adkins DL, Jones TA: D-amphetamine enhances skilled reaching after ischemic cortical lesions in rats. Neurosci Lett 2005, 380:214-218. 51. Lee JK, Kim JE, Sivula M, Strittmatter SM: Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J Neurosci 2004, 24:6209-6217. 52. Adkins-Muir DL, Jones TA: Cortical electrical stimulation combined with rehabilitative training: enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol Res 2003, 25:780-788. 53. Kleim JA, Bruneau R, VandenBerg P, MacDonald E, Mulrooney R, Pocock D: Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol Res 2003, 25:789-793. 54. Teskey GC, Flynn C, Goertzen CD, Monfils MH, Young NA: Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat. Neurol Res 2003, 25:794-800. 55. Biernaskie J, Chernenko G, Corbett D: Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci 2004, 24:1245-1254. Current Opinion in Neurobiology 2006, 16:638–644
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56. Hsu JE, Jones TA: Time-sensitive enhancement of motor learning with the less-affected forelimb after unilateral sensorimotor cortex lesions in rats. Eur J Neurosci 2005, 22:2069-2080. After unilateral sensorimotor cortex lesions in rats, the authors examined the effects of post-lesion rehabilitative training initiated at four or 25 days post-injury. Early training, but not late training, enhanced behavioral performance. Both groups showed contralateral neuroplasticity, but there was no difference between the groups. 57. Barbay S, Plautz EJ, Friel KM, Frost SB, Dancause N, Stowe AM, Nudo RJ: Behavioral and neurophysiological effects of delayed training following a small ischemic infarct in primary motor cortex of squirrel monkeys. Exp Brain Res 2006, 169:106-116. In a neurophysiological mapping study after small, focal infarct in M1 of adult squirrel monkeys, the authors demonstrate that early, but not late, rehabilitative training results in preservation of adjacent forelimb representations. 58. Kozlowski DA, James DC, Schallert T: Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 1996, 16:4776-4786.
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59. Humm JL, Kozlowski DA, Bland ST, James DC, Schallert T: Use-dependent exaggeration of brain injury: is glutamate involved? Exp Neurol 1999, 157:349-358. 60. Neumann-Haefelin T, Witte OW: Periinfarct and remote excitability changes after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 2000, 20:45-52. 61. Kolb B, Morshead C, Gonzalez C, Kim M, Gregg C, Shingo T, Weiss S: Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. J Cereb Blood Flow Metab 2006, in press. In this exciting paper, the authors applied epidermal growth factor (EGF), erythropoietin (EPO) or both to rats up to seven days after MCAo. The remarkable results show that the cavity that normally appears after such a lesion became filled with cells that stain positively for neuronal antigens. The EGF and EPO treated animals improved significantly compared with control groups. Timing of treatment revealed a window of efficacy favoring early treatment in the first few days. Furthermore, the presence of EGF seemed to attract precursor cells to the site of the lesion. Finally, removal of the regenerated tissue appeared to reinstate the original deficit. This study provides evidence for direct links among growth factor activation of precursor cells, cortical tissue re-growth and functional recovery.
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Current Opinion in Neurobiology 2006, 16:638–644 This review comes from a themed issue on Motor systems Edited by Eve Marder and Peter L Strick Available online 3rd November 2006 0959-4388/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.conb.2006.10.004
Introduction The cerebral cortex adapts to changing environmental demands throughout an individual’s life. Dendrites and spines branch and proliferate, synapses form and degenerate, and the efficacy of synaptic contacts is modulated within a complex intracortical network. Thus, it is not surprising that after an injury to the cerebral cortex, the structure and function of sensory and motor regions is drastically altered. Limited motor recovery can occur spontaneously after injury to the motor cortex; therefore, it will be interesting to determine which neural mechanisms underlie such recovery. Post-injury plasticity has been documented not only at the molecular, synaptic, cellular, network and systems levels in experimental animals but also many of these plasticity events have been correlated with alterations in cortical function using neuroimaging and stimulation techniques in humans. Basic phenomenology is now giving way to specific hypotheses regarding the mechanisms by which motor function is re-acquired after injury. In this review, we summarize some of the important new findings in this evolving field. Current Opinion in Neurobiology 2006, 16:638–644
Early demonstrations of post-injury plasticity Direct evidence that adjacent regions of the cortex are functionally altered after cortical injury can be traced to surface stimulation studies by Glees and Cole [1] in the early 1950s. After a focal injury to the primary motor cortex (M1) thumb representation, the damaged representation reappeared in the adjacent cortical territory. Studies in the somatosensory cortex by Jenkins et al. [2] seemed to parallel these results. However, using intracortical microstimulation (ICMS) techniques, somewhat different findings were observed in motor cortex by Nudo et al. in the 1990s [3,4]. Small, subtotal lesions were made in a portion of the M1 distal forelimb representation (DFL) in squirrel monkeys, and the animals were allowed to recover spontaneously (i.e. without the benefit of rehabilitative training) for several weeks. In contrast to earlier findings, the remaining DFL was reduced in size, giving way to expanded proximal representations [3]. Importantly, in animals that underwent rehabilitative training with the impaired limb, the DFL was preserved [4]. These results, in addition to others since then, have led to the conclusion that behavioral experience is a potent modulator of post-injury cortical plasticity.
New insights into the cellular and molecular mechanisms underlying local reorganization Although studies of representational maps in motor cortex are largely phenomenological, it is now clear that focal cortical injury results in specific neurophysiological and neuroanatomical changes in both adjacent and remote cortical tissue. Structural alterations occur in adult mammalian cortex as a consequence of experience [5]. Not surprisingly, focal cortical injury results in local neuroanatomical changes. Between three and 14 days after cortical infarction, rats demonstrate increased growthassociated protein 43 (GAP-43) immunoreactivity, suggesting neurite outgrowth in the peri-infarct region [6,7]. Between 14 and 60 days post-infarct, synaptophysin staining is significantly elevated, signifying increased synaptogenesis [6]. Although these studies used somewhat indirect measures, axonal sprouting has been demonstrated definitively in peri-infarct tissue in the rat barrel cortex using tract-tracing methods [8]. Local, surviving neurons become hyperexcitable, with associated upregulation of N-methyl D-aspartate (NMDA) receptors and downregulation of g-aminobutyric acid subtype A (GABAa) receptors [9]. Recent data in rodent models have now demonstrated that perilesional neurons (neurons in the intact cortical tissue adjacent to a focal injury) respond to injury with the www.sciencedirect.com
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expression of a specific and highly coordinated set of genes [10]. In a landmark study, Carmichael and coworkers [11] defined spatial and temporal patterns of expression profiles of growth-associated genes in the rat barrel field infarct model. They found that a focal infarct induces sequential waves of expression of growth-promoting genes throughout the period of axonal sprouting. Spatially, a growth-promoting region was distinguished in which growth-promoting proteins are increased, and growth-inhibitory proteins are decreased. This region corresponds to the zone of axonal sprouting found previously, and is distinct from the glial scar immediately adjacent to the infarct. It now appears that such neuronal growth programs are turned on early after focal infarct and might underlie the brain’s self-repair processes. A more recent study suggests that such growth programs are turned on even in aged brains, but demonstrate a unique temporal profile [12]. Exploiting this new understanding of cellular and molecular events following injury might provide new treatment approaches for recovery after CNS injury [13].
the M1 DFL and cutaneous inputs in the caudal portion [24]. Subtotal lesions of the rostral versus caudal sectors of the M1 DFL result in dissociable deficits related to the nature of the somatosensory inputs [25]. Thus, lesions in M1 do more than disrupt motor output pathways through corticofugal tracts. Such lesions effectively disconnect motor cortex from the somatosensory system.
Recent studies in human stroke survivors suggest that the intact, peri-infarct cortex plays a role in neurological recovery [14–16]. In an functional magnetic resonance imaging (fMRI) study, Cramer et al. [17] demonstrated that stroke survivors with good recovery show activity in the peri-infarct rim, although this activity is diminished compared with that in controls. In addition, after larger infarcts and in patients with poor behavioral outcome there appears to be a shift in activity towards the nonstroke hemisphere [18]. Furthermore, after several weeks of rehabilitation, motor representations in the injured hemisphere are enlarged relative to the initial post-injury map [19,20]. Also, constraint-induced movement therapy, in which goal-directed movement with the impaired hand is encouraged, produces a significant enlargement of the representation of the paretic limb in the injured hemisphere [21], closely paralleling results in non-human primates. Thus, a more normal fMRI pattern, in which the majority of neuronal activation is located in the hemisphere contralateral to the impaired hand (i.e., the injured hemisphere), seems to be associated with better recovery [22].
Although local axonal sprouting and synaptogenesis have been found in the peri-infarct cortex, until recently relatively little was known regarding changes in longrange intracortical networks after focal injury. We recently examined the intracortical connections of the reorganized PMv DFL after an MI DFL injury [29]. Quantitative examinations of the terminal fields of PMv intracortical fibers demonstrated little change, with the exception of one cortical area. Each animal that had sustained an injury to the M1 DFL displayed a remarkably consistent, dense cluster of PMv terminal boutons within the primary somatosensory cortex (S1) hand representation. This projection from PMv to S1 was sparse to non-existent prior to the lesion, and thus represents a novel intracortical connection between frontal and parietal cortex that was induced by the lesion. It has been known for some time that after cortical lesions in rats, corticostriatal fibers, which primarily connect various motor areas with the ipsilateral striatum, sprout from the intact (contralesional) cortex and terminate in the contralateral striatum, that is, on the side of the lesion [30]. Under certain conditions, the intact cortex can send novel projections to denervated portions of the red nucleus and spinal cord as well [31]. This recent study in nonhuman primates represents the first evidence of a major alteration of intracortical wiring patterns among different cortical fields (see Figure 1).
Plastic events remote from the cortical injury Mammalian brains are endowed with a rich intracortical network that enables reciprocal communication among the various sensory and motor areas. Injury to motor cortex causes potent disruption of integrated sensorimotor networks, resulting in loss of fine motor control [23]. For example, M1 normally receives substantial input from somatosensory cortex, conveying proprioceptive and cutaneous information that is presumably integrated with motor output commands in M1. These somatosensory inputs terminate in M1 in a segregated fashion, with proprioceptive inputs primarily in the rostral portion of www.sciencedirect.com
Even when the motor cortex is left intact after middle cerebral artery occlusion (MCAo), motor maps as defined by ICMS are disrupted, as recently demonstrated in rats by Gharbawie et al. [26]. The excitability of areas remote from the site of infarct is altered for significant periods of time after injury. Upregulation of NMDA receptors and downregulation of GABAa receptors has been observed in both the ipsilesional and the contralesional hemisphere [27]. Reorganization of motor maps also occurs in remote motor areas interconnected with the injured territory. For example, examination several months after a near-total lesion in the M1 DFL in squirrel monkeys shows that the ventral premotor cortex (PMv) DFL has expanded [28].
Sprouting of axons after cortical injury appears to be activity-dependent. After a focal ischemic infarct in rats, synchronous neuronal activity is a signal for post-infarct axonal sprouting to be initiated from the intact cortical hemisphere to peri-infarct cortex and the contralateral dorsal striatum [32]. It follows that differences in postinfarct behavioral experience will influence which areas Current Opinion in Neurobiology 2006, 16:638–644
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Figure 1
Schematic illustration of the effects of a unilateral cortical lesion (red circle) on spared cortical tissue as depicted in a nonhuman primate brain. Time-dependent neurophysiological and neuroanatomical alterations occur in the peri-infarct region (pink region surrounding lesion) and remote cortical areas. These include alteration in neurophysiological maps of motor representations, neurotransmitter receptor regulation, dendritic sprouting (not shown), local and remote axonal sprouting (short and long green arrows, respectively) and synaptogenesis (small black dots). These changes are accompanied by waves of growth-promoting and growth-inhibiting proteins (large white and black circles, respectively) that might trigger axonal sprouting and provide guidance to regenerating axons. Similar changes have been documented in the contralesional (undamaged) cortex, and are thought to be related to behavioral compensation in the ipsilesional forelimb, and possibly recovery of function by the contralesional forelimb. Recent studies suggest that lesion size is an important factor in determining the role of remote cortical plasticity. Concentric circles in PM denote expanded motor representations. Abbreviations: M1, primary motor cortex; PM, premotor cortex; S1, primary somatosensory cortex.
of cortex become targets for sprouting axons by differentially activating task-specific cortical areas. Unilateral damage to motor cortex in rats results in timedependent changes in the contralateral motor cortex [33]. Dendritic arborization occurs within about two weeks post-lesion, followed by an increase in synaptogenesis in layer V by about one month post-lesion. These changes are thought to be associated with behavioral compensation of the ipsilesional (less-affected) limb (Figure 1). Luke et al. [34] have demonstrated that after a unilateral lesion in the sensorimotor cortex, rats actually performed better with the ipsilesional limb than sham-operated controls, demonstrating this hyper-reliance, or extreme tendency to use the ipsilesional limb for balance, support, grasping and grooming. These rats also demonstrated increased synapses per neuron in layer V of motor cortex, and alterations in the morphology of synaptic boutons. Bury and Jones [35] provided evidence that compensatory hyper-reliance is related to denervation-induced changes rather than to increased forelimb use. Current Opinion in Neurobiology 2006, 16:638–644
In contrast to hyper-reliance and improved behavioral capacity with the ipsilesional limb demonstrated in rats, a growing number of studies in human stroke survivors with unilateral lesions has demonstrated impaired motor control of the ipsilesional distal forelimb [36–38]. Whether ipsilesional impairments result from disruption of callosal connections, ipsilateral corticospinal pathways, or pathways at some other level of the neuraxis is as yet unclear. Finally, although it is widely known that CNS injury increases neurogenesis, the role of neural stem cells and progenitor cells in recovery after injury has been unclear [39]. However, Zhang et al. [40] have demonstrated that after stroke in adult rats, immature neurons in the subventricular zone (SVZ) migrate in a chain-like structure towards the ischemic border in the striatum. Similar results were found by Komitova et al. [41]. Importantly, the results of Komitova et al. demonstrate that post-infarct environmental enrichment results in increased numbers of neural stem and/or progenitor cells and neurogenesis in the SVZ. Finally, using laser-capture microdissection, Liu et al. www.sciencedirect.com
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[42] analyzed gene expression profiles of endogenous SVZ progenitor cells in adult mice after MCAo. They found that SVZ cells after stroke expressed many genes involved in neurogenesis during embryonic development that are not present in normal SVZ cells. Thus, the notion that the ontogenetic environment is recapitulated after CNS injury is gaining support. Whether neural stem cells or progenitor cells become incorporated into cortical networks, or function as reservoirs for growth-promoting and growth-inhibiting proteins after stroke, is an important question for future research. Nonetheless, evidence for endogenous neurogenesis in the adult brain after injury, and the role of post-injury behavioral experience on this process, has prompted guarded optimism for proceeding with cellular therapies for neurological disorders, such as stroke [43].
tex lesion in rats was lessened by larger infarcts. One possible interpretation of these data is that if lesions are small, recovery of function can be accomplished largely by ipsilesional plasticity mechanisms. In that case, contralesional plasticity is more involved with increasing compensatory behaviors of the ipsilesional limb. By contrast, when lesions are large, ipsilesional plasticity mechanisms are limited, and contralesional plasticity is more involved with recovery of function of the contralesional limb. The current data are thus in accordance with previous studies suggesting that lesion size is a major factor involved in the initiation of the vicarious processes that purportedly plays a role in recovery from CNS lesions.
Re-emergence of the mass action principle
One of the most crucial questions that must be addressed by basic research is whether there is a period of time after cortical injury in which the remaining, intact system is more amenable to rehabilitative interventions, through drugs [49–51], electrical stimulation [52–54], behavior (physiotherapy) or some combination of treatments. The time-dependent cascade of events in peri-infarct and remote areas would suggest that neuroplasticity mechanisms have a long time course, although effects might diminish with time. Recent studies on animal models have begun to confirm that behavioral training after focal injury is most effective for restoring baseline behavioral performance, peri-infarct neurophysiological maps and enhanced neuroanatomical changes in the contralesional hemisphere when introduced within the first week after injury. In a rat MCAo model, Biernaskie [55] found that functional outcome and dendritic branching patterns in the contralesional hemisphere were attenuated when rehabilitation was initiated at 14 or 30 days post-infarct. After a focal cortical infarct in rats, Hsu and Jones [56] showed that delaying reach training for 25 days resulted in poorer behavioral recovery compared with that after training initiated at 4 days post-injury, but no differences in synaptic morphology in the contralesional hemisphere. In a nonhuman primate model of focal ischemia in the M1 DFL, Barbay et al. [57] showed that delayed training resulted in attenuated maintenance of the spared M1 DFL. However, previous studies demonstrated an exaggerated lesion after early excessive use of the impaired forelimb (by casting the unimpaired limb) in rats [58]. It is thought that such excessive use can exacerbate NMDA-mediated excitotoxicity, because the peri-infarct region is hyperexcitable after injury [59,60]. However, as these recent studies demonstrate, at least in conditions of moderate post-injury use, the early exaggeration of the lesion is not observed.
More than 75 years ago, Lashley [44,45] postulated his classic theories regarding the relationship between cerebral mass and behavioral change. According to his hypothesis, lesion volume is generally assumed to be associated with the severity of deficits, whereas lesion location is related to the specificity of deficits. Frost et al. [28] recently demonstrated that the PMv DFL expands linearly with respect to the size of the M1 injury. An interpretation formed on the basis of Lashley’s principles would suggest that after small M1 lesions, the surviving M1 tissue could potentially subserve the recovery of function. For example, after a small, subtotal lesion in the M1 DFL, the adjacent, intact DFL might be able to accommodate some degree of functional recovery, and thus, this local region might be the focus of reorganization of motor maps. After larger lesions, reorganization of the adjacent tissue might not suffice. As more and more of the M1 DFL is destroyed, there might no longer be sufficient distal representations (and associated descending fibers) to enable recovery to occur by this process. More distant forelimb motor representations, perhaps those in premotor cortical areas, or even the contralateral hemisphere, might then be engaged. Biernaskie et al. [46] have recently examined the effects of lesion size after MCAo on responses in the contralesional hemisphere. Following recovery, the role of the contralesional (undamaged) cortex in recovery was examined by microinjecting lidocaine to deactivate it. If the original deficits were reinstated, it would infer that the contralateral cortex participated in recovery. Reinstatement of behavioral deficits in the lesion-affected limb was only seen in animals with large infarcts. Smaller infarcts followed by lidocaine disruption didn’t seem to cause any effects, and the subjects behaved no differently than controls. Similar findings were found by Shanina et al. [47] using small photothrombotic lesions followed by a second lesion on the contralateral side. Finally, Hsu and Jones [48] recently demonstrated that the paradoxical hyperfunctionality of the ipsilesional forelimb after unilateral sensorimotor corwww.sciencedirect.com
Is there a sensitive period for post-injury plasticity and recovery potential?
Conclusions Injury to the motor cortex results in a potent disruption of coordinated networks and their underlying emergent properties, resulting in loss of fine motor control, and Current Opinion in Neurobiology 2006, 16:638–644
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the employment of compensatory movement strategies. It now appears that such a disruption to the cortical motor network triggers a major reassembly of inter- and intraareal cortical networks. Post-injury behavioral experience appears to be crucial to the reassembly of adaptive modules. Recent data suggest that the basic intracortical wiring plan is substantially altered. Waves of growthpromoting and growth-inhibiting proteins are expressed in the peri-infarct tissue and might initiate and guide novel axonal connections. This new information provides both a challenge and an opportunity to understand the inherent restorative mechanisms of the brain after stroke. If the brain possesses mechanisms for vicarious of function, we might be able to exploit such mechanisms to maximize recovery.
Update Although several recent studies have demonstrated that SVZ progenitor cells migrate to the site of injury, substantial growth of new neural tissue has not been observed. However, in a new study in rats, Kolb et al. [61] found that following cortical injury and subsequent therapeutic treatment, the injury cavity became filled with cells that stain positively for neuronal antigens. These events were correlated with significantly improved behavioral recovery. This study is remarkable as it validates the therapeutic potential for treatments that induce regeneration of new tissue after injury.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest
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caudal lesions in the primary motor cortex hand representation. J Neurophysiol 2005, 94:1312-1324. This study provides a behavioral correlate for the well-known segregation of cutaneous and proprioceptive inputs into the primary motor cortex in primates. 26. Gharbawie OA, Gonzalez CL, Williams PT, Kleim JA, Whishaw IQ: Middle cerebral artery (MCA) stroke produces dysfunction in adjacent motor cortex as detected by intracortical microstimulation in rats. Neuroscience 2005, 130:601-610. The authors demonstrate that after a MCAo, much of the motor cortex remains intact. However, microstimulation mapping reveals disrupted movement topography. 27. Redecker C, Luhmann HJ, Hagemann G, Fritschy JM, Witte OW: Differential downregulation of GABAA receptor subunits in widespread brain regions in the freeze-lesion model of focal cortical malformations. J Neurosci 2000, 20:5045-5053. 28. Frost SB, Barbay S, Friel KM, Plautz EJ, Nudo RJ: Reorganization of remote cortical regions after ischemic brain injury: a potential substrate for stroke recovery. J Neurophysiol 2003, 89:3205-3214. 29. Dancause N, Barbay S, Frost SB, Plautz EJ, Chen D, Zoubina EV, Stowe AM, Nudo RJ: Extensive cortical rewiring after brain injury. J Neurosci 2005, 25:10167-10179. This study demonstrates that after an ischemic lesion in the M1 DFL, axons in the spared PMv DFL ipsilateral to the lesion send novel projections to the ipsilateral S1, presumably re-establishing connections between cortical somatosensory and motor fields destroyed by the lesion. 30. Napieralski JA, Butler AK, Chesselet MF: Anatomical and functional evidence for lesion-specific sprouting of corticostriatal input in the adult rat. J Comp Neurol 1996, 373:484-497. 31. Chen P, Goldberg DE, Kolb B, Lanser M, Benowitz LI: Inosine induces axonal rewiring and improves behavioral outcome after stroke. Proc Natl Acad Sci USA 2002, 99:9031-9036. 32. Carmichael ST, Chesselet MF: Synchronous neuronal activity is a signal for axonal sprouting after cortical lesions in the adult. J Neurosci 2002, 22:6062-6070. 33. Jones TA, Schallert T: Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci 1994, 14:2140-2152. 34. Luke LM, Allred RP, Jones TA: Unilateral ischemic sensorimotor cortical damage induces contralesional synaptogenesis and enhances skilled reaching with the ipsilateral forelimb in adult male rats. Synapse 2004, 54:187-199. 35. Bury SD, Jones TA: Facilitation of motor skill learning by callosal denervation or forced forelimb use in adult rats. Behav Brain Res 2004, 150:43-53. 36. Hermsdorfer J, Laimgruber K, Kerkhoff G, Mai N, Goldenberg G: Effects of unilateral brain damage on grip selection, coordination, and kinematics of ipsilesional prehension. Exp Brain Res 1999, 128:41-51. 37. Yarosh CA, Hoffman DS, Strick PL: Deficits in movements of the wrist ipsilateral to a stroke in hemiparetic subjects. J Neurophysiol 2004, 92:3276-3285. 38. Quaney BM, Perera S, Maletsky R, Luchies CW, Nudo RJ: Impaired grip force modulation in the ipsilesional hand after unilateral middle cerebral artery stroke. Neurorehabil Neural Repair 2005, 19:338-349. 39. Komitova M, Johansson BB, Eriksson PS: On neural plasticity, new neurons and the postischemic milieu: an integrated view on experimental rehabilitation. Exp Neurol 2006, 199:42-55. 40. Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, Ho KL, Morshead C, Chopp M: Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab 2004, 24:441-448. 41. Komitova M, Mattsson B, Johansson BB, Eriksson PS: Enriched environment increases neural stem/progenitor cell www.sciencedirect.com
proliferation and neurogenesis in the subventricular zone of stroke-lesioned adult rats. Stroke 2005, 36:1278-1282. The authors demonstrate that after MCAo, rats display neural progenitor cells, putative neural stem cells and neural precursors in the SVZ. Environmental enrichment resulted in increased numbers of putative neural stem cells and neuroblasts that migrated in chain-like structures towards the infarct. 42. Liu XS, Zhang ZG, Zhang RL, Gregg S, Morris DC, Wang Y, Chopp M: Stroke induces gene profile changes associated with neurogenesis and angiogenesis in adult subventricular zone progenitor cells. J Cereb Blood Flow Metab 2006, In press, DOI:10.1038/sj.jcbfm.9600371. This study examined gene expression profiles of SVZ cells in the adult mouse after MCAo. Stroke SVZ cells expressed many genes thought to be involved in neurogenesis, and normally expressed during embryonic development. 43. Lindvall O, Kokaia Z: Stem cells for the treatment of neurological disorders. Nature 2006, 441:1094-1096. 44. Lashley K: Brain Mechanisms and Intelligence: A Quantitative Study of Injuries to the BrainUniversity of Chicago Press; 1929. 45. Lashley KS: Basic neural mechanisms in behavior. Psychol Rev 1930, 37:1-24. 46. Biernaskie J, Szymanska A, Windle V, Corbett D: Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats. Eur J Neurosci 2005, 21:989-999. After MCAo in rats, the authors tracked recovery of forelimb function for four weeks. Then lidocaine was microinjected over the contralesional motor cortex to determine if the original deficits would be reinstated. Reinstatement of deficits occurred only with large lesions. 47. Shanina EV, Schallert T, Witte OW, Redecker C: Behavioral recovery from unilateral photothrombotic infarcts of the forelimb sensorimotor cortex in rats: role of the contralateral cortex. Neuroscience 2006, 139:1495-1506. After a unilateral photothrombotic lesion in the rat sensorimotor cortex, a second lesion was made in the contralateral cortex at 2, 7 or 10 days after the first infarct. The second lesion only affected the forelimb contralateral to the second lesion, and did not reinstate the original deficit. 48. Hsu JE, Jones TA: Contralesional neural plasticity and functional changes in the less-affected forelimb after large and small cortical infarcts in rats. Exp Neurol 2006, 201:471-494. After small or large unilateral sensorimotor cortex lesions in rats, enhanced motor skill learning was found in the ipsilesional forelimb, and was accompanied by neuroplastic changes in the contralesional cortex. However, neuroplastic changes were muted after large lesions. Performance was best in rats with small lesions. 49. Barbay S, Zoubina EV, Dancause N, Frost SB, Eisner-Janowicz I, Stowe AM, Plautz EJ, Nudo RJ: A single injection of d-amphetamine facilitates improvements in motor training following a focal cortical infarct in squirrel monkeys. Neurorehabil Neural Repair 2006, in press. 50. Adkins DL, Jones TA: D-amphetamine enhances skilled reaching after ischemic cortical lesions in rats. Neurosci Lett 2005, 380:214-218. 51. Lee JK, Kim JE, Sivula M, Strittmatter SM: Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J Neurosci 2004, 24:6209-6217. 52. Adkins-Muir DL, Jones TA: Cortical electrical stimulation combined with rehabilitative training: enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol Res 2003, 25:780-788. 53. Kleim JA, Bruneau R, VandenBerg P, MacDonald E, Mulrooney R, Pocock D: Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol Res 2003, 25:789-793. 54. Teskey GC, Flynn C, Goertzen CD, Monfils MH, Young NA: Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat. Neurol Res 2003, 25:794-800. 55. Biernaskie J, Chernenko G, Corbett D: Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci 2004, 24:1245-1254. Current Opinion in Neurobiology 2006, 16:638–644
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56. Hsu JE, Jones TA: Time-sensitive enhancement of motor learning with the less-affected forelimb after unilateral sensorimotor cortex lesions in rats. Eur J Neurosci 2005, 22:2069-2080. After unilateral sensorimotor cortex lesions in rats, the authors examined the effects of post-lesion rehabilitative training initiated at four or 25 days post-injury. Early training, but not late training, enhanced behavioral performance. Both groups showed contralateral neuroplasticity, but there was no difference between the groups. 57. Barbay S, Plautz EJ, Friel KM, Frost SB, Dancause N, Stowe AM, Nudo RJ: Behavioral and neurophysiological effects of delayed training following a small ischemic infarct in primary motor cortex of squirrel monkeys. Exp Brain Res 2006, 169:106-116. In a neurophysiological mapping study after small, focal infarct in M1 of adult squirrel monkeys, the authors demonstrate that early, but not late, rehabilitative training results in preservation of adjacent forelimb representations. 58. Kozlowski DA, James DC, Schallert T: Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 1996, 16:4776-4786.
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59. Humm JL, Kozlowski DA, Bland ST, James DC, Schallert T: Use-dependent exaggeration of brain injury: is glutamate involved? Exp Neurol 1999, 157:349-358. 60. Neumann-Haefelin T, Witte OW: Periinfarct and remote excitability changes after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 2000, 20:45-52. 61. Kolb B, Morshead C, Gonzalez C, Kim M, Gregg C, Shingo T, Weiss S: Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. J Cereb Blood Flow Metab 2006, in press. In this exciting paper, the authors applied epidermal growth factor (EGF), erythropoietin (EPO) or both to rats up to seven days after MCAo. The remarkable results show that the cavity that normally appears after such a lesion became filled with cells that stain positively for neuronal antigens. The EGF and EPO treated animals improved significantly compared with control groups. Timing of treatment revealed a window of efficacy favoring early treatment in the first few days. Furthermore, the presence of EGF seemed to attract precursor cells to the site of the lesion. Finally, removal of the regenerated tissue appeared to reinstate the original deficit. This study provides evidence for direct links among growth factor activation of precursor cells, cortical tissue re-growth and functional recovery.
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