2012_abr - plasticity of cortical maps. multiple triggers for adaptive reorganization

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DOI: 10.1177/1073858410397894

2012 18: 133 originally published online 2 June 2011NeuroscientistChristian Xerri

Spinal Cord InjuryPlasticity of Cortical Maps: Multiple Triggers for Adaptive Reorganization following Brain Damage and

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Plasticity of Cortical Maps: Multiple Triggers for Adaptive Reorganization following Brain Damage and Spinal Cord Injury

Christian Xerri1

Abstract

Sensory and motor representations embedded in topographic cortical maps are use-dependent, dynamically maintained, and self-organizing functional mosaics that constitute idiosyncratic entities involved in perceptual and motor learning abilities. Studies of cortical map plasticity have substantiated the view that local reorganization of sensory and motor areas has great significance in recovery of function following brain damage or spinal cord injury. In addition, the transfer of function to distributed cortical areas and subcortical structures represents an adaptive strategy for functional compensation. There is a growing consensus that subject-environment interactions, by continuously refining the canvas of synaptic connectivity and reshaping the anatomical and functional architecture of neural circuits, promote adaptive behavior throughout life. Taking advantage of use-dependent neural plasticity, early initiated rehabilitative procedures improve the potential for recovery.

Keywords

somatosensory, motor, tactile, lesion, sensorimotor pathways, recovery, training, neuroplasticity

Over the past 30 years, extensive research has been con-ducted in the field of cortical plasticity, under the impetus of seminal studies on the somatosensory and motor sys-tems revealing that the cerebral cortex is a dynamic assem-bly of highly interconnected and spatially distributed neuronal networks whose morphological and functional connectivity is continuously modified by use-dependent plasticity mechanisms. Salient experience and intensive training lead to widespread organizational changes within the subcortical and cortical representations involved in sensory perception and motor control, thereby promoting new sensorimotor and cognitive skills. The study of corti-cal plasticity has greatly benefited from animal research tracking changes at levels ranging from synapses and single cells to neuronal populations and networks. Recent developments in multielectrode recording and optical imaging techniques allow for recording neuronal popula-tion activity in awake and behaving animals and thus in a relevant behavioral context. In addition, brain imaging studies in humans have opened up new avenues for study-ing functional reorganization in widely distributed corti-cal networks.

Both basic and clinical research has clearly estab-lished that disruption of neuronal networks after damage

to the peripheral or central nervous system triggers large-scale reorganization at multiple levels of the brain and spinal cord. This neural reorganization may under-pin functional recovery by engaging neuroplasticity mech-anisms guided by the subject’s experience. The present review examines current ideas and recent advances in animal and human research on somatosensory and motor map plasticity, shedding light on both local and distributed changes that take place following spinal cord injury or brain damage. Although the focus of this review is on cortical map plasticity, cortical changes are, to a large extent, shaped by interdependent modifications at all levels of the neuraxis. The relevance of use-dependent cortical map remodeling to neurorehabilitation practice is discussed.

The Neuroscientist18(2) 133 –148© The Author(s) 2012Reprints and permission: http://www. sagepub.com/journalsPermissions.navDOI: 10.1177/1073858410397894http://nro.sagepub.com

397894 NRO18210.1177/1073858410397894XerriThe Neuroscientist

1Integrative and Adaptive Neurosciences, University of Provence/CNRS, Marseille, France

Corresponding Author:Christian Xerri, Integrative and Adaptive Neurosciences, UMR 6149, University of Provence/CNRS, Pole 3C, case B, 3 Place Victor Hugo, 13331 Marseille cedex 03, France Email: [email protected]

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134 The Neuroscientist 18(2)

Cortical Reorganization following StrokeFrom perilesional Remodeling to Widespread Recruitment of New Areas

In 1950, using surface stimulation electrodes in macaques, Glees and Cole provided the first demonstration that after a focal lesion targeting the motor representation of the thumb in the primary motor cortex (M1), a new represen-tation emerged within a cortical zone adjacent to the lesion site. Later, an intracortical microstimulation study (Nudo and Milliken 1996) showed that after a subtotal ischemic lesion targeting the M1 hand representation in squirrel monkeys, the size of the remaining sectors of the hand map substantially decreased, giving way to expanding proximal motor representations. In contrast, using micro-electrode recordings in the owl monkey, Jenkins and oth-ers (1990) reported that, after a focal ischemic lesion that permanently destroyed the cutaneous representation of two digit tips in area 3b of S1, a new representation serv-ing the deprived skin surfaces emerged in the peri-infarct cortical sectors bordering the lesion. The discrepancies between these two studies may be accounted for by dif-ferences in the extent of the ischemic damage (smaller in the somatosensory cortex), as well as disuse of the affected hand after injury to the motor cortex. Brown and others (2009) used in vivo voltage-sensitive dye imaging (VSD) to track the spatiotemporal dynamics of somato-sensory information flow within the reorganized cortical areas following ischemic damage to the forelimb somato-sensory cortex to determine whether these areas processed sensory information with modified spatiotemporal pro-files. They showed that after an initial loss of responsive-ness, forelimb-evoked activation (mainly subthreshold depolarizations) emerged eight weeks after the lesion, first in the spared regions of the forelimb somatosensory area and then in neighboring peri-infarct hindlimb somatosen-sory areas, motor areas, and posteromedial retrosplenial cortex. The postlesion activations were found to be unchar-acteristically long lasting, presumably as a result of a decrease of GABAergic inhibition or increase of N-methyl-D-aspartate (NMDA) receptor expression. Interestingly, the remapped peri-infarct areas exhibited high levels of dendritic spine turnover, received more numerous con-nections from the retrosplenial cortex, and sent more projections to the striatum. In contrast, connectivity with the contralateral cortex and striatum, as well as the ipsi-lateral thalamus, was not modified.

Clinical investigations have confirmed that the spared, peri-infarct cortex may be involved in neurological recov-ery (Cramer and others 1997; Jaillard and others 2005; Teasell and Kalra 2005). But in these animal and clinical

studies, the recovery developed spontaneously, with no attempt being made to monitor sensorimotor activity over the postoperative time. A transcranial magnetic stimula-tion (TMS) study in stroke patients revealed a reduced excitability in the motor cortex near the site of the injury, with a decreased cortical representation of the impaired movements (Butefisch and others 2006; Traversa and others 1997). It is plausible that such an effect resulted from the injury-induced disuse of the affected limb.

After a focal cortical infarct damaging a substantial part of the forepaw representation in S1 in rats, we found that the cutaneous representations were surprisingly well preserved in the perilesional zones in the animals exposed to an enriched environment for three weeks, contrary to rats exposed to an impoverished environment in which the cutaneous representations were further deteriorated, relative to the initial postinjury map (Xerri and Zennou-Azogui 2003) (Fig. 1). Interestingly, after a single session of physiotherapy in stroke patients, the cortical motor output to the paretic muscles was significantly expanded, and manual dexterity was improved (Liepert and others 2000). The authors reported that both motor output map and motor function changes were partially reversed one day later. A number of studies have tackled the issue of the influence of training on cortical map plasticity fol-lowing brain damage. Nudo and Milliken (1996) con-firmed that, in contrast to untrained monkeys, in animals that benefited from a rehabilitative training involving the impaired forelimb, the undamaged sectors of the distal forelimb motor map were preserved or even increased in size. This finding suggests that the efficacy of local net-work neurons projecting to hand motoneurons was main-tained in these trained animals. Along the same lines, Ramanathan and others (2006) showed that rehabilita-tion training resulted in a significant increase in the motor representation of complex movement sequences following a focal motor cortex lesion. The extent of func-tional recovery was found to correlate with the magnitude of cortical remodeling and the ability to reexpress the movement patterns disrupted by the injury through intra-cortical microstimulation. The S1 areas that cooperate to mediate complex tactile functions are extensively inter-connected: Area 3b projects mainly to areas 1 and 2, whereas area 1 is also reciprocally connected with areas 2 and 3b. This network provides a substrate for distributed changes after a focal lesion affecting one of its constitu-ent areas. We used the same rehabilitative manual dexter-ity training as in Nudo’s study, but after a focal ischemic lesion that targeted the cutaneous representation of two digits in area 3b and hence impaired digital dexterity pri-marily engaging these digits. We found that new repre-sentations emerged several millimeters away from the lesion, in the neighboring cutaneous map of area 1.



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Emergent cutaneous representations were even recorded within adjacent sectors of the noncutaneous area 3a that for-merly received only proprioceptive inputs (Xerri and oth-ers 1996; Xerri and others 1999). The pattern of cortical changes across monkeys was found to be idiosyncratic, depending on individual digit use and retrieval strategies. Indeed, the skin surfaces that regained a representation in ectopic cortical regions were located on the fingers cru-cially engaged in the retrieval task during the rehabilita-tive training. Notably, as the manual dexterity recovered,

the animals gradually reused the digits that had regained a tactile sensitivity through this experience-dependent somatosensory map remodeling. Although the causal role of this cross-areal recruitment or emergence of tactile representation was not assessed in this study, the specificity of map changes strongly suggests that the experience-driven substitution occurring between dis-crete somatosensory areas was crucial in mediating resto-ration of fine sensorimotor regulation following the focal ischemic injury. Along the same lines, studies in

Figure 1. Effects of housing conditions on the reorganization of the somatotopic maps in S1 after focal ischemic injury. Representative forepaw maps obtained prior to and three weeks after the lesion induction in two rats housed in standard environments before the lesion and in impoverished or enriched environments after the lesion. The injured areas defined on the basis of neuronal recording are outlined on the prelesion maps (dashed lines). The cortical sectors electrophysiologically silent or displaying a decreased spontaneous activity with no evoked response are illustrated on the postlesion maps. Note that the forepaw representation was best preserved in the rat housed in an enriched environment, whereas a subsequent degradation was observed in the perilesion area in the rat housed in an impoverished environment (modified from Xerri and Zennou-Azogui 2003). Glabrous skin, hairy skin and non cutaneous or proprioceptive representational zones are shown with bright, dark and light colors, respectively.




stroke patients who benefited from rehabilitation for sev-eral weeks revealed a substantial recruitment of motor representations in the damaged hemisphere (Carey JR and others 2002; Traversa and others 1997; Liepert and others 1998).

Frost and colleagues (2003) have documented how an ischemic infarct resulting in a partial or complete destruc-tion of the M1 hand area affected the ventral premotor area (PMv), which sends intracortical projections to M1. The authors reported that lesions damaging more than 50% of the hand area in M1 induced an expansion of the PMv hand representation. The area of expansion could reach 50% in the case where the lesion affected the whole hand area. This compensatory reorganization in a distant premotor area after injury to M1 is presumed to provide a neural substrate for the postlesion recovery of fine manual skills. Five months after ischemic injury to the M1 hand area, cortical map reorganization in PMv was accompanied by a proliferation of PMv terminal fields and the occurrence of retrogradely labeled cell bodies within areas 1 and 2 of S1, presumably in the hand representation zone, suggesting the formation of new connections within these remote areas (Dancause and others 2005). Furthermore, alterations were found in the trajectories of axons origi-nating from PMv near the site of the lesion. The rewiring of corticocortical connections involved in the transmis-sion of new cutaneous and proprioceptive inputs between PMv and areas 1 and 2 may have played a compensatory role in the behavioral recovery documented by Frost and others (2003).

Electrophysiological cortical mapping has the advan-tage of probing cortical changes with high spatial resolu-tion. However, as the number of mapping sessions per animal is limited and the area that can be mapped is spa-tially restricted, this procedure does not allow assessment of the time course of changes over spatially distributed cortical areas. By contrast, brain imaging techniques, including TMS, fMRI, PET, electroencephalography (EEG), and magnetoencephalography (MEG) permit such an extensive exploration but with a more limited spatial res-olution. These brain imaging techniques have provided evidence that subcortical or cortical strokes induce distributed recruitment of anatomical and functionally interconnected regions in the ipsilateral or contralateral hemispheres assumed to sustain functional recovery in patients (Cholet and others 1991; Weder and Seitz 1994). For instance, in chronic stroke patients with focal subcor-tical damage, a temporary disruption of activity by tran-scranial magnetic stimulation in the premotor cortex of the ipsilesional hemisphere induced a deterioration in the use of the impaired limb (Werhahn and others 2003; Fridman and others 2004; Butefisch and others 2006), suggesting that the spared regions may have participated in behavioral recovery.

Typically, after a subcortical stroke, brain imaging studies have documented prominent activations in the unaffected hemisphere in the early stages of recovery, whereas cortical activations were found to shift toward the affected hemisphere in later stages (Cramer and oth-ers 1997; Marshall and others 2000; Carey JR and others 2002). Interestingly, in a longitudinal PET study, Calautti, Leroy, Guincestre, and Baron (2001) reported that two months after a unilateral striatocapsular infarction, over-activations took place bilaterally in the hand area of the primary sensorimotor cortices (SM1), as well as in the premotor (PM) and supplementary motor areas (SMAs) of the unaffected hemisphere during a thumb-to-index tapping task with the paretic hand. Overactivations remained but were less prominent in the affected hemisphere SM1 and PM at eight months, indicating a decrease in the recruitment of the bilateral motor networks and a signifi-cant change in the interhemispheric balance as the func-tional recovery progressed. However, new overactivations were found at eight months in some patients, in the left prefrontal areas, the putamen, and the premotor cortex, suggesting late-appearing compensatory reorganization. Despite relative homogeneity in the infarct size and loca-tion, as well as in clinical symptoms, idiosyncratic pat-terns of compensatory overactivation after injury to the corticospinal pathway revealed interindividual differ-ences in sensorimotor strategies and cognitive processes to reinstate the motor performance.

It is uncertain whether the contralesional activation early after stroke results from a functional compensation or simply reflects a loss of transcallosal inhibition. Furthermore, despite a relative consensus that functional recruitment of compensatory networks evolves over time as recovery progresses, there is no general agreement as to whether the contralesional activations sustain a better or faster recovery (see Loubinoux and others 2007). For example, an fMRI study in stroke patients with hemiparesis caused by infarctions in the corticospinal tract showed that recovery of the paretic hand was associated with a rela-tive increase in activity in the contralateral (ipsilesional) SMC compared with the ipsilateral (contralesional) SMC, as well as a relative decrease in the prefrontal and the ipsilateral posterior parietal regions (Marshall and others 2000). In a PET analysis, Calautti, Leroy, Guincestre, Marie, and others (2001) corroborated these findings by assessing changes in motor abilities (thumb-to-index tap-ping) and laterality index in patients with subcortical, striatocapsular infarction. They found that S1-M1 activa-tion tended to shift toward the unaffected hemisphere over time but that this shift was associated with less com-plete functional recovery. A longitudinal fMRI explora-tion in a rat model of stroke that induced acute dysfunction of the contralateral forelimb indicated that functional recovery was related to a decreased involvement of the



Xerri 137

contralesional hemisphere and a gradual restoration of responses in the peri-infarction zones (Dijkhuizen and others 2001). Consistent with this finding, other studies have shown that the best recovery for paresis was achieved if the sensorimotor network normally subserving the impaired functions regained functional activity and was reintegrated in the active neural network (Calautti and Baron 2003; Fujii and Nakada 2003; Loubinoux and others 2003; Ward and others 2006; Calautti and others 2007; Loubinoux and others 2007). Interestingly, fMRI data showed that an early recruitment of the supplemen-tary motor area and ipsilesional inferior Brodmann area (BA) 40 was positively correlated with motor recov-ery, whereas activation of the prefrontal cortex and parietal cortex in the contralesional hemisphere pre-dicted a slower and less complete recovery (Loubinoux and others 2003).

Overall, the bulk of evidence indicates that within the first few days to weeks of the recovery process, an increased activity takes place in motor areas bilaterally but primarily in the contralesional hemisphere. Then, in a later stage of the recovery process, spanning three to six months, contralesional activation is often reduced, whereas some degree of refocusing of activation occurs in perilesional and other spared motor regions in the injured hemisphere (Marshall and others 2000; Nhan and others 2004; Ward and others 2004; Carey LM and others 2006). All of these remote changes may be accounted for by sustained alterations of the neuronal excitability of distant areas following cortical damage, through NMDA receptor up-regulation and gamma-aminobutyric acid A (GABA

A) receptor down-regulation, which has been doc-

umented in both the ipsilesional and contralesional hemi-spheres (Witte and Stoll 1997; Witte 1998; Redecker and others 2002).

Rehabilitation-induced improvements have been asso-ciated with contralesional hemisphere activation (Schaechter and others 2002; Dechaumont and others 2004; Kimberley and others 2004). Furthermore, Loubinoux and col-leagues (2007) investigated prognosis factors indicative of the quality of the outcome in the case of capsular lesions and observed that the higher the early activation in the ipsilesional BA 4, S1, and insula, the better the recovery one year later. Their findings also suggested that there is a benefit associated with increasing ipsilesional M1 activity shortly after stroke, as a rehabilitative approach in mildly impaired patients. Interestingly, a recent fMRI study indicates that the pattern of brain activation present in the first few days after stroke correlates with subse-quent motor recovery, suggesting that rehabilitative inter-vention may facilitate the recovery process by targeting the structures engaged early on after stroke (Marshall and others 2009).

Postlesion Training Exerts Protective Effects following Cortical Damage, but Overuse during an Early Critical Period Is HarmfulThe elucidation of use-dependent cortical reorganization and recovery-associated plastic changes has inspired post-stroke motor rehabilitation procedures. It has been argued that behavioral recovery may be enhanced if compensa-tory strategies leading to learned nonuse and presumably to disadvantageous cortical reorganization following brain injury are counteracted (Levere 1980; Taub and others 1994). Therefore, constraint-induced movement therapy (CIMT) involving a forced use of the impaired limb in animals and stroke patients has received particular atten-tion. Indeed, relatively rapid beneficial effects of CIMT on recovery have been reported (Wolf and others 1989; Taub and others 1993; van der Lee and others 1999; Wolf and others 2006; Myint and others 2008).

Early implementation of CIMT therapy was thought to be beneficial, as early use of the affected limb may mini-mize or prevent learned nonuse. In addition, early train-ing of the impaired limb is likely to promote and optimize postlesion neuroplasticity. However, initiation of CIMT (Kozlowski and others 1996) or early training without immobilization of the intact forelimb (Risedal and others 1999) in the very early stage of focal ischemia was also shown to increase lesion volume and impede motor recov-ery of the affected limb in the rat. In contrast, constrain-ing the intact limb (Humm and others 1998) or training the affected limb seven days after the onset of brain dam-age resulted in the best performances and did not induce enlarged cortical infarct volumes. These studies raised the concern that an early postlesion vulnerable period may exist. The involvement of NMDA receptors in this use-dependent exacerbation of brain injury has been sug-gested (Humm and others 1999). As indicated above, after a focal ischemic lesion to the forepaw area in S1, cortical recordings in rats exposed to an impoverished environment for three weeks showed an expansion of the ischemic zone as well as a compression and fragmenta-tion of the remaining cutaneous forepaw representation within the spared cortical sectors surrounding the lesion. In contrast, in animals housed in enriched conditions, the ischemic zone did not grow, and only a limited compres-sion of the forepaw map was found, with a preservation of most representational sectors (Xerri and Zennou-Azogui 2003). We thus postulated that whereas intensive training within a critical time window after focal cortical ischemia may be detrimental for the peri-infarct tissue and consequently for behavioral recovery, moderate stimulation initiated early after the lesion could have pro-tective effects on peri-infarct cortical representations. In




fact, we showed that early cutaneous stimulation deliv-ered to the forepaw for short daily periods during the first postlesion week was sufficient to induce the preservation effects reported in the enriched rats. In addition, we observed that these effects were less pronounced when a similar stimulation regimen was delivered during the sec-ond postlesion week, whereas a lack of stimulation resulted in the outward expansion of the ischemic zone along with the severe loss of cortical representations reported in previous studies. Furthermore, the preserva-tion effect within the forepaw map appeared to be specifi-cally related to the stimulated skin surfaces (Fig. 2).

A direct causal relationship between structural or func-tional changes in the brain and improvement of sensorim-otor abilities has yet to be demonstrated. Nevertheless, using TMS, Liepert and others (1998, 2000) were the first to show that CIMT enlarged the initially smaller-than-normal ipsilesional motor map of the paretic hand in stroke patients, whereas opposite changes were recorded in the contralesional motor map, thus rebalancing the hand motor representations between the two hemispheres. Shifts of the center of the output map in the affected hemisphere were compatible with the recruitment of adja-cent brain areas. In addition, the amount of map expansion was found to correlate with motor ability improvement (Liepert and others 1998; Sawaki and others 2008), con-sistent with the findings from nonhuman primate studies described in this review. Six months after the CIMT treatment, motor performance remained at a high level, whereas the cortical area sizes in the two hemispheres became almost identical, indicating a return toward a nor-mal balance of interhemisphere excitability (Liepert and others 2000). After combining restraint of the unaffected limb with gradual exercises for the affected limb in stroke patients, the extent of improvement in hand function was found to be correlated with increases in fMRI activ-ity in the premotor and secondary somatosensory corti-ces contralateral to the affected hand, as well as in superior posterior regions of the cerebellar hemispheres bilaterally (Johansen-Berg and others 2002). These find-ings suggest that the therapy-induced recruitment in sen-sorimotor regions was associated with successful motor rehabilitation.

It is noteworthy that the degree of change in contrale-sional M1 activation in stroke patients during the early period of CIMT has predictive value for the motor recov-ery achieved by the end of therapy (Dong and others 2006). However, changes in brain activation related to CIMT-induced motor improvement vary over time and among individual stroke patients. Differences in the brain reorganization patterns, which may underlie CIMT-induced motor improvement, are very likely accounted for by differences in the infarct and size and whether the

white matter is damaged or not (Hamzei and others 2006). There is, however, a controversy relating to whether the extent of injury to the corticospinal tract (CST) affects the magnitude of motor gain in response to CIMT (Kuhnke and others 2008; Gauthier and others 2009).

Cortical Reorganization following Spinal Cord InjuryRemapping of Cortical Area through Changes in Ascending and Descending Pathways

Spinal cord injuries (SCIs) cause local neuronal and glial cell death and disruption of ascending as well as descend-ing axon pathways, thus resulting in varying degrees of paralysis, sensory loss, and sphincter disturbance below the lesion level. The majority of SCI in humans occurs at cervical levels (Jackson and others 2004) and severely impairs hands and forelimbs. As spinal cord lesions rarely cause complete transection (Raineteau and Schwab 2001), the spared fiber tracts determine the functions that will be preserved and provide the basis for functional restoration. The potential for such improvement may be significant even with a small amount of pathway sparing. Substantial central nervous system reorganization is possible because cortical and subcortical structures as well as much of the local spinal cord circuitry remain intact and partially interconnected through spared axonal pathways. In addi-tion to plastic changes of neural circuits within the spinal cord (Sasaki and others 2004), adaptive modifications take place in subcortical and cortical structures.

The sensory and motor cortices undergo extensive reorganization following SCI, as shown in rat and human studies (Raineteau and Schwab 2001; Kaas and others 2008). Several months after unilateral dorsal column sec-tion at cervical (C3/C4) levels, the deprived hand region of the somatosensory map in area 3b of S1 regained responsiveness through stimulation of the facial cutane-ous surfaces (Jain and others 1997). Thus, S1 cortical neurons became responsive to cutaneous inputs conveyed through the trigeminal pathway, which was unaffected by the spinal cord section (Jain and others 1997). Indeed, inputs from the face were found to sprout in the medulla from the trigeminal nucleus into the denervated cuneate nucleus (Jain and others 2000). The spared spinothalamic pathway was thus unable to spontaneously reactivate the cortical map and hence to contribute to functional recov-ery. When a small portion of the dorsal column nuclei was preserved, the corresponding inputs were able to expand within the deprived cortex (Jain and others 2000). An fMRI study in rats showed that after midthoracic spi-nal cord transection, deafferented hindlimb territories in



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Figure 2. Selective effects of tactile stimulation on the remodeling of the somatotopic maps in S1 after focal ischemic injury. Individual pre- and postlesion maps recorded in rats whose contralateral forepaw was either not stimulated or stimulated during the first or second postlesion week on a rotating textured cylinder. Stimulations were delivered on the glabrous skin of digits over two daily sessions of 30 minutes interrupted by a 15-minute resting period. Representation of the stimulated skin surfaces was less degraded when tactile stimulations were delivered over the first postlesion week.




S1 exhibited responses to electrical stimulation of the unaffected forepaw that were presumably mediated by both spinothalamic and dorsal column nuclei pathways (Endo and others 2007). Reallocation of the deprived cor-tical area was found to occur as early as three days after the lesion. PET findings in both hemiplegic and paraple-gic patients revealed an expansion of the motor cortical hand area toward the cortical leg area (Bruehlmeier and others 1998). Similarly, stimulation of the motor cortical areas with injured descending axons produces move-ments of body parts adjacent to those formerly repre-sented within the disturbed areas (Huntley 1997).

The possibility that cortical maps undergo adaptive remodeling following partial SCI has received little atten-tion until recently and thus remains to be thoroughly investigated. In paraplegic patients, movements of the contralesional fingers have been shown to evoke increased activation in the corresponding M1 cortex (Curt and oth-ers 2002), possibly related to the observation that the con-tralesional limbs are used extensively to compensate for dysfunctional ipsilesional limbs (Tattersall and Turner 2000). Ghosh and others (2009) investigated the somato-sensory representation and corticospinal projections of the nondeprived, ipsilesional cortex, which was assumed to participate in the spontaneous recovery of the ipsilesional hindlimbs following C3/4 lateral hemisection in adult rats. Combining blood oxygenation level–dependent functional magnetic resonance (BOLD fMRI) imaging, VSD imaging, and anatomical tracing of the CST in the intact cortex, they focused on the reorganization of the sensorimotor cortical representations correlated with forelimb overuse and hindlimb recovery. In keeping with previous findings regarding experience-dependent plas-ticity of cortical maps, their BOLD fMRI and VSD data showed that the representation of the unimpaired, over-used forepaw, in the ipsilesional cortex, was enhanced by 30% to 70% one month after injury and about 75% at three months. This expansion was mainly seen in the forepaw motor area, thus suggesting increased sensorimotor inter-actions through strengthened horizontal interconnections (see Rioult-Pedotti and others 1998). However, this study does not allow determining whether this cortical change was accounted for by intensive use itself or acquisition of new movement strategies after the lesion. VSD imaging in intact animals showed that electrical stimulation of the forepaw, which activated both tactile and proprioceptive pathways, induced early responses within the contralat-eral sensorimotor areas as well as delayed and weaker activation in the ipsilateral motor area. Somatosensory rep-resentation of the forepaw was strictly controlateral, whereas cortical activation was bilateral in the sensorimotor areas in response to hindlimb stimulation, although contra-lateral activation was found to be faster and stronger. Three months after the hemisection, a substantial but delayed

activation was recorded in the ipsilateral nondeprived sensorimotor cortex after stimulation of the ipsilesional hindpaw. This activation was presumably mediated by the injury-spared spinothalamic pathway (Giesler and others 1976). By contrast, and similarly to the intact rat, no response was evoked by stimulation of the ipsile-sional forepaw. Interestingly, anterograde tract tracing from the nondeprived cortex revealed a sprouting of intact-side CST axons that recrossed the midline, thus innervating lumbar and cervical spinal cord segments below the injury. Retrograde tracing indicated that the origin of the sprouting was the ipsilateral caudal and ros-tral forelimb areas of S1 and the secondary somatosen-sory area (S2). The somatotopic similarity of this ipsilateral projection with the contralateral CST in intact rat indicated that this new projection remodeled the ipsi-lateral forelimb map. However, the lack of recovery of the ipsilesional forelimb in skilled walking may be, at least partly, accounted for by the absence of somatosen-sory input from the forepaw to the ipsilesional cortex from which the new corticospinal representation origi-nated. In addition, because the electrical stimulation acti-vated both tactile and proprioceptive receptors, and given that VSD responses are mainly generated by subthreshold inputs, the sensory modality involved in the cortical map changes documented in this study remains contentious.

We noted earlier that deprived sectors of the primary somatosensory cortex (S1) had not regained neuronal responsiveness to natural cutaneous stimulation in rats and monkeys following high cervical lesions damaging the dorsal column pathway (Jain and others 1995; Jain and others 1997). However, when cortical responses were evoked via both the spinothalamic and dorsal column pathways by electrical stimulation (Chang and Shyu 2001; Lilja and others 2006), as in the fMRI study by Endo and others (2007), the sensory-deprived hindlimb territory was found to be invaded by the adjacent fore-limb representation following complete spinal cord transection at the midthoracic level. In line with previous studies (Fouad and others 2001; Weidner and others 2001; Bareyre and others 2004), we recently reported a spontaneous, although incomplete, recovery of fore- and hindlimb motor skills in rats subjected to spinal cord hemisection between C4 and C5 (Martinez and others 2009) (Fig. 3A). We found that without training, the animals exhibited an enduring impairment of forepaw tactile sensitivity (Fig. 3B) that was consistent with the loss of activation in the contralesional forepaw cortical map within the S1 cortex (Fig. 4A,B) (see also Onifer and others 2005; Ghosh and others 2009). In agreement with previous reports (Eidelberg and others 1986; Kuhtz-Buschbeck and others 1996; Fouad and others 2000; Gulino and others 2007), we showed that in the rats subjected to a sensorimotor rehabilitative procedure,



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through induced locomotion on various tactile textures, recovery of quadrupedal locomotion was greatly improved within a few weeks (Fig. 3A). A more gradual compensa-tion of tactile deficits was observed over a three-month period (Fig. 3B). This tactile recovery was accompanied by a reemergence of formerly abolished somatosensory-evoked responses in the deprived forepaw cortical

Figure 3. Effects of sensorimotor training on recovery of deficits in locomotor and tactile abilities following cervical spinal cord injury (SCI). (A) Initial deficits of forelimb locomotor capacities assessed with ladder walking test were similar in the lesioned (L) and lesioned-trained (LT) rats subjected to locomotion on carpets of different textures and roughnesses imposed by a carousel (linear speed: 8 m/min). LT rats’ sensorimotor capacities improved faster and were more completely restored than those of the L rats, from the 14th postlesion day (P < .00005). (B) The L rats did not show any improvement in tactile abilities assessed by the adhesive removal test over the two-month postlesion period. In contrast, the LT rats’ tactile scores gradually improved between days 14 and 56 (P < .00002). Nevertheless, the LT rats’ locomotor and tactile scores remained lower than those of the Sh (sham) group, at the end of the time period examined (P < .005). Statistical differences between the Sh versus L and LT animals are shown by # and between the L and LT rats by * symbols. Modified from Martinez and others (2009).

area. Notably, the recovered tactile sensitivity was correlated with the areal extent of restored cutaneous representations serving the forepaw ipsilateral to the hemisection (Fig. 4C,D). We found that the reactivated forepaw areas were somatotopically organized in these trained rats. Therefore, we speculated that training-induced synaptic reinforcement or synaptogenesis within preexisting networks allowed alternative sensory path-ways, presumably the spinothalamic fibers crossing below the site of injury and conveying somatosensory inputs from the affected forepaw, to maintain the somatotopic distribution of dorsal root fibers entering the spinal cord. Optimization of somatosensory stimuli improving the efficacy of the cortical afferent signals transmitted through residual and/or new afferent path-ways should ameliorate stimulation-based therapeutic procedures aimed at restoring lost sensation and motor skills. Nevertheless, in SCI patients requiring intensive care and often suffering from depression, early reha-bilitation is difficult to perform, and recovery may thus be delayed.

Cerebral changes after SCI are not restricted to pri-mary somatosensory or motor areas with somatotopically organized ascending or descending pathways. Indeed, reorganization involves more widespread areas than pre-viously thought. For example, the expansion of the face representation in the deprived 3b hand area after unilat-eral transection of the dorsal columns described previ-ously was also found in the secondary somatosensory and parietal ventral cortices, which retained access to spino-thalamic inputs after the lesion (Tandon and others 2009). In addition, movement of the intact upper limb was found to evoke increased fMRI activation of motor representa-tions in the parietal cortex, supplementary motor area, and cerebellum in paraplegic patients (Curt and others 2002). In hemiplegic or paraplegic patients, PET data revealed not only an expansion of the cortical hand area toward the cortical leg area but also an enhanced bilateral activation of the thalamus and cerebellum (Bruehlmeier and others 1998). Changes in the activation pattern of motor-related cortical areas over the postlesion period may reflect the recruitment of a new or reorganized net-work compensating for functional deficits after SCI. Nishimura and others (2007) combined PET scanning and reversible pharmacological inactivation of motor cortical regions to assess changes in brain activity asso-ciated with recovery of visually guided reach and preci-sion grip in macaque monkeys subjected to unilateral transection of the lateral corticospinal tract at the C4/C5 spinal cord segments. This lesion, which was rostral to the segments where hand motoneurons are located, spared a large proportion of indirect corticomotoneuroral pathways, except for those mediated by segmental inter-neurons. Their findings suggest that cortical changes




Figure 4. Alteration of the S1 somatotopic forepaw map and recovery of tactile abilities induced by sensorimotor training following cervical spinal cord unilateral hemisection. Individual cortical maps were obtained from sham (A), lesioned (B), and lesioned-trained (C, D) rats. Potentials evoked from somatosensory natural stimulation were abolished in the forepaw area of the lesioned rats, whereas somatotopically organized cutaneous and proprioceptive responses reemerged in the lesioned-trained rats two months after the spinal cord contralateral hemisection. Note the expansion of the lower lip representation (chin) within the adjacent forepaw cortical sectors in the lesioned rat (B). The time to remove a strip of adhesive tape applied on the plantar surface of each forepaw was taken as an indicator of tactile sensitivity. An index of asymmetry between the ipsi- and contralesional forepaw was calculated. Note the correlation between the forepaw tactile ability and the extent of restored cutaneous forepaw representation (E); the smaller the asymmetry score, the larger the cutaneous area in the cortical map. Scale bar: 1 mm. The dashed lines encompass the cortical area mapped with microelectrode recordings. Modified from Martinez and others (2009).



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depend on the recovery stage. Indeed, the functional res-toration was accompanied by increased activity in the ipsi- and contralateral M1 cortices and the vermis of the cerebellar cortex during the first two weeks postlesion. Enhanced activation was recorded in more extensive regions of the contralesional M1 and ipsilesional PMv cortex during the late stage (more than three months postlesion). As brain imaging studies do not prove cau-sality between changes in the pattern of cortical network activation and functional recovery, Nishimura and others (2007) applied focal reversible inactivation of the digit regions of M1 and PMv cortices by microinjections of muscimol, a GABA

A receptor antagonist. They then

assessed the finger dexterity of the ipsilesional hand prior to the SCI and at the early and late recovery stages. The severe deficits in finger movements induced by this bio-chemical inactivation of M1 and PMv areas corroborated the time-dependent contributions of these areas revealed by the PET findings. The authors proposed the involve-ment of indirect corticomotoneuronal pathways from contralateral and ispilateral M1 (through callosal fibers or via subcortical pathways) to C3/C4 propriospinal motoneurons. The corresponding axons passing through the ventral part of the lateral funiculus and driving digit motoneurons or originating from other cortical areas inhibited in the intact state would be disinhibited follow-ing damage to the ipsilateral direct corticomotoneuronal pathway and thus would contribute to the recovery of hand and arm movements. The observation of mirror hand movement on the intact side during the early recov-ery stage is consistent with the possible involvement of the disinhibited ipsilesional M1. As recovery pro-gresses, recruitment of the contralesional M1 and bilat-eral PMv underpinned by plastic changes of the neural circuits would ensure more stable motor control, whereas the contribution of the ipsilesional M1 would decrease with a return of the former inhibition. Further experi-ments are needed to provide a clear picture of the neural pathways assumed to mediate the functional recovery. In the study by Nishimura and others, finger dexterity spon-taneously recovered within a few months. Nevertheless, the precision grip task used to assess the recovery resulted in a form of postoperative training. Therefore, the respec-tive contribution of controlled rehabilitative training ver-sus task-dependent exercise to the functional compensation after SCI needs to be clarified.

Implications of Plastic Changes for Neurorehabilitation following SCIPlasticity of the somatosensory and motor maps is a mul-tilevel process that operates in the cortex, subcortical nuclei of ascending or descending pathways, and spinal cord. The sudden loss of function following brain damage or

spinal cord injury appears to trigger neuroplasticity mechanisms. As spinal cord lesions typically result in the formation of an astroglial barrier, axonal regeneration is not likely to occur. In contrast, use-dependent modula-tion of sensory and motor signals can potentially reshape the anatomical and functional architecture of vicariant or substitutive neural circuits. The so-called spontaneous reorganization of somatosensory and motor systems refers to a situation in which no rehabilitation procedure is used to boost the experience-dependent neuroplasticity mech-anisms such as collateral sprouting of spared fibers; growth of new dendritic spines, known as synaptic target sites; synapse turnover; and changes in synaptic efficacy, which promote compensation through alternate pathways and connections.

There is ample evidence that enriched housing and sen-sorimotor experience ameliorate functional outcomes after various CNS lesions, including SCI (Ohlsson and Johansson 1995; Lankhorst and others 2001; Koopmans and others 2006), and elicit substantial changes in dendritic spine shape and density as well as synaptic structures and neu-rochemistry (Globus and others 1973; for review, see Holtmaat and Svoboda 2009). Spine morphology being a critical determinant of synaptic function (Yuste and others 2000), it is relevant that remodeling of dendritic spine structures occurs in the motor cortex after SCI (Kim and others 2006). It is thus important to underscore that follow-ing SCI, environmental enrichment was found to promote dendritic spine morphological changes assumed to facili-tate the maturation and efficiency of synaptic structures within the motor cortex (Kim and others 2008).

Neuroplastic changes in ascending pathways have received little attention compared to those in descending pathways. It has been shown in monkeys that substantial recovery of manual dexterity occurs even if very few sensory afferents from the hand are preserved after the ascending afferents in the dorsal columns of the spinal cord were severed at a high cervical level. The lesion leaves intact only a few branches of afferents from the hand in the dorsal column pathway while preserving afferent terminations on neurons in the spinal cord and the spinothalamic pathways. In such a case, skilled use of the hand is strongly impaired but recovers gradually over a few weeks, as the spared afferents from the hand sprouted in the brainstem relay nuclei and come to activate larger sectors of hand representation in the S1 cortex (Jain and others 2000).

Remapping of the motor cortex after SCI reflects changes in CST fibers and neural connectivity modifying corticospinal influences onto spinal motoneurons. However, other descending pathways, such as the rubrospinal (Raineteau and others 2002) or reticulospinal (Ballermann and Fouad 2006) tracts, which have been shown to rein-nervate neuronal targets within the spinal cord, are likely




to contribute to functional recovery. For example, sprout-ing of the reticulospinal fibers in the lumbar segments of the spinal cord was observed in animals exhibiting locomotor restoration (Ballermann and Fouad 2006). Nevertheless, sprouting of spared corticospinal fibers lead-ing to formation of new synapses and providing alternate transmission streams from the cortex to neuronal targets in the spinal cord (Maier and Schwab 2006; Fouad and Tse 2008) is very likely the best candidate to mediate behavioral restoration. Spontaneous collateral sprouting of CST fibers has been demonstrated in the cervical seg-ments of the spinal cord following a thoracic dorsal hemi-section (Fouad and others 2001). This anatomical rewiring promoted the formation of new intraspinal circuits in adult rats (Courtine and others 2008). Furthermore, after incomplete thoracic spinal cord injury in rats, transected hindlimb CST axons were found to sprout into the cervi-cal gray matter and establish connections with short and long propriospinal neurons (PSNs; Bareyre and others 2004). Interestingly, 12 weeks after the injury, synaptic contacts with long PSNs that bridged the lesion were maintained, whereas contacts with short PSNs that did not bridge the lesion were lost. Long PSNs extended their ter-minal arborization onto lumbar motor neurons, thereby creating a new intraspinal circuit relaying cortical input to its original spinal targets. Microstimulation of the hindlimb motor cortex and placing reaction to light touch of the foot after a secondary CST lesion above the cervical reorganization in rats that had recovered suggested that recovery was mediated, at least in part, by the CST sprout-ing and formation of new circuits. Cortical labeling fol-lowing intramuscular injection of VRP, a retrograde transynaptic tracer, showed an increase in the percentage of hindlimb-connected cortical neurons in ectopic loca-tions, in the forelimb area or outside the motor areas, hence revealing a substantial reorganization of cortical motor maps. Therefore, after incomplete spinal cord injury, exten-sive spontaneous remodeling occurs, based on axonal sprout formation, stabilization, and elimination. A crucial ques-tion for rehabilitation in humans is whether the refinement of the newly formed contacts through a selective stabiliza-tion of those that established functionally appropriate connections is driven by experience-dependent plasticity mechanisms. Sprouting of the spared ventral CST follow-ing interruption of the dorsal corticospinal tract has been shown to parallel recovery of skilled reaching (Weidner and others 2001). Furthermore, the functional role of the sprouting has been confirmed by the reinstatement of behavioral deficits after the sectioning of the ventral CST. Interestingly, a study in rats subjected to immobilization of the unimpaired forelimb in a cast, immediately after lesion of the CST, revealed the growth of intact CST across the midline where axon collaterals extended fibers toward the ventral and dorsal horn and exhibited increased

innervation density in response to forced use of the deafferented limb (Maier and others 2008). Growth and arborization of CST fibers were accompanied by a full res-toration of forepaw sensorimotor skills on an irregular horizontal ladder, whereas animals that could not use their affected limb remained severely impaired. In addition, gene chip analysis of the denervated ventral horn revealed that forced-limb use led to the up-regulation of mRNAs involved in neuronal outgrowth, cytoskeletal rearrange-ments, adhesion and guidance, and synapse formation in the denervated cervical gray matter.

Importantly, reaching training has been shown to increase collateral sprouting of lesioned CST fibers ros-tral to the injury (Girgis and others 2007). This study revealed that the improvement on the trained task involv-ing reaching and grasping did not transfer onto another task requiring a related sensorimotor ability, such as walking on a horizontal ladder, but rather caused further impairment. Similarly, patients with incomplete SCI and trained to walk forward on a treadmill improved as a result of this training but displayed increased difficulties in walking backwards (Grasso and others 2004). Girgis and others (2007) suggested that competition between unused pathways and the spared descending fibers con-trolling fine motor movements strengthened by the training accounted for this detrimental effect. This task-dependent effect may be of particular relevance to the clinical appli-cation of rehabilitative training. Using a range of tasks might be less detrimental than a specific training but also less efficient in promoting the recovery of the impaired sensorimotor ability.

This section has focused on the mechanisms underly-ing changes in somatosensory and motor pathways. However, neuroplastic changes that facilitate functional recovery also promote structural and functional rearrange-ment of intraspinal neuronal networks (for review, see Rossignol and others 2008).

ConclusionsThis review has pointed out some aspects of the com-plexity of neural reorganization after brain damage and SCI. Because of this complexity, further investigations are required to clarify the temporal and spatial progres-sion of cortical representational changes as functional recovery proceeds. Examination of connections within and between maps is of particular relevance to decipher the anatomical and functional interplay underlying adap-tive postlesion reorganization. Understanding the dynam-ics of cortical remapping is also relevant for optimizing the impact of therapy on recovery. As recovery continues for months, therapeutic exercise has become a crucial part of rehabilitation intervention. Animal research has revealed that the onset and intensity of postlesion training are to



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be considered carefully in rehabilitative interventions targeting experience-dependent neuroplasticity. Future interventions designed to optimize functional recovery after SCI will hold promising potential by combining neurorehabilitative procedures, treatments with neuro-trophic substances facilitating axonal growth, and various local repair strategies. Ultimately, appropriate extrapola-tion of principles from animal research toward improving clinical practice is critical for the success of potential interventions in humans, whereas efficacy and safety of treatments are confronted with obvious limitations in translating animal research into clinical trials.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Financial Disclosure / Funding

The author(s) disclosed receipt of the following financial sup-port for the research, authorship, and/or publication of this article: from the CNRS, Ministry of Education and Research, and IRME (institute of research on spinal cord and brain).

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