Unilateral Sensorimotor Cortex Lesions Research Articles

Anti‐Nogo on the go: from animal models to a clinical trial

Small lesions of the adult central nervous system (CNS) often have a good prognosis with extensive functional recovery based in part on spontaneous neuritic sprouting and rearrangements of projections. This is well documented for the cortex, but these changes can also occur in the spinal cord. Nogo-A is a protein present in CNS myelin that inhibits neurite growth. Models of spinal cord injury (SCI) in rats and macaque monkeys demonstrate that treatment with function-blocking antibodies of Nogo-A results in an upregulation of growth-specific proteins, enhanced regenerative and compensatory sprouting of fibers, and the formation of new functional connections in the spinal cord. In animals with unilateral sensorimotor cortex lesions followed by Nogo-A antibody treatment, fibers from the intact corticofugal system crossed the midline, supplying innervation to the denervated brain stem or spinal cord. Behavioral tests showed marked improvements of functional recovery in the Nogo-A antibody treated spinal cord- or brain-injured animals. A Phase I clinical trial applying anti-Nogo-A antibody to subjects with acute SCI has been successfully conducted and a multicentric, multinational Phase II trial is currently in preparation.

Axonal plasticity is associated with motor recovery following amphetamine treatment combined with rehabilitation after brain injury in the adult rat

Clinical and laboratory studies have suggested that amphetamine treatment when paired with rehabilitation results in improved recovery of function after stroke or traumatic brain injury. In the present study, we investigated whether new anatomical pathways developed in association with improved motor function after brain damage and amphetamine treatment linked with rehabilitation. Following a unilateral sensorimotor cortex lesion in the adult rat, amphetamine (2 mg/kg) was administered in conjunction with physiotherapy sessions on postoperative days two and five. Physiotherapy was continued twice daily for the first 3 weeks after injury, and then once daily until week six. Performance on skilled forelimb reaching and ladder rung walking was used to assess motor improvement. Our results show that animals with sensorimotor cortical lesions receiving amphetamine treatment linked with rehabilitation had significant improvement in both tasks. Neuroanatomical tracing of efferent pathways from the opposite, non-damaged cortex resulted in the novel finding that amphetamine treatment linked with rehabilitation, significantly increased axonal growth in the deafferented basilar pontine nuclei. These results support the notion that pharmacological interventions paired with rehabilitation can enhance neuronal plasticity and thereby improve functional recovery after CNS injury.

Epidural cortical stimulation enhances motor function after sensorimotor cortical infarcts in rats

This study examined whether epidurally delivered cortical electrical stimulation (CS) improves the efficacy of motor rehabilitative training and alters neuronal density and/or cell proliferation in perilesion cortex following ischemic sensorimotor cortex (SMC) lesions. Adult rats were pre-trained on a skilled reaching task and then received partial unilateral SMC lesions and implantation of electrodes over the remaining SMC. Ten to fourteen days later, rats received daily reach training concurrent with anodal or cathodal 100 Hz CS or no stimulation (NoCS) for 18 days. To label newly generated cells, bromodeoxyuridine (BrdU; 50 mg/kg) was administered every third day of training. Both anodal and cathodal CS robustly enhanced reaching performance compared to NoCS controls. Neuronal density in the perilesion cortex was significantly increased in the cathodal CS group compared to the NoCS group. There were no significant group differences in BrdU-labeled cell density in ipsilesional cortex. Staining with Fluoro-Jade-B indicated that neurons continue to degenerate near the infarct at the time when cortical stimulation and rehabilitation were initiated. These data indicate that epidurally delivered CS greatly improves the efficacy of rehabilitative reach training following SMC damage and raise the possibility that cathodal CS may influence neuronal survival in perilesion cortex.

Visual cortical plasticity following unilateral sensorimotor cortical lesions in the neonatal rat

Previous work has shown that unilateral sensorimotor cortex (SMC) lesions in newborn rats resulted in an apparent shift of the motor cortex map in the spared hemisphere, particularly of the hindlimb cortex. In view of such findings, the present study was initiated to determine if the visual cortex located both ipsilateral and contralateral to neonatal SMC, or contralateral to occipital cortical (OC) lesions, would show similar remodeling. Visual evoked potentials (VEPs) were used to map the visual cortex electrophysiologically. The results show an expansion of the visual cortex, in both the contralateral and ipsilateral hemisphere, into normally motor cortical areas in adult animals that had sustained unilateral neonatal unilateral SMC lesions. In contrast, similar changes were not seen within the spared visual cortex after unilateral occipital cortical lesions, suggesting that the shift in the visual map was specifically in response to the SMC lesion and was not a generalized response to neonatal cortical damage. Histological analysis showed a functional expansion in the rostral boundary of visual cortex with no corresponding cytoarchitectural alterations.

Time‐sensitive enhancement of motor learning with the less‐affected forelimb after unilateral sensorimotor cortex lesions in rats

Unilateral damage to the forelimb region of the sensorimotor cortex (FLsmc) results in time-dependent changes in neuronal activity, structure and connectivity in the contralateral motor cortex of adult rats. These changes have been linked to facilitation of motor skill learning in the less-affected/ipsilesional forelimb, which is likely to promote its use in the development of behavioral compensation. The goal of this study was to determine whether an early post-lesion-sensitive time period exists for this enhanced learning and whether it is linked to synaptogenesis in the contralesional motor cortex. Rats were trained for 21 days on a skilled reaching task with the ipsilesional forelimb beginning 4 or 25 days after unilateral ischemic (endothelin-1-induced) FLsmc lesions or sham operations. As found previously, reaching performance was significantly enhanced in rats trained early post-lesion compared with sham-operates. In rats trained later post-lesion, performance was neither significantly different from time-matched sham-operates nor strikingly different from animals trained earlier post-lesion. In layer V of the contralesional motor cortex, stereological methods for light and electron microscopy revealed significantly more total, multisynaptic bouton and perforated synapses per neuron compared with sham-operates, but there were no significant differences between early- and late-trained lesion groups. Thus, there appears to be a sensitive time window for the maximal expression of the enhanced learning capacity of the less-affected forelimb but this window is broadly, rather than sharply, defined. These results indicate that relatively long-lasting lesion-induced neuronal changes are likely to underlie the facilitation of learning with the less-affected forelimb.

Cortical electrical stimulation combined with rehabilitative training: Enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats

This study assessed the behavioral and dendritic structural effects of combining subdural motor cortical electrical stimulation with motor skills training following unilateral sensorimotor cortex lesions in adult male rats. Rats were pre-operatively trained on a skilled forelimb reaching task, the Montoya staircase test, and then received endothelin-1 induced ischemic lesions of the sensorimotor cortex. Ten to 14 days later, electrodes were implanted over the peri-lesion cortical surface. Rats subsequently began 10 days of rehabilitative training on the reaching task in 1 of 3 conditions: 1. 50 Hz stimulation during training, 2. 250 Hz stimulation during training or 3. no stimulation. No significant difference in performance was found between the 250 Hz and no stimulation groups. The 50 Hz stimulation group had significantly greater rates of improvement with the impaired forelimb in comparison to 250 Hz and no stimulation groups combined. Fifty Hz stimulated animals also had a significant increase in the surface density of dendritic processes immunoreactive for the cytoskeletal protein, microtubule-associated protein 2, in the peri-lesion cortex compared to the other groups. These results support the efficacy of combining rehabilitative training with cortical electrical stimulation to improve functional outcome and cortical neuronal structural plasticity following sensorimotor cortical damage.

Facilitation of motor skill learning by callosal denervation or forced forelimb use in adult rats

Unilateral forelimb sensorimotor cortex lesions in adult rats produce a compensatory hyper-reliance on the forelimb ipsilateral to the lesion and temporally related glial and neural plasticity in the contralateral homotopic cortex. Recently, we found that these lesions enhance acquisition of a motor skills task with the ipsilateral, non-impaired, forelimb in comparison to shams. This effect might be related to a denervation-induced facilitation of neuroplastic changes in the motor cortex opposite the lesion and/or to the lesion-induced hyper-reliance on the non-impaired forelimb. The present study assessed whether increased forelimb use, denervation of motor cortical callosal afferents, or a combination of the two influences acquisition of a skilled reaching task. Adult rats with partial corpus callosum transections or sham procedures were either forced to rely on one forelimb or permitted normal forelimb use for 8 days. Rats were then trained for 14 days with their previously non-preferred forelimb (and the forced-use limb) on a unilateral pellet retrieval task. Compared to shams, transections produced a greater acquisition rate and asymptotic performance level on the task. Forced-use improved reaching performance relative to controls, but this effect was less enduring than the improvements produced by transections alone. The addition of forced-use to transections did not further enhance performance. These findings suggest that denervation-induced changes are likely to be a major contributor to the enhanced learning observed after unilateral sensorimotor cortex lesions.

Unilateral Sensorimotor Cortex Lesions in Adult Rats Facilitate Motor Skill Learning with the “Unaffected” Forelimb and Training-Induced Dendritic Structural Plasticity in the Motor Cortex

In humans and other animals, sufficient unilateral damage to the sensorimotor cortex can cause impairments in the opposite forelimb and the development of a hyper-reliance on the nonimpaired limb. This hyper-reliance is adaptive to the extent that it contributes to functional compensation for lesion-induced impairments. We have found that unilateral lesions of the forelimb region of the sensorimotor cortex (FLsmc) in rats, or callosal transections, cause neurons of the opposite motor cortex to become exceptionally responsive to changes in forelimb behavior. This enhanced responsiveness might facilitate learning of compensatory strategies with the nonimpaired forelimb after unilateral FLsmc lesions. The possibility that these lesions facilitate learning with the nonimpaired forelimb was addressed in this study. Rats were required to learn a skilled forelimb reaching task after either unilateral FLsmc lesions or sham operations. The trained limb in animals with lesions was the nonimpaired limb. Compared with shams, rats with unilateral lesions had a greater rate of acquisition and asymptotic performance level on the task, which was especially evident on more difficult trials. Quantitative measures of microtubule associated protein-2 (MAP2) immunostained dendrites indicated an enhancement of training-induced dendritic cytoskeletal changes in the motor cortex opposite lesions. Thus, unilateral FLsmc lesions facilitate learning of at least some types of motor skills using the nonimpaired forelimb as well as some of the neuronal changes associated with this learning. This facilitation could be a substrate underlying behavioral compensation for unilateral FLsmc damage and may contribute to the phenomenon of learned nonuse of the impaired limb.

Multiple synapse formation in the motor cortex opposite unilateral sensorimotor cortex lesions in adult rats

Unilateral damage to the forelimb region of the sensorimotor cortex (FLsmc) in adult rats has previously been found to result in dendritic growth and synaptogenesis in layer V of the contralateral motor cortex. The neuronal growth appears to be mediated in part by lesion-induced changes in the use of the forelimbs. Whether these neuronal changes involve alterations in the structure and/or configuration of synaptic connections in layer V has not previously been investigated. The present study used stereological measures to characterize structural alterations in axonal processes and synaptic connections using electron micrographs generated in a previous study of the motor cortex contralateral to FLsmc lesions. Of primary interest were synapses formed by multiple synaptic boutons (MSBs), which have recently been found to be a major component of experience-related neocortical plasticity, and synapses with perforated postsynaptic densities (PSDs), which are putatively associated with enhanced synaptic efficacy. In comparison with sham-operated rats, there was an increase in the proportion and ratio of synapses to neurons formed by MSBs and in synapses with perforated PSDs at 30 days after the lesions. Furthermore, perforated synapses formed by MSBs were markedly increased at 18 and 30 days after the lesion in comparison with sham-operated rats. Preceding these synaptic structural changes (at 10 days postlesion), myelinated axons were reduced in volume fraction and volume per neuron in comparison with sham-operated rats but returned to normal levels at subsequent time points. These results are consistent with a lesion-induced degeneration and subsequent sprouting of axons. Together, these data indicate that a major restructuring of synaptic connectivity occurs in the cortex opposite FLsmc lesions in adult animals. This lesion-induced restructuring may be guided by ongoing changes in the use of the forelimbs.

Multiple synapse formation in the motor cortex opposite unilateral sensorimotor cortex lesions in adult rats

Unilateral damage to the forelimb region of the sensorimotor cortex (FLsmc) in adult rats has previously been found to result in dendritic growth and synaptogenesis in layer V of the contralateral motor cortex. The neuronal growth appears to be mediated in part by lesion-induced changes in the use of the forelimbs. Whether these neuronal changes involve alterations in the structure and/or configuration of synaptic connections in layer V has not previously been investigated. The present study used stereological measures to characterize structural alterations in axonal processes and synaptic connections using electron micrographs generated in a previous study of the motor cortex contralateral to FLsmc lesions. Of primary interest were synapses formed by multiple synaptic boutons (MSBs), which have recently been found to be a major component of experience-related neocortical plasticity, and synapses with perforated postsynaptic densities (PSDs), which are putatively associated with enhanced synaptic efficacy. In comparison with sham-operated rats, there was an increase in the proportion and ratio of synapses to neurons formed by MSBs and in synapses with perforated PSDs at 30 days after the lesions. Furthermore, perforated synapses formed by MSBs were markedly increased at 18 and 30 days after the lesion in comparison with sham-operated rats. Preceding these synaptic structural changes (at 10 days postlesion), myelinated axons were reduced in volume fraction and volume per neuron in comparison with sham-operated rats but returned to normal levels at subsequent time points. These results are consistent with a lesion-induced degeneration and subsequent sprouting of axons. Together, these data indicate that a major restructuring of synaptic connectivity occurs in the cortex opposite FLsmc lesions in adult animals. This lesion-induced restructuring may be guided by ongoing changes in the use of the forelimbs. J. Comp. Neurol. 414:57–66, 1999. © 1999 Wiley-Liss, Inc.

Use-Dependent Exaggeration of Neuronal Injury after Unilateral Sensorimotor Cortex Lesions.

Use-Dependent Exaggeration of Neuronal Injury after Unilateral Sensorimotor Cortex Lesions.

Effects of bilateral and unilateral locus coeruleus lesions on beam-walking recovery after subsequent unilateral sensorimotor cortex suction-ablation in the rat

The recovery of beam-walking ability following a unilateral sensorimotor cortex lesion in the rat is hypothesized to be noradrenergically-mediated. We carried out two experiments to further test this hypothesis. In the first experiment, bilateral 6-hydroxydopamine locus coeruleus (LC) lesions or sham LC lesions were made 2 weeks prior to a right sensorimotor cortex suction-ablation lesion or sham cortex lesion. In the second experiment, unilateral left or right LC lesions or sham LC lesions were made 2 weeks prior to a right sensorimotor cortex lesion or sham cortex lesion. Beam-walking recovery was measured over the 12 days following cortex lesioning in each experiment. Bilateral, unilateral left, and unilateral right LC lesions resulted in impaired recovery. These data provide additional support for the hypothesis that beam-walking recovery after sensorimotor cortex injury is, at least in part, noradrenergically mediated.

Use-Dependent Exaggeration of Neuronal Injury after Unilateral Sensorimotor Cortex Lesions

Unilateral injury to the forelimb representation area of the sensorimotor cortex (FL-SMC) in adult rats causes over-reliance on the unimpaired forelimb for postural-motor movements, as well as overgrowth of layer V pyramidal cell dendrites in the homotopic cortex of the noninjured hemisphere. The overgrowth appears to be use-dependent because it can be prevented by restricting movements of the unimpaired forelimb. Additionally, restricting the unimpaired forelimb in animals with FL-SMC damage results in significantly greater behavioral dysfunction when examined 2 d after cast removal (compared to that after impaired-limb immobilization, or no limb immobilization). In the present study, the long-term behavioral and anatomical effects of limb immobilization were examined. Animals with FL-SMC lesions were fitted with casts immediately after the lesion that immobilized the impaired forelimb, the unimpaired forelimb, or neither forelimb for 15 d. Immobilization of the nonimpaired forelimb resulted in chronic prevention of dendritic growth and severe and chronic behavioral deficits. In addition, immobilization of the nonimpaired forelimb resulted in a dramatic exaggeration of the neuronal injury, presumably attributable to forced overuse of the impaired limb. Immobilization of the impaired forelimb resulted in no detectable neural changes and in only slightly increased and longer-lasting behavioral asymmetries (compared to nonimmobilized, lesioned animals), presumably attributable to mild disuse of the impaired limb. Immobilization of a single forelimb in nonlesioned rats resulted in no significant behavioral or anatomical changes. Together, these results suggest that although behavioral experience can enhance neural growth after brain injury, the region surrounding the injury may be vulnerable to behavioral pressure during the early postlesion period.

Effects of trazodone and desipramine on motor recovery in brain-injured rats.

Rats pretrained to walk a narrow balance beam received unilateral sensorimotor cortex lesions, resulting in a contralateral transient paresis that lasted 14 days. In a dose-dependent manner, a single injection of the antidepressant trazodone given 24 hours after injury transiently slowed motor recovery compared with injured controls. After final recovery level of motor function, a reinjection of trazodone reinstated the hemiparesis for up to 6 hours. In other animals, a single injection of the antidepressant desipramine significantly facilitated motor performance when compared with injured controls. Desipramine had no deleterious motor effect when administered to animals that had recovered on the beam-walking task. These findings would suggest that the predominantly noradrenergic neurotransmitter effects of desipramine may facilitate, and those of the predominantly serotonergic trazodone may hinder, the recovery of locomotor performance after cortical injury in rats. Further studies appear indicated, including applying these findings to the clinical setting.

Norepinephrine depletion impairs motor recovery following sensorimotor cortex injury in the rat

Beam-walking in the rat provides a method for investigating the effects of drugs on motor recovery following unilateral injury to the sensorimotor cortex. In the present experiment, the impact of norepinephrine depletion on beam-walking recovery was investigated. Groups of rats were first given either the neurotoxin DSP-4 or saline. Two weeks later, the animals were trained at the beam-walking task. Rats were then subjected to either a unilateral sensorimotor cortex lesion or sham operation. Recovery of beam-walking performance was measured over the next 12 days. Pretreatment with DSP-4 significantly slowed the rate of recovery but did not significantly affect sham-operated rats. Norepinephrine was significantly diminished in both lesioned and sham-operated rats that had been given DSP-4. These results are consistent with the hypothesis that recovery of beam-walking in the rat is mediated, at least in part, through noradrenergic neurons.

Clonidine impairs recovery of beam-walking after a sensorimotor cortex lesion in the rat

Beam-walking in the rat is a useful model for studying the effects of drugs on motor recovery following brain injury. In the present experiment, the effect of clonidine HCl on beam-walking recovery was investigated. Groups of rats were first trained to traverse a narrow elevated beam and then subjected to a right sensorimotor cortex suction-ablation injury. After 24 h, each rat received a single dose of clonidine HCl (20, 60, or 200 μg/kg, i.p., salt weight) or saline. Recovery of beam-walking ability was scored over the next 12 days. Treatment with clonidine significantly slowed the rate of recovery (Kruskal-Wallis H = 8.755,df= 3; 0.02 < P < 0.05). Furthermore, the impairment persisted for at least 5 days after the rats were treated (Kruskal-Wallis H = 8.47,df= 3; 0.02 < P < 0.05). These data are consistent with the hypothesis that norepinephrine, working through central α 2-adrenergic receptors, influences motor recovery after a unilateral sensorimotor cortex lesion in the rat. Since many stroke patients are treated with centrally acting antihypertensive drugs, the potential effects of specific classes of these drugs during the recovery period, should be carefully considered.

Influence of lesion size and location on amphetamine-facilitated recovery of beam-walking in rats.

Amphetamine treatment facilitates recovery of beam-walking in rats with unilateral sensorimotor cortex lesions. Lesion extent was studied in amphetamine- and saline-treated rats selected for rapid and slow recoveries. Lesion volume, lesion depth, and the amount of medial cortex damage were not different among the 4 groups of rats. When the data were analyzed without regard to drug treatment, both lesion depth in rostral forebrain and maximum amount of medial cortex damage negatively correlated with recovery rate. Thus, lesion extent influences the rate of recovery of beam-walking in rats but does not explain the lack of effectiveness of amphetamine in selected animals.

Seizures and recovery from experimental brain damage

The effects of the γ-aminobutyric acid antagonist, pentylenetetrazol (PTZ), on recovery from somatosensory and motor asymmetries after unilateral sensorimotor cortex lesions were investigated. Behavior was assessed using a bilateral tactile stimulation test and a measure of forelimb motor coordination. Immediately after surgery, the PTZ-treated and saline (SAL) control groups both exhibited severe ipsilateral behavioral asymmetries. Rats receiving PTZ recovered significantly faster from somatosensory asymmetry than those receiving SAL. Recovery was complete in the PTZ group within 3 postoperative weeks, while the SAL group failed to reach a comparable level until 2 months after surgery. There was no difference between PTZ and SAL groups on recovery of forelimb motor coordination. No difference in lesion size between the SAL and the PTZ groups could be found. These data are consistent with the hypothesis that post-traumatic neuronal depression may contribute to the severity of sensorimotor deficits observed after brain damage.

Is sprouting the result of a persistent neonatal connection?

The present study aims to test the hypothesis that early neonatal connections might account for certain sprouting phenomena in the central nervous system. Fink-Heimer's method for degenerating axons, electron microscopy and autoradiography were used to trace the neonatal corticofugal projections from the sensorimotor cortex (SMC) of albino rats. The results showed that neonatal corticofugal projections to the superior colliculus, red nucleus and spinal cord were unilateral and could not explain the bilateral corticofugal projections to these areas soon after neonatal SMC lesions [8, 10, 12, 13]. The presence of a neonatal contralateral corticopontine projection is also not sufficient to account for the presence of a contralateral corticopontine projection seen after neonatal unilateral SMC lesion, but might account for the contralateral corticopontine projection seen after neonatal unilateral cerebellar hemispherectomy [11].