Behavioral recovery and anatomical plasticity in adult rats after cortical lesion and treatment with monoclonal antibody IN-1

We have previously reported that monoclonal antibody (mAb) IN-1 treatment after ischemic infarct in adult rats results in significant recovery of skilled forelimb use. Such recovery was correlated with axonal outgrowth from the intact, opposite motor cortex into deafferented subcortical motor areas. In the present study, we investigated the effects of mAb IN-1 treatment after adult sensorimotor cortex (SMC) aspiration lesion on behavioral recovery and neuroanatomical plasticity in the corticospinal tract. Adult rats underwent unilateral SMC aspiration lesion and treatment with either mAb IN-1 or a control Ab, or no treatment. Animals were then tested over a 6-week period in the skilled forelimb use task and the skilled ladder rung walking task. We found that animals treated with mAb IN-1 after SMC lesion fully recovered the use of forelimb reaching, but showed no improvement in digit grasping as tested in the skilled forelimb use task. The mAb IN-1 treatment group was also significantly improved as compared to control groups in the skilled ladder rung walking test. Furthermore, neuroanatomical tracing revealed a significant increase in the corticospinal projections into the deafferented motor areas of the spinal cord after mAb IN-1 treatment. These results indicate that treatment with mAb IN-1 after cortical aspiration lesion induces remodeling of motor pathways resulting in recovery in only certain behavioral tasks, suggesting that the cause of brain damage influences behavioral recovery after mAb IN-1 treatment.     

Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat

Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke occurs. One unique therapy that may improve functional recovery after stroke is blockade of the neurite inhibitory protein Nogo-A with the monoclonal antibody IN-1, through enhancement of neuroanatomical plasticity from uninjured areas of the central nervous system. In the present study, we combined IN-1 treatment with an ischemic lesion (permanent middle cerebral artery occlusion) to determine the effect of Nogo-A neutralization on cortical plasticity and functional recovery. We report here that, following ischemic stroke and treatment with IN-1, adult rats demonstrated functional recovery on a forelimb-reaching task and new cortico-efferent projections from the opposite, unlesioned hemisphere. These results support the efficacy of Nogo-A blockade as a treatment for ischemic stroke and implicate plasticity from the unlesioned hemisphere as a mechanism for recovery.     

Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors

Injuries of the spinal cord often result in an irretrievable loss of motor and sensory functions of all body parts situated below the lesion site. Functional recovery is restricted mainly due to the limited regeneration and plasticity of injured axons in the adult central nervous system. Over the last few years different experimental approaches have led to axonal growth and functional benefits in animal models. This review focuses on the effects of the neutralization of myelin-associated neurite growth inhibitors, in particular Nogo-A, using the monoclonal antibody IN-1. Acute mAb IN-1 treatment of adult CNS lesioned rats results in extensive plastic changes of neuronal connections and regenerative fiber growth. In two different lesion paradigms (i.e. pyramidal tract lesion and incomplete spinal cord lesion in adult rats), the mAb IN-1-treated animals always showed a higher degree of recovery in various behavioral tests. These observations, together with electrophysiological results, suggest that neuronal CNS circuits of mAb IN-1-treated animals can be rearranged, and that sprouting and regenerating axons form functionally meaningful connections.     

Regenerating corticospinal fibers in the Marmoset (Callitrix jacchus) after spinal cord lesion and treatment with the anti-Nogo-A antibody IN-1

Neutralizing the myelin-associated growth inhibitor Nogo-A in adult spinal cord-injured rats can promote regeneration of injured and compensatory sprouting of uninjured axons. Nogo-A is present in humans, making its neutralization a possible novel treatment option for paraplegic patients. In this study we examined the effects of an extensively used anti-Nogo-A antibody (mAb IN-1) on the regenerative capabilities of lesioned corticospinal tract (CST) axons in a primate, the Marmoset monkey. Unilateral thoracic lesions of the CST were performed in six adult Marmosets, followed by the application of mAb IN-1 into the cerebrospinal fluid circulation by a graft of hybridoma cells. A unilateral injection of biotin dextran amine into the motor cortex was performed to analyse sprouting and regeneration of the lesioned axons. In the control antibody-treated animal CST fibers stopped rostral to the lesion site and often showed retraction bulbs. In contrast, in four out of five mAb IN-1-treated animals fine labeled neurites had grown into, through and around the lesion site. Thus, this study provides first anatomical evidence that in primates, the neutralization of the myelin-associated inhibitor Nogo-A results in increased regenerative sprouting and growth of lesioned spinal cord axons.     

Evidence for bilateral control of skilled movements: ipsilateral skilled forelimb reaching deficits and functional recovery in rats follow motor cortex and lateral frontal cortex lesions

Unilateral damage to cortical areas in the frontal cortex produces sensorimotor deficits on the side contralateral to the lesion. Although there are anecdotal reports of bilateral deficits after stroke in humans and in experimental animals, little is known of the effects of unilateral lesions on the same side of the body. The objective of the present study was to make a systematic examination of the motor skills of the ipsilateral forelimb after frontal cortex lesions to either the motor cortex by devascularization of the surface blood vessels (pial stroke), or to the lateral cortex by electrocoagulation of the distal branches of the middle cerebral artery (MCA stroke). Plastic processes in the intact hemisphere were documented using Golgi-Cox dendritic analysis and by intracortical microstimulation analysis. Although tests of reflexive responses in forelimb placing identified a contralateral motor impairment following both cortical lesions, quantitative and qualitative measures of skilled reaching identified a severe ipsilateral impairment from which recovery was substantial but incomplete. Golgi-impregnated pyramidal cells in the forelimb area showed an increase in dendritic length and branching. Electrophysiological mapping showed normal size forelimb representations in the lesioned rats relative to control animals. The finding of an enduring ipsilateral impairment in skilled movement is consistent with a large but more anecdotal literature in rats, nonhuman primates and humans, and suggests that plastic changes in the intact hemisphere are related to that hemisphere's contribution to skilled movement.     

Bone marrow stromal cells enhance inter- and intracortical axonal connections after ischemic stroke in adult rats

We investigated axonal plasticity in the bilateral motor cortices in rats after unilateral stroke and bone marrow stromal cell (BMSC) treatment. Rats were subjected to permanent right middle cerebral artery occlusion followed by intravenous administration of phosphate-buffered saline or BMSCs 1 day later. Adhesive-removal test and modified neurologic severity score were performed weekly to monitor limb functional deficit and recovery. Anterograde tracing with biotinylated dextran amine injected into the right motor cortex was used to assess axonal sprouting in the contralateral motor cortex and ipsilateral rostral forelimb area. Animals were killed 28 days after stroke. Progressive functional recovery was significantly enhanced by BMSCs. Compared with normal animals, axonal density in both contralateral motor cortex and ipsilateral rostral forelimb area significantly increased after stroke. Bone marrow stromal cells markedly enhanced such interhemispheric and intracortical connections. However, labeled transcallosal axons in the corpus callosum were not altered with either stroke or treatment. Both interhemispheric and intracortical axonal sprouting were significantly and highly correlated with behavioral outcome after stroke. This study suggests that, after stroke, cortical neurons surviving in the peri-infarct motor cortex undergo axonal sprouting to restore connections between different cerebral areas. Bone marrow stromal cells enhance axonal plasticity, which may underlie neurologic functional improvement.     

Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats

In many recovering hemiparetic stroke patients, movement of the affected limb elicits ipsilateral activation of sensorimotor areas within the undamaged hemisphere, which is not observed in control subjects. Following middle cerebral artery occlusion, rats received intensive enriched-rehabilitation (ER) of the impaired forelimb for 4 weeks. Weekly assessments on a skilled reaching test demonstrated significant improvement in ischemic animals over 4 weeks of ER (P < 0.05). We hypothesized that if the undamaged forelimb motor cortex contributed to improved forelimb function, then inhibition of neural activity within this region should reinstate (at least some of) the initial motor impairment. After 3 and 4 weeks of ER, animals received a microinjection of lidocaine hydrochloride into the undamaged motor cortex and were re-assessed on reaching ability. The behavioral effect of lidocaine challenge was dependent on the size of the infarct: animals with large infarcts were rendered unable to retrieve any food pellets and had great difficulty even contacting a pellet with the affected forepaw. Small-infarct animals were only moderately affected (25% reduction in success) by lidocaine, an effect similar to that observed in control animals. Qualitative assessments of recovered reaching after 4 weeks of rehabilitation revealed that impairments in forelimb lift, advance and aim were exacerbated (P < 0.05) following lidocaine-inactivation of the undamaged motor cortex of animals with large ischemic infarcts. In animals with small infarcts, lidocaine challenge only impaired limb advance. Thus, recruitment of the undamaged hemisphere may depend on the functional integrity of the remaining sensorimotor system. These data suggest that, in the rat, the undamaged (ipsilateral) motor system may contribute to compensatory recovery of the affected forelimb.     

Cholinergic upregulation by optogenetic stimulation of nucleus basalis after photothrombotic stroke in forelimb somatosensory cortex improves endpoint and motor but not sensory control of skilled reaching in mice

A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including cortical plasticity, attention, and sensorimotor behavior. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with endpoint, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for acute treatment of stroke.     

Task-specific compensation and recovery following focal motor cortex lesion in stressed rats

One reason for the difficulty to develop effective therapies for stroke is that intrinsic factors, such as stress, may critically influence pathological mechanisms and recovery. In cognitive tasks, stress can both exaggerate and alleviate functional loss after focal ischemia in rodents. Using a comprehensive motor assessment in rats, this study examined if chronic stress and corticosterone treatment affect skill recovery and compensation in a task-specific manner. Groups of rats received daily restraint stress or oral corticosterone supplementation for two weeks prior to a focal motor cortex lesion. After lesion, stress and corticosterone treatments continued for three weeks. Motor performance was assessed in two skilled reaching tasks, skilled walking, forelimb inhibition, forelimb asymmetry and open field behavior. The results revealed that persistent stress and elevated corticosterone levels mainly limit motor recovery. Treated animals dropped larger amounts of food in successful reaches and showed exaggerated loss of forelimb inhibition early after lesion. Stress also caused a moderate, but non-significant increase in infarct size. By contrast, stress and corticosterone treatments promoted reaching success and other quantitative measures in the tray reaching task. Comparative analysis revealed that improvements are due to task-specific development of compensatory strategies. These findings suggest that stress and stress hormones may partially facilitate task-specific and adaptive compensatory movement strategies. The observations support the notion that hypothalamic-pituitary-adrenal axis activation may be a key determinant of recovery and motor system plasticity after ischemic stroke.     

Parallel stages of learning and recovery of skilled reaching after motor cortex stroke: "oppositions" organize normal and compensatory movements

Forelimb/hand motor cortex injury in rodents and primates causes impairments in skilled paw/hand movements that includes a period of movement absence followed by functional recovery/compensation. Although the postsurgical period of movement absence has been attributed to "shock" or "diaschisis", the behavior of animals during this period has not been fully described. Here, rats were trained to reach for single food pellets from a shelf and then the vasculature of the forelimb region of the sensorimotor cortex contralateral to the reaching limb was removed. A control group received a posterior parietal cortex devasularization. Frame-by-frame video analysis of reaching behavior showed that the stages of the acquisition of skilled reaching and the stages of recovery after motor cortex stroke were similar. The animals sequentially learn three relationships or "oppositions" between a body part and the food target. The oppositions are invariant relationships but each can be achieved with movements that can vary from reach to reach and between rats. A snout-pellet opposition organizes the movements of orienting, a paw-pellet opposition organizes limb transport and grasping the pellet in the digits, and a mouth-pellet opposition organizes limb withdrawal and the release of the food into the mouth. The three oppositions and the movements that they recruit were disrupted after motor cortex damage, but not parietal cortex damage. The oppositions were reestablished after stroke in the order in which they were acquired prior to stroke. Enduring impairments were more noticeable in transport and withdrawal oppositions. That the stages of recovery from motor cortex stroke parallel those of initial acquisition are discussed in relation to contemporary explanations of diaschisis and the contribution of motor cortex to motor learning.     

Corticostriatal plasticity is restricted by myelin-associated neurite growth inhibitors in the adult rat.

After unilateral cortical lesions in neonatal rats, the spared unablated hemisphere is known to demonstrate remarkable neuroanatomical plasticity in corticofugal connectivity. This same type of structural plasticity is not seen after similar lesions in adult rats. One possibility for the lack of such a plastic response in the adult central nervous system may be the presence of myelin-associated neurite growth inhibitory proteins NI-35/NI-250. These proteins have previously been found to play a crucial role in preventing axotomized fibers from regenerating after adult rat spinal cord lesions. The aim of this study was to determine if blocking these inhibitory proteins by the application of the specific monoclonal antibody IN-1 would enhance corticostriatal plasticity from the spared hemisphere after unilateral cortical lesions in adult rats. Six- to 8-week-old Lewis rats underwent unilateral aspiration lesion of the sensorimotor cortex. Animals were immediately treated with either monoclonal antibody IN-1 or a control antibody released from hybridoma cells in Millipore filter capsules. After a survival period of 12 weeks, the opposite sensorimotor cortex was stereotaxically injected with the anterograde tracer biotinylated dextran amine, and biotinylated dextran amine-positive corticostriatal fibers were analyzed. The monoclonal antibody IN-1-treated animals showed an increase in corticostriatal fibers in the dorsolateral striatum contralateral to the injection site compared with control antibody-treated animals or normal controls, indicating a specific sprouting response in the deafferented zone. These results support the idea that through blockade of myelin-associated neurite inhibitory proteins, lesion-induced corticofugal plasticity is possible even in the adult central nervous system.     

A novel phosphodiesterase type 4 inhibitor, HT-0712, enhances rehabilitation-dependent motor recovery and cortical reorganization after focal cortical ischemia

Rehabilitation-dependent motor recovery after cerebral ischemia is associated with functional reorganization of residual cortical tissue. Recovery is thought to occur when remaining circuitry surrounding the lesion is "retrained" to assume some of the lost function. This reorganization is in turn supported by synaptic plasticity within cortical circuitry and manipulations that promote plasticity may enhance recovery. Activation of the cAMP/CREB pathway is a key step for experience-dependent neural plasticity. Here we examined the effects of the prototypical phosphodiesterase inhibitor 4 (PDE4) rolipram and a novel PDE inhibitor (HT-0712), known to enhance cAMP/CREB signaling and cognitive function, on restoration of motor skill and cortical function after focal cerebral ischemia. Adult male rats were trained on a skilled reaching task to establish a baseline level of motor performance. Intracortical microstimulation was then used to derive high-resolution maps of forelimb movement representations within the caudal forelimb area of motor cortex contralateral to the trained paw. A focal ischemic infarct was created within approximately 30% of the caudal forelimb area. The effects of administering either rolipram or the novel PDE4 inhibitor HT-0712 during rehabilitation on motor recovery and restoration of movement representations within residual motor cortex were examined. Both compounds significantly enhanced motor recovery and induced an expansion of distal movement representations that extended beyond residual motor cortex. The expansion beyond the initial residual cortex was not observed in vehicle injected controls. Furthermore, the motor recovery seen in the HT-0712 animals was dose dependent. Our results suggest that PDE4 inhibitors during motor rehabilitation facilitate behavioral recovery and cortical reorganization after ischemic insult to levels significantly greater than that observed with rehabilitation alone.     

Neuronal plasticity and formation of new synaptic contacts follow pyramidal lesions and neutralization of Nogo-A: a light and electron microscopic study in the pontine nuclei of adult rats

Regeneration and compensatory sprouting are limited after lesions in the mature mammalian central nervous system in contrast to the developing central nervous system (CNS). After neutralization of the growth inhibitor Nogo-A, however, massive sprouting and rearrangements of fiber connections occurred after unilateral pyramidal tract lesions in adult rats: Corticofugal fibers from the lesioned side crossed the midline of the brainstem and innervated the contralateral basilar pontine nuclei. To determine whether these newly sprouted fibers formed synaptic contacts, we analyzed the corticofugal fibers in the basilar pontine nuclei contralateral to the lesion by light and electron microscopy 2 weeks after pyramidotomy and treatment with the Nogo-A-inhibiting monoclonal antibody IN-1 (mAb IN-1). The mAb IN-1, but not a control antibody, led to structural changes in the basilar pons ipsilateral and contralateral to the lesion site. Fibers sprouted across the pontine midline and terminated topographically. They established asymmetric synaptic contacts with the characteristics of normal corticopontine terminals. These results show that adult CNS fibers are able to sprout and to form new synaptic contacts after a lesion when a growth-permissive microenvironment is provided.     

Skilled reaching training promotes astroglial changes and facilitated sensorimotor recovery after collagenase-induced intracerebral hemorrhage

Spontaneous intracerebral hemorrhage (ICH) is the most devastating type of stroke and a leading cause of disability and mortality worldwide. Although rehabilitation improves recovery after ICH the cellular mechanisms involved are poorly understood. We decided to examine if skilled (SK) and unskilled (US) training after sham or intracerebral hemorrhage (ICH) surgeries would induce GFAP+ astrocytic changes and whether these modifications can be associated with functional improvement. A 4-week course of motor training, involving either skilled and unskilled training began seven days after surgery; sensorimotor recovery was evaluated using Staircase, ladder walk and cylinder tests. Histological and morphometric analyses were used to assess GFAP+ cell bilaterally in forelimb sensorimotor cortex and dorsolateral striatum. All behavioral tests showed that ICH-SK rats experienced a greater degree of recovery when compared to ICH no task or ICH-US groups; no behavioral differences were found among all sham groups. Astrocytic density was increased in all analyzed structures for ICH no task, ICH-SK and ICH-US rats. Morphological analysis revealed an increased number of primary processes in ipsilateral (to lesion) sensorimotor cortex for all ICH groups. Present results also revealed that both ICH and SK induced an increased length of GFAP+ primary process; there was a further increase in length processes for ICH-SK group in sensorimotor cortex and ipsilateral striatum. We suggest that skilled reaching is an effective intervention to promote astrocytic plasticity and recovery after ICH.     

Increased corticofugal plasticity after unilateral cortical lesions combined with neutralization of the IN-1 antigen in adult rats.

If damage to the central nervous system (CNS) occurs early in life, extensive rearrangements of the remaining fiber systems as well as regeneration of lesioned fibers take place. In the rat or hamster, newly grown projections have been described only if the lesion occurred within the first two weeks postnatally. This decreasing growth ability correlates with CNS maturation and the progression of myelination. Myelin contains the potent neurite growth inhibitors NI-35/250 that are crucially involved in the failure of long-distance regeneration and the lack of compensatory structural plasticity after adult CNS lesions. In this study, we show that extensive remodeling occurs well after the termination of the growth permissive period in the adult rat if we neutralize the inhibitory properties of myelin with the monoclonal antibody IN-1. After ablation of one motor cortex and treatment with the antibody IN-1, we observed that the remaining corticospinal tract (CST) from the spared hemisphere sprouted into the denervated, contralateral red nucleus and pons. In the pons, these fibers terminated in a typical somatotopic pattern. For comparison with neonatal plasticity, we performed the same lesion in two-day-old rats (no antibody). This lesion led as well to sprouting of the remaining CST into denervated brainstem nuclei, resulting in a bilateral corticofugal projection. Our results show that neutralization of myelin-associated neurite-growth inhibitors after CNS lesions leads to a structural remodeling of the spared corticofugal fibers in adult rats, a process normally restricted to a short postnatal period.     

Both compensation and recovery of skilled reaching following small photothrombotic stroke to motor cortex in the rat

Large lesions produced by stroke to the forelimb region of motor cortex of the rat feature post-stroke improvement that in the main is due to compensation. The present study describes both recovery and compensation of forelimb use in a reach-to-eat (skilled reaching) task following small photothrombotic stroke. The rats were pretrained before stroke, and then assessed using endpoint measures and biometric movement analysis during rehabilitation in the acute and chronic post-stroke periods. Histological and MRI analysis indicated that the stroke consisted of a small lesion surrounded by cortex featuring scattered cell loss, likely of the large pyramidal cells that characterize the forelimb region of motor cortex. The stroke reduced reaching success, especially on the most demanding measure of success on first reach attempts, in the acute period, but with rehabilitation, performance returned to pre-stroke levels. Reach movements as assessed by biometric measures were severely impaired acutely but displayed significant recovery chronically although this recovery was not complete. The results suggest that not only do rats show post-stroke compensation in skilled reaching but they can also display functional recovery. It is suggested that recovery is mediated by the spared neurons in the peri-infarct region of forelimb motor cortex. The results demonstrate the utility of a small lesion model for studying post-stroke neural and behavioral change and support the view that optimal post-stroke treatment should be directed toward limiting tissue loss.     

Endurance exercise facilitates relearning of forelimb motor skill after focal ischemia

Endurance exercise (i.e. running), by up-regulating brain-derived neurotrophic factor (BDNF) and other modulators of synaptic plasticity, improves attention and learning, both critical components of stroke rehabilitation. We hypothesized that, following middle cerebral artery occlusion in male Sprague-Dawley rats, endurance exercise would act synergistically with a challenging skilled forelimb task to facilitate motor recovery. Animals were randomly assigned to one of four rehabilitation conditions: no rehabilitation, running only, reach training only, and reach training preceded by running (run/reach training) for 5 weeks beginning 5 days after stroke. The behavioral outcome, morphological change and mRNA expression of proteins implicated in neuroplasticity (BDNF, synapsin I and microtubule-associated protein 2) were compared. Endurance exercise on a motorized running wheel, prior to reach training, enhanced recovery of skilled reaching ability but did not transfer to gross motor skills such as postural support (forelimb asymmetry test) and gait (ladder rung walking test). Microtubule-associated protein 2 staining density in the run/reach group was slightly enhanced in the contralateral motor cortex compared with the contralateral sensory and ipsilateral cingulate cortices, suggesting that running preceding reach training may have resulted in more dendritic branching within the motor cortex in this group. No significant differences in mRNA levels were detected among the training paradigms; however, there was a trend toward greater BDNF and synapsin I mRNA in the reaching groups. These findings suggest that exercise facilitates learning of subsequent challenging reaching tasks after stroke, which has the potential to optimize outcomes in patients with stroke.     

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

Abstract

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.     

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.