Interhemispheric connections of the ventral premotor cortex in a new world primate

This study describes the pattern of interhemispheric connections of the ventral premotor cortex (PMv) distal forelimb representation (DFL) in squirrel monkeys. Our objectives were to describe qualitatively and quantitatively the connections of PMv with contralateral cortical areas. Intracortical microstimulation techniques (ICMS) guided the injection of the neuronal tract tracers biotinylated dextran amine or Fast blue into PMv DFL. We classified the interhemispheric connections of PMv into three groups. Major connections were found in the contralateral PMv and supplementary motor area (SMA). Intermediate interhemispheric connections were found in the rostral portion of the primary motor cortex, the frontal area immediately rostral and ventral to PMv (FR), cingulate motor areas (CMAs), and dorsal premotor cortex (PMd). Minor connections were found inconsistently across cases in the anterior operculum (AO), posterior operculum/inferior parietal cortex (PO/IP), and posterior parietal cortex (PP), areas that consistently show connections with PMv in the ipsilateral hemisphere. Within-case comparisons revealed that the percentage of PMv connections with contralateral SMA and PMd are higher than the percentage of PMv connections with these areas in the ipsilateral hemisphere; percentages of PMv connections with contralateral M1 rostral, FR, AO, and the primary somatosensory cortex are lower than percentages of PMv connections with these areas in the ipsilateral hemisphere. These studies increase our knowledge of the pattern of interhemispheric connection of PMv. They help to provide an anatomical foundation for understanding PMv's role in motor control of the hand and interhemispheric interactions that may underlie the coordination of bimanual movements.     

Neonatal frontal lesion in unilateral hemisphere enhances the development of the intact higher motor cortex in the rat

The influence of the neonatal frontal lesion in unilateral cerebral hemisphere for the organization of intact forelimb motor cortex in the rat was investigated by intracortical microstimulation (ICMS). The relative size of the rostral forelimb area (RFL) compared to the caudal forelimb area (CFL) in the ipsilateral motor field of lesioned rat was significantly greater than those of contralateral in normal and lesioned rats. The optimal sites of the stimulation for ipsilateral responses in lesioned rats were located in the RFL, while the optimal sites for contralateral were located caudolaterally, as for those of normal rats. At the ipsilateral optimal sites within the RFL in the lesioned animals, the threshold for the ipsilateral responses was lower than that for the contralateral responses. That is, the intact hemisphere of the animal preferentially developed the RFL rather than the CFL, for the ipsilateral forelimb. This may suggest a critical role for the RFL in individual forelimb motor control within the normal hemisphere.     

Corpus callosum connections of subdivisions of motor and premotor cortex, and frontal eye field in a prosimian primate, Otolemur garnetti

The callosal connections of motor and premotor fields in the frontal cortex of galagos were examined by placing multiple tracers into the primary motor area (M1), dorsal premotor area (PMD), ventral premotor area (PMV), supplementary motor area (SMA), and frontal eye field (FEF) following intracortical microstimulation. Retrogradely labeled neurons in the opposite hemisphere were plotted and superimposed onto brain sections stained with myelin and cytochrome oxidase for architectonic analysis. The main callosal connections of M1 and the caudal portion of PMD (PMDc) were with homotopic sites, and the major callosal connections of the rostral portion of PMD (PMDr), SMA, and FEF were with homotopic sites and adjoining cortex in the frontal lobe. In addition, M1 forelimb representation had sparse callosal connections, whereas M1 trunk and face representations, as well as the premotor areas, had dense callosal connections. The sparse interhemispheric connections of the forelimb sector of M1 suggests that the control of each forelimb is largely from the contralateral M1 in galagos, as in other primates.     

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.     

MiR-17-92 enriched exosomes derived from multipotent mesenchymal stromal cells enhance axon-myelin remodeling and motor electrophysiological recovery after stroke

MiR-17-92 cluster enriched exosomes derived from multipotent mesenchymal stromal cells (MSCs) increase functional recovery after stroke. Here, we investigate the mechanisms underlying this recovery. At 24 h (h) post transient middle cerebral artery occlusion, rats received control liposomes or exosomes derived from MSCs infected with pre-miR-17-92 expression lentivirus (Exo-miR-17-92⁺) or control lentivirus (Exo-Con) intravenously. Compared to the liposomes, exosomes significantly reduced the intracortical microstimulation threshold current of the contralateral cortex for evoking impaired forelimb movements (day 21), increased the neurite and myelin density in the ischemic boundary area, and contralesional axonal sprouting into the caudal forelimb area of ipsilateral side and in the denervated spinal cord (day 28), respectively. The Exo-miR-17-92⁺ further enhanced axon-myelin remodeling and electrophysiological recovery compared with the EXO-Con. Ex vivo cultured rat brain slice data showed that myelin and neuronal fiber density were significantly increased by Exo-miR-17-92⁺, while significantly inhibited by application of the PI3K/Akt/mTOR pathway inhibitors. Our studies suggest that the miR-17-92 cluster enriched MSC exosomes enhanced neuro-functional recovery of stroke may be attributed to an increase of axonal extension and myelination, and this enhanced axon-myelin remodeling may be mediated in part via the activation of the PI3K/Akt/mTOR pathway induced by the downregulation of PTEN.     

Altered mechanisms of motor-evoked potential generation after transient focal cerebral ischemia in the rat: implications for transcranial magnetic stimulation

We recently demonstrated that a long-lasting transmission defect in cortical synapses caused motor dysfunction after brief middle cerebral artery (MCA) occlusion in the rat despite rapid recovery of axons. In this experimental study, we have examined the impact of differential recovery of synapses and axons on generation of motor-evoked potentials (MEP) recorded from contralateral paralyzed and ipsilateral unaffected muscles, to gain insight into mechanisms of MEPs recorded from stroke patients by transcranial magnetic stimulation (TMS). MEPs generated by focal electrical stimulation of the forelimb area of motor cortex were simultaneously recorded from the brain stem, contra- and ipsilateral forelimb and contralateral hindlimb muscles in rats subjected to transient MCA occlusion. The effect of ischemia on cortical activity and axonal conduction was differentially studied by proximal or distal occlusion of the MCA. Regional cerebral blood flow changes in the forelimb area were monitored by laser-Doppler flowmetry during ischemia and reperfusion. In addition, synaptic transmission within the forelimb area of motor cortex was examined by intracellular and extracellular recording of potentials generated by stimulation of the premotor area. No MEP response was recorded during ischemia. Upon reperfusion: (i) motor axons readily regained their excitability and cortical stimulation caused successive pyramidal volleys (recorded as D waves from the brain stem) and a MEP from contralateral paralytic muscles although synaptic activation of motor pathways was not feasible; (ii) the amplitude of pyramidal volley was increased; (iii) MEPs with a longer latency were recorded from the ipsilateral forelimb. In conclusion, differential recovery of synapses and axons after ischemia may account for some previously unexplained findings (such as preserved MEPs in paralysed muscles) observed in cortical stimulation studies of stroke patients.     

Suppression of activity in the forelimb motor cortex temporarily enlarges forelimb representation in the homotopic cortex in adult rats

After forelimb motor cortex (FMC) damage, the unaffected homotopic motor cortex showed plastic changes. The present experiments were designed to clarify the electrophysiological nature of these interhemispheric effects. To this end, the output reorganization of the FMC was investigated after homotopic area activity was suppressed in adult rats. FMC output was compared after lidocaine-induced inactivation (L-group) or quinolinic acid-induced lesion (Q-group) of the contralateral homotopic cortex. In the Q-group of animals, FMC mapping was performed, respectively, 3 days (Q3D group) and 2 weeks (Q2W group) after cortical lesion. In each animal, FMC output was assessed by mapping movements induced by intracortical microstimulation (ICMS) in both hemispheres (hemisphere ipsilateral and contralateral to injections). The findings demonstrated that in the L-group, the size of forelimb representation was 42.2% higher than in the control group ( P  < 0.0001). The percentage of dual forelimb–vibrissa movement sites significantly increased over the controls ( P  < 0.0005). The dual-movement sites occupied a strip of the map along the rostrocaudal border between the forelimb and vibrissa representations. This form of interhemispheric diaschisis had completely reversed, with the recovery of the baseline map, 3 days after the lesion in the contralateral FMC. This restored forelimb map showed no ICMS-induced changes 2 weeks after the lesion in the contralateral FMC. The present results suggest that the FMCs in the two hemispheres interact continuously through predominantly inhibitory influences that preserve the forelimb representation and the border vs. vibrissa representation.     

Brain reorganization after stroke

After a stroke, recovery that continues beyond 3 or 4 weeks has been attributed to plasticity, a reorganization of the brain in which functions previously performed by the ischemic area are assumed by other ipsilateral or contralateral brain areas. Neuronal plasticity has been variously attributed to redundancy (parallel distributed pathways), changes in synaptic strength, axonal sprouting with formation of new synapses, assumption of function by contralateral homologous cortex, and substitution of uncrossed pathways. Transcranial magnetic stimulation, positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and 128-electrode high-resolution electroencephalography have been successfully applied to demonstrate cortical reorganization after hemiplegia. Recording the motor potential is a promising noninvasive method for the localization of motor control after hemispheric lesions. Most patients with hemiparetic stroke show some improvement, usually during the first 3 to 6 months after the ictus. Improvement and prognosis depend on a number of variables including volume and location of the infarction, age of the patient, and the elimination of risk factors to avoid future episodes (i.e., dietary control of lipids, the elimination of tobacco, and the control of diabetes and hypertension). Currently, emphasis has been placed on fibrinolytic treatment in the first 3 hours to prevent or minimize neurological deficit. Aside from the above listed factors, improvement after stroke may be due to reorganization of the brain, particularly the cerebral cortex, and repair of damaged tissue and recanalization. It is also important to relate such changes to functional improvement and successful rehabilitation.     

Adult rat motor cortex connections to thalamus following neonatal and juvenile frontal cortical lesions: WGA-HRP and amino acid studies

Frontal cortex was removed in 1- and 30-day-old rats. When both groups reached 90 days of age, the forelimb motor/sensory cortex in the unlesioned hemisphere was injected with wheat germ agglutinin-horseradish peroxidase (WGA-HRP) or tritiated leucine. Thalamic neurons were retrogradely labeled only ipsilateral to the WGA-HRP injection site in both neonatally and juvenile-lesioned subjects. Ventrolateral (VL), ventromedial (VM), centromedial (CM), centrolateral (CL), parafascicular (PF), posteromedial (POm), and posterior (PO) thalamic nuclei were labeled. This and the demonstration of only ipsilateral thalamocortical connections at birth helped explain the marked thalamic atrophy which developed ipsilateral to neonatal frontal cortex lesions. Death of thalamic neurons after neonatal removal of their normal cortical target could be due to their failure to sprout into the opposite cortex because that cortex was already innervated by the opposite thalamus at birth. Leucine motor/sensory cortex injections in both neonatally and juvenile-lesioned subjects labeled the ipsilateral VL, VM, CM, CL, PF, POm, and PO thalamic nuclei; contralateral CM, CL, and PF thalamic nuclei; ipsilateral medial, ventral, and lateral pontine nuclei; and parts of the contralateral pontine nuclei. The ipsilateral connections were always more robust than the contralateral connections. The contralateral corticothalamic and corticopontine projections, however, were much more numerous and widespread in neonatally compared to juvenile-lesioned subjects. The greater sparing of some motor functions said to occur in neonatal compared to adult motor cortex-lesioned subjects could be due to the plasticity of corticothalamic, corticopontine, and other corticofugal pathways, but not to the plasticity of thalamocortical pathways.     

Compensatory sprouting and impulse rerouting after unilateral pyramidal tract lesion in neonatal rats.

After lesions of the developing mammalian CNS, structural plasticity and functional recovery are much more pronounced than in the mature CNS. We investigated the anatomical reorganization of the corticofugal projections rostral to a unilateral lesion of the corticospinal tract at the level of the medullary pyramid (pyramidotomy) and the contribution of this reorganization and other descending systems to functional recovery. Two-day-old (P2) and adult rats underwent a unilateral pyramidotomy. Three months later the corticofugal projections to the red nucleus and the pons were analyzed; a relatively large number of corticorubral and corticopontine fibers from the lesioned side had crossed the midline and established an additional contralateral innervation of the red nucleus and the pons. Such anatomical changes were not seen after adult lesions. Intracortical microstimulation of the primary motor cortex with EMG recordings of the elbow flexor muscles were used to investigate possible new functional connections from the motor cortex of the pyramidotomy side to the periphery. In rats lesioned as adults, stimulation of the motor cortex ipsilateral to the pyramidotomy never elicited EMG activity. In contrast, in P2 lesioned rats bilateral forelimb EMGs were found. EMG latencies were comparable for the ipsilateral and contralateral responses but were significantly longer than in unlesioned animals. Transient inactivation of both red nuclei with the GABA receptor agonist muscimol led to a complete loss of these bilateral movements. Movements and EMGs reappeared after wash-out of the drug. These results suggest an important role of the red nucleus in the reconnection of the cortex to the periphery after pyramidotomy.     

Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke.

Bone marrow stromal cells (BMSCs) facilitate functional recovery in rats after stroke when administered acutely (1 day) or subacutely (7 days). In this study, we postponed the time of cell transplantation to 1 month after stroke. Female retired breeder rats were subjected to 2 h of middle cerebral artery occlusion (MCAo). Male BMSCs (3 x 10(6)) or phosphate-buffered saline were administered intravenously, and the animals were killed 3 months later. An additional population of nontreated rats was killed at 1 month after MCAo. Significant recovery of behavior was found in BMSC-treated rats beginning at 1 month after cell injection in the modified neurologic severity score test and the adhesive-removal test compared with control animals (P<0.05). In situ hybridization showed that BMSCs survived and preferentially localized to the ipsilateral hemisphere. Double staining revealed that approximately 13% and 6% Y-chromosome-positive cells expressed the astrocyte marker, glial fibrillary acidic protein, and the neuronal marker, microtubule-associated protein-2, respectively. In addition, BMSC treatment reduced scar thickness, and increased the number of proliferating cells and oligodendrocyte precursor cells along the subventricular zone in the ipsilateral hemisphere. Expression of the chemokine stromal-cell-derived factor-1 (SDF-1) was significantly increased along the ischemic boundary zone compared with the corresponding areas in the contralateral hemisphere at 1 month and 4 months (P<0.01) after stroke. The SDF-1 receptor, CXC-chemokine receptor-4 (CXCR4), was expressed in BMSCs both in vitro and in vivo. Our data show that the time window of BMSC therapy is at least 1 month after stroke; the interaction of SDF-1/CXCR4 may contribute to the trafficking of transplanted BMSCs.     

Ipsilateral connections of the ventral premotor cortex in a new world primate

The present study describes the pattern of connections of the ventral premotor cortex (PMv) with various cortical regions of the ipsilateral hemisphere in adult squirrel monkeys. Particularly, we 1) quantified the proportion of inputs and outputs that the PMv distal forelimb representation shares with other areas in the ipsilateral cortex and 2) defined the pattern of PMv connections with respect to the location of the distal forelimb representation in primary motor cortex (M1), primary somatosensory cortex (S1), and supplementary motor area (SMA). Intracortical microstimulation techniques (ICMS) were used in four experimentally naïve monkeys to identify M1, PMv, and SMA forelimb movement representations. Multiunit recording techniques and myelin staining were used to identify the S1 hand representation. Then, biotinylated dextran amine (BDA; 10,000 MW) was injected in the center of the PMv distal forelimb representation. After tangential sectioning, the distribution of BDA‐labeled cell bodies and terminal boutons was documented. In M1, labeling followed a rostrolateral pattern, largely leaving the caudomedial M1 unlabeled. Quantification of somata and terminals showed that two areas share major connections with PMv: M1 and frontal areas immediately rostral to PMv, designated as frontal rostral area (FR). Connections with this latter region have not been described previously. Moderate connections were found with PMd, SMA, anterior operculum, and posterior operculum/inferior parietal area. Minor connections were found with diverse areas of the precentral and parietal cortex, including S1. No statistical difference between the proportions of inputs and outputs for any location was observed, supporting the reciprocity of PMv intracortical connections. J. Comp. Neurol. 495:374–390, 2006. © 2006 Wiley‐Liss, Inc.     

A study of forelimb movements evoked by intracortical microstimulation after hemicerebellectomy in newborn, young and adult rats

Microstimulation of the cerebral motor cortex in normal adult rats evokes low-threshold contralateral and high-threshold ipsilateral forelimb movements. The present study examined the effects of hemicerebellar ablation at different postnatal ages on the current threshold values needed to evoke forelimb movements by intracortical stimulation. Animals that received hemicerebellar lesions at various ages were electrophysiologically tested 4-6 months postoperatively. In all groups, including non-lesion control animals, forelimb movements contralateral to the stimulating electrode were evoked at threshold values of 7-11 microA. Ipsilateral forelimb movements for control animals as well as those receiving cerebellar lesions at 45 or 120 days of age showed significantly higher mean threshold current values, ranging from 38 to 45 microA. In contrast, the mean threshold current values for ipsilateral forelimb movements in adult animals sustaining hemicerebellar lesions at 2, 10 or 21 days of age were significantly lowered, ranging from 16 to 22 microA. Secondary lesions of spared cerebellar tissue or callosal fibers in adult animals that had sustained hemicerebellectomy at two days of age had no effect on the current intensities needed to evoke forelimb responses. In comparison, lesions of the cerebral cortex contralateral to the stimulated cortex increased the threshold for ipsilateral movements and medullary pyramidal lesions ipsilateral to the stimulated cortex both reduced the number of responses and increased the threshold current intensities needed to evoke them. These data indicate that hemicerebellectomy within 3 weeks of age can induce electrophysiological alterations in the responses mediated by the corticospinal tract. These results support previous suggestions of the cerebral cortical involvement in compensation for neonatal cerebellar lesions.     

The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography

We have studied regional cerebral blood flow changes in 6 patients after their recovery from a first hemiplegic stroke. All had a single well-defined hemispheric lesion and at least a brachial monoparesis that subsequently recovered. Each patient had 6 measurements of cerebral blood flow by positron tomography with 2 scans at rest, 2 during movement of fingers of the recovered hand, and 2 during movement of fingers of the normal hand. When the normal fingers were moved, regional cerebral blood flow increased significantly in contralateral primary sensorimotor cortex and in the ipsilateral cerebellar hemisphere. When the fingers of the recovered hand were moved, significant regional cerebral blood flow increases were observed in both contralateral and ipsilateral primary sensorimotor cortex and in both cerebellar hemispheres. Other regions, namely, insula, inferior parietal, and premotor cortex, were also bilaterally activated with movement of the recovered hand. We have also demonstrated, by using a new technique of image analysis, different functional connections between the thalamic nuclei and specific cortical and cerebellar regions during these movements. Our results suggest that ipsilateral motor pathways may play a role in the recovery of motor function after ischemic stroke.     

Manganese-enhanced MRI of brain plasticity in relation to functional recovery after experimental stroke.

Restoration of function after stroke may be associated with structural remodeling of neuronal connections outside the infarcted area. However, the spatiotemporal profile of poststroke alterations in neuroanatomical connectivity in relation to functional recovery is still largely unknown. We performed in vivo magnetic resonance imaging (MRI)-based neuronal tract tracing with manganese in combination with immunohistochemical detection of the neuronal tracer wheat-germ agglutinin horseradish peroxidase (WGA-HRP), to assess changes in intra- and interhemispheric sensorimotor network connections from 2 to 10 weeks after unilateral stroke in rats. In addition, functional recovery was measured by repetitive behavioral testing. Four days after tracer injection in perilesional sensorimotor cortex, manganese enhancement and WGA-HRP staining were decreased in subcortical areas of the ipsilateral sensorimotor network at 2 weeks after stroke, which was restored at later time points. At 4 to 10 weeks after stroke, we detected significantly increased manganese enhancement in the contralateral hemisphere. Behaviorally, sensorimotor functions were initially disturbed but subsequently recovered and plateaued 17 days after stroke. This study shows that manganese-enhanced MRI can provide unique in vivo information on the spatiotemporal pattern of neuroanatomical plasticity after stroke. Our data suggest that the plateau stage of functional recovery is associated with restoration of ipsilateral sensorimotor pathways and enhanced interhemispheric connectivity.     

Mouse intracerebral hemorrhage models produce different degrees of initial and delayed damage,axonal sprouting,and recovery

The mechanisms of delayed damage and recovery after intracerebral hemorrhage (ICH) remain poorly defined. Two rodent models of ICH are commonly used: injection of the enzyme collagenase (cICH) and injection of autologous blood (bICH). In mice, we compared the effects of these two models on initial and delayed tissue damage, motor system connections, and behavioral recovery. There is no difference in lesion size between models. Injection of autologous blood causes greater mass effect and early mortality. However, cICH produces greater edema, inflammation, and cell death. Injection of the enzyme collagenase causes greater loss of cortical connections and secondary shrinkage of the striatum. Intracerebral hemorrhage occurs within the motor system connections of the striatum. Mapping of the projections of the forelimb motor area shows a significant sprouting in motor cortex projections only in cICH. Both models of ICH produce deficits in forelimb motor control. Behavioral recovery occurs by 5 weeks in cICH and 9 weeks in bICH. In summary, cICH and bICH differ in almost every facet of initial and delayed stroke pathophysiology, with cICH producing greater initial and secondary tissue damage and greater motor system axonal sprouting than bICH. Motor recovery occurs in both models, suggesting that motor system axonal sprouting in cICH is not causally associated with recovery.     

Interhemispheric transfer of paired associative stimulation-induced plasticity in the human motor cortex

To evaluate the interhemispheric interaction of paired associative stimulation (PAS)-induced plasticity, we performed a transcranial magnetic stimulation study on nine healthy volunteers after PAS, motor evoked potentials were significantly enhanced in both the nonstimulated and stimulated primary motor cortex (M1). Short-interval intracortical inhibition and intracortical facilitation were not changed in the nonstimulated M1, but interhemispheric inhibition was significantly reduced after PAS. Motor evoked potential enhancement in the nonstimulated M1 was significantly correlated to that in the stimulated M1 and tended to correlate with the degree of pre-PAS interhemispheric inhibition. These results show that PAS-induced plasticity in the dominant M1 can transfer to contralateral M1 depending on the amount of plastic change induced in the stimulated M1 and, also probably, on the amount of transcallosal connection.     

Topography of corticopontine remodelling after cortical lesions in newborn rats

Autoradiographic and axonal degeneration staining techniques were combined in individual animals to study the distribution of corticopontine fibers. In normal animals, forelimb and hindlimb motor cortical projections terminated somatotopically within the ipsilateral pontine nuclei. Sparse crossed projections also displayed a somatotopic pattern. After unilateral sensorimotor cortical lesions in newborn rats, an increase in the crossed corticopontine fibers arising from the opposite unablated motor cortex was observed at maturity. These fibers distributed in a topographic pattern similar to the normal ipsilateral corticopontine pattern; forelimb motor cortical projections terminated rostral to hindlimb motor cortical fibers. The specific distribution of the anomalous fibers suggests that they constitute a functional pathway.     

Delayed treatment with monoclonal antibody IN-1 1 week after stroke results in recovery of function and corticorubral plasticity in adult rats.

Neuronal death due to ischemic stroke results in permanent deficits in sensory, language, and motor functions. The growth-restrictive environment of the adult central nervous system (CNS) is an obstacle to functional recovery after stroke and other CNS injuries. In this regard, Nogo-A is a potent neurite growth-inhibitory protein known to restrict neuronal plasticity in adults. Previously, we have found that treatment with monoclonal antibody (mAb) IN-1 to neutralize Nogo-A immediately after stroke enhanced motor cortico-efferent plasticity and recovery of skilled forelimb function in rats. However, immediate treatment for stroke is often not clinically feasible. Thus, the present study was undertaken to determine whether cortico-efferent plasticity and functional recovery would occur if treatment with mAb IN-1 was delayed 1 week after stroke. Adult rats were trained on a forelimb-reaching task, and the middle cerebral artery was occluded to induce focal cerebral ischemia to the forelimb sensorimotor cortex. After 1 week, animals received mAb IN-1 treatment, control antibody, or no treatment, and were tested for 9 more weeks. To assess cortico-efferent plasticity, the sensorimotor cortex opposite the stroke lesion was injected with an anterograde neuroanatomical tracer. Behavioral analysis demonstrated a recovery of skilled forelimb function, and anatomical studies revealed neuroplasticity at the level of the red nucleus in animals treated with mAb IN-1, thus demonstrating the efficacy of this treatment even if administered 1 week after stroke.     

Allogeneic bone marrow stromal cells promote glial–axonal remodeling without immunologic sensitization after stroke in rats

We evaluated the effects of allogeneic bone marrow stromal cell treatment of stroke on functional outcome, glial–axonal architecture, and immune reaction. Female Wistar rats were subjected to 2 h of middle cerebral artery occlusion. Rats were injected intravenously with PBS, male allogeneic ACI – or syngeneic Wistar –bone marrow stromal cells at 24 h after ischemia and sacrificed at 28 days. Significant functional recovery was found in both cell-treated groups compared to stroke rats that did not receive BMSCs, but no difference was detected between allogeneic and syngeneic cell-treated rats. No evidence of T cell priming or humoral antibody production to marrow stromal cells was found in recipient rats after treatment with allogeneic cells. Similar numbers of Y-chromosome⁺ cells were detected in the female rat brains in both groups. Significantly increased thickness of individual axons and myelin, and areas of the corpus callosum and the numbers of white matter bundles in the striatum were detected in the ischemic boundary zone of cell-treated rats compared to stroked rats. The areas of the contralateral corpus callosum significantly increased after cell treatment compared to normal rats. Processes of astrocytes remodeled from hypertrophic star-like to tadpole-like shape and oriented parallel to the ischemic regions after cell treatment. Axonal projections emanating from individual parenchymal neurons exhibited an overall orientation parallel to elongated radial processes of reactive astrocytes of the cell-treated rats. Allogeneic and syngeneic bone marrow stromal cell treatment after stroke in rats improved neurological recovery and enhanced reactive oligodendrocyte and astrocyte related axonal remodeling with no indication of immunologic sensitization in adult rat brain.