Contralesional Forelimb Research Articles

Supraspinal Sensorimotor and Pain-Related Reorganization after a Hemicontusion Rat Cervical Spinal Cord Injury.

Because the presence of pain impedes motor recovery in individuals with spinal cord injury (SCI), it is necessary to understand their supraspinal substrates in translational animal models. Using functional magnetic resonance imaging (fMRI) in a rat model of hemicontusion cervical SCI, supraspinal changes were mapped and correlated with sensorimotor behavioral outcomes. Female adult rats underwent sham or SCI using a 2.5 mm impactor and 150 kdyn force. SCI permanently impaired motor activity in only the ipsilesional forelimb along with thermal hyperalgesia at 5 and 6 weeks. Spinal MRI at 8 weeks after SCI showed ipsilateral T1 and T2 lesions with no discernable lesions across shams. fMRI mapping during electrical forepaw stimulation indicated SCI-induced sensorimotor reorganization with an expansion of the contralesional forelimb representation. Resting state fMRI-based functional connectivity density (FCD), a marker of regional neuronal hubs, increased or decreased across brain regions involved in nociception. FCD increases after SCI were in the primary and secondary somatosensory cortices (S1 and S2), anterior cingulate cortex (ACC), insula, and the pre-frontal cortex (PFC), and decreases were across the hippocampus, thalamus, hypothalamus, and amygdala in SCI. Resting state functional connectivity (RSFC) assessments from the FCD altered regions of interest indicated cortico-cortical RSFC increases and cortico-insular, cortico-thalamic, and cortico-hypothalamic RSFC decreases after SCI. Hippocampus, amygdala, and thalamus showed decreased RSFC with most cortical regions and between themselves except the hippocampus-amygdala network, which showed increased RSFC after SCI. Whereas select nociceptive region's intrinsic activity associated strongly with evoked pain behaviors after SCI (e.g., PFC, ACC, hippocampus, thalamus, hypothalamus, M1, and S1BF) other nociceptive regions had weaker associations (e.g., amygdala, insula, auditory cortex, S1FL, S1HL, S2, and M2), but differed significantly in their intrinsic activities between sham and SCI. The weaker associated nociceptive regions may possibly encode both the evoked and affective components of pain.

Remote Corticospinal Tract Degeneration After Cortical Stroke in Rats May Not Preclude Spontaneous Sensorimotor Recovery

Background. Recovery of motor function after stroke appears to be related to the integrity of axonal connections in the corticospinal tract (CST) and corpus callosum, which may both be affected after cortical stroke. Objective. In the present study, we aimed to elucidate the relationship of changes in measures of the CST and transcallosal tract integrity, with the interhemispheric functional connectivity and sensorimotor performance after experimental cortical stroke. Methods. We conducted in vivo diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and behavior testing in twenty-five male Sprague Dawley rats recovering from unilateral photothrombotic stroke in the sensorimotor cortex. Twenty-three healthy rats served as controls. Results. A reduction in the number of reconstructed fibers, a lower fractional anisotropy, and higher radial diffusivity in the ipsilesional but intact CST, reflected remote white matter degeneration. In contrast, transcallosal tract integrity remained preserved. Functional connectivity between the ipsi- and contralesional forelimb regions of the primary somatosensory cortex significantly reduced at week 8 post-stroke. Comparably, usage of the stroke-affected forelimb was normal at week 28, following significant initial impairment between day 1 and week 8 post-stroke. Conclusions. Our study shows that post-stroke motor recovery is possible despite degeneration in the CST and may be supported by intact neuronal communication between hemispheres.

Visualization and Quantification of Post-stroke Neural Connectivity and Neuroinflammation Using Serial Two-Photon Tomography in the Whole Mouse Brain.

Whole-brain volumetric microscopy techniques such as serial two-photon tomography (STPT) can provide detailed information on the roles of neuroinflammation and neuroplasticity throughout the whole brain post-stroke. STPT automatically generates high-resolution images of coronal sections of the entire mouse brain that can be readily visualized in three dimensions. We developed a pipeline for whole brain image analysis that includes supervised machine learning (pixel-wise random forest models via the “ilastik” software package) followed by registration to a standardized 3-D atlas of the adult mouse brain (Common Coordinate Framework v3.0; Allen Institute for Brain Science). These procedures allow the detection of cellular fluorescent signals throughout the brain in an unbiased manner. To illustrate our imaging techniques and automated image quantification, we examined long-term post-stroke motor circuit connectivity in mice that received a motor cortex photothrombotic stroke. Two weeks post-stroke, mice received intramuscular injections of pseudorabies virus (PRV-152), a trans-synaptic retrograde herpes virus driving expression of green fluorescent protein (GFP), into the affected contralesional forelimb to label neurons in descending tracts to the forelimb musculature. Mice were sacrificed 3 weeks post-stroke. We also quantified sub-acute neuroinflammation in the post-stroke brain in a separate cohort of mice following a 60 min transient middle cerebral artery occlusion (tMCAo). Naive e450+-labeled splenic CD8+ cytotoxic T cells were intravenously injected at 7, 24, 48, and 72 h post-tMCAo. Mice were sacrificed 4 days after stroke. Detailed quantification of post-stroke neural connectivity and neuroinflammation indicates a role for remote brain regions in stroke pathology and recovery. The workflow described herein, incorporating STPT and automated quantification of fluorescently labeled features of interest, provides a framework by which one can objectively evaluate labeled neuronal or lymphocyte populations in healthy and injured brains. The results provide region-specific quantification of neural connectivity and neuroinflammation, which could be a critical tool for investigating mechanisms of not only stroke recovery, but also a wide variety of brain injuries or diseases.

Remote Changes in Cortical Excitability after Experimental Traumatic Brain Injury and Functional Reorganization.

Although cognitive and behavioral deficits are well known to occur following traumatic brain injury (TBI), motor deficits that occur even after mild trauma are far less known, yet are equally persistent. This study was aimed at making progress toward determining how the brain reorganizes in response to TBI. We used the adult rat controlled cortical impact injury model to study the ipsilesional forelimb map evoked by electrical stimulation of the affected limb, as well as the contralesional forelimb map evoked by stimulation of the unaffected limb, both before injury and at 1, 2, 3, and 4 weeks after using functional magnetic resonance imaging (fMRI). End-point c-FOS immunohistochemistry data following 1 h of constant stimulation of the unaffected limb were acquired in the same rats to avoid any potential confounds due to altered cerebrovascular coupling. Single and paired-pulse sensory evoked potential (SEP) data were recorded from skull electrodes over the contralesional cortex in a parallel series of rats before injury, at 3 days, and at 1, 2, 3, and 4 weeks after injury in order to determine whether alterations in cortical excitability accompanied reorganization of the cortical map. The results show a transient trans-hemispheric shift in the ipsilesional cortical map as indicated by fMRI, remote contralesional increases in cortical excitability that occur in spatially similar regions to altered fMRI activity and greater c-FOS activation, and reduced or absent ipsilesional cortical activity chronically. The contralesional changes also were indicated by reduced SEP latency within 3 days after injury, but not by blood oxygenation level-dependent fMRI until much later. Detailed interrogation of cortical excitability using paired-pulse electrophysiology showed that the contralesional cortex undergoes both an early and a late post-injury period of hyper-excitability in response to injury, interspersed by a period of relatively normal activity. From these data, we postulate a cross-hemispheric mechanism by which remote cortex excitability inhibits ipsilesional activation by rebalanced cortical excitation-inhibition.

Motor impairment and compensation in a hemiparkinsonian rat model: correlation between dopamine depletion severity, cerebral metabolism and gait patterns

BackgroundIn Parkinson’s disease (PD), cerebral dopamine depletion is associated with PD subtype-specific metabolic patterns of hypo- and hypermetabolism. It has been hypothesised that hypometabolism reflects impairment, while hypermetabolism may indicate compensatory activity. In order to associate metabolic patterns with pathophysiological and compensatory mechanisms, we combined resting state [18F]FDG-PET (to demonstrate brain metabolism in awake animals), [18F]FDOPA-PET (dopamine depletion severity) and gait analysis in a unilateral 6-hydroxydopamine rat model.ResultsWe found unilateral nigro-striatal dopaminergic loss to decrease swing speed of the contralesional forelimb and stride length of all paws in association with depletion severity. Depletion severity was found to correlate with compensatory changes such as increased stance time of the other three paws and diagonal weight shift to the ipsilesional hind paw. [18F]FDG-PET revealed ipsilesional hypo- and contralesional hypermetabolism; metabolic deactivation of the ipsilesional network needed for sensorimotor integration (hippocampus/retrosplenial cortex/lateral posterior thalamus) was solely associated with bradykinesia, but hypometabolism of the ipsilesional rostral forelimb area was related to both pathological and compensatory gait changes. Mixed effects were also found for hypermetabolism of the contralesional midbrain locomotor region, while contralesional striatal hyperactivation was linked to motor impairments rather than compensation.ConclusionsOur results indicate that ipsilesional hypo- and contralesional hypermetabolism contribute to both motor impairment and compensation. This is the first time when energy metabolism, dopamine depletion and gait analysis were combined in a hemiparkinsonian model. By experimentally increasing or decreasing compensational brain activity, its potential and limits can be further investigated.

Anti-Parkinsonian Activity of Hemantane on a Model of Hemiparkinsonian Syndrome in Rats.

Hemantane demonstrated a pronounced antiparkinsonian activity in the model of hemiparkinsonian syndrome provoked in rats by unilateral intracerebral injection of 6-hydroxydopamine, which was comparable to efficacy of levodopa in decreasing the duration of cataleptogenic state and the degree of akinesia of the contralesional forelimb assessed in the cylinder test. In the stepping test, hemantane exerted a long-term effect in contrast to levodopa, which diminished its beneficial action to the treatment day 21. In the swing test, the behavior normalized only by hemantane.

Diffusional kurtosis and diffusion tensor imaging reveal different time-sensitive stroke-induced microstructural changes.

Diffusion MRI is a promising, clinically feasible imaging technique commonly used to describe white matter changes after stroke. We investigated the sensitivity of diffusion MRI to detect microstructural alterations in gray matter after sensorimotor cortex stroke in adult male rats. The mean diffusivity (MD) and mean kurtosis of perilesional motor cortex were compared with measures in the contralesional forelimb area of sensorimotor cortex at 2 hours, 24 hours, 72 hours, or 25 days after surgery. MD and mean kurtosis were correlated to the surface densities of glia, dendrites, and axons. Perilesional mean kurtosis was increased at 72 hours and 25 days after stroke, whereas MD was no longer different from contralesional sensorimotor cortex at 24 hours after stroke. There was a significant increase in the density of glial processes at 72 hours after stroke in perilesional motor cortex, which correlated with perilesional MD. These data support that mean kurtosis and MD provide different but complimentary information on acute and chronic changes in perilesional cortex. Glia infiltration is associated with pseudonormalization of MD in the perilesional motor cortex at 72 hours after lesion; however, this association is absent 25 days after lesion. These data suggest that there are likely several different, time-specific microstructural changes underlying these 2 complimentary diffusion measures.

Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

Early poststroke rehabilitation effectively improves recovery of function, likely by engaging multiple plasticity processes through use-dependent activation of neural circuits. The loci of such neuroplastic reorganization have not been examined during the initial phase of behavioral recovery. In the current study, we sought to evaluate sub-components of rehabilitation and to identify brain sites first engaged by early rehabilitation. Rats were subjected to endothelin-1 ischemia and placed in either enriched environment (EE), daily reach training (RT), combination of enriched environment and reach training (ER), or standard housing (ST) starting 7 days post ischemia. Functional and histopathological assessments were made after 2, 5, and 10 days of treatment. Animals exposed to 10 days of ER treatment exhibited significantly more use-dependent neuronal activity (FosB/ΔFosB expression) in perilesional cortex than those exposed to EE, RT, or ST treatments. Similar trends were observed in both perilesional striatum and contralesional forelimb motor cortex. This use-dependent plasticity was not explained by differences in neuronal death, inflammation, or lesion volume. The increased activity likely contributes to the neuroplastic changes and functional recovery observed after extended periods of rehabilitation. Importantly, EE or RT alone did not lead to enhanced activity suggesting that combination therapy is necessary to promote maximum recovery.

Training following unilateral cervical spinal cord injury in rats affects the contralesional forelimb

Rehabilitative training is an essential component of current therapeutic strategies for spinal cord injured individuals. However, there are still various open questions that need to be answered in order to optimize training strategies. For example, why can animals trained in a single task perform worse compared to untrained animals when tested in untrained tasks. Such results suggest a potential competition among motor tasks over spared neuronal circuitry. Whether training induced competition for neuronal circuitry may also exist between injured and spared circuitries of the ipsi- and contralesional extremity is currently unknown. Here we investigated whether training restricted to the frontlimb ipsilateral to cervical spinal injury (IF) can impact motor performance of the contralesional frontlimb (CF) in a rat model of cervical SCI. We compared CF performance following general motor training of all limbs (horizontal ladder), following specific training of the IF (pellet reaching), as well as following a combination of both training paradigms. Our findings indicate that adding ipsilateral side-specific training to general training can negatively impact performance of the CF, without resulting in any improvement of performance of the IF. In conclusion, our results emphasize that important decisions have to be made when designing rehabilitative training strategies, ideally taking into account more than the primarily affected extremity.

Delayed anti-nogo-a therapy improves function after chronic stroke in adult rats.

we have shown that anti-Nogo-A immunotherapy to neutralize the neurite growth inhibitory protein Nogo-A results in functional improvement and enhanced plasticity after ischemic stroke in the adult rat. The present study investigated whether functional improvement and neuronal plasticity can be induced by this immunotherapy when administered to the chronic stroke-impaired rat. adult rats were trained to perform the skilled forelimb reaching test, followed by permanent middle cerebral artery occlusion to impair the preferred forelimb. Nine weeks after stroke, animals showing a profound deficit were randomly distributed to 3 groups: no treatment, control antibody, or anti-Nogo-A antibody (11C7). Animals were tested weekly after stroke surgery and daily after antibody treatment until the end of the study. Biotin dextran amine tracing was injected into the nonlesioned forelimb motor cortex at the end of behavioral testing to determine axonal plasticity. all rats showed similar forelimb impairment before treatment. Animals treated with anti-Nogo-A immunotherapy started to show improvement 3 weeks after treatment. Such improvement became significantly better than stroke-only control and control Ab-treated animals, and persisted to the end of the study. Biotin dextran amine-labeled axonal fiber analysis also showed significant enhanced corticorubral axonal sprouting from the contralesional forelimb motor cortex to the deafferented red nucleus in the anti-Nogo-A immunotherapy rats. these results indicate that improvement of chronic neurological deficits and enhancement of neuronal plasticity can be induced in the adult rat with anti-Nogo-A immunotherapy, and that this therapy may be used to restore function even when administered long after ischemic brain damage has occurred.

Large‐scale reorganization of corticofugal fibers after neonatal hemidecortication for functional restoration of forelimb movements

As an experimental model to study the mechanism of large-scale network plasticity of the juvenile brain, functional compensation after neonatal brain damage was studied in rats that received unilateral decortication at postnatal day 5. These animals exhibited a marked ability in reaching and grasping movements in the contralesional side of the forelimb when tested at 10-14 weeks of age. Additional lesion of the sensorimotor cortex in the remaining contralesional hemisphere at this stage resulted in severe impairment of both forelimbs. It was suggested that the sensorimotor cortex on the contralesional side was controlling the movements of both forelimbs. Following the injection of an anterograde tracer into the remaining sensorimotor cortex, the corticofugal axons from the remaining sensorimotor cortex were found to issue aberrant projections to the contralateral red nucleus, contralateral superior colliculus, contralateral pontine nuclei, ipsilateral dorsal column nucleus and ipsilateral gray matter of the cervical spinal cord, all of which appeared to be necessary for the control of contralesional forelimb movements. These results suggest that the forelimb movements on the contralesional side were compensated by large-scale reorganization of the corticofugal axons from the remaining sensorimotor cortex.

The Effects of Repeated Rehabilitation “Tune-Ups” on Functional Recovery After Focal Ischemia in Rats

Background. For most stroke survivors, rehabilitation therapy is the only treatment option available. The beneficial effects of early rehabilitation on neuroplasticity and functional recovery have been modeled in experimental stroke using a combination of enriched environment and rehabilitation. However, the impact of a secondary intervention, such as a periodic return to therapy, remains unclear. Objective. This study examines whether a return to enriched rehabilitation (ie, “tune-up”) can further promote functional recovery or produce beneficial changes in brain plasticity in the chronic phase of stroke recovery. Methods. Rats were exposed to focal ischemia (endothelin-1 applied to forelimb sensorimotor cortex and dorsolateral striatum) and allowed to recover either in standard housing or in a combination of enriched environment and rehabilitative reaching for 9 weeks. Animals were then exposed to rotating periods of standard housing (5 weeks) and intensive “tune-up” therapy consisting of various sensorimotor/cognitive activities (2 weeks). Functional recovery was assessed using the Montoya staircase, beam-traversing, and cylinder tests, and Golgi—Cox analysis was used to examine dendritic complexity in the contralesional forelimb motor cortex. Results. Although early enriched rehabilitation significantly improved sensorimotor function in both the beam and staircase tests, “tune-up” therapy had no effect on recovery. Golgi—Cox analysis revealed no effect of treatment on dendritic complexity. Conclusions. This study reaffirms the benefits of early rehabilitation for functional recovery after stroke. However, “tune-up” therapy provided no benefit in ischemic animals regardless of earlier rehabilitation experience. It is possible that alternative approaches in the chronic phase may prove more effective.

Motor recovery and axonal plasticity with short-term amphetamine after stroke.

There is considerable debate regarding the efficacy of amphetamine to facilitate motor recovery after stroke or experimental brain injury. Different drug dosing and timing schedules and differing physical rehabilitation strategies may contribute to outcome variability. The present study was designed to ascertain (1) whether short-term amphetamine could induce long-term functional motor recovery in rats after an ischemic lesion modeling stroke in humans; (2) how different levels of physical rehabilitation interact with amphetamine to enhance forelimb-related functional outcome; and (3) whether motor improvement was associated with axonal sprouting from intact corticoefferent pathways originating in the contralesional forelimb motor cortex. After permanent middle cerebral artery occlusion, rats received vehicle or amphetamine during the first postoperative week (2 mg/kg, subcutaneously on Postoperative Days 2, 5, and 8). In both treatment groups, separate cohorts of rats were exposed to different levels of "physical rehabilitation" represented by a control environment, enriched environment, or enriched environment with additional sessions of focused activity. Skilled forelimb performance was assessed using the forelimb reaching task and ladder rung walk test. Anterograde tracing with biotinylated dextran amine was used to assess new fiber outgrowth to denervated motor areas. All treatment groups showed significant motor improvement as compared with control-housed, vehicle-treated animals. However, animals housed in an enriched environment that received amphetamine paired with focused activity sessions performed significantly better than any other treatment group and was the only group to achieve complete motor recovery (ie, reached preoperative performance) by 8 weeks. This recovery was associated with axonal sprouting into deafferentated subcortical areas from contralesional projection neurons. This study suggests that, after stroke, short-term pairing of amphetamine with sufficiently focused activity is an effective means of inducing long-term improvement in forelimb motor function. The anatomic data suggests that corticoefferent plasticity in the form of axonal sprouting contributes to the maintenance of motor recovery.

Abnormalities in skilled reaching movements are improved by peripheral anesthetization of the less-affected forelimb after sensorimotor cortical infarcts in rats

Unilateral damage to sensorimotor cortical (SMC) regions can profoundly impair skilled reaching function in the contralesional forelimb. Such damage also results in impairments and compensatory changes in the less-affected/ipsilesional forelimb, but these effects remain poorly understood. Furthermore, anesthetization of the ipsilesional hand in humans with cerebral infarcts has been reported to produce transient functional improvements in the paretic hand [Floel A, Nagorsen U, Werhahn KJ, Ravindran S, Birbaumer N, Knecht S, et al. Influence of somatosensory input on motor function in patients with chronic stroke. Ann Neurol 2004;56:206–12; Voller B, Floel A, Werhahn KJ, Ravindran S, Wu CW, Cohen LG. Contralateral hand anesthesia transiently improves poststroke sensory deficits. Ann Neurol 2006;59:385–8]. One aim of this study was to sensitively assay the bilateral effects of unilateral ischemic SMC damage on performance of a unimanual skilled reaching task (the single pellet retrieval task) that rats had acquired pre-operatively with each forelimb. The second aim was to determine whether partially recovered contralesional reaching function is influenced by anesthetization of the ipsilesional forelimb. Unilateral SMC lesions were found to result in transient ipsilesional impairments in reaching success and significant ipsilesional abnormalities in reaching movements compared with sham-operates. There were major contralesional reaching impairments which improved during a 4 week training period, but movements remained significantly abnormal. Anesthetization of the ipsilesional forelimb with lidocaine at this time attenuated the contralesional movement abnormalities. These findings indicate that unilateral ischemic SMC lesions impair skilled reaching behavior in both forelimbs. Furthermore, after partial recovery in the contralesional forelimb, additional improvements can be induced by transient anesthetization of the ipsilesional forelimb. This is consistent with the effects of unilateral anesthetization in humans which have been attributed to the modulation of competitive interhemispheric interactions. The present findings suggest that such interactions are also likely to influence skilled reaching function in rats.

Differential recovery of multimodal MRI and behavior after transient focal cerebral ischemia in rats.

The association between recovery of brain function and behavior after transient cerebral ischemia in animals and humans is incompletely characterized. Quantitative diffusion- (DWI), perfusion- (PWI), T(2)-weighted (T(2)WI), and functional magnetic resonance imaging (fMRI) were performed before, during, and up to 1 day after 20-mins transient middle cerebral artery occlusion (tMCAO; n=6) or sham operation (n=6) in male Sprague-Dawley rats. Viability thresholds were employed to calculate diffusion, perfusion, and T(2) lesion volumes. Region of interest analysis was used to evaluate structural and functional MR signal changes within the sensorimotor network, which were then related to corresponding behavioral measures. Post-mortem 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed 24 h after ischemia. Transient middle cerebral artery occlusion produced lesions on DWI and PWI, which fully recovered by 30 mins after reperfusion. Ipsilesional fMRI responses to hypercapnia and forepaw stimulation were significantly impaired after ischemia and did not fully normalize until 3 and 24 h after tMCAO, respectively. No abnormalities were observed on imaging or TTC at 24 h despite significant behavioral dysfunctions including contralesional forelimb impairment and ipsilesional neglect. No MRI, behavioral, or TTC anomalies were observed in sham-operated rats. There were no significant correlations between MRI parameters, behavior, and TTC in either group. Together, these results suggest that normal findings on diffusion, perfusion, and T(2) imaging shortly after transient ischemia may not indicate normal tissue status as indicated by fMRI and behavior, which may help explain the persistence of neurologic deficits in patients with normal conventional MRI after cerebral ischemia.

Correlation between Brain Reorganization, Ischemic Damage, and Neurologic Status after Transient Focal Cerebral Ischemia in Rats: A Functional Magnetic Resonance Imaging Study

The pattern and role of brain plasticity in stroke recovery has been incompletely characterized. Both ipsilesional and contralesional changes have been described, but it remains unclear how these relate to functional recovery. Our goal was to correlate brain activation patterns with tissue damage, hemodynamics, and neurologic status after temporary stroke, using functional magnetic resonance imaging (fMRI). Transverse relaxation time (T2)-weighted, diffusion-weighted, and perfusion MRI were performed at days 1 (n = 7), 3 (n = 7), and 14 (n = 7) after 2 hr unilateral middle cerebral artery occlusion in rats. Functional activation and cerebrovascular reactivity maps were generated from contrast-enhanced fMRI during forelimb stimulation and hypercapnia, respectively. Before MRI, rats were examined neurologically. We detected loss of activation responses in the ipsilesional sensorimotor cortex, which was related to T2 lesion size (r = -0.858 on day 3, r = -0.979 on day 14; p < 0.05). Significant activation responses in the contralesional hemisphere were detected at days 1 and 3. The degree of shift in balance of activation between the ipsilesional and contralesional hemispheres, characterized by the laterality index, was linked to the T2 and apparent diffusion coefficient in the ipsilesional contralesional forelimb region of the primary somatosensory cortex and primary motor cortex at day 1 (r = -0.807 and 0.782, respectively; p < 0.05) and day 14 (r = -0.898 and -0.970, respectively; p < 0.05). There was no correlation between activation parameters and perfusion status or cerebrovascular reactivity. Finally, we found that the laterality index and neurologic status changed in parallel over time after stroke, so that when all time points were grouped together, neurologic status was inversely correlated with the laterality index (r = -0.571; p = 0.016). This study suggests that the degree of shift of activation balance toward the contralesional hemisphere early after stroke increases with the extent of tissue injury and that functional recovery is associated mainly with preservation or restoration of activation in the ipsilesional hemisphere.