Motor compensation and its effects on neural reorganization after stroke.

Stroke instigates a dynamic process of repair and remodelling of remaining neural circuits, and this process is shaped by behavioural experiences. The onset of motor disability simultaneously creates a powerful incentive to develop new, compensatory ways of performing daily activities. Compensatory movement strategies that are developed in response to motor impairments can be a dominant force in shaping post-stroke neural remodelling responses and can have mixed effects on functional outcome. The possibility of selectively harnessing the effects of compensatory behaviour on neural reorganization is still an insufficiently explored route for optimizing functional outcome after stroke.

Segmentation-Less, Automated, Vascular Vectorization.

Recent advances in two-photon fluorescence microscopy (2PM) have allowed large scale imaging and analysis of blood vessel networks in living mice. However, extracting network graphs and vector representations for the dense capillary bed remains a bottleneck in many applications. Vascular vectorization is algorithmically difficult because blood vessels have many shapes and sizes, the samples are often unevenly illuminated, and large image volumes are required to achieve good statistical power. State-of-the-art, three-dimensional, vascular vectorization approaches often require a segmented (binary) image, relying on manual or supervised-machine annotation. Therefore, voxel-by-voxel image segmentation is biased by the human annotator or trainer. Furthermore, segmented images oftentimes require remedial morphological filtering before skeletonization or vectorization. To address these limitations, we present a vectorization method to extract vascular objects directly from unsegmented images without the need for machine learning or training. The Segmentation-Less, Automated, Vascular Vectorization (SLAVV) source code in MATLAB is openly available on GitHub. This novel method uses simple models of vascular anatomy, efficient linear filtering, and vector extraction algorithms to remove the image segmentation requirement, replacing it with manual or automated vector classification. Semi-automated SLAVV is demonstrated on three in vivo 2PM image volumes of microvascular networks (capillaries, arterioles and venules) in the mouse cortex. Vectorization performance is proven robust to the choice of plasma- or endothelial-labeled contrast, and processing costs are shown to scale with input image volume. Fully-automated SLAVV performance is evaluated on simulated 2PM images of varying quality all based on the large (1.4×0.9×0.6 mm3 and 1.6×108 voxel) input image. Vascular statistics of interest (e.g. volume fraction, surface area density) calculated from automatically vectorized images show greater robustness to image quality than those calculated from intensity-thresholded images.

A Window of Vascular Plasticity Coupled to Behavioral Recovery after Stroke.

Stroke causes remodeling of vasculature surrounding the infarct, but whether and how vascular remodeling contributes to recovery are unclear. We established an approach to monitor and compare changes in vascular structure and blood flow with high spatiotemporal precision after photothrombotic infarcts in motor cortex using longitudinal 2-photon and multiexposure speckle imaging in mice of both sexes. A spatially graded pattern of vascular structural remodeling in peri-infarct cortex unfolded over the first 2 weeks after stroke, characterized by vessel loss and formation, and selective stabilization of a subset of new vessels. This vascular structural plasticity was coincident with transient activation of transcriptional programs relevant for vascular remodeling, reestablishment of peri-infarct blood flow, and large improvements in motor performance. Local vascular plasticity was strongly predictive of restoration of blood flow, which was in turn predictive of behavioral recovery. These findings reveal the spatiotemporal evolution of vascular remodeling after stroke and demonstrate that a window of heightened vascular plasticity is coupled to the reestablishment of blood flow and behavioral recovery. Our findings support that neovascularization contributes to behavioral recovery after stroke by restoring blood flow to peri-infarct regions. These findings may inform strategies for enhancing recovery from stroke and other types of brain injury.SIGNIFICANCE STATEMENT An improved understanding of neural repair could inform strategies for enhancing recovery from stroke and other types of brain injury. Stroke causes remodeling of vasculature surrounding the lesion, but whether and how the process of vascular remodeling contributes to recovery of behavioral function have been unclear. Here we used longitudinal in vivo imaging to track vascular structure and blood flow in residual peri-infarct cortex after ischemic stroke in mice. We found that stroke created a restricted period of heightened vascular plasticity that was associated with restoration of blood flow, which was in turn predictive of recovery of motor function. Therefore, our findings support that vascular remodeling facilitates behavioral recovery after stroke by restoring blood flow to peri-infarct cortex.

Rehabilitative Training Interacts with Ischemia-Instigated Spine Dynamics to Promote a Lasting Population of New Synapses in Peri-Infarct Motor Cortex.

After subtotal infarcts of primary motor cortex (M1), motor rehabilitative training (RT) promotes improvements in paretic forelimb function that have been linked with its promotion of structural and functional reorganization of peri-infarct cortex, but how the reorganization unfolds is scantly understood. Cortical infarcts also instigate a prolonged period of dendritic spine turnover in peri-infarct cortex. Here we investigated the possibility that synaptic structural responses to RT in peri-infarct cortex reflect, in part, interactions with ischemia-instigated spine turnover. This was tested after artery-targeted photothrombotic M1 infarcts or Sham procedures in adult (4 months) C57BL/6 male and female GFP-M line (n = 24) and male yellow fluorescent protein-H line (n = 5) mice undergoing RT in skilled reaching or no-training control procedures. Regardless of training condition, spine turnover was increased out to 5 weeks postinfarct relative to Sham, as was the persistence of new spines formed within a week postinfarct. However, compared with no-training controls, new spines formed during postinfarct weeks 2-4 in mice undergoing RT persisted in much greater proportions to later time points, by a magnitude that predicted behavioral improvements in the RT group. These results indicate that RT interacts with ischemia-instigated spine turnover to promote preferential stabilization of newly formed spines, which is likely to yield a new population of mature synapses in peri-infarct cortex that could contribute to cortical functional reorganization and behavioral improvement. The findings newly implicate ischemia-instigated spine turnover as a mediator of cortical synaptic structural responses to RT and newly establish the experience dependency of new spine fates in the postischemic turnover context.SIGNIFICANCE STATEMENT Motor rehabilitation, the main treatment for motor impairments after stroke, is far from sufficient to normalize function. A better understanding of neural substrates of rehabilitation-induced behavioral improvements could be useful for understanding how to optimize it. Here, we investigated the nature and time course of synaptic responses to motor rehabilitative training in vivo Focal ischemia instigated a period of synapse turnover in peri-infarct motor cortex of mice. Rehabilitative training increased the stability of new synapses formed during the initial weeks after the infarct, the magnitude of which was correlated with improvements in skilled motor performance. Therefore, the maintenance of new synapses formed after ischemia could represent a structural mechanism of rehabilitative training efficacy.

Coordinated Plasticity of Synapses and Astrocytes Underlies Practice-Driven Functional Vicariation in Peri-Infarct Motor Cortex.

Motor rehabilitative training after stroke can improve motor function and promote topographical reorganization of remaining motor cortical movement representations, but this reorganization follows behavioral improvements. A more detailed understanding of the neural bases of rehabilitation efficacy is needed to inform therapeutic efforts to improve it. Using a rat model of upper extremity impairments after ischemic stroke, we examined effects of motor rehabilitative training at the ultrastructural level in peri-infarct motor cortex. Extensive training in a skilled reaching task promoted improved performance and recovery of more normal movements. This was linked with greater axodendritic synapse density and ultrastructural characteristics of enhanced synaptic efficacy that were coordinated with changes in perisynaptic astrocytic processes in the border region between head and forelimb areas of peri-infarct motor cortex. Disrupting synapses and motor maps by infusions of anisomycin (ANI) into anatomically reorganized motor, but not posterior parietal, cortex eliminated behavioral gains from rehabilitative training. In contrast, ANI infusion in the equivalent cortical region of intact animals had no effect on reaching skills. These results suggest that rehabilitative training efficacy for improving manual skills is mediated by synaptic plasticity in a region of motor cortex that, before lesions, is not essential for manual skills, but becomes so as a result of the training. These findings support that experience-driven synaptic structural reorganization underlies functional vicariation in residual motor cortex after motor cortical infarcts.SIGNIFICANCE STATEMENT Stroke is a leading cause of long-term disability. Motor rehabilitation, the main treatment for physical disability, is of variable efficacy. A better understanding of neural mechanisms underlying effective motor rehabilitation would inform strategies for improving it. Here, we reveal synaptic underpinnings of effective motor rehabilitation. Rehabilitative training improved manual skill in the paretic forelimb and induced the formation of special synapse subtypes in coordination with structural changes in astrocytes, a glial cell that influences neural communication. These changes were found in a region that is nonessential for manual skill in intact animals, but came to mediate this skill due to training after stroke. Therefore, motor rehabilitation efficacy depends on synaptic changes that enable remaining brain regions to assume new functions.

Preferential stabilization of newly formed dendritic spines in motor cortex during manual skill learning predicts performance gains, but not memory endurance.

Previous findings that skill learning is associated with the formation and preferential stabilization of new dendritic spines in cortex have raised the possibility that this preferential stabilization is a mechanism for lasting skill memory. We investigated this possibility in adult mice using in vivo two-photon imaging to monitor spine dynamics on superficial apical dendrites of layer V pyramidal neurons in motor cortex during manual skill learning. Spine formation increased over the first 3 days of training on a skilled reaching task, followed by increased spine elimination. A greater proportion of spines formed during the first 3 training days were lost if training stopped after 3, compared with 15 days. However, performance gains achieved in 3 training days persisted, indicating that preferential new spine stabilization was non-essential for skill retention. Consistent with a role in ongoing skill refinement, the persistence of spines formed early in training strongly predicted performance improvements. Finally, while we observed no net spine density change on superficial dendrites, the density of spines on deeper apical branches of the same neuronal population was increased regardless of training duration, suggestive of a potential role in the retention of the initial skill memory. Together, these results indicate dendritic subpopulation-dependent variation in spine structural responses to skill learning, which potentially reflect distinct contributions to the refinement and retention of newly acquired motor skills.

Experience with the "good" limb induces aberrant synaptic plasticity in the perilesion cortex after stroke.

Following unilateral stroke, the contralateral (paretic) body side is often severely impaired, and individuals naturally learn to rely more on the nonparetic body side, which involves learning new skills with it. Such compensatory hyper-reliance on the "good" body side, however, can limit functional improvements of the paretic side. In rats, motor skill training with the nonparetic forelimb (NPT) following a unilateral infarct lessens the efficacy of rehabilitative training, and reduces neuronal activation in perilesion motor cortex. However, the underlying mechanisms remain unclear. In the present study, we investigated how forelimb movement representations and synaptic restructuring in perilesion motor cortex respond to NPT and their relationship with behavioral outcomes. Forelimb representations were diminished as a result of NPT, as revealed with intracortical microstimulation mapping. Using transmission electron microscopy and stereological analyses, we found that densities of axodendritic synapses, especially axo-spinous synapses, as well as multiple synaptic boutons were increased in the perilesion cortex by NPT. The synaptic density was negatively correlated with the functional outcome of the paretic limb, as revealed in reaching performance. Furthermore, in animals with NPT, there was dissociation between astrocytic morphological features and axo-spinous synaptic density in perilesion motor cortex, compared with controls. These findings demonstrate that skill learning with the nonparetic limb following unilateral brain damage results in aberrant synaptogenesis, potentially of transcallosal projections, and this seems to hamper the functionality of the perilesion motor cortex and the paretic forelimb.

Motor System Reorganization After Stroke: Stimulating and Training Toward Perfection.

Stroke instigates regenerative responses that reorganize connectivity patterns among surviving neurons. The new connectivity patterns can be suboptimal for behavioral function. This review summarizes current knowledge on post-stroke motor system reorganization and emerging strategies for shaping it with manipulations of behavior and cortical activity to improve functional outcome.

The long-term structural plasticity of cerebellar parallel fiber axons and its modulation by motor learning.

Presynaptic axonal varicosities, like postsynaptic spines, are dynamically added and eliminated even in mature neuronal circuitry. To study the role of this axonal structural plasticity in behavioral learning, we performed two-photon in vivo imaging of cerebellar parallel fibers (PFs) in adult mice. PFs make excitatory synapses on Purkinje cells (PCs) in the cerebellar cortex, and long-term potentiation and depression at PF-PC synapses are thought to play crucial roles in cerebellar-dependent learning. Time-lapse vital imaging of PFs revealed that, under a control condition (no behavioral training), ∼10% of PF varicosities appeared and disappeared over a period of 2 weeks without changing the total number of varicosities. The fraction of dynamic PF varicosities significantly diminished during training on an acrobatic motor skill learning task, largely because of reduced addition of new varicosities. Thus, this form of motor learning was associated with greater structural stability of PFs and a slight decrease in the total number of varicosities. Together with prior findings that the number of PF-PC synapses increases during similar training, our results suggest that acrobatic motor skill learning involves a reduction of some PF inputs and a strengthening of others, probably via the conversion of some preexisting PF varicosities into multisynaptic terminals.

Subventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke.

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce neural repair and recovery. We also provide evidence that CXCL12 from peri-infarct vasculature signals to CXCR4-expressing cells arising from the SVZ to direct their ectopic migration. These results support a model in which vasculature surrounding the site of injury attracts cells from the SVZ, and these cells subsequently provide trophic support that drives neural repair and recovery.

Chronic self-administration of alcohol results in elevated ΔFosB: comparison of hybrid mice with distinct drinking patterns.

BACKGROUND: The inability to reduce or regulate alcohol intake is a hallmark symptom for alcohol use disorders. Research on novel behavioral and genetic models of experience-induced changes in drinking will further our knowledge on alcohol use disorders. Distinct alcohol self-administration behaviors were previously observed when comparing two F1 hybrid strains of mice: C57BL/6J x NZB/B1NJ (BxN) show reduced alcohol preference after experience with high concentrations of alcohol and periods of abstinence while C57BL/6J x FVB/NJ (BxF) show sustained alcohol preference. These phenotypes are interesting because these hybrids demonstrate the occurrence of genetic additivity (BxN) and overdominance (BxF) in ethanol intake in an experience dependent manner. Specifically, BxF exhibit sustained alcohol preference and BxN exhibit reduced alcohol preference after experience with high ethanol concentrations; however, experience with low ethanol concentrations produce sustained alcohol preference for both hybrids. In the present study, we tested the hypothesis that these phenotypes are represented by differential production of the inducible transcription factor, ΔFosB, in reward, aversion, and stress related brain regions. RESULTS: Changes in neuronal plasticity (as measured by ΔFosB levels) were experience dependent, as well as brain region and genotype specific, further supporting that neuronal circuitry underlies motivational aspects of ethanol consumption. BxN mice exhibiting reduced alcohol preference had lower ΔFosB levels in the Edinger-Westphal nucleus than mice exhibiting sustained alcohol preference, and increased ΔFosB levels in central medial amygdala as compared with control mice. BxN mice showing sustained alcohol preference exhibited higher ΔFosB levels in the ventral tegmental area, Edinger-Westphal nucleus, and amygdala (central and lateral divisions). Moreover, in BxN mice ΔFosB levels in the Edinger-Westphal nucleus and ventral tegmental regions significantly positively correlated with ethanol preference and intake. Additionally, hierarchical clustering analysis revealed that many ethanol-naïve mice with overall low ΔFosB levels are in a cluster, whereas many mice displaying sustained alcohol preference with overall high ΔFosB levels are in a cluster together. CONCLUSIONS: By comparing and contrasting two alcohol phenotypes, this study demonstrates that the reward- and stress-related circuits (including the Edinger-Westphal nucleus, ventral tegmental area, amygdala) undergo significant plasticity that manifests as reduced alcohol preference.

Skill learning induced plasticity of motor cortical representations is time and age-dependent.

Movement representations in the motor cortex can reorganize to support motor skill learning during young adulthood. However, little is known about how motor representations change during aging or whether their change is influenced by continued practice of a skill after it is learned. We used intracortical microstimulation to characterize the organization of the forelimb motor cortex in young and aged C57/BL6 mice after short (2-4 weeks) or long (8 weeks) durations of training on a skilled reaching task or control procedures. In young mice, a short duration of reach training increased the area of proximal forelimb movement representations at the expense of distal representations. Following a longer training duration, ratios of proximal to distal movements returned to baseline, even with ongoing practice and skill maintenance. However, lingering changes were evident in thresholds for eliciting distal forelimb movements, which declined over the longer training period. In aged mice, movement representations and movement thresholds failed to change after either duration of training. Furthermore, there was an age-related loss of digit representations and performance decrements on other sensorimotor tests. Nevertheless, in quantitative measures of reaching success, aged mice learned and performed the skilled reaching task at least as well as younger mice. These results indicate that experience-driven topographical reorganization of motor cortex varies with age, as well as time, and is partially dissociable from behavioral performance. They also support an enduring capacity to learn new manual skills during aging, even as more youthful forms of cortical plasticity and sensorimotor function are lost.

The organization of the forelimb representation of the C57BL/6 mouse motor cortex as defined by intracortical microstimulation and cytoarchitecture.

The organization of forelimb representation areas of the monkey, cat, and rat motor cortices has been studied in depth, but its characterization in the mouse lags far behind. We used intracortical microstimulation (ICMS) and cytoarchitectonics to characterize the general organization of the C57BL/6 mouse motor cortex, and the forelimb representation in more detail. We found that the forelimb region spans a large area of frontal cortex, bordered primarily by vibrissa, neck, shoulder, and hindlimb representations. It included a large caudal forelimb area, dominated by digit representation, and a small rostral forelimb area, containing elbow and wrist representations. When the entire motor cortex was mapped, the forelimb was found to be the largest movement representation, followed by head and hindlimb representations. The ICMS-defined motor cortex spanned cytoarchitecturally identified lateral agranular cortex (AGl) and also extended into medial agranular cortex. Forelimb and hindlimb representations extended into granular cortex in a region that also had cytoarchitectural characteristics of AGl, consistent with the primary motor-somatosensory overlap zone (OL) characterized in rats. Thus, the mouse motor cortex has homologies with the rat in having 2 forelimb representations and an OL but is distinct in the predominance of digit representations.

Diamond Raman laser and Yb fiber amplifier for in vivo multiphoton fluorescence microscopy.

Here we introduce a fiber amplifier and a diamond Raman laser that output high powers (6.5 W, 1.3 W) at valuable wavelengths (1060 nm, 1250 nm) for two-photon excitation of red-shifted fluorophores. These custom excitation sources are both simple to construct and cost-efficient in comparison to similar custom and commercial alternatives. Furthermore, they operate at a repetition rate (80 MHz) that allows fast image acquisition using resonant scanners. With our system we demonstrate compatibility with fast resonant scanning, the ability to acquire neuronal images, and the capability to image vasculature at deep locations (>1 mm) within the mouse cerebral cortex.

Reflections of experience-expectant development in repair of the adult damaged brain.

Behavioral experience has long been known to influence functional outcome after brain injury, but only recently has its pervasive role in the reorganization of the adult brain after damage become appreciated. We briefly review findings from animal models on the role of experience in shaping neuronal events after stroke-like injury. Experience-dependent neural plasticity can be enhanced or impaired by brain damage, depending upon injury parameters and timing. The neuronal growth response to some experiences is heightened due to interactions with denervation-induced plasticity. This includes compensatory behavioral strategies developed in response to functional impairments. Early behavioral experiences can constrain later experience-dependent plasticity, leading to suboptimal functional outcome. Time dependencies and facets of neural growth patterns are reminiscent of experience-expectant processes that shape brain development. As with sensitive periods in brain development, this process may establish behavioral patterns early after brain injury which are relatively resistant to later change.

Training in a cooperative bimanual skilled reaching task, the popcorn retrieval task, improves unimanual function after motor cortical infarcts in rats.

Disuse of the paretic hand after stroke is encouraged by compensatory reliance on the nonparetic hand, to exacerbate impairment and potentially constrain motor rehabilitation efficacy. Rodent stroke model findings support that learning new unimanual skills with the nonparetic forelimb diminishes functional improvements that can be driven by rehabilitative training of the paretic forelimb. The influence of learning new ways of skillfully using the two hands together on paretic side function is much less clear. To begin to explore this, we developed a new cooperative bimanual skilled reaching task for rats, the Popcorn Retrieval Task. After motor cortical infarcts impaired an established unimanual reaching skill in the paretic forelimb, rats underwent a 7 week period of de novo bimanual training (BiT) or no-training control procedures (Cont). Probes of paretic forelimb unimanual performance revealed significant improvements during and after the training period in BiT vs. Cont. We additionally observed a striking change in the bimanual task strategy over training days: a switch from the paretic to the nonparetic forelimb for initiating reach-to-grasp sequences. This motivated another study to test whether rats that established the bimanual skill prior to the infarcts would similarly switch handedness, which they did not, though paretic paw use for manipulative movements diminished. These results indicate that unimanual function of the paretic side can be improved by novel bimanual skill practice, even when it involves compensatory reliance on the nonparetic hand. They further support the suitability of the Popcorn Retrieval Task for studying bimanual skill learning effects in rats.

Reactive astrocytes facilitate vascular repair and remodeling after stroke.

Brain injury causes astrocytes to assume a reactive state that is essential for early tissue protection, but how reactive astrocytes affect later reparative processes is incompletely understood. In this study, we show that reactive astrocytes are crucial for vascular repair and remodeling after ischemic stroke in mice. Analysis of astrocytic gene expression data reveals substantial activation of transcriptional programs related to vascular remodeling after stroke. In vivo two-photon imaging provides evidence of astrocytes contacting newly formed vessels in cortex surrounding photothrombotic infarcts. Chemogenetic ablation of a subset of reactive astrocytes after stroke dramatically impairs vascular and extracellular matrix remodeling. This disruption of vascular repair is accompanied by prolonged blood flow deficits, exacerbated vascular permeability, ongoing cell death, and worsened motor recovery. In contrast, vascular structure in the non-ischemic brain is unaffected by focal astrocyte ablation. These findings position reactive astrocytes as critical cellular mediators of functionally important vascular remodeling during neural repair.

A First Step Toward the Operationalization of the Learned Non-Use Phenomenon: A Delphi Study.

BACKGROUND: The negative discrepancy between residual functional capacity and reduced use of the contralesional hand, frequently observed after a brain lesion, has been termed Learned Non-Use (LNU) and is thought to depend on the interaction of neuronal mechanisms during recovery and learning-dependent mechanisms. OBJECTIVE: Albeit the LNU phenomenon is generally accepted to exist, currently, no transdisciplinary definition exists. Furthermore, although therapeutic approaches are implemented in clinical practice targeting LNU, no standardized diagnostic routine is described in the available literature. Our objective was to reach consensus regarding a definition as well as synthesize knowledge about the current diagnostic procedures. METHODS: We used a structured group communication following the Delphi method among clinical and scientific experts in the field, knowledge from both, the work with patient populations and with animal models. RESULTS: Consensus was reached regarding a transdisciplinary definition of the LNU phenomenon. Furthermore, the mode and strategy of the diagnostic process, as well as the sources of information and outcome parameters relevant for the clinical decision making, were described with a wide range showing the current lack of a consistent universal diagnostic approach. CONCLUSIONS: The need for the development of a structured diagnostic procedure and its implementation into clinical practice is emphasized. Moreover, it exists a striking gap between the prevailing hypotheses regarding the mechanisms underlying the LNU phenomenon and the actual evidence. Therefore, basic research is needed to bridge between bedside and bench and eventually improve clinical decision making and further development of interventional strategies beyond the field of stroke rehabilitation.

Stroke: working toward a prioritized world agenda.

BACKGROUND AND PURPOSE: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. METHODS: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. RESULTS: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent "silo" mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a "Brain Health" concept that enables promotion of preventive measures. CONCLUSIONS: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

Lesion size-dependent synaptic and astrocytic responses in cortex contralateral to infarcts in middle-aged rats.

In young adult rats, unilateral lesions of the sensorimotor cortex lead to neuronal structural plasticity and synaptogenesis in the contralateral motor cortex, which is connected to the lesion site by transcallosal fibers. The contralesional neural plasticity varies with lesion size and results from the convergence of denervation-induced reactive plasticity and behavioral asymmetries. It was unknown whether similar effects occur in older animals. Furthermore, the coordination of synaptic responses with that of perisynaptic astrocytes had not been investigated. In this study, middle-aged rats (14-16 months old) were given sham-operations or unilateral ischemic lesions of the sensorimotor cortex. Fifty days later, numerical densities of neurons and synapses and morphological characteristics of astrocytic processes in layer V of the contralesional motor cortex were measured using stereological light and electron microscopy methods. Lesions resulted in behavioral asymmetries, but no significant synapse addition in the contralesional motor cortex. Synapse number per neuron was negatively correlated with lesion size and reduced opposite larger lesions compared with smaller ones. Astrocytic changes were also lesion size-dependent. Astrocytic hypertrophy was observed only after smaller lesions and was associated with greater coverage and greater numbers of synapses. These findings are consistent with those in younger rats indicating an inverse relationship between lesion size and adaptive neuronal restructuring in denervated cortex. However, they indicate that the synaptogenic reaction to this lesion is relatively limited in older animals. Finally, the results indicate that structural plasticity of perisynaptic astrocytes parallels, and could play a role in shaping, synaptic responses to postischemic denervation.