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1.  Experience-dependent neural plasticity in the adult damaged brain 
Behavioral experience is at work modifying the structure and function of the brain throughout the lifespan, but it has a particularly dramatic influence after brain injury. This review summarizes recent findings on the role of experience in reorganizing the adult damaged brain, with a focus on findings from rodent stroke models of chronic upper extremity (hand and arm) impairments. A prolonged and widespread process of repair and reorganization of surviving neural circuits is instigated by injury to the adult brain. When experience impacts these same neural circuits, it interacts with degenerative and regenerative cascades to shape neural reorganization and functional outcome. This is evident in the cortical plasticity resulting from compensatory reliance on the “good” forelimb in rats with unilateral sensorimotor cortical infarcts. Behavioral interventions (e.g., rehabilitative training) can drive functionally beneficial neural reorganization in the injured hemisphere. However, experience can have both behaviorally beneficial and detrimental effects. The interactions between experience-dependent and injury-induced neural plasticity are complex, time-dependent, and varied with age and other factors. A better understanding of these interactions is needed to understand how to optimize brain remodeling and functional outcome.
Learning outcomes
Readers will be able to describe (a) experience effects that are maladaptive for behavioral outcome after brain damage, (b) manipulations of experience that drive functionally beneficial neural plasticity, and (c) reasons why rehabilitative training effects can be expected to vary with age, training duration and timing.
doi:10.1016/j.jcomdis.2011.04.011
PMCID: PMC3162127  PMID: 21620413
neurorehabilitation; cortical plasticity; learned non-use; skill learning; stroke; animal models
2.  Recovery after brain injury: mechanisms and principles 
The past 20 years have represented an important period in the development of principles underlying neuroplasticity, especially as they apply to recovery from neurological injury. It is now generally accepted that acquired brain injuries, such as occur in stroke or trauma, initiate a cascade of regenerative events that last for at least several weeks, if not months. Many investigators have pointed out striking parallels between post-injury plasticity and the molecular and cellular events that take place during normal brain development. As evidence for the principles and mechanisms underlying post-injury neuroplasticity has been gleaned from both animal models and human populations, novel approaches to therapeutic intervention have been proposed. One important theme has persisted as the sophistication of clinicians and scientists in their knowledge of neuroplasticity mechanisms has grown: behavioral experience is the most potent modulator of brain plasticity. While there is substantial evidence for this principle in normal, healthy brains, the injured brain is particularly malleable. Based on the quantity and quality of motor experience, the brain can be reshaped after injury in either adaptive or maladaptive ways. This paper reviews selected studies that have demonstrated the neurophysiological and neuroanatomical changes that are triggered by motor experience, by injury, and the interaction of these processes. In addition, recent studies using new and elegant techniques are providing novel perspectives on the events that take place in the injured brain, providing a real-time window into post-injury plasticity. These new approaches are likely to accelerate the pace of basic research, and provide a wealth of opportunities to translate basic principles into therapeutic methodologies.
doi:10.3389/fnhum.2013.00887
PMCID: PMC3870954  PMID: 24399951
motor cortex; stroke; traumatic brain injury; axonal sprouting; motor learning; recovery
3.  Infiltrating Blood-Derived Macrophages Are Vital Cells Playing an Anti-inflammatory Role in Recovery from Spinal Cord Injury in Mice 
PLoS Medicine  2009;6(7):e1000113.
Using a mouse model of spinal injury, Michal Schwartz and colleagues tested the effect of macrophages on the recovery process and demonstrate an important anti-inflammatory role for a subset of infiltrating monocyte-derived macrophages that is dependent upon their expression of interleukin 10.
Background
Although macrophages (MΦ) are known as essential players in wound healing, their contribution to recovery from spinal cord injury (SCI) is a subject of debate. The difficulties in distinguishing between different MΦ subpopulations at the lesion site have further contributed to the controversy and led to the common view of MΦ as functionally homogenous. Given the massive accumulation in the injured spinal cord of activated resident microglia, which are the native immune occupants of the central nervous system (CNS), the recruitment of additional infiltrating monocytes from the peripheral blood seems puzzling. A key question that remains is whether the infiltrating monocyte-derived MΦ contribute to repair, or represent an unavoidable detrimental response. The hypothesis of the current study is that a specific population of infiltrating monocyte-derived MΦ is functionally distinct from the inflammatory resident microglia and is essential for recovery from SCI.
Methods and Findings
We inflicted SCI in adult mice, and tested the effect of infiltrating monocyte-derived MΦ on the recovery process. Adoptive transfer experiments and bone marrow chimeras were used to functionally distinguish between the resident microglia and the infiltrating monocyte-derived MΦ. We followed the infiltration of the monocyte-derived MΦ to the injured site and characterized their spatial distribution and phenotype. Increasing the naïve monocyte pool by either adoptive transfer or CNS-specific vaccination resulted in a higher number of spontaneously recruited cells and improved recovery. Selective ablation of infiltrating monocyte-derived MΦ following SCI while sparing the resident microglia, using either antibody-mediated depletion or conditional ablation by diphtheria toxin, impaired recovery. Reconstitution of the peripheral blood with monocytes resistant to ablation restored the lost motor functions. Importantly, the infiltrating monocyte-derived MΦ displayed a local anti-inflammatory beneficial role, which was critically dependent upon their expression of interleukin 10.
Conclusions
The results of this study attribute a novel anti-inflammatory role to a unique subset of infiltrating monocyte-derived MΦ in SCI recovery, which cannot be provided by the activated resident microglia. According to our results, limited recovery following SCI can be attributed in part to the inadequate, untimely, spontaneous recruitment of monocytes. This process is amenable to boosting either by active vaccination with a myelin-derived altered peptide ligand, which indicates involvement of adaptive immunity in monocyte recruitment, or by augmenting the naïve monocyte pool in the peripheral blood. Thus, our study sheds new light on the long-held debate regarding the contribution of MΦ to recovery from CNS injuries, and has potentially far-reaching therapeutic implications.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Every year, spinal cord injuries paralyze about 11,000 people in the US. The spinal cord, which contains bundles of nervous system cells called neurons, is the communication highway between the brain and the body. Messages from the brain travel down the spinal cord to control movement, breathing and other bodily functions; messages from the skin and other sensory organs travel up the spinal cord to keep the brain informed about the body. The bones of the spine normally protect the spinal cord but, if these are broken or displaced, the spinal cord can be cut or compressed, which interrupts the information flow. Damage near the top of the spinal cord paralyzes the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause other medical problems, including the loss of bladder and bowel control. Currently, there is no effective treatment for spinal cord injuries, which usually cause permanent disability because the damaged nerve fibers rarely regrow.
Why Was This Study Done?
After a spinal cord injury, immune system cells called macrophages accumulate at the injury site. Some of these macrophages—so-called monocyte-derived macrophages—come into (infiltrate) the spinal cord from the blood in response to the injury, whereas others—microglia—are always in the nervous system. Although macrophages are essential for wound healing in other parts of the body, it is unclear whether they have good or bad effects in the spinal cord. Many experts believe that immune system cells hinder healing in the spinal cord and should be suppressed or eliminated, but other scientists claim that macrophages secrete factors that stimulate nerve regrowth. Furthermore, although some macrophages elsewhere in the body have proinflammatory (potentially deleterious) effects, others have anti-inflammatory (beneficial) effects. So do the infiltrating monocyte-derived macrophages and the resident microglia (which are proinflammatory) have different functions at spinal cord injury sites? In this study, the researchers try to answer this important question.
What Did the Researchers Do and Find?
The researchers bruised a small section of the spinal cord of adult mice and then investigated the effect of infiltrating monocyte-derived macrophages on the recovery process. Monocyte-derived macrophages and microglia cannot be distinguished using standard staining techniques so to study their behavior after spinal cord injury the researchers introduced labeled monocyte-derived macrophages into their experimental animals by using adoptive transfer (injection of genetically labeled monocytes into the animals) or by making bone marrow chimeras. In this second technique, the animals' monocyte-derived macrophages (but not their microglia) were killed by irradiating the animals before injection of genetically labeled bone marrow, the source of monocytes. Using these approaches, the researchers found that monocyte-derived macrophages collected at the margins of spinal cord injury sites whereas microglia accumulated throughout the sites. When the pool of monocyte-derived macrophages in the mice was increased by adoptive transfer or by using a technique called “CNS-specific vaccination,” more monocyte-derived macrophages infiltrated the injury site and the animals' physical recovery from injury improved. Conversely, removal of the infiltrating monocyte-derived macrophages from the injury site reduced the animals' physical recovery. Other experiments indicated that the infiltrating monocyte-derived macrophages have a beneficial, local anti-inflammatory effect that is dependent on their expression of interleukin-10 (an anti-inflammatory signaling molecule).
What Do These Findings Mean?
These findings provide new information about the contribution of monocyte-derived macrophages to spontaneous recovery from spinal cord injury, a contribution that has long been debated. In particular, the findings suggest that this subset of macrophages (but not the resident microglia) has a beneficial effect on spinal cord injuries that is mediated by their production of the anti-inflammatory molecule interleukin-10. The findings also show that the effect of these monocyte-derived macrophages can be boosted, at least in mice. Although results obtained in experiments done in animals do not always accurately reflect what happens in people, this new understanding of the different functions of microglia and infiltrating monocyte-derived macrophages after injury to the spinal cord may eventually lead to the development of better treatments for spinal cord injuries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000113.
The MedlinePlus encyclopedia provides information about spinal cord injuries (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke provides detailed information about spinal cord injury, including information on current research into the problem (in English and Spanish)
MedlinePlus provides an interactive tutorial on spinal cord injury and a list of links to additional information (in English and Spanish)
doi:10.1371/journal.pmed.1000113
PMCID: PMC2707628  PMID: 19636355
4.  Neural Plasticity After Spinal Cord Injury 
Current pharmaceutical design  2005;11(11):1441-1450.
Spinal cord injury (SCI) has devastating physical and socioeconomical impact. However, some degree of functional recovery is frequently observed in patients after SCI. There is considerable evidence that functional plasticity occurs in cerebral cortical maps of the body, which may account for functional recovery after injury. Additionally, these plasticity changes also occur at multiple levels including the brainstem, spinal cord, and peripheral nervous system. Although the interaction of plasticity changes at each level has been less well studied, it is likely that changes in subcortical levels contribute to cortical reorganization. Since the permeability of the blood-brain barrier (BBB) is changed, SCI-induced factors, such as cytokines and growth factors, can be involved in the plasticity events, thus affecting the final functional recovery after SCI. The mechanism of plasticity probably differs depending on the time frame. The reorganization that is rapidly induced by acute injury is likely based on unmasking of latent synapses resulting from modulation of neurotransmitters, while the long-term changes after chronic injury involve changes of synaptic efficacy modulated by long-term potentiation and axonal regeneration and sprouting. The functional significance of neural plasticity after SCI remains unclear. It indicates that in some situations plasticity changes can result in functional improvement, while in other situations they may have harmful consequences. Thus, further understanding of the mechanisms of plasticity could lead to better ways of promoting useful reorganization and preventing undesirable consequences.
PMCID: PMC3562709  PMID: 15853674
Spinal Cord Injury; Plasticity; Reorganization; Cortex; Blood-Brain Barrier
5.  Influence of Inflammation on Poststroke Plasticity 
Neural Plasticity  2013;2013:258582.
Age-related brain injuries including stroke are a leading cause of morbidity and mental disability worldwide. Most patients who survive stroke experience some degree of recovery. The restoration of lost functions can be explained by neuronal plasticity, understood as brain ability to reorganize and remodel itself in response to changed environmental requirements. However, stroke triggers a cascade of events which may prevent the normal development of the plastic changes. One of them may be inflammatory response initiated immediately after stroke, which has been found to contribute to neuronal injury. Some recent evidence though has suggested that inflammatory reaction can be also neuroprotective. This paper attempts to discuss the influence of poststroke inflammatory response on brain plasticity and stroke outcome. We also describe the recent anti-inflammatory strategies that have been effective for recovery in experimental stroke.
doi:10.1155/2013/258582
PMCID: PMC3595668  PMID: 23533818
6.  Constraint-Induced Movement Therapy for Rehabilitation of Arm Dysfunction After Stroke in Adults 
Executive Summary
Objective
The purpose of this evidence-based analysis is to determine the effectiveness and cost of CIMT for persons with arm dysfunction after a stroke.
Clinical Need: Condition and Target Population
A stroke is a sudden loss of brain function caused by the interruption of blood flow to the brain (ischemic stroke) or the rupture of blood vessels in the brain (hemorrhagic stroke). A stroke can affect any number of areas including the ability to move, see, remember, speak, reason, and read and write. Stroke is the leading cause of adult neurological disability in Canada; 300,000 people or 1% of the population live with its effects. Up to 85% of persons experiencing a complete stroke have residual arm dysfunction which will interfere with their ability to live independently. Rehabilitation interventions are the cornerstone of care and recovery after a stroke.
Constraint-Induced Movement Therapy
Constraint-Induced Movement (CIMT) is a behavioural approach to neurorehabilitation based on the principle of ‘learned non-use’. The term is derived from studies in nonhuman primates in which somatosensory deafferentation of a single forelimb was performed and after which the animal then failed to use that limb. This failure to use the limb was deemed ‘learned non-use’. The major components of CIMT include: i) intense repetitive task-oriented training of the impaired limb ii) immobilization of the unimpaired arm, and iii) shaping. With regard to the first component, persons may train the affected arm for several hours a day for up to 10-15 consecutive days. With immobilization, the unaffected arm may be restrained for up to 90% of waking hours. And finally, with shaping, the difficulty of the training tasks is progressively increased as performance improves and encouraging feedback is provided immediately when small gains are achieved.
Research Question
What is the effectiveness and cost of CIMT compared with physiotherapy and/or occupational therapy rehabilitative care for the treatment of arm dysfunction after stroke in persons 18 years of age and older?
Research Methods
Literature Search
Search Strategy
A literature search was performed on January 21, 2011 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Library, Centre for Reviews and Dissemination. (Appendix 1) A preliminary search completed in August 2010 found a Cochrane Systematic review published in 2009. As a result, the literature search for this evidence-based analysis was designed to include studies published from January 1, 2008 to January 21, 2011.
Inclusion Criteria
Systematic reviews of randomized controlled trials with or without meta-analysis.
Study participants 18 years of age and older with arm dysfunction after stroke.
Studies comparing the use of CIMT with occupational therapy and/or physiotherapy rehabilitative care (usual care) to improve arm function.
Studies which described CIMT as having the following three components: i) restraining unimpaired arm and/or wrist with a sling, hand splint or cast; ii) intensive training with functional task practice of the affected arm; iii) application of shaping methodology during training. No restriction was placed on intensity or duration of treatment otherwise.
Duration and intensity of therapy is equal in treatment and control groups.
Therapy beginning a minimum of one month after stroke.
Published between 2008 and 2011.
Exclusion Criteria
Narrative reviews, case series, case reports, controlled clinical trials.
Letters to the editor
Grey literature.
Non-English language publications.
Outcomes of Interest
Primary Outcome
Arm motor function: Action Research Arm Test (ARAT)
Secondary Outcome
Arm motor impairment: Fugl-Meyer Motor Assessment (FMA)
Activities of daily living (ADL): Functional Independence Measure (FIM), Chedoke Arm and Hand Inventory
Perceived motor function: Motor Activity Log (MAL) Amount of Use (AOU) and Quality of Movement (QOM) scales
Quality of Life: Stroke Impact Scale (SIS)
Summary of Findings
A significant difference was found in our primary outcome of arm motor function measured with the Action Research Arm Test in favour of CIMT compared with usual care delivered with the same intensity and duration. Significant differences were also found in three of the five secondary outcome measures including Arm Motor Impairment and Perceived Motor Function Amount of Use and Quality of Use. There was a nonsignificant effect found with the FIM score and the quality of life Stroke Impact Scale outcome measure. The nonsignificant effect found with the scale score and the quality of life score may be a factor of a nonresponsive outcome measure (FIM scale) and/or a type II statistical error from an inadequate sample size. The quality of evidence was moderate for arm motor function and low for all other outcome measures except quality of life, which was very low.
Summary of Results*
CI, Confidence Intervals; n, Sample Size
PMCID: PMC3377570  PMID: 23074418
7.  Functional MRI and Diffusion Tensor Imaging of Brain Reorganization After Experimental Stroke 
Translational Stroke Research  2012;3(1):36-43.
The potential of the adult brain to reorganize after ischemic injury is critical for functional recovery and provides a significant target for therapeutic strategies to promote brain repair. Despite the accumulating evidence of brain plasticity, the interaction and significance of morphological and physiological modifications in post-stroke brain tissue remain mostly unclear. Neuroimaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) enable in vivo assessment of the spatial and temporal pattern of functional and structural changes inside and outside ischemic lesion areas. This can contribute to the elucidation of critical aspects in post-stroke brain remodeling. Task/stimulus-related fMRI, resting-state fMRI, or pharmacological MRI enables direct or indirect measurement of neuronal activation, functional connectivity, or neurotransmitter system responses, respectively. DTI allows estimation of the structural integrity and connectivity of white matter tracts. Together, these MRI methods provide an unprecedented means to (a) measure longitudinal changes in tissue structure and function close by and remote from ischemic lesion areas, (b) evaluate the organizational profile of neural networks after stroke, and (c) identify degenerative and restorative processes that affect post-stroke functional outcome. Besides, the availability of MRI in clinical institutions as well as research laboratories provides an optimal basis for translational research on stroke recovery. This review gives an overview of the current status and perspectives of fMRI and DTI applications to study brain reorganization in experimental stroke models.
doi:10.1007/s12975-011-0143-8
PMCID: PMC3284658  PMID: 22408692
Brain plasticity; Functional connectivity; Diffusion tensor imaging; Functional MRI; Neuronal network; Stroke
8.  Microglial Involvement in Neuroplastic Changes Following Focal Brain Ischemia in Rats 
PLoS ONE  2009;4(12):e8101.
The pathogenesis of ischemic stroke is a complex sequence of events including inflammatory reaction, for which the microglia appears to be a major cellular contributor. However, whether post-ischemic activation of microglial cells has beneficial or detrimental effects remains to be elucidated, in particular on long term brain plasticity events. The objective of our study was to determine, through modulation of post-stroke inflammatory response, to what extent microglial cells are involved in some specific events of neuronal plasticity, neurite outgrowth and synaptogenesis. Since microglia is a source of neurotrophic factors, the identification of the brain-derived neurophic factor (BDNF) as possible molecular actor involved in these events was also attempted. As a means of down-regulating the microglial response induced by ischemia, 3-aminobenzamide (3-AB, 90 mg/kg, i.p.) was used to inhibit the poly(ADP-ribose) polymerase-1 (PARP-1). Indeed, PARP-1 contributes to the activation of the transcription factor NF-kB, which is essential to the upregulation of proinflammatory genes, in particular responsible for microglial activation/proliferation. Experiments were conducted in rats subjected to photothrombotic ischemia which leads to a strong and early microglial cells activation/proliferation followed by an infiltration of macrophages within the cortical lesion, events evaluated at serial time points up to 1 month post-ictus by immunostaining for OX-42 and ED-1. Our most striking finding was that the decrease in acute microglial activation induced by 3-AB was associated with a long term down-regulation of two neuronal plasticity proteins expression, synaptophysin (marker of synaptogenesis) and GAP-43 (marker of neuritogenesis) as well as to a significant decrease in tissue BDNF production. Thus, our data argue in favour of a supportive role for microglia in brain neuroplasticity stimulation possibly through BDNF production, suggesting that a targeted protection of microglial cells could represent an innovative approach to potentiate post-stroke neuroregeneration.
doi:10.1371/journal.pone.0008101
PMCID: PMC2779656  PMID: 19956568
9.  Neural bases of recovery after brain injury 
Substantial data have accumulated over the past decade indicating that the adult brain is capable of substantial structural and functional reorganization after stroke. While some limited recovery is known to occur spontaneously, especially within the first month post-stroke, there is currently significant optimism that new interventions based on the modulation of neuroplasticity mechanisms will provide greater functional benefits in a larger population of stroke survivors. To place this information in the context of current thinking about brain plasticity, this review outlines the basic theories of why spontaneous recovery occurs, and introduces important principles to explain the effects of post-stroke behavioral experience on neural plasticity.
Learning outcomes
Readers will be able to: (a) explain the three classic theories to explain spontaneous recovery after focal brain injury, (b) explain the neurophysiological effects of post-injury rehabilitative therapy on functional organization in motor cortex, (c) readers will be able to describe some of the variables that impact the effects of post-stroke behavioral experience on neuroplasticity, and (d) readers will be able to explain some of the current laboratory-based approaches to modifying brain circuits after stroke that might soon be translated to human application.
doi:10.1016/j.jcomdis.2011.04.004
PMCID: PMC3162095  PMID: 21600588
stroke; plasticity; recovery; rehabilitation
10.  Neurophysiology of Robot-Mediated Training and Therapy: A Perspective for Future Use in Clinical Populations 
The recovery of functional movements following injury to the central nervous system (CNS) is multifaceted and is accompanied by processes occurring in the injured and non-injured hemispheres of the brain or above/below a spinal cord lesion. The changes in the CNS are the consequence of functional and structural processes collectively termed neuroplasticity and these may occur spontaneously and/or be induced by movement practice. The neurophysiological mechanisms underlying such brain plasticity may take different forms in different types of injury, for example stroke vs. spinal cord injury (SCI). Recovery of movement can be enhanced by intensive, repetitive, variable, and rewarding motor practice. To this end, robots that enable or facilitate repetitive movements have been developed to assist recovery and rehabilitation. Here, we suggest that some elements of robot-mediated training such as assistance and perturbation may have the potential to enhance neuroplasticity. Together the elemental components for developing integrated robot-mediated training protocols may form part of a neurorehabilitation framework alongside those methods already employed by therapists. Robots could thus open up a wider choice of options for delivering movement rehabilitation grounded on the principles underpinning neuroplasticity in the human CNS.
doi:10.3389/fneur.2013.00184
PMCID: PMC3826107  PMID: 24312073
motor cortex; spinal cord; rehabilitation; motor learning; motor adaptation
11.  The first decade of research on constrained-induced treatment approaches for aphasia rehabilitation 
Approaches for treating post-stroke language impairments (aphasia) based upon Constraint-Induced (CI) principles were first introduced in 2001. CI principles as previously applied to upper extremity and locomotor retraining in stroke survivors were derived from basic neuroscience. They comprise forced-use of the affected modality, a gradual rebuilding of targeted functions using a highly intensive treatment protocol, administered in a behaviorally-relevant context.
CI-based approaches have stimulated considerable neurorehabilitation research interest in the past decade. The original CI aphasia treatment protocol was tailored to improve functional communication in chronic aphasia (i.e., 6–12 months after stroke) and more recently, it has been adapted to treat language impairments in acute stroke survivors as well. Moreover, CI therapy applied to aphasia has been used as a model to assess language network plasticity in response to treatment using functional imaging techniques.
In the following paper, we review the first 10 years of behavioral and functional brain imaging research on CI-based approaches for aphasia rehabilitation.
doi:10.1016/j.apmr.2011.06.040
PMCID: PMC3594770  PMID: 22202189
language impairment; stroke; neurorehabilitation; forced-use
12.  The functional significance of cortical reorganization and the parallel development of CI therapy 
For the nineteenth and the better part of the twentieth centuries two correlative beliefs were strongly held by almost all neuroscientists and practitioners in the field of neurorehabilitation. The first was that after maturity the adult CNS was hardwired and fixed, and second that in the chronic phase after CNS injury no substantial recovery of function could take place no matter what intervention was employed. However, in the last part of the twentieth century evidence began to accumulate that neither belief was correct. First, in the 1960s and 1970s, in research with primates given a surgical abolition of somatic sensation from a single forelimb, which rendered the extremity useless, it was found that behavioral techniques could convert the limb into an extremity that could be used extensively. Beginning in the late 1980s, the techniques employed with deafferented monkeys were translated into a rehabilitation treatment, termed Constraint Induced Movement therapy or CI therapy, for substantially improving the motor deficit in humans of the upper and lower extremities in the chronic phase after stroke. CI therapy has been applied successfully to other types of damage to the CNS such as traumatic brain injury, cerebral palsy, multiple sclerosis, and spinal cord injury, and it has also been used to improve function in focal hand dystonia and for aphasia after stroke. As this work was proceeding, it was being shown during the 1980s and 1990s that sustained modulation of afferent input could alter the structure of the CNS and that this topographic reorganization could have relevance to the function of the individual. The alteration in these once fundamental beliefs has given rise to important recent developments in neuroscience and neurorehabilitation and holds promise for further increasing our understanding of CNS function and extending the boundaries of what is possible in neurorehabilitation.
doi:10.3389/fnhum.2014.00396
PMCID: PMC4072972  PMID: 25018720
CI therapy; cortical reorganization; neurorehabilitation; neuroplasticity; stroke; traumatic brain injury; cerebral palsy; multiple sclerosis
13.  Two Faces of Chondroitin Sulfate Proteoglycan in Spinal Cord Repair: A Role in Microglia/Macrophage Activation 
PLoS Medicine  2008;5(8):e171.
Background
Chondroitin sulfate proteoglycan (CSPG) is a major component of the glial scar. It is considered to be a major obstacle for central nervous system (CNS) recovery after injury, especially in light of its well-known activity in limiting axonal growth. Therefore, its degradation has become a key therapeutic goal in the field of CNS regeneration. Yet, the abundant de novo synthesis of CSPG in response to CNS injury is puzzling. This apparent dichotomy led us to hypothesize that CSPG plays a beneficial role in the repair process, which might have been previously overlooked because of nonoptimal regulation of its levels. This hypothesis is tested in the present study.
Methods and Findings
We inflicted spinal cord injury in adult mice and examined the effects of CSPG on the recovery process. We used xyloside to inhibit CSPG formation at different time points after the injury and analyzed the phenotype acquired by the microglia/macrophages in the lesion site. To distinguish between the resident microglia and infiltrating monocytes, we used chimeric mice whose bone marrow-derived myeloid cells expressed GFP. We found that CSPG plays a key role during the acute recovery stage after spinal cord injury in mice. Inhibition of CSPG synthesis immediately after injury impaired functional motor recovery and increased tissue loss. Using the chimeric mice we found that the immediate inhibition of CSPG production caused a dramatic effect on the spatial organization of the infiltrating myeloid cells around the lesion site, decreased insulin-like growth factor 1 (IGF-1) production by microglia/macrophages, and increased tumor necrosis factor alpha (TNF-α) levels. In contrast, delayed inhibition, allowing CSPG synthesis during the first 2 d following injury, with subsequent inhibition, improved recovery. Using in vitro studies, we showed that CSPG directly activated microglia/macrophages via the CD44 receptor and modulated neurotrophic factor secretion by these cells.
Conclusions
Our results show that CSPG plays a pivotal role in the repair of injured spinal cord and in the recovery of motor function during the acute phase after the injury; CSPG spatially and temporally controls activity of infiltrating blood-borne monocytes and resident microglia. The distinction made in this study between the beneficial role of CSPG during the acute stage and its deleterious effect at later stages emphasizes the need to retain the endogenous potential of this molecule in repair by controlling its levels at different stages of post-injury repair.
Michal Schwartz and colleagues describe the role of chondroitin sulfate proteoglycan in the repair of injured tissue and in the recovery of motor function during the acute phase after spinal cord injury.
Editors' Summary
Background.
Every year, spinal cord injuries paralyze about 10,000 people in the United States. The spinal cord, which contains bundles of nervous system cells called neurons, is the communication superhighway between the brain and the body. Messages from the brain travel down the spinal cord to control movement, breathing, and other bodily functions; messages from the skin and other sensory organs travel up the spinal cord to keep the brain informed about the body. All these messages are transmitted along axons, long extensions on the neurons. The spinal cord is protected by the bones of the spine but if these are displaced or broken, the axons can be compressed or cut, which interrupts the information flow. Damage near the top of the spinal cord paralyzes the arms and legs (tetraplegia); damage lower down paralyzes the legs only (paraplegia). Spinal cord injuries also cause other medical problems, including the loss of bowel and bladder control. Currently there is no effective treatment for spinal cord injuries. Treatment with drugs to reduce inflammation has, at best, only modest effects. Moreover, because damaged axons rarely regrow, most spinal cord injuries are permanent.
Why Was This Study Done?
One barrier to recovery after a spinal cord injury seems to be an inappropriate immune response to the injury. After an injury, microglia (immune system cells that live in the nervous system), and macrophages (blood-borne immune system cells that infiltrate the injury) become activated. Microglia/macrophage activation can be either beneficial (the cells make IGF-1, a protein that stimulates axon growth) or destructive (the cells make TNF-α, a protein that kills neurons), so studies of microglia/macrophage activation might suggest ways to treat spinal cord injuries. Another possible barrier to recovery is “chondroitin sulfate proteoglycan” (CSPG). This is a major component of the scar tissue (the “glial scar”) that forms around spinal cord injuries. CSPG limits axon regrowth, so attempts have been made to improve spinal cord repair by removing CSPG. But if CSPG prevents spinal cord repair, why is so much of it made immediately after an injury? In this study, the researchers investigate this paradox by asking whether CSPG made in the right place and in the right amount might have a beneficial role in spinal cord repair that has been overlooked.
What Did the Researchers Do and Find?
The researchers bruised a small section of the spinal cord of mice to cause hind limb paralysis, and then monitored the recovery of movement in these animals. They also examined the injured tissue microscopically, looked for microglia and infiltrating macrophages at the injury site, and measured the production of IGF-1 and TNF-α by these cells. Inhibition of CSPG synthesis immediately after injury impaired the functional recovery of the mice and increased tissue loss at the injury site. It also altered the spatial organization of infiltrating macrophages at the injury site, reduced IGF-1 production by these microglia/macrophages, and increased TNF-α levels. In contrast, when CSPG synthesis was not inhibited until two days after the injury, the mice recovered well from spinal cord injury. Furthermore, the interaction of CSPG with a cell-surface protein called CD44 activated microglia/macrophages growing in dishes and increased their production of IGF-1 but not of molecules that kill neurons.
What Do These Findings Mean?
These findings suggest that, immediately after a spinal cord injury, CSPG is needed for the repair of injured neurons and the recovery of movement, but that later on the presence of CSPG hinders repair. The findings also indicate that CSPG has these effects, at least in part, because it regulates the activity and localization of microglia and macrophages at the injury site and thus modulates local immune responses to the damage. Results obtained from experiments done in animals do not always accurately reflect the situation in people, so these findings need to be confirmed in patients with spinal cord injuries. However, they suggest that the effect of CSPG on spinal cord repair is not an inappropriate response to the injury, as is widely believed. Consequently, careful manipulation of CSPG levels might improve outcomes for people with spinal cord injuries.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050171.
The MedlinePlus encyclopedia provides information about spinal cord injuries; MedlinePlus provides an interactive tutorial and a list of links to additional information about spinal cord injuries (in English and Spanish)
The US National Institute of Neurological Disorders and Stroke also provides information about spinal cord injury (in English and Spanish)
Wikipedia has a page on glial scars (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050171
PMCID: PMC2517615  PMID: 18715114
14.  The Role of Astrocytes in Mediating Exogenous Cell-Based Restorative Therapy for Stroke 
Glia  2013;62(1):1-16.
Astrocytes have not been a major therapeutic target for the treatment of stroke, with most research emphasis on the neuron. Given the essential role that astrocytes play in maintaining physiological function of the central nervous system and the very rapid and sensitive reaction astrocytes have in response to cerebral injury or ischemic insult, we propose to replace the neurocentric view for treatment with a more nuanced astrocytic centered approach. In addition, after decades of effort in attempting to develop neuroprotective therapies, which target reduction of the ischemic lesion, there are no effective clinical treatments for stroke, aside from thrombolysis with tissue plasminogen activator, which is used in a small minority of patients. A more promising therapeutic approach, which may affect nearly all stroke patients, may be in promoting endogenous restorative mechanisms, which enhance neurological recovery. A focus of efforts in stimulating recovery post stroke is the use of exogenously administered cells. The present review focuses on the role of the astrocyte in mediating the brain network, brain plasticity, and neurological recovery post stroke. As a model to describe the interaction of a restorative cell-based therapy with astrocytes, which drives recovery from stroke, we specifically highlight the subacute treatment of stroke with multipotent mesenchymal stromal cell therapy.
doi:10.1002/glia.22585
PMCID: PMC3947888  PMID: 24272702
stroke; marrow stromal cells; microRNA; exosomes; Shh; tPA; restoration; plasticity
15.  Pharmacologic approaches to cerebral aging and neuroplasticity: insights from the stroke model 
Brain plasticity is an intrinsic characteristic of the nervous system that allows continuous remodeling of brain functions in pathophysiological conditions. Although normal aging is associated with morphological modifications and decline of cerebral functions, brain plasticity is at least partially preserved in elderly individuals. A growing body of evidence supports the notion that cognitive enrichment and aerobic training induce a dynamic reorganization of higher cerebral functions, thereby helping to maintain operational skills in the elderly and reducing the incidence of dementia. The stroke model clearly shows that spontaneous brain plasticity exists after a lesion, even in old patients, and that it can be modulated through external factors like rehabilitation and drugs. Whether drugs can be used with the aim of modulating the effects of physical training or cognitive stimulation in healthy aged people has not been addressed until now. The risk:benefit ratio will be the key question with regard to the ethical aspect of this challenge. We review in this article the main aspects of human brain plasticity as shown in patients with stroke, the drug modulation of brain plasticity and its consequences on recovery, and finally we address the question of the influence of aging on brain plasticity.
PMCID: PMC3622470  PMID: 23576890
brain plasticity; aging; stroke; recovery; pharmacology
16.  Neurorehabilitation using the virtual reality based Rehabilitation Gaming System: methodology, design, psychometrics, usability and validation 
Background
Stroke is a frequent cause of adult disability that can lead to enduring impairments. However, given the life-long plasticity of the brain one could assume that recovery could be facilitated by the harnessing of mechanisms underlying neuronal reorganization. Currently it is not clear how this reorganization can be mobilized. Novel technology based neurorehabilitation techniques hold promise to address this issue. Here we describe a Virtual Reality (VR) based system, the Rehabilitation Gaming System (RGS) that is based on a number of hypotheses on the neuronal mechanisms underlying recovery, the structure of training and the role of individualization. We investigate the psychometrics of the RGS in stroke patients and healthy controls.
Methods
We describe the key components of the RGS and the psychometrics of one rehabilitation scenario called Spheroids. We performed trials with 21 acute/subacute stroke patients and 20 healthy controls to study the effect of the training parameters on task performance. This allowed us to develop a Personalized Training Module (PTM) for online adjustment of task difficulty. In addition, we studied task transfer between physical and virtual environments. Finally, we assessed the usability and acceptance of the RGS as a rehabilitation tool.
Results
We show that the PTM implemented in RGS allows us to effectively adjust the difficulty and the parameters of the task to the user by capturing specific features of the movements of the arms. The results reported here also show a consistent transfer of movement kinematics between physical and virtual tasks. Moreover, our usability assessment shows that the RGS is highly accepted by stroke patients as a rehabilitation tool.
Conclusions
We introduce a novel VR based paradigm for neurorehabilitation, RGS, which combines specific rehabilitative principles with a psychometric evaluation to provide a personalized and automated training. Our results show that the RGS effectively adjusts to the individual features of the user, allowing for an unsupervised deployment of individualized rehabilitation protocols.
doi:10.1186/1743-0003-7-48
PMCID: PMC2949710  PMID: 20860808
17.  A Simple Rule for Dendritic Spine and Axonal Bouton Formation Can Account for Cortical Reorganization after Focal Retinal Lesions 
PLoS Computational Biology  2013;9(10):e1003259.
Lasting alterations in sensory input trigger massive structural and functional adaptations in cortical networks. The principles governing these experience-dependent changes are, however, poorly understood. Here, we examine whether a simple rule based on the neurons' need for homeostasis in electrical activity may serve as driving force for cortical reorganization. According to this rule, a neuron creates new spines and boutons when its level of electrical activity is below a homeostatic set-point and decreases the number of spines and boutons when its activity exceeds this set-point. In addition, neurons need a minimum level of activity to form spines and boutons. Spine and bouton formation depends solely on the neuron's own activity level, and synapses are formed by merging spines and boutons independently of activity. Using a novel computational model, we show that this simple growth rule produces neuron and network changes as observed in the visual cortex after focal retinal lesions. In the model, as in the cortex, the turnover of dendritic spines was increased strongest in the center of the lesion projection zone, while axonal boutons displayed a marked overshoot followed by pruning. Moreover, the decrease in external input was compensated for by the formation of new horizontal connections, which caused a retinotopic remapping. Homeostatic regulation may provide a unifying framework for understanding cortical reorganization, including network repair in degenerative diseases or following focal stroke.
Author Summary
The adult brain is less hard-wired than traditionally thought. About ten percent of synapses in the mature visual cortex is continually replaced by new ones (structural plasticity). This percentage greatly increases after lasting changes in visual input. Due to the topographically organized nerve connections from the retina in the eye to the primary visual cortex in the brain, a small circumscribed lesion in the retina leads to a defined area in the cortex that is deprived of input. Recent experimental studies have revealed that axonal sprouting and dendritic spine turnover are massively increased in and around the cortical area that is deprived of input. However, the driving forces for this structural plasticity remain unclear. Using a novel computational model, we examine whether the need for activity homeostasis of individual neurons may drive cortical reorganization after lasting changes in input activity. We show that homeostatic growth rules indeed give rise to structural and functional reorganization of neuronal networks similar to the cortical reorganization observed experimentally. Understanding the principles of structural plasticity may eventually lead to novel treatment strategies for stimulating functional reorganization after brain damage and neurodegeneration.
doi:10.1371/journal.pcbi.1003259
PMCID: PMC3794906  PMID: 24130472
18.  The interaction between training and plasticity in the post-stroke brain 
Current opinion in neurology  2013;26(6):609-616.
Purpose of review
Recovery after stroke can occur either via reductions in impairment or through compensation. Studies in humans and non-human animal models show that most recovery from impairment occurs in the first 1 to 3 months after stroke as a result of both spontaneous reorganization and increased responsiveness to enriched environments and training. Improvement from impairment is attributable to a short-lived sensitive period of post-ischemic plasticity defined by unique genetic, molecular, physiological and structural events. In contrast, compensation can occur at any time after stroke. Here we address both the biology of the brain's post-ischemic sensitive period and the difficult question of what kind of training (task-specific vs. a stimulating environment for self-initiated exploration of various natural behaviors) best exploits this period.
Recent findings
Data suggest that three important variables determine the degree of motor recovery from impairment: (i) the timing, intensity, and approach to training with respect to stroke onset, (ii) the unique post-ischemic plasticity milieu, and (iii) the extent of cortical reorganization.
Summary
Future work will need to further characterize the unique interaction between types of training and post-ischemic plasticity, and find ways to augment and prolong the sensitive period using pharmacological agents or non-invasive brain stimulation.
doi:10.1097/WCO.0000000000000025
PMCID: PMC4012223  PMID: 24136129
Motor recovery; spontaneous recovery; motor learning; ischemia; neurological rehabilitation
19.  Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date 
The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuroinflammatory cascade has been reported to be activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory reaction is tumor necrosis factor (TNF)-α, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF-α has been shown to have an important role within the central nervous system; its properties include activation of microglia and astrocytes, influence on blood–brain barrier permeability, and influences on glutamatergic transmission and synaptic plasticity. TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF-α activity during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In some studies using animal models, researchers have reported a limitation of TBI-induced cerebral ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.
doi:10.2147/DDDT.S67655
PMCID: PMC4232043  PMID: 25422582
tumor necrosis factor inhibitors; brain injury; stroke; TBI; traumatic brain injury
20.  Harnessing neuroplasticity for clinical applications 
Brain  2011;134(6):1591-1609.
Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.
doi:10.1093/brain/awr039
PMCID: PMC3102236  PMID: 21482550
neuroplasticity; retraining; therapeutics; clinical assessment
21.  Epidemiology of Stroke: Legacy of the Framingham Heart Study 
Global heart  2013;8(1):67-75.
In the present historical review, we highlight several articles outlining contributions of the Framingham Heart Study over the span of nearly seven decades to our understanding of the epidemiology of blood pressure (BP), atrial fibrillation and genetic factors as they relate to cerebrovascular disease. In 1970, Framingham investigators led by William Kannel, explored the epidemiological relations of BP and its various components to risk of ischemic stroke as well as hemorrhage, and noted the greater impact of hypertension to risk of stroke compared to other cardiovascular outcomes. Framingham investigators changed the prevalent concepts in terms of the contribution of BP components to stroke risk; i.e. they showed systolic pressure to be no less important a component for stroke risk than the diastolic or mean arterial pressures. In addition, they challenged the notion that hypertension was a normal consequence of increasing age, as connoted by the term “essential” hypertension. They also refuted the idea that blood pressure elevation in the elderly is innocuous by demonstrating that increased stroke risk persisted in advanced age in hypertensive persons. Thirty years later, the Framingham Study attained long term follow up of an entire generation of participants with excellent retention to follow-up, thus providing an opportunity to study hypertension and risk of stroke in a general population sample. Framingham investigators examined the impact of various BP components over a 50-year follow-up in normotensive and untreated hypertensive individuals as regards stroke risk, and showed the long term importance of antecedent (midlife) hypertension in future stroke risk . Similarly by calling attention to the importance of chronic non-valvular atrial fibrillation as a contributor to stroke, particularly in the elderly, FHS investigators confirmed the clinical observations of the founder of stroke neurology, C. Miller Fisher, M.D., who had made the clinical and pathological association of AF to stroke. Lastly, in the dawn of the era of individualized preventive medicine, FHS is participating in the effort to further our understanding of the role of genetic factors to stroke incidence.
The contributions of the Framingham Heart Study have been many and have shaped our understanding of the relation of BP, AF and other risk factors to stroke risk, thereby setting the stage for clinical trials which demonstrated how control of these risk contributors could prevent stroke and enable stroke prevention. FHS investigators are collaborating with other geneticists and epidemiologists internationally to elucidate the role of genetic factors and stroke susceptibility, which is likely continue to shape the practice of preventive cardiovascular medicine.
doi:10.1016/j.gheart.2012.12.007
PMCID: PMC3601756  PMID: 23527318
22.  Magnetic Resonance Imaging to Visualize Stroke and Characterize Stroke Recovery: A Review 
The global burden of stroke continues to grow. Although stroke prevention strategies (e.g., medications, diet, and exercise) can contribute to risk reduction, options for acute interventions (e.g., thrombolytic therapy for ischemic stroke) are limited to the minority of patients. The remaining patients are often left with profound neurological disabilities that substantially impact quality of life, economic productivity, and increase caregiver burden. In the last decade, however, the future outlook for such patients has been tempered by movement toward the view that the brain is capable of reorganizing after injury. Many now view brain recovery after stroke as an area of scientific research with large potential for therapeutic advances, far into the future (Broderick and William, 2004). As a probe of brain anatomy, function and physiology, magnetic resonance imaging (MRI) is a non-invasive and highly versatile modality that promises to play a particularly important role in such research. Here we provide a basic review of MRI physical principles and applications for assessing stroke, looking toward the future role MRI may play in improving stroke rehabilitation methods and stroke recovery.
doi:10.3389/fneur.2013.00060
PMCID: PMC3664317  PMID: 23750149
stroke; stroke recovery; magnetic resonance imaging; diffusion; perfusion; functional MRI; arterial spin labeling; review
23.  Indestructible plastic: the neuroscience of the new aging brain 
In recent years, research on experience-dependent plasticity has provided valuable insight on adaptation to environmental input across the lifespan, and advances in understanding the minute cellular changes underlying the brain’s capacity for self-reorganization have opened exciting new possibilities for treating illness and injury. Ongoing work in this line of inquiry has also come to deeply influence another field: cognitive neuroscience of the normal aging. This complex process, once considered inevitable or beyond the reach of treatment, has been transformed into an arena of intense investigation and strategic intervention. However, important questions remain about this characterization of the aging brain, and the assumptions it makes about the social, cultural, and biological space occupied by cognition in the older individual and body. The following paper will provide a critical examination of the move from basic experiments on the neurophysiology of experience-dependent plasticity to the growing market for (and public conception of) cognitive aging as a medicalized space for intervention by neuroscience-backed technologies. Entangled with changing concepts of normality, pathology, and self-preservation, we will argue that this new understanding, led by personalized cognitive training strategies, is approaching a point where interdisciplinary research is crucial to provide a holistic and nuanced understanding of the aging process. This new outlook will allow us to move forward in a space where our knowledge, like our new conception of the brain, is never static.
doi:10.3389/fnhum.2014.00219
PMCID: PMC3990104  PMID: 24782746
plasticity; aging; cognitive training; computerized training; neurotechnology; cognitive decline; normality; biocapital
24.  Transplantation of Bone Marrow Stromal Cells Enhances Nerve Regeneration of the Corticospinal Tract and Improves Recovery of Neurological Functions in a Collagenase-Induced Rat Model of Intracerebral Hemorrhage 
Molecules and Cells  2013;36(1):17-24.
The reorganization of brain structures after intracerebral hemorrhage (ICH) insult is crucial to functional outcome. Although the pattern of neuronal rewiring is well-documented after ischemic stroke, the study of brain plasticity after ICH has been focusing on the enhancement of dendritic complexity. Here we hypothesized that functional restoration after ICH involves brain reorganization which may be favorably modulated by stem cell transplantation. In this study, bone marrow stromal cells (BMSCs) were transplanted into the perilesional sites of collagenase-induced ICH in adult rats one day after ICH injury. Forelimb functional recovery was monitored with modified limb placing and vibrissae-elicited forelimb placement tests. Anterograde and retrograde tracing were used to assess the reorganization of bilateral forelimb areas of the sensorimotor cortex. We found that in rats transplanted with BMSCs after ICH injury, axonal sprouting occurred in the contralateral caudal forelimb area of the cortex, and was significantly higher than in ICH rat models that received only the vehicle (P < 0.01). The number of positive neurons in the ipsilateral rostral forelimb area of the cortex of the BMSC group was 1.5– to 4.5-fold greater than in the vehicle group (P < 0.05). No difference was found between the BMSC and vehicle groups in hemispheric atrophy or labeled neurons in the ipsilateral caudal forelimb area (P = 0.193). Scores for improved functional behavior in the BMSC group were in accord with the results from histology. Neuronal plasticity of the denervated corticospinal tract at bilateral forelimb areas of the cortex in the collagenase-induced ICH rat models was significantly enhanced by BMSC transplantation. BMSC transplantation may facilitate functional recovery after ICH injury.
doi:10.1007/s10059-013-2306-9
PMCID: PMC3887925  PMID: 23807046
bone marrow stromal cell; intracerebral hemorrhage; neuronal plasticity
25.  Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord 
Experimental neurology  2007;209(2):407-416.
The failure of injured axons to regenerate following spinal cord injury deprives brain neurons of their normal sources of activation. These injuries also result in the reorganization of affected areas of the central nervous system that is thought to drive both the ensuing recovery of function and the formation of maladaptive neuronal circuitry. Better understanding of the physiological consequences of novel synaptic connections produced by injury and the mechanisms that control their formation are important to the development of new successful strategies for the treatment of patients with spinal cord injuries. Here we discuss the anatomical, physiological and behavioral changes that take place in response to injury-induced plasticity after damage to the dorsal column pathway in rats and monkeys. Complete section of the dorsal columns of the spinal cord at a high cervical level in monkeys and rats interrupts the ascending axon branches of low threshold mechanoreceptor afferents subserving the forelimb and the rest of the lower body. Such lesions render the corresponding part of the somatotopic representation of primary somatosensory cortex totally unresponsive to tactile stimuli. There are also behavioral consequences of the sensory loss, including an impaired use of the hand/forelimb in manipulating small objects. In monkeys, if some of the afferents from the hand remain intact after dorsal column lesions, these remaining afferents extensively reactivate portions of somatosensory cortex formerly representing the hand. This functional reorganization develops over a postoperative period of one month, during which hand use rapidly improves. These recoveries appear to be mediated, at least in part, by the sprouting of preserved afferents within the cuneate nucleus of the dorsal column-trigeminal complex. In rats, such functional collateral sprouting has been promoted by the post-lesion digestion of the perineuronal net in the cuneate nucleus. Thus, this and other therapeutic strategies have the potential of enhancing sensorimotor recoveries after spinal cord injuries in humans.
doi:10.1016/j.expneurol.2007.06.014
PMCID: PMC2268113  PMID: 17692844

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