Cortical stimulation (CS) as a means to modulate regional activity and excitability in cortex is emerging as a promising approach for facilitating rehabilitative interventions after brain damage, including stroke. In this study, we investigated whether CS-induced functional improvements are linked with synaptic plasticity in peri-infarct cortex and vary with the severity of impairments. Adult rats that were proficient in skilled reaching received subtotal unilateral ischemic sensorimotor cortex (SMC) lesions and implantation of chronic epidural electrodes over remaining motor cortex. Based on the initial magnitude of reaching deficits, rats were divided into severely and moderately impaired subgroups. Beginning two weeks post-surgery, rats received 100 Hz cathodal CS at 50% of movement thresholds or no-stimulation control procedures (NoCS) during 18 days of rehabilitative training on a reaching task. Stereological electron microscopy methods were used to quantify axodendritic synapse subtypes in motor cortical layer V underlying the electrode. In moderately, but not severely impaired rats, CS significantly enhanced recovery of reaching success. Sensitive movement analyses revealed that CS partially normalized reaching movements in both impairment subgroups compared to NoCS. Additionally, both CS subgroups had significantly greater density of axodendritic synapses and moderately impaired CS rats had increases in presumed efficacious synapse subtypes (perforated and multiple synapses) in stimulated cortex compared to NoCS. Synaptic density was positively correlated with postrehabilitation reaching success. In addition to providing further support that CS can promote functional recovery, these findings suggest that CS-induced functional improvements may be mediated by synaptic structural plasticity in stimulated cortex.Keywords motor rehabilitation; skilled reaching; synaptic plasticity; perforated synapses; multisynaptic boutons; stroke Motor impairments are among the most common disabilities caused by stroke (Thom et al., 2006). Motor rehabilitative training can reduce these impairments but it is often insufficient * Corresponding author. The University of Texas, 1 University Station A8000, Austin, TX 78712. Phone: +1 512 475-7763, Fax: +1 512 475-7765, dladkins@mail.utexas.edu. ‡ D.L.A and J.E.H. contributed equally to this work.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptExp Neurol. Author manuscript; available in PMC 2011 January 10. to restore normal levels of function (Duncan et al., 2000;Dobkin, 2004). Recent studies in ...

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Background and Purpose-Behavioral experience can drive brain plasticity, but we lack sufficient knowledge to optimize its therapeutic use after stroke. Methods-We outline recent findings from rodent models of cortical stroke of how experiences interact with postinjury events to influence synaptic connectivity and functional outcome. We focus on upper extremity function. Results-After unilateral cortical infarcts, behavioral experiences shape neuronal structure and activity in both hemispheres. Key Words: learned nonuse Ⅲ motor cortex Ⅲ motor rehabilitation Ⅲ synaptic plasticity B ehavioral experience can cause dendrites to grow and regress, synapses to change in efficacy, vasculature and glia to be modified, and, sometimes, neurons to be added or lost. 1 It is at work continuously and across the lifespan. It is safe to assume that it will be a factor in stroke recovery. However, what pragmatic use can we make of this? Currently, experience, in the form of physical therapy and rehabilitation, is the major tool available for treatment in the chronic poststroke period, but we lack the knowledge required to optimize its use alone or in combination with other treatments. Animal research is beginning to reveal how behavioral experience interacts with degenerative and regenerative cascades after stroke onset. This research suggests that the nature and timing of behavioral experiences can have a major influence on brain reorganization with good, bad, and mixed consequences for functional outcome. Shaping Postinjury ExperienceBrain damage can impair and enhance experience-dependent plasticity depending on the region and time window after the injury. 1,2 We have found that, in rats with unilateral ischemic sensorimotor cortical lesions, the contralesional motor cortex, in concert with transcallosal degenerative changes, becomes more sensitive to behavioral experiences of the ipsilesional "unaffected" forelimb ( Figure). 3 After these lesions, rats spontaneously begin to rely more on the unaffected forelimb and this drives the growth of synapses and dendrites in the contralesional cortex. More synapses also have ultrastructural characteristics of enhanced efficacy. These effects occur more robustly than those resulting from similar asymmetrical forelimb experience in intact animals. Thus, this is an example of injury-induced enhancement of experiencedependent plasticity.The facilitation of plasticity in the contralesional cortex may enhance an animal's ability to learn compensatory ways of using the unaffected forelimb. Consistent with this, even in the presence of significant impairments in the "unaffected" limb, some types of skill acquisition with this limb are enhanced, an effect that is lesion size-and time-sensitive. 3,4 However, there is a cost for the impaired limb. When rats were trained to use the unaffected limb for skilled reaching in the weeks after injury, it reduced neuronal activation (as assayed by FosB/⌬FosB expression) in the remaining periinfarct motor cortex, a region that is important for recovery of ...

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. 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.

Unilateral damage to the forelimb region of the sensorimotor cortex (FLsmc) results in time-dependent changes in neuronal activity, structure and connectivity in the contralateral motor cortex of adult rats. These changes have been linked to facilitation of motor skill learning in the less-affected/ipsilesional forelimb, which is likely to promote its use in the development of behavioral compensation. The goal of this study was to determine whether an early post-lesion-sensitive time period exists for this enhanced learning and whether it is linked to synaptogenesis in the contralesional motor cortex. Rats were trained for 21 days on a skilled reaching task with the ipsilesional forelimb beginning 4 or 25 days after unilateral ischemic (endothelin-1-induced) FLsmc lesions or sham operations. As found previously, reaching performance was significantly enhanced in rats trained early post-lesion compared with sham-operates. In rats trained later post-lesion, performance was neither significantly different from time-matched sham-operates nor strikingly different from animals trained earlier post-lesion. In layer V of the contralesional motor cortex, stereological methods for light and electron microscopy revealed significantly more total, multisynaptic bouton and perforated synapses per neuron compared with sham-operates, but there were no significant differences between early- and late-trained lesion groups. Thus, there appears to be a sensitive time window for the maximal expression of the enhanced learning capacity of the less-affected forelimb but this window is broadly, rather than sharply, defined. These results indicate that relatively long-lasting lesion-induced neuronal changes are likely to underlie the facilitation of learning with the less-affected forelimb.