Neuroscience Forefront ReviewRehabilitation and plasticity following stroke: Insights from rodent models
Introduction
Stroke is one of the leading causes of long-term disability. Stroke patients show varying degrees and types of neurological deficits, that depend on size and location of the brain lesion. Focal strokes affecting the motor cortex result in motor impairments, and functional deficits in the upper limbs are particularly devastating as they impact on everyday activities such as eating, drinking, writing etc. There is an obvious need for appropriate animal models to guide the development of more effective rehabilitation therapies after stroke. In this article, I concentrate on studies of rehabilitation and plasticity following ischemic lesions to forelimb motor cortical areas, with a specific emphasis on rodent models (see Table 1). Detailed kinematic analyses have demonstrated striking similarities between human upper extremity and rodent forelimb movements, particularly during reaching behavior, suggesting that rodents can be effectively used in experimental studies with potential translatability to the human condition (Klein et al., 2012). Rodent models are also particularly suited to determine, in a well-controlled setting, the optimal timing and combination of restorative procedures. Finally, the availability of several experimental tools (optogenetics, transgenesis) for studying and manipulating the functional organization of the rodent motor system holds great promise for the identification of the neural mechanisms and specific circuits underlying motor recovery.
Section snippets
Spontaneous restoration of function following stroke: recovery vs. compensation
Limited but significant restoration of function occurs spontaneously after an ischemic damage to the motor cortex. These functional gains are mostly confined to an early “critical period” after the injury, extending for a few months in humans and about one month in rodents (Nakayama et al., 1994, Cramer, 2008, Zeiler and Krakauer, 2013). Restoration of forelimb function after stroke is typically assessed with a battery of behavioral tasks, and the degree of improvement depends on both the size
Role of the contralesional hemisphere in functional restoration
Several studies in humans have addressed the role of perilesional vs. contralesional motor areas in recovery and compensation following stroke. One approach is the use of functional neuroimaging to map activation of ipsilesional and contralesional areas longitudinally following stroke and relate these measures with tests of motor function. Generally, these reports indicate an enhanced activity in the contralesional hemisphere early after stroke (about 10 days), followed by a relative increase of
Circuit reorganization, map plasticity and sprouting in the perilesional cortex
Several longitudinal changes have been described to occur in perilesional areas after a focal ischemic stroke. Initially there is a robust reduction of activity and a loss of responsiveness of cortical areas surrounding the injury (Rehme et al., 2011). Subsequently, peri-infarct areas show changes in the excitation/inhibition ratio, with downregulation of GABA-A receptors and upregulation of NMDA receptors (e.g. Schiene et al., 1996). This increase of the excitation/inhibition ratio may explain
Glial and neurovascular plasticity after stroke: potential role in recovery
In addition to neuronal plasticity, a focal ischemic stroke potently impacts on the organization of glial and endothelial cells. Specifically, astrocytes react quite rapidly with changes in morphology, proliferation, and gene expression, and form a glial scar that separates the injury site from healthy surrounding tissue (Choudhury and Ding, 2015). Astrocytes in the scar express a variety of neurite-growth inhibitors, including CSPGs, that limit functional recovery. However, astrocytes have
Physical rehabilitation and recovery
Spontaneous reorganization of spared circuits often allows only limited restoration of function after stroke, prompting the search for effective therapeutic interventions. One option is to provide the animals with enhanced sensorimotor stimulation, as compared to standard laboratory cages. This housing condition is known as “enriched environment” (Sale et al., 2014) and consists of keeping the animals in big groups, and large cages where a variety of objects are present (toys, tunnels,
Robotic rehabilitation after stroke
Recently, robotic training devices have been introduced in neurorehabilitation therapies after brain damage (Lo et al., 2010). There are two main advantages of robotic-based rehabilitation as compared to traditional physiotherapy: (i) it provides an intensive and highly repeatable “dosage” of therapy, which can be varied to continuously challenge the patient’s neuromuscular system; (ii) it offers a quantitative and objective evaluation of the outcome for each patient, since the mechatronic
Combination of rehabilitation with plasticizing treatments
There is a general consensus in the literature that physical rehabilitation should be coupled with pharmacological interventions that render the spared CNS networks more susceptible to experience-dependent modifications. Specifically, a major focus of current research is on the delivery of “plasticizing” treatments that enhance the modifiability of spared circuits and the formation of novel neural connections, that can then be selected and strengthened by physical rehabilitation. These
Cell-based therapies for functional restoration after stroke
Transplantation of stem cells has been employed in several studies to improve functional recovery after ischemic damage. Various cell types have been tested in preclinical models (Zhang and Chopp, 2013). In particular, induced pluripotent stem cells (iPSCs) are particularly attractive since they are derived from adult differentiated somatic cells (e.g. fibroblasts, typically via the expression of specific reprogramming genes), thus allowing the generation of patient-specific cells and
Conclusions
Rodent models offer a unique opportunity to dissect mechanisms of spontaneous plasticity and circuit reorganization of the motor system after stroke. Experimental interventions aimed at increasing this plasticity are effective in promoting recovery, particularly when coupled with motor training that instructs newly formed connections to generate functionally meaningful patterns of activity. Future goals will include the implementation of less invasive strategies to promote neuroplasticity and a
Acknowledgments
This work was supported by a grant from Fondazione Pisa (# 158/2011). I thank Silvestro Micera, Carmelo Chisari, and all the members of my laboratory for constructive discussions about the topics covered in this review.
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