Enriched Rehabilitation Reduces Abnormal Motor Synergies and Enhances Motor Plasticity Following Severe Stroke in Rats.

BACKGROUND: Stroke results in loss of upper motor neuron control over voluntary movements and emergence of abnormal synergies. Presently, it is unclear to what extent poststroke recovery reflects true recovery (restitution), compensation, or some combination of these processes. Here, we investigated this question using behavioral and kinematic analyses of skilled reaching in rats subjected to severe stroke that affected both the forelimb motor cortex and dorsolateral striatum. METHODS: After stroke, male rats either spontaneously recovered or received enriched rehabilitation. We assessed forelimb motor recovery using behavioral and kinematic outcome measures. To provide insights into the mechanisms underlying the effects of rehabilitation on behavior, we used intracortical microstimulation and FosB (protein fosB) immunostaining techniques. RESULTS: Enriched rehabilitation significantly improved food pellet retrieval in the staircase-reaching task. Rehabilitation resulted in several poststroke flexion synergies returning to prestroke patterns, and across subjects, these changes correlated with the intensity of rehabilitation. Enriched rehabilitation increased the proportion of distal movement representation in the perilesional cortex and increased use-dependent activation in the ipsilesional red nucleus. CONCLUSIONS: These results provide evidence that enriched rehabilitation enhances recovery, at least in part, by restitution of forelimb function following severe stroke. Furthermore, the restitution of function is associated with changes in multiple motor-related structures at different levels of the central nervous system. A better understanding of the processes that underlie improved motor performance, along with the identification of midbrain circuits activated by rehabilitation, represent new insights and potential targets for optimizing poststroke recovery.

Synergistic Effects of Enriched Environment and Task-Specific Reach Training on Poststroke Recovery of Motor Function.

BACKGROUND AND PURPOSE: Reach training in concert with environmental enrichment provides functional benefits after experimental stroke in rats. The present study extended these findings by assessing whether intensive task-specific reach training or enrichment initiated alone would provide similar functional benefit. Additionally, we investigated whether the 70% recovery rule, or a combined model of initial poststroke impairment, cortical infarct volume, and rehabilitation intensity, could predict recovery in the single-pellet task, as previously found for the Montoya staircase. METHODS: Rats were trained on single-pellet reaching before middle cerebral artery occlusion via intracerebral injection of ET-1 (endothelin-1). There were 4 experimental groups: stroke+enrichment, stroke+reaching, stroke+enrichment+reaching, and sham+enrichment+reaching. Reaching rehabilitation utilized a modified Whishaw box that encouraged impaired forelimb reaching for 6 hours per day, 5 days per week, for 4 weeks. All treatment paradigms began 7 days after ischemia with weekly assessment on the single-pellet task during rehabilitation and again 4 weeks after rehabilitation concluded. RESULTS: Rats exposed to the combination of enrichment and reaching showed the greatest improvement in pellet retrieval and comparable performance to shams after 3 weeks of treatment, whereas those groups that received a monotherapy remained significantly impaired at all time points. Initial impairment alone did not significantly predict recovery in single-pellet as the 70% rule would suggest; however, a combined model of cortical infarct volume and rehabilitation intensity predicted change in pellet retrieval on the single-pellet task with the same accuracy as previously shown with the staircase, demonstrating the generalizability of this model across reaching tasks. CONCLUSIONS: Task-specific reach training and environmental enrichment have synergistic effects in rats that persist long after rehabilitation ends, and this recovery is predicted by infarct volume and rehabilitation intensity.

Characterizing Spontaneous Motor Recovery Following Cortical and Subcortical Stroke in the Rat.

BACKGROUND: Stroke is a leading cause of neurological disability, often resulting in long-term motor impairments due to damage to cortical or subcortical motor areas. Despite the high prevalence of subcortical strokes in the clinical population, preclinical research has primarily focused on investigating and treating cortical strokes. Moreover, while both humans and animals show spontaneous recovery following stroke, little is known about how injury location affects this process. OBJECTIVE: To capture the heterogeneity of human stroke and examine how stroke location affects spontaneous motor recovery following damage to cortical, subcortical, or a combination of both areas. METHODS: Endothelin-1 (ET-1), a potent vasoconstrictor, was used to produce focal infarcts in the forelimb motor cortex (FMC), the dorsolateral striatum (DLS) or both the FMC and DLS in male Sprague-Dawley rats. The spontaneous recovery profile of animals was followed over an 8-week period using a battery of behavioral tasks assessing motor function and limb preference. RESULTS: All 3 groups showed significant impairments on the Montoya staircase, beam, and cylinder tests following stroke, with the combined group (FMC + DLS) having the largest and most persistent impairments. Importantly, spontaneous recovery was not simply dependent on lesion volume, but on location, and the behavioral test employed. CONCLUSIONS: Stroke location markedly and differentially influences the level of spontaneous functional recovery, which is only captured by using multiple outcome measures. These results illustrate the need for preclinical stroke models to align with the heterogeneity of human stroke, especially with respect to lesion location, size, and outcome measures.

Does Stroke Rehabilitation Really Matter? Part A: Proportional Stroke Recovery in the Rat.

BACKGROUND: In human upper-limb stroke, initial level of functional impairment or corticospinal tract injury can accurately predict the degree of poststroke recovery, independent of rehabilitation practices. This proportional recovery rule implies that current rehabilitation practices may play little or no role in brain repair, with recovery largely a result of spontaneous biological recovery processes. OBJECTIVE: The present study sought to determine if similar biomarkers predict recovery of poststroke function in rats, indicating that an endogenous biological recovery process might be preserved across mammalian species. METHODS: Using a cohort of 593 male Sprague-Dawley rats, we predicted poststroke change in pellet retrieval in the Montoya staircase-reaching task based on initial impairment alone. Stratification of the sample into "fitters" and "nonfitters" of the proportional recovery rule using hierarchical cluster analysis allowed identification of distinguishing characteristics of these subgroups. RESULTS: Approximately 30% of subjects were identified as fitters of the rule. These rats showed recovery in proportion to their initial level of impairment of 66% (95% CI = 62%-70%). This interval overlaps with those of multiple human clinical trials. A number of variables, including less severe infarct volumes and initial poststroke impairments distinguished fitters of the rule from nonfitters. CONCLUSIONS: These findings suggest that proportional recovery is a cross-species phenomenon that can be used to uncover biological mechanisms contributing to stroke recovery.

Does Stroke Rehabilitation Really Matter? Part B: An Algorithm for Prescribing an Effective Intensity of Rehabilitation.

BACKGROUND: The proportional recovery rule suggests that current rehabilitation practices may have limited ability to influence stroke recovery. However, the appropriate intensity of rehabilitation needed to achieve recovery remains unknown. Similarities between rodent and human recovery biomarkers may allow determination of rehabilitation thresholds necessary to activate endogenous biological recovery processes. OBJECTIVE: We determined the relative influence that clinically relevant biomarkers of stroke recovery exert on functional outcome. These biomarkers were then used to generate an algorithm that prescribes individualized intensities of rehabilitation necessary for recovery of function. METHODS: A retrospective cohort of 593 male Sprague-Dawley rats was used to identify biomarkers that best predicted poststroke change in pellet retrieval in the Montoya staircase-reaching task using multiple linear regression. Prospective manipulation of these factors using endothelin-1-induced stroke (n = 49) was used to validate the model. RESULTS: Rehabilitation was necessary to reliably predict recovery across the continuum of stroke severity. As infarct volume and initial impairment increased, more intensive rehabilitation was required to engage recovery. In this model, we prescribed the specific dose of daily rehabilitation required for rats to achieve significant motor recovery using the biomarkers of initial poststroke impairment and infarct volume. CONCLUSIONS: Our algorithm demonstrates an individualized approach to stroke rehabilitation, wherein imaging and functional performance measures can be used to develop an optimized rehabilitation paradigm for rats, particularly those with severe impairments. Exploring this approach in human patients could lead to an increase in the proportion of individuals experiencing recovery of lost motor function poststroke.

Exercise and Environmental Enrichment as Enablers of Task-Specific Neuroplasticity and Stroke Recovery.

Improved stroke care has resulted in greater survival, but >50% of patients have chronic disabilities and 33% are institutionalized. While stroke rehabilitation is helpful, recovery is limited and the most significant gains occur in the first 2-3 months. Stroke triggers an early wave of gene and protein changes, many of which are potentially beneficial for recovery. It is likely that these molecular changes are what subserve spontaneous recovery. Two interventions, aerobic exercise and environmental enrichment, have pleiotropic actions that influence many of the same molecular changes associated with stroke injury and subsequent spontaneous recovery. Enrichment paradigms have been used for decades in adult and neonatal animal models of brain injury and are now being adapted for use in the clinic. Aerobic exercise enhances motor recovery and helps reduce depression after stroke. While exercise attenuates many of the signs associated with normal aging (e.g., hippocampal atrophy), its ability to reverse cognitive impairments subsequent to stroke is less evident. It may be that stroke, like other diseases such as cancer, needs to use multimodal treatments that augment complimentary neurorestorative processes.

Enriched rehabilitation promotes motor recovery in rats exposed to neonatal hypoxia-ischemia.

Despite continuous improvement in neonatology there is no clinically effective treatment for perinatal hypoxia ischemia (HI). Therefore, development of a new therapeutic intervention to minimize the resulting neurological consequences is urgently needed. The immature brain is highly responsive to environmental stimuli, such as environmental enrichment but a more effective paradigm is enriched rehabilitation (ER), which combines environmental enrichment with daily reach training. Another neurorestorative strategy to promote tissue repair and functional recovery is cyclosporine A (CsA). However, potential benefits of CsA after neonatal HI have yet to be investigated. The aim of this study was to investigate the effects of a combinational therapy of CsA and ER in attempts to promote cognitive and motor recovery in a rat model of perinatal hypoxic-ischemic injury. Seven-day old rats were submitted to the HI procedure and divided into 4 groups: CsA+Rehabilitation; CsA+NoRehabilitation; Vehicle+Rehabilitation; Vehicle+NoRehabilitation. Behavioural parameters were evaluated pre (experiment 1) and post 4 weeks of combinational therapy (experiment 2). Results of experiment 1 demonstrated reduced open field activity of HI animals and increased foot faults relative to shams in the ladder rung walking test. In experiment 2, we showed that ER facilitated acquisition of a staircase skilled-reaching task, increased number of zone crosses in open-field exploration and enhanced coordinated limb use during locomotion on the ladder rung task. There were no evident deficits in novel object recognition testing. Delayed administration of CsA, had no effect on functional recovery after neonatal HI. There was a significant reduction of cortical and hemispherical volume and hippocampal area, ipsilateral to arterial occlusion in HI animals; combinational therapy had no effect on these morphological measurements. In conclusion, the present study demonstrated that ER, but not CsA was the main contributor to enhanced recovery of motor ability after neonatal HI.