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

Abstract

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.

Is Environmental Enrichment Ready for Clinical Application in Human Post-stroke Rehabilitation?

“…EE alone is not effective in promoting recovery of skilled forelimb movements (e.g., reaching; Grabowski et al, 1993 ), since there is no opportunity to engage in this activity in standard EE configurations. As such, to fill this void our group adds a daily reaching task component to EE which dramatically improves the level of recovery provided by EE (Biernaskie and Corbett, 2001 ; Biernaskie et al, 2004 ; Jeffers and Corbett, 2018 ). Thus, the ideal definition of EE, unlike typical stroke rehabilitation in the clinic, encompasses a changing environment that encourages socialization, exercise, sensory and cognitive stimulation, and task-specific therapy targeting the primary impairment.…”

“…Using a modified EE paradigm in which EE was combined with daily reach training (i.e., enriched rehabilitation, ER), it was found that EE, running exercise and reach training all produce a uniform pattern of activation throughout all layers of the sensorimotor cortex after stroke, however ER causes a more specific pattern of activation, targeting layer II and layer III motor neurons (Clarke et al, 2014 ). Recently, we showed that ER is more effective than either EE alone or reach training alone at restoring skilled forelimb function after stroke (Jeffers and Corbett, 2018 ). Similarly, others have shown a synergistic benefit when EE is paired with either resistance exercise or increased social interaction (Brenes et al, 2016 ; Prado Lima et al, 2018 ).…”

“…The pattern emerging from studies using EE to promote post-stroke recovery is that the whole is greater than the sum of the parts (Jeffers and Corbett, 2018 ). In this regard, EE shares similarity with other pleiotropic treatments such as exercise, hypothermia and ischemic tolerance, that have proven to be effective in reducing ischemic damage to the brain (Iadecola and Anrather, 2011 ).…”

“…EE may provide one such adjunctive intervention for increasing non-specific therapy dose, as this treatment paradigm provides a stimulating environment that enhances stroke recovery in rodents across a variety of impairment domains without requiring provision of specific training (Ohlsson and Johansson, 1995 ; Risedal et al, 2002 ; Livingston-Thomas et al, 2016 ). Furthermore, this stimulating environment has a potentiating effect on task-specific therapy, resulting in recovery beyond what would have occurred with either EE, or task-specific therapy alone (Jeffers and Corbett, 2018 ).…”

“…While clinical EE has attempted to mirror the physical, social and cognitive focus of preclinical EE, the opportunity for more strenuous exercise, similar to rodent running wheels, is lacking. Further, few clinical studies to date have attempted to include more task-specific rehabilitation into their EE paradigm similar to ER, which preclinical work has shown to be even more advantageous than EE alone (Jeffers and Corbett, 2018 ). Nonetheless, taking these differences into account, there are considerable research opportunities to better align preclinical and clinical EE and ER research.…”