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.

Self-reported sleep disturbances among people who have had a stroke: a cross-sectional analysis.

BACKGROUND: Sleep disturbances and their potential association with stroke remains understudied at a population level. We sought to determine the prevalence of sleep disturbances among people who have effects of stroke compared with the general population. METHODS: We used data from people aged 18 years or older who responded to the sleep and chronic disease modules of the 2017-2018 cycle of the Canadian Community Health Survey (CCHS). We measured sleep disturbances by self-reports of having trouble staying awake most or all of the time; either short (< 5 h) or long (> 9 h) nightly sleep duration; having trouble going to or staying asleep most or all of the time; and never, rarely or sometimes having refreshing sleep. We used log-binomial and multinomial regression to investigate prevalence of sleep disturbances among respondents who reported effects of stroke compared with others, adjusting for confounding factors. RESULTS: We included 46 404 CCHS respondents, 682 of whom reported effects of stroke. The prevalence of sleep disturbances for those with effects of stroke was higher than among others in the sample with regard to trouble staying awake (13.0% v. 6.1%; adjusted relative risk [RR] 2.16, 95% confidence interval [CI] 1.59-2.94), short or long duration sleep (28.9% v. 10.0%; adjusted RR 1.93, 95% CI 1.57-2.38), trouble going to or staying asleep, (28.1% v. 17.6%; adjusted RR 1.53, 95% CI 1.28-1.83) and lack of refreshing sleep (41.1% v. 37.1%; adjusted RR 1.30, 95% CI 1.14-1.49). The prevalence of at least 1 reported measure of sleep disturbance was 61.6% among those with effects of stroke, compared with 48.2% among others (adjusted RR 1.28, 95% CI 1.18-1.40). INTERPRETATION: Self-report of having effects of stroke was associated with increased prevalence of sleep disturbances compared with the general population. Sleep disturbances were reported by a high proportion of respondents with effects of stroke, indicating the importance of screening for related disorders.

Validity of Bioelectric Impedance in Relation to Dual-Energy X-Ray Absorptiometry for Measuring Baseline and Change in Body Composition After an Exercise Program in Stroke.

ABSTRACT: Vanzella, LM, Lawand, R, Shuaib, M, Oh, P, Corbett, D, and Marzolini, S. Validity of bioelectric impedance in relation to dual-energy x-ray absorptiometry for measuring baseline and change in body composition after an exercise program in stroke. J Strength Cond Res 36(12): 3273-3279, 2022-Exercise is an important strategy to improve fat-free mass (FFM) and reduce percent fat mass (FM%). However, no study has reported on a valid, cost-effective method to measure changes in body composition after stroke. The purpose of the study is to determine the level of agreement between bioelectrical impedance analysis (BIA) and dual-energy x-ray absorptiometry (DXA) for assessing baseline and change in FFM and FM% after an exercise training intervention for individuals with mobility deficits after stroke. Fat-free mass and FM% were measured by BIA and DXA at the beginning and after 6 months of participation in an exercise program for individuals with mobility deficits after stroke. Forty-two subjects after stroke were included. Overall, Bland-Altman plots revealed that BIA overestimated the baseline FFM and FM% by only -0.4 ± 1.8 kg and -2.8 ± 1.8%, respectively. BIA underestimated changes in FFM by 0.33 ± 0.45 kg and overestimated changes in FM% by -0.40 ± 0.68%. The 95% CI of the mean bias for baseline FFM was -7.1 to 6.3 kg and -11.8 to 6.0% for FM%, demonstrating good agreement. The 95% CI for the change in FFM was -3.8 to 4.5 kg and -5.0 to 4.2% for FM%, which reflected good agreement. BIA is a good tool for assessing qualitative baseline and change in FFM and FM%. Body composition is important for the prescription and evaluation of rehabilitation programs designed for individuals after stroke. Our results provide clinicians and researchers with a better understanding of the utility of BIA to measure body composition at baseline and in response to exercise interventions in this population.

Poststroke Impairment and Recovery Are Predicted by Task-Specific Regionalization of Injury.

Lesion size and location affect the magnitude of impairment and recovery following stroke, but the precise relationship between these variables and functional outcome is unknown. Herein, we systematically varied the size of strokes in motor cortex and surrounding regions to assess effects on impairment and recovery of function. Female Sprague Dawley rats (N = 64) were evaluated for skilled reaching, spontaneous limb use, and limb placement over a 7 week period after stroke. Exploration and reaching were also tested in a free ranging, more naturalistic, environment. MRI voxel-based analysis of injury volume and its likelihood of including the caudal forelimb area (CFA), rostral forelimb area (RFA), hindlimb (HL) cortex (based on intracranial microstimulation), or their bordering regions were related to both impairment and recovery. Severity of impairment on each task was best predicted by injury in unique regions: impaired reaching, by damage in voxels encompassing CFA/RFA; hindlimb placement, by damage in HL; and spontaneous forelimb use, by damage in CFA. An entirely different set of voxels predicted recovery of function: damage lateral to RFA reduced recovery of reaching, damage medial to HL reduced recovery of hindlimb placing, and damage lateral to CFA reduced recovery of spontaneous limb use. Precise lesion location is an important, but heretofore relatively neglected, prognostic factor in both preclinical and clinical stroke studies, especially those using region-specific therapies, such as transcranial magnetic stimulation.SIGNIFICANCE STATEMENT By estimating lesion location relative to cortical motor representations, we established the relationship between individualized lesion location, and functional impairment and recovery in reaching/grasping, spontaneous limb use, and hindlimb placement during walking. We confirmed that stroke results in impairments to specific motor domains linked to the damaged cortical subregion and that damage encroaching on adjacent regions reduces the ability to recover from initial lesion-induced impairments. Each motor domain encompasses unique brain regions that are most associated with recovery and likely represent targets where beneficial reorganization is taking place. Future clinical trials should use individualized therapies (e.g., transcranial magnetic stimulation, intracerebral stem/progenitor cells) that consider precise lesion location and the specific functional impairments of each subject since these variables can markedly affect therapeutic efficacy.

Advancing Stroke Recovery Through Improved Articulation of Nonpharmacological Intervention Dose.

Dose articulation is a universal issue of intervention development and testing. In stroke recovery, dose of a nonpharmaceutical intervention appears to influence outcome but is often poorly reported. The challenges of articulating dose in nonpharmacological stroke recovery research include: (1) the absence of specific internationally agreed dose reporting guidelines; (2) inadequate conceptualization of dose, which is multidimensional; and (3) unclear and inconsistent terminology that incorporates the multiple dose dimensions. To address these challenges, we need a well-conceptualized and consistent approach to dose articulation that can be applied across stroke recovery domains to stimulate critical thinking about dose during intervention development, as well as promote reporting of planned intervention dose versus actually delivered dose. We followed the Design Research Paradigm to develop a framework that guides how to articulate dose, conceptualizes the multidimensional nature and systemic linkages between dose dimensions, and provides reference terminology for the field. Our framework recognizes that dose is multidimensional and comprised of a duration of days that contain individual sessions and episodes that can be active (time on task) or inactive (time off task), and each individual episode can be made up of information about length, intensity, and difficulty. Clinical utility of this framework was demonstrated via hypothetical application to preclinical and clinical domains of stroke recovery. The suitability of the framework to address dose articulation challenges was confirmed with an international expert advisory group. This novel framework provides a pathway for better articulation of nonpharmacological dose that will enable transparent and accurate description, implementation, monitoring, and reporting, in stroke recovery research.

Timing and Dose of Upper Limb Motor Intervention After Stroke: A Systematic Review.

This systematic review aimed to investigate timing, dose, and efficacy of upper limb intervention during the first 6 months poststroke. Three online databases were searched up to July 2020. Titles/abstracts/full-text were reviewed independently by 2 authors. Randomized and nonrandomized studies that enrolled people within the first 6 months poststroke, aimed to improve upper limb recovery, and completed preintervention and postintervention assessments were included. Risk of bias was assessed using Cochrane reporting tools. Studies were examined by timing (recovery epoch), dose, and intervention type. Two hundred and sixty-one studies were included, representing 228 (n=9704 participants) unique data sets. The number of studies completed increased from one (n=37 participants) between 1980 and 1984 to 91 (n=4417 participants) between 2015 and 2019. Timing of intervention start has not changed (median 38 days, interquartile range [IQR], 22-66) and study sample size remains small (median n=30, IQR 20-48). Most studies were rated high risk of bias (62%). Study participants were enrolled at different recovery epochs: 1 hyperacute (<24 hours), 13 acute (1-7 days), 176 early subacute (8-90 days), 34 late subacute (91-180 days), and 4 were unable to be classified to an epoch. For both the intervention and control groups, the median dose was 45 (IQR, 600-1430) min/session, 1 (IQR, 1-1) session/d, 5 (IQR, 5-5) d/wk for 4 (IQR, 3-5) weeks. The most common interventions tested were electromechanical (n=55 studies), electrical stimulation (n=38 studies), and constraint-induced movement (n=28 studies) therapies. Despite a large and growing body of research, intervention dose and sample size of included studies were often too small to detect clinically important effects. Furthermore, interventions remain focused on subacute stroke recovery with little change in recent decades. A united research agenda that establishes a clear biological understanding of timing, dose, and intervention type is needed to progress stroke recovery research. Prospective Register of Systematic Reviews ID: CRD42018019367/CRD42018111629.

Influence of metabolic syndrome on cerebral perfusion and cognition.

Vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH) and memory deficits, and often occurs concurrently with metabolic syndrome (MetS). Despite their common occurrence, it is unknown whether CCH and MetS act synergistically to exacerbate VCI-associated pathology. Here, using male Sprague-Dawley rats, we examined the effects of a clinically relevant model of adolescent-onset MetS and adult-onset CCH on neuro-vascular outcomes, combining a cafeteria diet with a 2-vessel occlusion (2VO) model. Using longitudinal imaging, histology, and behavioural assessments, we identified several features of MetS and CCH including reduced cerebral blood volume, white matter atrophy, alterations in hippocampal cell density, and memory impairment. Furthermore, we identified a number of significant associations, potentially predictive of MetS and pathophysiological outcomes. White matter volume was positively correlated to HDL cholesterol; hippocampal cell density was negatively correlated to fasted blood glucose; cerebral blood flow and volume was negatively predicted by the combination of 2VO surgery and increased fasted blood glucose. These results emphasize the importance of including comorbid conditions when modeling VCI, and they outline a highly translational preclinical model that could be used to investigate potential interventions to mitigate VCI-associated pathology and cognitive decline.

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.

Neurovascular unit remodelling in the subacute stage of stroke recovery.

Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm3 or ~20% of the total brain volume) was induced in adult Sprague-Dawley rats via direct injection of endothelin-1 (ET-1) into the right sensori-motor cortex, producing sustained impairment in left forelimb reaching ability. Resting perfusion and vascular reactivity to hypercapnia in the peri-lesional cortex were elevated by approximately 60% and 80% respectively seven days following stroke. At the same time, the normal topological pattern of local field potential (LFP) responses to peripheral somatosensory stimulation was abolished and the average power of spontaneous LFP activity attenuated by approximately 50% relative to the contra-lesional cortex, suggesting initial response attenuation within the peri-infarct zone. By 21 days after stroke, perilesional blood flow resolved, but peri-lesional vascular reactivity remained elevated. Concomitantly, the LFP response amplitudes increased with distance from the site of ET-1 injection, suggesting functional remodelling from the core of the lesion to its periphery. This notion was further buttressed by the lateralization of spontaneous neuronal activity: by day 21, the average ipsi-lesional power of spontaneous LFP activity was almost twice that of the contra-lesional cortex. Over the observation period, the peri-lesional cortex exhibited increased vascular density, along with neuronal loss, astrocytic activation, and recruitment and activation of microglia and macrophages, with neuronal loss and inflammation extending beyond the peri-lesional cortex. These findings highlight the complex relationship between neurophysiological state and behaviour and provide evidence of highly dynamic functional changes in the peri-infarct zone weeks following the ischemic insult, suggesting an extended temporal window for therapeutic interventions.

The Ontario Neurodegenerative Disease Research Initiative (ONDRI).

Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.

Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke.

Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect. SIGNIFICANCE STATEMENT: There have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long-term functional recovery is an important outcome in patients. In an attempt to identify agents that promote functional recovery, we discovered that an FDA-approved soy isoflavone, daidzein, improved stroke-induced behavioral deficits via enhancing cholesterol homeostasis in chronic stroke, and this occurs without causing adverse effects in the acute phase. With its known safety in humans, the study suggests that the early and chronic use of daidzein serves as a potential strategy to promote functional recovery in stroke patients.

Promoting brain health through exercise and diet in older adults: a physiological perspective.

The rise in incidence of age-related cognitive impairment is a global health concern. Ageing is associated with a number of changes in the brain that, collectively, contribute to the declines in cognitive function observed in older adults. Structurally, the ageing brain atrophies as white and grey matter volumes decrease. Oxidative stress and inflammation promote endothelial dysfunction thereby hampering cerebral perfusion and thus delivery of energy substrates and nutrients. Further, the development of amyloid plaques and neurofibrillary tangles contributes to neuronal loss. Of interest, there are substantial inter-individual differences in the degree to which these physical and functional changes impact upon cognitive function as we grow older. This review describes how engaging in physical activity and cognitive activities and adhering to a Mediterranean style diet promote 'brain health'. From a physiological perspective, we discuss the effects of these modifiable lifestyle behaviours on the brain, and how some recent human trials are beginning to show some promise as to the effectiveness of lifestyle behaviours in combating cognitive impairment. Moreover, we propose that these lifestyle behaviours, through numerous mechanisms, serve to increase brain, cerebrovascular and cognitive reserve, thereby preserving and enhancing cognitive function for longer.

Prescribing Aerobic Exercise Intensity without a Cardiopulmonary Exercise Test Post Stroke: Utility of the Six-Minute Walk Test.

BACKGROUND: The cardiopulmonary exercise test (CPET) is an established method for determining target exercise training intensity (ventilatory threshold [VAT]) and cardiovascular risk; unfortunately, CPET is not readily accessible to people post stroke. The objective of this study was to determine the utility of the 6-minute walk test (6MWT) as a less resource-intensive alternative to CPET for prescribing exercise intensity to people post stroke with motor impairments. METHODS: Sixty participants (male, 71.7%; 13.5 ± 22.5 [mean ± standard deviation] months post stroke; age 64.5 ± 12.5 years, with a Chedoke-McMaster Stroke Assessment score of 4.9 ± .9 of the leg) underwent 6MWT, CPET, balance, strength, and cognition assessments. RESULTS: 6MWT heart rate (hr) was significantly lower than VAT-hr (92.3 ± 14.8 beats⋅min(-1) versus 99.8 ± 15.7 beats⋅min(-1), respectively, P < .001; correlation r = .7, P < .001). Bland-Altman analysis revealed that the 6MWT underestimated the VAT-hr by 7.7 ± 11.5%. The 95% confidence interval of the mean bias was large (14.8% and -30.3%), reflecting poor agreement, with 71.7% (n = 43) of the participants unable to reach a walking intensity at or above the VAT-hr. Lower oxygen uptake at the VAT (ß = .655, P = .004), higher 6MWT-hr (ß = 1.07, P = .01), and better balance (ß = 1.128, P = .04) were associated with greater utility of the 6MWT for prescribing exercise. CONCLUSIONS: The 6MWT-hr was not interchangeable with the target training VAT-hr determined by CPET. However, in combination with CPET, the 6MWT will indicate when deficits preclude walking alone as the primary exercise modality for optimizing cardiovascular fitness. Future studies to develop a less resource-intensive, multimodal alternative to the CPET for prescribing exercise are needed. A modality that minimizes the effect of stroke deficits, specifically poor balance, should be included.

Factors Affecting Attendance at an Adapted Cardiac Rehabilitation Exercise Program for Individuals with Mobility Deficits Poststroke.

OBJECTIVE: The aim of this study was to determine the factors affecting attendance at an adapted cardiac rehabilitation program for individuals poststroke. METHODS: A convenience sample of ambulatory patients with hemiparetic gait rated 20 potential barriers to attendance on a 5-point Likert scale upon completion of a 6-month program of 24 prescheduled weekly sessions. Sociodemographic characteristics, depressive symptoms, cardiovascular fitness, and comorbidities were collected by questionnaire or medical chart. RESULTS: Sixty-one patients attended 77.3 ± 12% of the classes. The longer the elapsed time from stroke, the lower the attendance rate (r = -.34, P = .02). The 4 greatest barriers influencing attendance were severe weather, transportation problems, health problems, and traveling distance. Health problems included hospital readmissions (n = 6), influenza/colds (n = 6), diabetes and cardiac complications (n = 4), and musculoskeletal issues (n = 2). Of the top 4 barriers, people with lower compared to higher income had greater transportation issues (P = .004). Greater motor deficits of the stroke-affected leg were associated with greater barriers related to health issues (r = .7, P = .001). The only sociodemographic factor associated with a higher total mean barrier score was non-English as the primary language spoken at home (P = .002); this factor was specifically related to the barriers of cost (P = .007), family responsibilities (P = .018), and lack of social support (P = .001). No other associations were observed. CONCLUSION: Barriers to attendance were predominantly related to logistic/transportation and health issues. People who were more disadvantaged socioeconomically (language, finances), and physically (stroke-related deficits) were more affected by these barriers. Strategies to reduce these barriers, including timely referral to exercise programs, need to be investigated.

Prevalence of Individuals Experiencing the Effects of Stroke in Canada: Trends and Projections.

BACKGROUND AND PURPOSE: Previous estimates of the number and prevalence of individuals experiencing the effects of stroke in Canada are out of date and exclude critical population groups. It is essential to have complete data that report on stroke disability for monitoring and planning purposes. The objective was to provide an updated estimate of the number of individuals experiencing the effects of stroke in Canada (and its regions), trending since 2000 and forecasted prevalence to 2038. METHODS: The prevalence, trends, and projected number of individuals experiencing the effects of stroke were estimated using region-specific survey data and adjusted to account for children aged <12 years and individuals living in homes for the aged. RESULTS: In 2013, we estimate that there were 405 000 individuals experiencing the effects of stroke in Canada, yielding a prevalence of 1.15%. This value is expected to increase to between 654 000 and 726 000 by 2038. Trends in stroke data between 2000 and 2012 suggest a nonsignificant decrease in stroke prevalence, but a substantial and rising increase in the number of individuals experiencing the effects of stroke. Stroke prevalence varied considerably between regions. CONCLUSIONS: Previous estimates of stroke prevalence have underestimated the true number of individuals experiencing the effects of stroke in Canada. Furthermore, the projected increases that will result from population growth and demographic changes highlight the importance of maintaining up-to-date estimates.

Epidermal growth factor and erythropoietin infusion accelerate functional recovery in combination with rehabilitation.

BACKGROUND AND PURPOSE: Rehabilitation is the only treatment option for chronic stroke deficits, but unfortunately, it often provides incomplete recovery. In this study, a novel combination of growth factor administration and rehabilitation therapy was used to facilitate functional recovery in a rat model of cortical stroke. METHODS: Ischemia was induced via injection of endothelin-1 into the sensorimotor cortex. This was followed by either a 2-week infusion of epidermal growth factor and erythropoietin or artificial cerebrospinal fluid into the ipsilateral lateral ventricle. Two weeks after ischemia, animals began an 8-week enriched rehabilitation program. Functional recovery was assessed after ischemia using the Montoya staircase-reaching task, beam-traversing, and cylinder test of forelimb asymmetry. RESULTS: The combination of growth factor infusion and rehabilitation led to a significant acceleration in recovery in the staircase task. When compared with controls, animals receiving the combination treatment attained significant recovery of function at 4 weeks after stroke, whereas those receiving rehabilitation alone did not recover until 10 weeks. Significant recovery was also observed on the beam-traversing and cylinder tasks. CONCLUSIONS: Combining behavioral rehabilitation with growth factor infusion accelerates motor recovery. These data suggest a promising new avenue of combination therapies that may have the potential to reduce the rehabilitation time necessary to recover from sensorimotor deficits arising from stroke.

Plasticity during stroke recovery: from synapse to behaviour.

Reductions in blood flow to the brain of sufficient duration and extent lead to stroke, which results in damage to neuronal networks and the impairment of sensation, movement or cognition. Evidence from animal models suggests that a time-limited window of neuroplasticity opens following a stroke, during which the greatest gains in recovery occur. Plasticity mechanisms include activity-dependent rewiring and synapse strengthening. The challenge for improving stroke recovery is to understand how to optimally engage and modify surviving neuronal networks, to provide new response strategies that compensate for tissue lost to injury.

How can you mend a broken brain? Neurorestorative approaches to stroke recovery.

BACKGROUND: Stroke is a devastating disorder that strikes approximately 15 million people worldwide. While most patients survive stroke, many are left with lifelong impairments, thereby making stroke the leading cause of permanent neurological disability. Despite this, there are a few options for treatment of acute stroke. Restoration of blood flow using clot-dissolving drugs has produced impressive benefits in some patients. However, for these drugs to be effective, they must be given soon after stroke onset and relatively only a few stroke patients reach hospital within this time. Side effects of these compounds further limit their use. SUMMARY: Enhancing the brain's endogenous capacity for reorganization and self-repair offers the most promise for victims of stroke. Indeed, many stroke patients show considerable spontaneous functional improvement. Findings in the last 15 years suggest that stroke and related injury create a cerebral milieu similar to that of early brain development, a period characterized by rapid neuronal growth and neuroplasticity. A variety of interventions (e.g., stem cells, delivery of growth factors) are currently being explored in order to enhance neuroplasticity and reorganizational processes that are important for recovery of function. An emerging concept is that combinational or 'cocktail' therapies are more effective than single interventions in improving stroke recovery. Among these, one of the most promising therapies is enriched rehabilitation, a combination of environmental enrichment and task-specific therapy (e.g., reach training). KEY MESSAGES: Neurorestorative approaches to brain reorganization and repair are providing new insights into how neural circuits respond to injury and how this knowledge can be used for optimizing stroke rehabilitation practice.

Mechanisms of Post-Stroke Fatigue: A Follow-Up From the Third Stroke Recovery and Rehabilitation Roundtable.

BACKGROUND: Post-stroke fatigue (PSF) is a significant and highly prevalent symptom, whose mechanisms are poorly understood. The third Stroke Recovery and Rehabilitation Roundtable paper on PSF focussed primarily on defining and measuring PSF while mechanisms were briefly discussed. This companion paper to the main paper is aimed at elaborating possible mechanisms of PSF. METHODS: This paper reviews the available evidence that potentially explains the pathophysiology of PSF and draws parallels from fatigue literature in other conditions. We start by proposing a case for phenotyping PSF based on structural, functional, and behavioral characteristics of PSF. This is followed by discussion of a potentially significant role of early inflammation in the development of fatigue, specifically the impact of low-grade inflammation and its long-term systemic effects resulting in PSF. Of the many neurotransmitter systems in the brain, the dopaminergic systems have the most evidence for a role in PSF, along with a role in sensorimotor processing. Sensorimotor neural network dynamics are compromised as highlighted by evidence from both neurostimulation and neuromodulation studies. The double-edged sword effect of exercise on PSF provides further insight into how PSF might emerge and the importance of carefully titrating interventional paradigms. CONCLUSION: The paper concludes by synthesizing the presented evidence into a unifying model of fatigue which distinguishes between factors that pre-dispose, precipitate, and perpetuate PSF. This framework will help guide new research into the biological mechanisms of PSF which is a necessary prerequisite for developing treatments to mitigate the debilitating effects of post-stroke fatigue.

A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

RATIONALE: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. METHODS: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. RESULTS: We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. CONCLUSIONS: By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue.