•Exercise 24–48h post-stroke reduced lesion volume more than later onset exercise.•Post-stroke exercise effects on the older brain and in the long term are not known.•Moderate intensity is most ...effective in reducing lesion volume.•Moderate intensity exercise decreases inflammation and increases neurogenesis.•Higher intensity exercise increases angiogenesis in perilesional area and striatum.
Aerobic exercise (AE) enhances neuroplasticity and improves functional outcome in animal models of stroke, however the optimal parameters (days post-stroke, intensity, mode, and duration) to influence brain repair processes are not known. We searched PubMed, CINAHL, PsychInfo, the Cochrane Library, and the Central Register of Controlled Clinical Trials, using predefined criteria, including all years up to July 2013 (English language only). Clinical studies were included if participants had experienced an ischemic or hemorrhagic stroke. We included animal studies that utilized any method of global or focal ischemic stroke or intracerebral hemorrhage. Any intervention utilizing AE-based activity with the intention of improving cardiorespiratory fitness was included. Of the 4250 titles returned, 47 studies (all in animal models) met criteria and measured the effects of exercise on brain repair parameters (lesion volume, oxidative damage, inflammation and cell death, neurogenesis, angiogenesis and markers of stress). Our synthesized findings show that early-initiated (24–48h post-stroke) moderate forced exercise (10m/min, 5–7 days per week for about 30min) reduced lesion volume and protected perilesional tissue against oxidative damage and inflammation at least for the short term (4 weeks). The applicability and translation of experimental exercise paradigms to clinical trials are discussed.
The first Stroke Recovery and Rehabilitation Roundtable established a game changing set of new standards for stroke recovery research. Common language and definitions were required to develop an ...agreed framework spanning the four working groups: translation of basic science, biomarkers of stroke recovery, measurement in clinical trials and intervention development and reporting. This paper outlines the working definitions established by our group and an agreed vision for accelerating progress in stroke recovery research.
•Behavioral testing is indispensable for deepening our understanding of brain plasticity and in developing restorative therapies for stroke.•Here we review the most common behavioral tests used to ...assess sensorimotor impairment and recovery, cognition and mood in stroke animals.•Guidance is provided to help select the most appropriate behavioral tests to further improve translational success of experimental studies.
Functional recovery after an experimental stroke can be assessed by multiple behavioral tests, however, there is no consensus about which test to use in long-term stroke recovery studies or whether the tests are affected by stroke surgery, post-operative care or behavioral compensation due to repeated testing. This review describes the tests most commonly used to assess motor and sensorimotor function, cognition and mood in stroke animals. Although it is difficult to predict the direction of future research, it may be possible to prevent false-positive results by selecting an appropriate task or a battery of tasks. It is also expected that the upcoming stroke recovery recommendations and the improved dialogue between academy, industry and healthcare professionals will further promote translational success.
The first Stroke Recovery and Rehabilitation Roundtable established a game changing set of new standards for stroke recovery research. Common language and definitions were required to develop an ...agreed framework spanning the four working groups: translation of basic science, biomarkers of stroke recovery, measurement in clinical trials and intervention development and reporting. This paper outlines the working definitions established by our group and an agreed vision for accelerating progress in stroke recovery research.
Chronic impairment of forelimb and digit movement is a common problem after stroke that is resistant to therapy. Previous studies have demonstrated that enrichment improves behavioral outcome after ...focal ischemia; however, postischemic enrichment alone is not capable of enhancing fine digit and forelimb function. Therefore, we combined environmental enrichment with daily skilled-reach training to assess the effect of intensive task-specific rehabilitation on long-term functional outcome. Rats were subjected to either endothelin-1-induced focal ischemia or sham surgery and subsequently designated to enriched-rehabilitation or standard-housing treatment groups starting 15 d after ischemia. Functional assessment of the affected forelimb at 4 and 9 weeks after treatment revealed that ischemic plus enrichment (IE) animals had improved approximately 30% on the staircase-reaching task and were indistinguishable from sham animals for both latency and foot faults in a beam-traversing task. In contrast, ischemic plus standard (IS) animals remained significantly impaired on both tasks. Interestingly, both ischemic groups (IE and IS) relied on the nonaffected forelimb during upright weight-bearing movements, a pattern that persisted for the duration of the experiment. Dendritic arborization of layer V pyramidal cells within the undamaged motor cortex was examined using a Golgi-Cox procedure. IE animals showed enhanced dendritic complexity and length compared with both IS and sham groups. These results suggest that enrichment combined with task-specific rehabilitative therapy is capable of augmenting intrinsic neuronal plasticity within noninjured, functionally connected brain regions, as well as promoting enhanced functional outcome.
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.
Many promising findings from pre-clinical research have failed to translate to the clinic due to their inability to incorporate human disease co-morbidity. A variety of rodent diets and feeding ...durations are currently used in models of human metabolic syndrome, obesity and diabetes. One model, the Cafeteria (CAF) diet, makes use of grocery store-purchased food items that more closely approximate the human ultra-processed diet than commercial high-fat or high-sugar rodent diets. The present study describes the development of metabolic syndrome in rats fed a CAF diet as well as the recovery of metabolic syndrome following a healthy “lifestyle” change. In addition, we explored the effects of CAF diet on spatial learning and memory and on neuroinflammation. Three-week old male Sprague-Dawley rats were fed a CAF diet for three months that consisted of 16 highly palatable human food items along with standard chow and a 12% sucrose solution to mimic soda consumption. Thereafter, a sub-group of CAF diet rats was switched to a chow diet (SWT) for one month. Both CAF and SWT groups were compared to control rats maintained on a standard chow diet (SD). Prior to the diet switch, CAF and SWT animals developed features akin to metabolic syndrome. Both groups of rats displayed significant abdominal obesity with increased visceral adiposity, hyperinsulinemia, glucose intolerance and dyslipidemia with elevated serum triglyceride levels and reduced HDL cholesterol. Switching to a chow diet for one month completely reversed these features in SWT animals. Although acquisition of the Barnes maze was not affected by the CAF diet, these animals exhibited greater hippocampal neuroinflammation compared to both SD and SWT rats as assessed by Iba1 staining. These results demonstrate that the CAF diet is very effective in creating metabolic syndrome with hippocampal inflammation in rats over a relatively short time span. This model may be of great heuristic importance in determining potential reversibility of metabolic and cerebrovascular pathologies across the lifespan and as a co-morbid factor in other disease models such as stroke.
•A palatable Cafeteria diet reliably models human-like metabolic syndrome in the rat.•The Cafeteria diet increases Iba1+ microglial cell density in the hippocampus.•Spatial memory, determined using the Barnes maze, is not impaired by Cafeteria diet.•Metabolic syndrome and inflammation are reversed by standard diet-feeding.
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.
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 (
= 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.
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.
Environmental enrichment (EE) has been widely used as a means to enhance brain plasticity mechanisms (e.g., increased dendritic branching, synaptogenesis, etc.) and improve behavioral function in ...both normal and brain-damaged animals. In spite of the demonstrated efficacy of EE for enhancing brain plasticity, it has largely remained a laboratory phenomenon with little translation to the clinical setting. Impediments to the implementation of enrichment as an intervention for human stroke rehabilitation and a lack of clinical translation can be attributed to a number of factors not limited to: (i) concerns that EE is actually the "normal state" for animals, whereas standard housing is a form of impoverishment; (ii) difficulty in standardizing EE conditions across clinical sites; (iii) the exact mechanisms underlying the beneficial actions of enrichment are largely correlative in nature; (iv) a lack of knowledge concerning what aspects of enrichment (e.g., exercise, socialization, cognitive stimulation) represent the critical or active ingredients for enhancing brain plasticity; and (v) the required "dose" of enrichment is unknown, since most laboratory studies employ continuous periods of enrichment, a condition that most clinicians view as impractical. In this review article, we summarize preclinical stroke recovery studies that have successfully utilized EE to promote functional recovery and highlight the potential underlying mechanisms. Subsequently, we discuss how EE is being applied in a clinical setting and address differences in preclinical and clinical EE work to date. It is argued that the best way forward is through the careful alignment of preclinical and clinical rehabilitation research. A combination of both approaches will allow research to fully address gaps in knowledge and facilitate the implementation of EE to the clinical setting.
PDF
