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.

To maximize the effectiveness of rehabilitative therapies after stroke, it is critical to determine when the brain is most responsive (i.e., plastic) to sensorimotor experience after injury and to focus such efforts within this period. Here, we compared the efficacy of 5 weeks of enriched rehabilitation (ER) initiated at 5 d (ER5), ER14, or ER30 after focal ischemia, as judged by functional outcome and neuromorphological change. ER5 provided marked improvement in skilled forelimb reaching ability and ladder-rung-and narrow-beam-walking tasks and attenuated the stroke-induced reliance on the unaffected forepaw for postural support. ER14 provided improvement to a somewhat lesser extent, whereas recovery was diminished after ER30 such that motor function did not differ from ischemic animals exposed to social housing.To examine potential neural substrates of the improved function, we examined dendritic morphology in the undamaged motor cortex because our previous work (Biernaskie and Corbett, 2001) suggested that recovery was associated with enhanced dendritic growth in this region. ER5 increased the number of branches and complexity of layer V neurons compared with both social housing and control animals. Dendritic arbor after ER14 (although increased) and ER30 did not differ from those exposed to social housing. These data suggest that the poststroke brain displays heightened sensitivity to rehabilitative experience early after the stroke but declines with time. These findings have important implications for rehabilitation of stroke patients, many of whom experience considerable delays before therapy is initiated.

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.

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.

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.

Intracerebral hemorrhage (ICH) is characterized by parenchymal hematoma formation with surrounding inflammation. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of neurological diseases defined by inflammation and cell death. To investigate the expression profile and pathogenic aspects of MMPs in ICH, we examined MMP expression in vivo using a collagenase-induced rat model of ICH. ICH increased brain MMP-2, -3, -7, and -9 mRNA levels relative to sham-injected (control) animals in the vicinity of the hematoma, but MMP-12 (macrophage metalloelastase) was the most highly induced MMP (>80-fold). Immunohistochemistry showed MMP-12 to be localized in activated monocytoid cells surrounding the hematoma. In vitro studies showed that thrombin, released during ICH, induced MMP-12 expression in monocytoid cells, which was reduced by minocycline application. Similarly, in vivo minocycline treatment significantly reduced MMP-12 levels in brain. Neuropathological studies disclosed marked glial activation and apoptosis after ICH that was reduced by minocycline treatment. Neurobehavioral outcomes also were improved with minocycline treatment compared with untreated ICH controls. Thus, select MMPs exhibit increased expression after ICH, whereas minocycline is neuroprotective after ICH by suppressing monocytoid cell activation and downregulating MMP-12 expression.

In the gerbil, brief global forebrain ischemia induces profound habituation and working memory impairments that stem from delayed hippocampal CA1 death. Short duration postischemic hypothermia has been shown to reduce CA1 loss, but such reports are controversial, as it is thought that protection may be transient. The purpose of this study was to investigate whether prolonged postischemic hypothermia provided long-term CA1 and functional neuroprotection. Previously, 90% of anterior CA1 neurons were rescued (30 d survival) when 24 hr of hypothermia (32 degrees C) was induced 1 hr following a 5 min occlusion that otherwise produced more than 95% loss (Colbourne and Corbett, 1994). We now find about 70% CA1 savings with this same hypothermic treatment in gerbils that survived for 6 months postischemia. While this is a significant reduction from 30 day survival (medial CA1 only), it nonetheless shows, for the first time, persistent, if not permanent neuroprotection, especially in middle and lateral CA1. In addition, in non-treated animals, ischemia impaired learning in an open field and T-maze for up to 6 months. Postischemic hypothermia significantly reduced these deficits. Hypothermia (32 degrees), when initiated 4 hr after ischemia, rescued approximately 12% of CA1 neurons at 6 months with a slight behavioral benefit. Milder hypothermia (34 degrees C, 1-25 hr postischemia, 30 d survival) also reduced habituation impairments and saved approximately 60% of CA1 neurons. Similar trends were found at more caudal CA1 levels. These results clearly show that postischemic hypothermia provides effective and long-lasting neuroprotection, which depends upon the delay to initiation, duration, and degree of cooling and survival time. The protracted functional and histological benefit observed justifies further basic and clinical investigation.

Stroke is the leading cause of disability, causing impairments in movement and sensation. Animal models suggest that there is about a month of heightened plasticity in the brain early after stroke when most recovery from impairment occurs. This heightened plasticity occurs against background changes in excitatory/inhibitory balance, is apparent structurally as neurite remodeling, and changes in the extent and responsiveness of cortical maps. The best time for experience to improve outcome is unclear, but in animal models only very early (< 5 days from onset) and intense activities lead to increased histological damage. Conversely, late rehabilitation (>30 days) is much less effective both in terms of outcome and morphological changes. In clinical practice, rehabilitation after disabling strokes involves a relatively brief period of inpatient rehabilitation that does not come close to matching intensity levels investigated in animal models, and it involves training compensatory strategies with minimal impact on impairment. Research on the effect of Constraint-induced and robotic therapy has been conducted almost entirely in chronic stroke but earlier does seem better. Current rehabilitation treatments have a disappointingly modest effect on impairment early or late after stroke. Translation from animal models will require: (1) substantial increases in the intensity and dosage of treatments offered in the first month after stroke with an emphasis on impairment, (2) Treatment combination approaches, for example, non-invasive brain stimulation with robotics, based on current understanding of motor learning and brain plasticity, and (3) Research that emphasizes mechanistic phase II studies over premature phase III clinical trials.