The Effect of Upper Cervical Mobilization/Manipulation on Temporomandibular Joint Pain, Maximal Mouth Opening, and Pressure Pain Thresholds: A Systematic Review and Meta-Analysis.

Objective: To evaluate the efficacy of upper cervical joint mobilization and/or manipulation on reducing pain and improving maximal mouth opening (MMO) and pressure pain thresholds (PPTs) in adults with temporomandibular joint (TMJ) dysfunction compared with sham or other intervention. Data Sources: MEDLINE, CINAHL, EMBASE, and Cochrane Library from inception to June 3, 2022, were searched. Study Selection: Eight randomized controlled trials with 437 participants evaluating manual therapy (MT) vs sham and MT vs other intervention were included. Two reviewers independently extracted data and assessed risk of bias. Data Extraction: Two independent reviewers extracted information about origin, number of study participants, eligibility criteria, type of intervention, and outcome measures. Data Synthesis: Manual therapy was statistically significant in reducing pain compared with sham (mean difference [MD]: -1.93 points, 95% confidence interval [CI]: -3.61 to -0.24, P=.03), and other intervention (MD: -1.03 points, 95% CI: -1.73 to -0.33, P=.004), improved MMO compared with sham (MD: 2.11 mm, 95% CI: 0.26 to 3.96, P=.03), and other intervention (MD: 2.25 mm, 95% CI: 1.01 to 3.48, P<.001), but not statistically significant in improving PPT of masseter compared with sham (MD: 0.45 kg/cm2, 95% CI: -0.21 to 1.11, P=.18), and other intervention (MD: 0.42 kg/cm2, 95% CI: -0.19 to 1.03, P=.18), or the PPT of temporalis compared with sham (MD: 0.37 kg/cm2, 95% CI: -0.03 to 0.77, P=.07), and other intervention (MD: 0.43 kg/cm2, 95% CI: -0.60 to 1.45, P=.42). Conclusion: There appears to be limited benefit of upper cervical spine MT on TMJ dysfunction, but definitive conclusions cannot be made because of heterogeneity and imprecision of treatment effects.

Motor Rehabilitation Provides Modest Functional Benefits After Intracerebral Hemorrhage: a Systematic Review and Meta-Analysis of Translational Rehabilitation Studies.

Few certainties exist regarding the optimal type, timing, or dosage of rehabilitation after stroke. Despite differing injury mechanisms and recovery patterns following ischemic and hemorrhagic stroke, most translational stroke research is conducted after ischemia. As we enter the era of personalized medicine, exploring subtype-specific treatment efficacy is essential to optimizing recovery. Our objective was to characterize common rehabilitation interventions used after in vivo preclinical intracerebral hemorrhage (ICH) and assess the impact of post-ICH rehabilitation (vs. no-rehabilitation) on recovery of motor function. Following PRISMA guidelines, a systematic review (Academic Search Complete, CINAHL, EMBASE, Medline, PubMed Central) identified eligible articles published up to December 2022. Risk of bias (SYRCLE) and study quality (CAMARADES) were evaluated, and random-effects meta-analysis was used to assess treatment efficacy in recovery of forelimb and locomotor functions. Thirty articles met inclusion criteria, and 48 rehabilitation intervention groups were identified. Most used collagenase to model striatal ICH in young, male rodents. Aerobic exercise, enriched rehabilitation, and constraint-induced movement therapy represented ~ 70% of interventions. Study quality was low (median 4/10, range 2-8), and risk of bias was unclear. Rehabilitation provided modest benefits in skilled reaching, spontaneous impaired forelimb use, and locomotor function; however, effects varied substantially by endpoint, treatment type, and study quality. Rehabilitation statistically improves motor function after preclinical ICH, but whether these effects are functionally meaningful is unclear. Incomplete reporting and variable research quality hinder our capacity to analyze and interpret how treatment factors influence rehabilitation efficacy and recovery after ICH.

Learning and satisfaction in a student-led clinic.

BACKGROUND: Student-led clinics (SLCs) offer unique clinical placement experiences and address unmet community rehabilitation needs. There is growing evidence that SLCs provide high-quality experiential practice and adequate quality of patient care. The purpose of this study was to evaluate patient satisfaction with student-led care and students' perception of their learning experiences in a student-led physiotherapy clinic. METHODS: Eight participants with total hip arthroplasty attended 6 weeks of student-led group exercise classes. As a marker of quality of care, we assessed key outcomes including walking speed and endurance, lower extremity function, falls risk and self-reported quality of life after 3 and 6 weeks. Patients completed a satisfaction survey at the end of the program. Ten students who completed a placement during this time shared their perception of learning in the SLC. RESULTS: Student-led group exercise class was associated with improvements in walking speed and endurance, lower extremity function, a decrease in falls risk and improved quality of life. Patients were satisfied with their care. The SLC was a safe learning environment in which students felt well-supported to develop confidence and independence, were encouraged to reflect on performance and take responsibility for care provided. CONCLUSION: Patients are largely satisfied with the quality of care provided. High-quality authentic clinical learning opportunities provided in the SLC may offer pedagogical benefits over traditional practicums, and students are generally satisfied with their learning experiences. SLCs may provide a setting to expose students to research and gain appreciation for evidence-based practice.

Rodent models of intracerebral hemorrhage.

The collagenase and whole blood intracerebral hemorrhage (ICH) models are widely used to identify mechanisms of injury and to evaluate treatments. Despite preclinical successes, to date, no treatment tested in phase III clinical trials has benefited ICH patients. These failures call into question the predictive value of current ICH models. By highlighting differences between these common rodent models of ICH, we sought to help investigators choose the more appropriate model for their study and to encourage the use of both whenever possible. For instance, we previously reported substantial differences in the bleeding profile, progression of cell death, and functional outcome between these models. These and other differences influence the efficacy and mechanisms of action of various treatment modalities. Thus, in this review, we also summarize neuroprotective and rehabilitation findings in each model. We conclude that differences between ICH models along with our current inability to identify the more clinically predictive model necessitate that preclinical assessments should normally be done in both. Such an approach, coupled with better assessment practices, will likely improve chances of future clinical success.

Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats.

BACKGROUND AND PURPOSE: Brain-derived neurotrophic factor (BDNF) is involved in neuronal survival, synaptic plasticity, learning and memory, and neuroplasticity. Further, exogenous treatment with BDNF or exposing animals to enrichment and exercise regimens, which also increase BDNF, enhances behavioral recovery after brain injury. Thus, the beneficial effects of rehabilitation in promoting recovery after stroke may also depend on BDNF. We tested this hypothesis by evaluating the contribution of BDNF to motor skill relearning after endothelin-1-induced middle cerebral artery occlusion in rats. METHODS: Antisense BDNF oligonucleotide, which blocks the expression of BDNF (or saline vehicle) was infused into the contralateral lateral ventricle for 28 days after ischemia. Animals received either a graduated rehabilitation program, including running exercise and skilled reaching training, which simulates clinical practice, or no rehabilitation. Functional recovery was assessed with a battery of tests that measured skilled reaching, forelimb use asymmetry, and foraging ability. RESULTS: Rehabilitation significantly improved skilled reaching ability in the staircase task. Antisense BDNF oligonucleotide effectively blocked BDNF mRNA, and negated the beneficial effects of rehabilitation on recovery of skilled reaching. Importantly, antisense BDNF oligonucleotide did not affect reaching with the unaffected limb, body weight, infarct size, or foraging ability, indicating the treatment was specific to relearning of motor skill after ischemia. CONCLUSIONS: This study is the first to identify a critical role for BDNF in rehabilitation-induced recovery after stroke, and our results suggest that new treatments to enhance BDNF would constitute a promising therapy for promoting recovery of function after stroke.

Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion.

Many therapies have shown promise in preclinical stroke studies, but few benefit patients. A greater understanding of stroke pathophysiology is needed to successfully develop therapies, and this depends on appropriate animal models. The collagenase and blood infusion models of intracerebral hemorrhage (ICH) are widely used; yet, investigators often prefer using one model for a variety of reasons. Thus, we directly compared these to highlight advantages and limitations of each as well as the assessment approach. An ICH was created by infusing blood or bacterial collagenase into the rats' striatum. We matched initial hematoma volume in each model (Experiment 1) and assessed the time course of bleeding (Experiment 2). Functional deficits and the progression of injury were tracked over 6 weeks using behavior, magnetic resonance imaging, and histology (Experiment 3). Despite similar initial hematoma volumes, collagenase-induced ICH resulted in a greater blood-brain barrier breakdown and more damage to the striatum, substantia nigra, white matter, and cortex. Magnetic resonance imaging revealed faster hematoma resolution in the blood model, and little increase in the volume of tissue lost from 1 to 6 weeks. In contrast, tissue loss continued over 4 weeks in the collagenase model. Finally, functional deficits recovered more quickly and completely in the blood model. This study highlights key differences between these models and that neither closely replicates the human condition. Thus, both should be used whenever possible taking into account the significant differences between these models and their limitations. Furthermore, this work illustrates significant weaknesses with several outcome measures.

Long-term assessment of enriched housing and subventricular zone derived cell transplantation after focal ischemia in rats.

The potential for using stem cells to treat stroke has garnered much interest, but stem cell therapies must be rigorously tested in animal models before transplantation studies progress to clinical trials. An enriched environment enhances transplanted subventricular zone (SVZ) cell migration and functional benefit following stroke in rats. However, the ability of SVZ cells to survive, migrate, differentiate and promote functional recovery at protracted survival times (e.g., 3 months) has not been investigated. The vasoconstrictive peptide endothelin-1 was injected adjacent to the middle cerebral artery to produce focal ischemia. Seven days later, cells derived from the SVZ of adult mice (800,000 cells/rat or vehicle injection) were transplanted into the sensory-motor cortex and striatum, and rats were then housed in enriched or standard conditions. Rats in enriched housing had access to running wheels once per week. Recovery was assessed in the forelimb-use asymmetry task (cylinder) at 1, 2, or 3 months after transplantation immediately prior to euthanasia. Transplanted cell survival and migration were quantified using stereology. Cell phenotype was determined with immunohistochemistry and confocal microscopy. Enriched housing did not enhance survival or migration of transplanted SVZ cells at protracted survival times, and the majority (~99%) of cells died within 2 months of transplantation. Cell survival was significantly, and negatively, correlated with microglial activation. Many surviving cells expressed an astrocytic phenotype. Functional recovery was not improved at any time. Therapies involving transplantation of SVZ cells following stroke must be further optimized in order to enhance long-term cell survival and thereby maximize functional benefit.

The influence of hypothermia on outcome after intracerebral hemorrhage in rats.

BACKGROUND AND PURPOSE: Late hypothermia (HYPO) reduces injury after collagenase-induced intracerebral hemorrhage (ICH), whereas early HYPO does not because it exacerbates the protracted bleeding that occurs in this model. We hypothesized that early HYPO would not increase bleeding after whole blood infusion and thus expected early HYPO to improve outcome through reducing secondary consequences of ICH (eg, inflammation). METHODS: Autologous blood (100 microL) was infused into the striatum. Rats were maintained at normothermia or subjected to mild (33 degrees C to 35 degrees C) HYPO for 2 days starting 1 (HYPO-1) or 4 hours (HYPO-4) after ICH. Hematoma volume was measured at 12 hours to determine whether HYPO-1 aggravated bleeding. We measured blood-brain barrier (BBB) disruption and edema 2 days after ICH in all groups. At 4 days, we counted degenerating neurons, neutrophils, and iron-positive cells (eg, macrophages) in the lesioned hemisphere. Recovery was assessed using several behavioral tests (ie, staircase reaching task, ladder walking task, limb use cylinder test) over 7 or 30 days, at which time we quantified lesion volume. RESULTS: HYPO did not increase bleeding. Both HYPO treatments reduced BBB disruption and infiltration of inflammatory cells. HYPO-1 treatment modestly reduced edema and provided limited to no functional benefit in the behavioral tests. HYPO did not affect lesion volume. CONCLUSIONS: HYPO reduced edema, BBB disruption, and inflammation. Although encouraging, HYPO treatment must be improved so that histological and functional benefit are obtained before clinical investigation. Otherwise clinical failure is anticipated.

Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies.

Successful clinical translation of prospective cytoprotectants will likely occur only with treatments that improve functional recovery in preclinical (rodent) studies. Despite this assumption, many rely solely on histopathologic end points or the use of one or two simple behavioral tests. Presently, we used a battery of tests to gauge recovery after a unilateral intracerebral hemorrhagic stroke (ICH) targeting the striatum. In total, 60 rats (N=15 per group) were stereotaxically infused with 0 (SHAM), 0.06 (MILD lesion), 0.12 (MODERATE lesion), or 0.18 U (SEVERE lesion) of bacterial collagenase. This created a range of injury akin to moderate (from SEVERE to MODERATE or MODERATE to MILD lesion size approximately 30% reduction) and substantial cytoprotection (SEVERE to MILD lesion size--51% reduction). Post-ICH functional testing occurred over 30 days. Tests included the horizontal ladder and elevated beam tests, swimming, limb-use asymmetry (cylinder) test, a Neurologic Deficit Scale, an adhesive tape removal test of sensory neglect, and the staircase and single pellet tests of skilled reaching. Most tests detected significant impairments (versus SHAM), but only a few (e.g., staircase) frequently distinguished among ICH groups and none consistently differentiated among all ICH groups. However, by using a battery of tests we could behaviorally distinguish groups. Thus, preclinical testing would benefit from using a battery of behavioral tests as anything less may miss treatment effects. Such testing must be based on factors including the type of lesion, the postoperative delay and the time required to complete testing.

Skilled reaching impairments follow intrastriatal hemorrhagic stroke in rats.

The infusion of autologous blood into the brain of rats is a widely used model of intracerebral hemorrhage (ICH). Careful assessment of functional recovery is an essential part of preclinical testing (e.g., putative cytoprotectants). However, few tests detect long-term deficits in this model. In this study, we used the staircase and single pellet tests to characterize skilled reaching ability after striatal ICH. Rats were trained to reach for food pellets in these tasks before ICH, which was created by infusing 100muL of autologous blood into the striatum. We assessed reaching success in both tasks for 5 days starting 7 and 28 days after ICH. We counted the number of reaching attempts made with each forelimb in the staircase task and performed kinematic analysis of reaching in the single pellet task. The contralateral (to lesion) forelimb reaching success was significantly impaired in the staircase task 1 week after ICH, but this recovered to pre-surgical levels thereafter. Reaching deficits in the single pellet task were more severe and persistent. Detailed analysis of reaches on day 11 revealed several abnormalities in the following movement components: pronation, grasping, supinating the paw and releasing the pellet. At 1 month, only digit opening and supination were impaired. Accordingly, the single pellet task is better at detecting long-term skilled reaching impairments in the whole blood model of ICH. Thus, the single pellet task seems suited to cytoprotection and rehabilitation studies.

Mild to moderate hyperthermia does not worsen outcome after severe intracerebral hemorrhage in rats.

Hyperthermia worsens outcome in clinical and experimental studies of ischemic stroke. Thus, we tested whether hyperthermia aggravates intracerebral hemorrhage (ICH) in rats. A striatal hemorrhage was produced via an infusion of bacterial collagenase. In a preliminary experiment, we compared brain and core temperatures (via telemetry) during heating (infrared lamp). The brain temperature rise exceeded that produced by enforced core hyperthermia, which was used subsequently. In these experiments up to three hyperthermia conditions (versus normothermia) were tested including: hyperthermia (>38.5 degrees C) over the first (HYP-1) or second 24 h period (HYP-2) after ICH and 3 h of 40 degrees C hyperthermia starting 12 h after ICH (HYP-3). The HYP-1, HYP-2, and HYP-3 treatments did not affect functional deficits (e.g., spontaneous forelimb use, skilled reaching) or the volume of injury at 30 days. Furthermore, the HYP-1 treatment did not aggravate injury or deficits at 7 days. Bleeding and inflammation, which contribute to pathology, were not significantly altered by HYP-1 and HYP-3 treatments. Bleeding was assessed at 1 day, and macrophages and neutrophils were counted at 2 and 4 days. Accordingly, hyperthermia, under the present conditions, did not worsen outcome after striatal ICH.

Delayed onset of prolonged hypothermia improves outcome after intracerebral hemorrhage in rats.

Prolonged hypothermia reduces ischemic brain injury, but its efficacy after intracerebral hemorrhagic (ICH) stroke is unresolved. Rats were implanted with core temperature telemetry probes and subsequently subjected to an ICH, which was produced by infusing bacterial collagenase into the striatum. Animals were kept normothermic (NORMO), or were made mildly hypothermic (33-35 degrees C) for over 2 days starting 1 hour (HYP-1), 6 hours (HYP-6), or 12 hours (HYP-12) after collagenase infusion. Others were cooled for 7 hours beginning 1 hour after infusion (BRIEF). Skilled reaching, walking, and spontaneous forelimb use were assessed. Normothermic ICH rats sustained, on average, a 36.9-mm3 loss of tissue at 1 month. Only the HYP-12 group had a significantly smaller lesion (25.5 mm3). Some functional improvements were found with this and other hypothermia treatments. Cerebral edema was observed in NORMO rats, and was not lessened significantly by hypothermia (HYP-12). Blood pressure measurements, as determined by telemetry, in BRIEF rats showed that hypothermia increased blood pressure. This BRIEF treatment also resulted in significantly more bleeding at 12 hours after ICH (79.2 microL) versus NORMO-treated rats (58.4 microL) as determined by a spectrophotometric hemoglobin assay. Accordingly, these findings suggest that early hypothermia may fail to lessen lesion size owing to complications, such as elevated blood pressure, whereas much-delayed hypothermia is beneficial after ICH. Future experiments should assess whether counteracting the side effects of early hypothermia enhances protection.

Post-ischemic diazepam does not reduce hippocampal CA1 injury and does not improve hypothermic neuroprotection after forebrain ischemia in gerbils.

The hippocampal CA1 sector is especially vulnerable to brief forebrain ischemia. Excitotoxicity is widely thought to contribute to this cell death. Accordingly, drugs that presumably counteract excitotoxicity, such as GABAergic agonists, have been repeatedly tested and found to reduce CA1 cell loss. Post-ischemic diazepam reduces CA1 injury. However, diazepam also causes hypothermia, which by itself is neuroprotective. Most studies fail to adequately control for this confound. In this study, we tested whether diazepam reduces injury in temperature controlled gerbils subjected to brief forebrain ischemia. Furthermore, we tested whether diazepam augments hypothermic neuroprotection. All gerbils were implanted with a core temperature telemetry probe and a cannula for the subsequent insertion of a thermocouple probe to measure ischemic brain temperature. Subsequently, they were given a 5-min normothermic ischemic insult. In Experiment 1, two groups of gerbils were given 10 mg/kg doses of diazepam (i.p.) at both 30 and 90 min post-ischemia. Temperature was maintained in one group by heating lamps. Another group was administered saline. Diazepam reduced cell death at 7 days post-ischemia when the drug-induced hypothermia was permitted, but not when it was prevented. In Experiment 2, four groups of ischemic gerbils were treated starting at 12 h post-ischemia with prolonged hypothermia, diazepam and the combination or saline treatment. Hypothermia, but not diazepam, provided partial neuroprotection and diazepam did not augment hypothermic neuroprotection. Thus, neuroprotection with diazepam is solely due to hypothermia. These data do not support the clinical use of diazepam as a neuroprotectant after global ischemia.

Incomplete assessment of experimental cytoprotectants in rodent ischemia studies.

BACKGROUND: Inadequate preclinical testing (e.g., rodent studies) has been partly blamed for the failure of many cytoprotectants to effectively treat stroke in humans. For example, some drugs went to clinical trial without rigorous functional and histological assessment over long survival times. In this study, we characterized recent experimental practices in rodent cytoprotection experiments to determine whether the limitations of early studies have been rectified. METHODS: We identified 138 rodent cytoprotection studies published in several leading journals (Journal of Neuroscience, Stroke, Journal of Cerebral Blood Flow and Metabolism and Experimental Neurology) for 2000-2002 and compared these to those published in 1990. From each study we determined the ischemia model, age and sex of the animal, the histological and functional endpoints used, and the methodology used to assess intra- and postischemic temperature. RESULTS: Ninety-eight percent of recent studies used young adult rodents and most used males. Most studies (60%) did not assess functional outcome and survival times were often < or = 48 hr (66%) for focal ischemia and < or = 7 days (80%) for global ischemia. Over 60% of the experiments relied solely upon rectal temperature during ischemia and only 32.6% of ischemia studies measured temperature after surgery. The 1990 data were similar. CONCLUSIONS: Many investigators ignore the need to assess long-term functional and histological outcome and do not accurately represent clinical conditions of ischemia (e.g., use of aged animals). In addition, intra- and postischemic temperature measurement and control is frequently neglected or inadequately performed. Further clinical failures are likely.

A model of persistent learned nonuse following focal ischemia in rats.

BACKGROUND: After hemiplegic stroke, people often rely on their unaffected limb to complete activities of daily living. A component of residual motor dysfunction involves learned suppression of movement, termed learned nonuse. OBJECTIVE: To date, no rodent stroke model of persistent learned nonuse has been described that can facilitate understanding of this phenomenon and test interventions to overcome it. METHODS: Rats were trained in the staircase skilled-reaching and limb use asymmetry (cylinder) tasks. Endothelin-1 was injected into the cortex and striatum to create focal ischemia. Starting 7 days poststroke, half of the rats (ipsilateral training; n = 15) were trained to reach for food reward pellets in the tray-reaching task with the ipsilateral forelimb. Training lasted 20 days. Rats in the control group (control; n = 15) did not receive training. All rats then remained in their home cages for an additional 30 days. Performance on the cylinder and staircase tasks was assessed ~2 months poststroke. RESULTS: Ischemia caused significant functional impairments in all rats. Significant contralateral forelimb skilled-reaching recovery was evident in the control group at 2 months but not the ipsilateral training group. There was no difference in performance in the cylinder task. Similarly, the volume of brain injury (~66 mm(3)) was similar between groups. Ipsilateral forelimb training reduced poststroke motor recovery. CONCLUSION: This rodent model of persistent nonuse after stroke may be used to further understand mechanisms of learned nonuse as well as to evaluate pharmacological and rehabilitation treatments to overcome it.

A critical appraisal of experimental intracerebral hemorrhage research.

The likelihood of translating therapeutic interventions for stroke rests on the quality of preclinical science. Given the limited success of putative treatments for ischemic stroke and the reasons put forth to explain it, we sought to determine whether such problems hamper progress for intracerebral hemorrhage (ICH). Approximately 10% to 20% of strokes result from an ICH, which results in considerable disability and high mortality. Several animal models reproduce ICH and its underlying pathophysiology, and these models have been widely used to evaluate treatments. As yet, however, none has successfully translated. In this review, we focus on rodent models of ICH, highlighting differences among them (e.g., pathophysiology), issues with experimental design and analysis, and choice of end points. A Pub Med search for experimental ICH (years: 2007 to 31 July 2011) found 121 papers. Of these, 84% tested neuroprotectants, 11% tested stem cell therapies, and 5% tested rehabilitation therapies. We reviewed these to examine study quality (e.g., use of blinding procedures) and choice of end points (e.g., behavioral testing). Not surprisingly, the problems that have plagued the ischemia field are also prevalent in ICH literature. Based on these data, several recommendations are put forth to facilitate progress in identifying effective treatments for ICH.

Prolonged hypothermia in rat: a safety study using brain-selective and systemic treatments.

Hypothermia is an effective neuroprotectant for cardiac arrest and perinatal ischemic injury. Hypothermia also improves outcome after traumatic brain injury and stroke. Although the ideal treatment parameters (duration, delay, and depth) are not fully delineated, prolonged cooling is usually more effective than shorter periods. There is the concern that extended cooling may be hazardous to brain plasticity and cause damage. In order to evaluate this possibility, we assessed the effects of 3 days of systemic hypothermia (32°C) in rats subjected to a sham stroke surgery. There were no detrimental behavioral effects or signs of brain damage. As even longer cooling may be needed in some patients, we cooled (∼32°C) the right hemisphere of rats for 3 or 21 days. Physiological variables, functional outcome, and measures of cell injury were examined. Focal brain cooling for 21 days modestly decreased heart rate, blood pressure, and core temperature. However, focal hypothermia did not affect subsequent behavior (e.g., spontaneous limb usage), cell morphology (e.g., dendritic arborization, ultrastructure), or cause cell death. In conclusion, prolonged mild hypothermia did not harm the brain of normal animals. Further research is now needed to evaluate whether such treatments affect plasticity after brain injury.

Rehabilitation promotes recovery after whole blood-induced intracerebral hemorrhage in rats.

BACKGROUND: Rehabilitation improves recovery after intracerebral hemorrhage (ICH) caused by collagenase infusion into the striatum of rats by promoting dendritic growth and reducing brain injury in this model. OBJECTIVE: Effective preclinical testing requires multiple models because none, including the collagenase model, perfectly mimics human ICH. Thus, the authors assessed enhanced rehabilitation (ER), a combination of environmental enrichment and task-specific motor training, on skilled reaching, lesion size, and dendritic plasticity after whole blood-induced, striatal ICH. METHODS: Three groups of rats were trained to retrieve food in a reaching task prior to ICH. One group was euthanized at 7 days, whereas 2 groups survived 7 weeks post-ICH. Of the latter, 1 group received 2 weeks of ER starting at 7 days, whereas controls did not. Reaching success was assessed 6 weeks after ICH. Lesion volume and dendritic length and complexity (contralateral striatum) were assessed. RESULTS: The ICH caused reaching deficits that were markedly attenuated by ER as observed previously in the collagenase model. In contrast to that model, there was a time-dependent decline in dendritic length after untreated, whole blood-induced ICH. Furthermore, behavioral recovery was not accompanied by changes in lesion volume or contralateral dendritic morphology. CONCLUSIONS: Converging data from animal models support the use of rehabilitation for ICH patients. However, although rehabilitation effectively promotes behavioral recovery, the mechanisms of action vary by model making it difficult to predict clinical effects.

A critical threshold of rehabilitation involving brain-derived neurotrophic factor is required for poststroke recovery.

BACKGROUND: Enriched rehabilitation (ER; environmental enrichment plus skilled reaching) improves recovery after middle cerebral artery occlusion (MCAo) in rats. Fundamental issues such as whether ER is effective in other models, optimal rehabilitation intensity, and underlying recovery mechanisms have not been fully assessed. OBJECTIVE: The authors tested whether the efficacy of ER varies with ischemia model and assessed the importance of rehabilitation intensity and brain-derived neurotrophic factor (BDNF) in recovery. METHODS: Rats in experiment 1 received 8 weeks of ER or remained in standard housing. Functional outcome was assessed with the staircase and cylinder tasks. Surprisingly, ER provided no functional benefit in any model. In this experiment, ER was delivered during the light phase, whereas other studies delivered ER in the dark phase of the light cycle. It was hypothesized that in the light, rats engaged in less rehabilitation or alternatively that BDNF was lower. Experiment 2 tested these hypotheses. Following MCAo, rats received ER in either the light or dark phase of the light cycle. Functional outcome was assessed and BDNF levels were measured in the motor cortex and hippocampus. RESULTS: Recovery was accompanied by increased BDNF. This occurred only in rats that received ER in the dark and these animals reached more than those in the light condition. CONCLUSIONS: Data suggest that there is a critical threshold of rehabilitation, below which recovery will not occur, and that BDNF mediates functional recovery. The use of intensive rehabilitation therapies for stroke patients is strongly supported.

Prolonged, 24-h delayed peripheral inflammation increases short- and long-term functional impairment and histopathological damage after focal ischemia in the rat.

The incidence of infection among stroke patients is alarmingly high and both acute and delayed infections increase morbidity and mortality. Experimental studies support the acute clinical data, but little attention has focused on delayed systemic infections. Here, we investigated the effects of prolonged systemic inflammation either before or 24-h after ischemia. Systemic inflammation was induced by injecting rats with three separate doses of lipopolysaccharide (LPS; 50 mug/kg, i.p.) with core temperature monitoring for 48-h after middle cerebral artery occlusion (MCAo). Lipopolysaccharide injected before MCAo increased injury by approximately 30%, whereas delayed injection increased injury by approximately 85% (30-day survival). Proinflammatory cytokines assessed repeatedly for 72 h were significantly and persistently elevated with inflammation. This was accompanied by increases in microglia/macrophage and infiltrating leukocyte numbers in delayed LPS-treated animals. Behavioral assessments at 7 and 30 days revealed approximately 15% deficit in hindlimb function in animals treated with LPS 24-h after ischemia. Clearly, delayed and prolonged postischemic systemic inflammation has devastating effects on stroke outcome, in the absence of a prolonged febrile response. These findings, together with corroborative clinical data, emphasize the importance of early intervention to counteract the deleterious consequences of stroke-associated inflammation and infection.