Tissue Compliance and Intracranial Pressure Responses to Large Intracerebral Hemorrhage in Young and Aged Spontaneously Hypertensive Rats.

BACKGROUND: After a large intracerebral hemorrhage (ICH), the hematoma and swelling cause intracranial pressure (ICP) to increase, sometimes causing brain herniation and death. This is partly countered by widespread tissue compliance, an acute decrease in tissue volume distal to the stroke, at least in young healthy animals. Intracranial compensation dynamics seem to vary with age, but there is no data on old animals or those with hypertension, major factors influencing ICH risk and outcome. METHODS: We assessed hematoma volume, edema, ICP, and functional deficits in young and aged spontaneously hypertensive rats (SHRs) and young normotensive control strains after collagenase-induced ICH. Macroscopic and microscopic brain volume fractions, such as contralateral hemisphere volume, cortical thickness, and neuronal morphology, were assessed via histological and stereological techniques. RESULTS: Hematoma volume was 52% larger in young versus aged SHRs; surprisingly, aged SHRs still experienced proportionally worse outcomes following ICH, with 2× greater elevations in edema and ICP relative to bleed volume and 3× the degree of tissue compliance. Aged SHRs also experienced equivalent neurological deficits following ICH compared with their younger counterparts, despite the lack of significant age-related behavioral effects. Importantly, tissue compliance occurred across strains and age groups and was not impaired by hypertension or old age. CONCLUSIONS: Aged SHRs show considerable capacity for tissue compliance following ICH and seem to rely on such mechanisms more heavily in settings of elevated ICP. Therefore, the ICP compensation response to ICH mass effect varies across the lifespan according to risk factors such as chronic hypertension.

Intracranial Pressure Dysfunction Following Severe Intracerebral Hemorrhage in Middle-Aged Rats.

Rising intracranial pressure (ICP) aggravates secondary injury and heightens risk of death following intracerebral hemorrhage (ICH). Long-recognized compensatory mechanisms that lower ICP include reduced cerebrospinal fluid and venous blood volumes. Recently, we identified another compensatory mechanism in severe stroke, a decrease in cerebral parenchymal volume via widespread reductions in cell volume and extracellular space (tissue compliance). Here, we examined how age affects tissue compliance and ICP dynamics after severe ICH in rats (collagenase model). A planned comparison to historical young animal data revealed that aged SHAMs (no stroke) had significant cerebral atrophy (9% reduction, p ≤ 0.05), ventricular enlargement (9% increase, p ≤ 0.05), and smaller CA1 neuron volumes (21%, p ≤ 0.05). After ICH in aged animals, contralateral striatal neuron density and CA1 astrocyte density significantly increased (12% for neurons, 7% for astrocytes, p ≤ 0.05 vs. aged SHAMs). Unlike young animals, other regions in aged animals did not display significantly reduced cell soma volume despite a few trends. Nonetheless, overall contralateral hemisphere volume was 10% smaller in aged ICH animals compared to aged SHAMs (p ≤ 0.05). This age-dependent pattern of tissue compliance is not due to absent ICH-associated mass effect (83.2 mm3 avg. bleed volume) as aged ICH animals had significantly elevated mean and peak ICP (p ≤ 0.01), occurrence of ICP spiking events, as well as bilateral evidence of edema (e.g., 3% in injured brain, p ≤ 0.05 vs. aged SHAMs). Therefore, intracranial compliance reserve changes with age; after ICH, these and other age-related changes may cause greater fluctuation from baseline, increasing the chance of adverse outcomes like mortality.

Early, Intense Rehabilitation Fails to Improve Outcome After Intra-Striatal Hemorrhage in Rats.

BACKGROUND: The formation and degradation of an intracerebral hemorrhage causes protracted cell death, and an extended window for intervention. Experimental studies find that rehabilitation mitigates late cell death, with accelerated hematoma clearance as a potential mechanism. OBJECTIVE: We assessed whether early, intense, enriched rehabilitation (ER, environmental enrichment and massed skills training) enhances functional benefit, reduces brain injury, and augments hematoma clearance. METHODS: In experiment 1, rats (n = 56) were randomized to intervention in the light (-L) or dark phase (-D) of their housing cycle, then to 10 days of ER or control (CON) treatment after collagenase-induced striatal intracerebral hemorrhage (ICH). ER rats were treated from 5 to 14 days after ICH. Behavior and residual hematoma volume was assessed on day 14. In experiment 2, rats (n = 72) were randomized to ER-D10, ER-D20, or CON-D. ER rats completed 10 or 20 days of training in the dark. Rats were euthanized on day 60 for histology. In both experiments, behavioral assessment was completed pre-ICH, pre-ER (day 4 post-ICH), and post-ER (experiment 1: days 13-14; experiment 2: days 16-17 and 30-31). RESULTS: Reaching intensity was high but similar between ER-D10 and ER-L10. Unlike previous work, rehabilitation did not alter skilled reaching or hematoma resolution. Varying ER duration also did not affect reaching success or lesion volume. CONCLUSIONS: In contrast to others, and under these conditions, our findings show that striatal ICH was generally unresponsive to rehabilitation. This highlights the difficulty of replicating and extending published work, perhaps owing to small inter-study differences.

Targeting focal ischemic and hemorrhagic stroke neuroprotection: Current prospects for local hypothermia.

Therapeutic hypothermia (TH) has applications dating back millennia. In modern history, however, TH saw its importation into medical practice where investigations have demonstrated that TH is efficacious in ischemic insults, notably cardiac arrest and hypoxic-ischemic encephalopathy. As well, studies have been undertaken to investigate whether TH can provide benefit in focal stroke (i.e., focal ischemia and intracerebral hemorrhage). However, clinical studies have encountered various challenges with induction and maintenance of post-stroke TH. Most clinical studies have attempted to use body-wide cooling protocols, commonly hindered by side effects that can worsen post-stroke outcomes. Some of the complications and difficulties with systemic TH can be circumvented by using local hypothermia (LH) methods. Additional advantages include the potential for lower target temperatures to be achieved and faster TH induction rates with LH. This systematic review summarizes the body of clinical and preclinical LH focal stroke studies and raises key points to consider for future LH research. We conclude with an overview of LH neuroprotective mechanisms and a comparison of LH mechanisms with those observed with systemic TH. Overall, whereas many LH studies have been conducted preclinically in the context of focal ischemia, insufficient work has been done in intracerebral hemorrhage. Furthermore, key translational studies have yet to be done in either stroke subtype (e.g., varied models and time-to-treat, studies considering aged animals or animals with co-morbidities). Few clinical LH investigations have been performed and the optimal LH parameters to achieve neuroprotection are unknown.

An update to the Monro-Kellie doctrine to reflect tissue compliance after severe ischemic and hemorrhagic stroke.

High intracranial pressure (ICP) can impede cerebral blood flow resulting in secondary injury or death following severe stroke. Compensatory mechanisms include reduced cerebral blood and cerebrospinal fluid volumes, but these often fail to prevent raised ICP. Serendipitous observations in intracerebral hemorrhage (ICH) suggest that neurons far removed from a hematoma may shrink as an ICP compliance mechanism. Here, we sought to critically test this observation. We tracked the timing of distal tissue shrinkage (e.g. CA1) after collagenase-induced striatal ICH in rat; cell volume and density alterations (42% volume reduction, 34% density increase; p < 0.0001) were highest day one post-stroke, and rebounded over a week across brain regions. Similar effects were seen in the filament model of middle cerebral artery occlusion (22% volume reduction, 22% density increase; p ≤ 0.007), but not with the Vannucci-Rice model of hypoxic-ischemic encephalopathy (2.5% volume increase, 14% density increase; p ≥ 0.05). Concerningly, this 'tissue compliance' appears to cause sub-lethal damage, as revealed by electron microscopy after ICH. Our data challenge the long-held assumption that 'healthy' brain tissue outside the injured area maintains its volume. Given the magnitude of these effects, we posit that 'tissue compliance' is an important mechanism invoked after severe strokes.

The collagenase model of intracerebral hemorrhage in awake, freely moving animals: The effects of isoflurane.

Intracerebral hemorrhage (ICH) is a devastating stroke often modelled in rats. Isoflurane anesthetic, commonly used in preclinical research, affects general physiology (e.g., blood pressure) and electrophysiology (e.g., burst suppression) in many ways. These physiological changes may detract from the clinical relevance of the model. Here, we revised the standard collagenase model to produce an ICH in rats without anesthetic. Guide cannulas were implanted stereotaxically under anesthetic. After 3 days of recovery, collagenase was infused through an internal cannula into the striatum of animals randomly assigned to the non-anesthetized or isoflurane group. We assessed whether isoflurane affected hematoma volume, core temperature, movement activity, pain, blood pressure, and seizure activity. With a small ICH, there was a hematoma volume increased from 8.6 (±3.3, 95% confidence interval) µL in anesthetized rats to 13.2 (±3.1) µL in non-anesthetized rats (P = 0.008), but with a larger ICH, hematoma volumes were similar. Isoflurane decreased temperature by 1.3 °C (±0.16 °C, P < 0.001) for 2 h and caused a 35.1 (±1.7) mmHg group difference in blood pressure (P < 0.007) for 12 m. Blood glucose increased twofold after isoflurane procedures (P < 0.001). Pain, as assessed with the rat grimace scale, did not differ between groups. Seizure incidence rate (62.5%) in non-anesthetized ICH rats was similar to historic amounts (61.3%). In conclusion, isoflurane appears to have some significant and injury size-dependent effects on the collagenase model. Thus, when anesthetic effects are a known concern, the use of the standardized cannula infusion approach is scientifically and ethically acceptable.

Hypothermia: Impact on plasticity following brain injury.

Therapeutic hypothermia (TH) is a potent neuroprotectant against multiple forms of brain injury, but in some cases, prolonged cooling is needed. Such cooling protocols raise the risk that TH will directly or indirectly impact neuroplasticity, such as after global and focal cerebral ischemia or traumatic brain injury. TH, depending on the depth and duration, has the potential to broadly affect brain plasticity, especially given the spatial, temporal, and mechanistic overlap with the injury processes that cooling is used to treat. Here, we review the current experimental and clinical evidence to evaluate whether application of TH has any adverse or positive effects on postinjury plasticity. The limited available data suggest that mild TH does not appear to have any deleterious effect on neuroplasticity; however, we emphasize the need for additional high-quality preclinical and clinical work in this area.