Efficacy of Rehabilitation in Translational Models of Intracerebral Hemorrhage
Creators: Fedor, Brittany A
Publisher: name: University of Alberta Library
Year: 2024

<p>Intracerebral hemorrhage (ICH), a devastating stroke caused by the rupture of vasculature in the brain, is responsible for &lt;20% of all strokes, yet accounts for a disproportionately high burden of stroke related death and disability. The formation and degradation of the hematoma (blood clot) injures the brain through mechanisms of both immediate mechanical damage (primary injury) and delayed cellular damage (secondary injury). Clinical trials have yet to identify treatments that can reliably lessen injury and impairment after ICH; as such, treatment for hemorrhagic stroke remains limited to medical management and rehabilitation. Although rehabilitation is an essential component of post-stroke care, understanding of the optimal type, timing, and dosage of rehabilitation after stroke is limited.<br>
Preclinical (animal) models are frequently used to explore underlying mechanisms of injury and recovery after stroke, often with the goal of translating research findings to clinical practice. However, no single experimental model fully mimics the pathophysiology of human stroke, or the heterogeneity of location, stroke subtype, impairment, and comorbidities observed in the clinical population. Despite differing mechanisms of injury and patterns of recovery between ischemic and hemorrhagic stroke, most translational stroke research is conducted in experimental models of ischemia. As a result, much of our understanding of recovery after ICH is grounded in the assumption that the spatial and temporal dynamics of injury and recovery after ischemic and hemorrhagic stroke are similar, despite mounting evidence suggesting this is not entirely true. In this thesis I studied how modifiable treatment parameters such as intensity and timing of rehabilitation onset influence recovery in preclinical models of striatal ICH and focus on how to improve future preclinical rehabilitation studies to advance translational success.<br>
I first investigated whether early, intense enriched rehabilitation (ER) accelerated hematoma clearance and improved neurological and behavioural outcomes in the sub- acute (experiment 1) and chronic (experiment 2) phases of recovery after experimental striatal ICH in rats (Chapter 2). I hypothesized that ER initiated 5 days after ICH would provide enhanced behavioural benefit and accelerate hematoma clearance at 14 days after ICH; furthermore, increasing treatment duration (from 10 to 20 days) would confer greater behavioural and neurological benefit when measured 30 and 60 days after ICH, respectively. Contrary to both the hypothesis and previous findings, I did not detect a significant difference in hematoma clearance, recovery in skilled reaching, or volume of tissue loss compared to untreated controls.<br>
Owing to the difficulties in extending previous findings of rehabilitation accelerated hematoma clearance, I next sought to characterize the overall efficacy of rehabilitation therapies on motor recovery in translational models of ICH through the use of meta-analysis (Chapter 3). Rehabilitation provided modest benefits to motor recovery after ICH, however efficacy varied by treatment type and functional endpoint. In alignment with clinical findings, rehabilitation was most effective in animals with mild-moderate severity ICH. Interestingly, I found a complex relationship between intervention type and timing of treatment onset &lt;7 days after ICH, with interventions initiated between 48 hours-5 days after ICH providing no significant benefit. These results differ from those reported in a similar meta-analysis of rehabilitation in translational models of ischemic stroke, suggesting that response to rehabilitation may vary by stroke subtype. Finally, to address the varied quality in reporting and experimental design found in the reviewed literature, I developed a roadmap for researchers to follow to improve the quality of future translational rehabilitation research.<br>
Noting that the generalizability of translational research is likely reliant on whether experimental models reflect the pathophysiology and variability in recovery observed in clinical populations, I conducted a retrospective, exploratory post-hoc analysis to assess if proportional recovery occurs in preclinical models of subcortical ICH and whether any biomarkers predict recovery (Chapter 4). I found that proportional recovery does exist after experimental striatal ICH, but to a much lesser extent than reported elsewhere (30% vs. ~70%). Interestingly, differences in recovery after striatal ICH could not be linked to proposed biomarkers of lesion severity, internal capsule damage, or initial impairment.<br>
In this thesis I provide a comprehensive analysis of the efficacy of rehabilitation in translational models of ICH and discuss the complexity of evaluating how modifiable treatment parameters such as timing, intensity, and dose influence treatment efficacy. This work provides evidence for a complex relationship between intervention onset and treatment efficacy after ICH that is likely influenced by treatment type and/or intensity. Furthermore, it suggests that recovery and response to rehabilitation seemingly differ by stroke subtype. Together, these findings provide justification for future research that systematically manipulates intervention parameters and directly compares how recovery and response to treatment differ between ICH and ischemia.</p>