Determining the source of variability within experimental stroke models

Efficacy of stroke interventions are tested using rodent middle cerebral artery occlusion (MCAO) models of focal brain ischemia but these have a poor record of translating into clinically effective treatments. The majority of experimental stroke studies use lesion volume as the primary outcome measure. However, variability in MCAO lesion volume is high with significant differences generally tested using parametric analyses requiring a normal data distribution. Data from my laboratory over the last ten years (and confirmed by others) shows that MCAO lesion volume data is not normally distributed and results in a bimodal distribution of small (purely striatal) and large (striato-cortical) lesions. We aim to determine (i) whether variability in MCAO lesion data is due to differences in cerebrovascular anatomy and, (ii) whether refinement of the surgical technique can improve outcome reproducibility. Rodents show a large variability in the Circle of Willis and studies have shown this to produce variability in lesion volume thus, requiring increased animal numbers to achieve statistical significance. However, traditional methods to assess the Circle of Willis anatomy are conducted post-mortem following the induction of MCAO. Firstly, we will assess, using MRI, whether the reported variability in outcome following MCAO is dependent upon the anatomy of the Circle of Willis and if so, can we develop a screening technique to identify 'suitable' mice to undergo MCAO and therefore reduce the number of animals undergoing MCAO.  In addition, we will assess whether a refinement in the surgical approach used to permit reperfusion followng MCAO can be applied in mice.  This will allow reperfusion to occur irrespective of the completeness of the Circle of Willis which is currently the main limitation in determining the effectiveness of reperfusion. This should reduce the variability in reperfusion associated experimental stroke models and reduce the number of animals used.

• 2019 Research Review: Blood flow in mouse stroke models
• News: Reducing variability in experimental stroke models
• Further Funding: NC3Rs Skills & Knowledge Transfer Grant, Dissemination of refinements in mouse experimental stroke models to the scientific community, August 2017, £65,220
• Further Funding: NC3Rs PhD Studentship, Improving the welfare and monitoring of rodents undergoing experimental stroke studies, October 2015, £90,000