Moroz, T; (2014) Computational modelling of brain energy metabolism and circulation in the neonatal animal model. Doctoral thesis , UCL (University College London).

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Abstract

Hypoxic-ischaemic (HI) encephalopathy is a common cause of brain injury in neonates. The physiological processes occurring in the brain during asphyxia and in recovery are complex, and many aspects are not well understood. Piglets are often used as experimental models when investigating HI and testing new treatments. This thesis focuses on the development and application of a mathematical model of blood flow and energy metabolism in the piglet brain during oxygen deprivation. The model consists of differential and algebraic equations which aim to describe the relevant cerebral physiology. The multiscale nature of the model, and its level of simplification, arise from its aim of helping to interpret experimental non-invasive measurements from near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS). NIRS uses light to determine concentration changes of oxy and deoxyhaemoglobin in tissue. It can also detect changes in the oxidation of cytochrome-c-oxidase (CCO), an important marker of aerobic metabolism. This complements the information gained from MRS, which can measure the concentrations of key metabolites in tissue such as ATP, phosphocreatine and lactate. Multimodal monitoring with NIRS and MRS simultaneously gives a more complete picture of the metabolic state of the brain. The model has been compared with extensive multimodal data from piglets: both averaged, from brief anoxia studies, and individual datasets, from HI studies. Morris sensitivity analysis was implemented in order to systematically investigate the effects of altering all parameters. Optimisation of important parameters was also implemented. Simulations of anoxia lead to the suggestion that autoregulation in the newborn piglets was impaired. The consequences of cell death in the brain caused by HI were also investigated with simulations. The model is a novel tool which can be used to help test physiological hypotheses of clinical importance and increase understanding of the mechanisms of HI.

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