title: Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia.
abstract: Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue.
authors.affiliation: Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Caldwell
authors.affiliation: Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; CoMPLEX, University College London, London, United Kingdom.
authors.forename: Tracy
authors.initials: T
authors.lastname: Moroz
authors.affiliation: Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; CoMPLEX, University College London, London, United Kingdom.
authors.forename: Tharindi
authors.initials: T
authors.lastname: Hapuarachchi
authors.affiliation: Medical Physics and Bioengineering, UCLH NHS Foundation Trust, London, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.affiliation: Insititute for Women's Health, University College London, London, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
authors.affiliation: Biological Sciences, University of Essex, Colchester, United Kingdom.
authors.forename: Chris E
authors.initials: CE
authors.lastname: Cooper
authors.affiliation: Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.
authors.forename: Ilias
authors.initials: I
authors.lastname: Tachtsidis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000098:blood supply* / Q000378:metabolism* / Q000503:physiopathology; D002560:Cerebrovascular Circulation; D003198:Computer Simulation; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000503:physiopathology*; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D019265:Spectroscopy, Near-Infrared; D013552:Swine