Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia
Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia
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DOI：
10.1371/journal.pone.0140171
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发表时间：
2015-10-07
期刊：
影响因子：
3.7
通讯作者：
Tachtsidis, Ilias
中科院分区：
文献类型：
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作者：
Caldwell, Matthew;Moroz, Tracy;Tachtsidis, Ilias
缺氧-缺血（HI）是新生儿脑损伤的主要原因，常导致长期损伤或死亡。为了提高认识和试验新的治疗方法，仔猪被用作人类新生儿的临床前模型。我们已经扩展了早期仔猪脑生理学计算模型，用于在诱导HI发作期间记录的多模态实验数据。数据包括近红外光谱（NIRS）和磁共振光谱（MRS）的监测，该模型模拟了产生测量信号的循环和代谢过程。模型扩展包括模拟用于诱导HI的颈动脉闭塞，包括细胞质pH，以及由于细胞死亡而导致的代谢功能丧失。模型行为与两只仔猪的数据进行比较，其中一只在HI后恢复，而另一只没有。通过敏感性分析确定行为重要的模型参数，并对这些参数进行优化以模拟实验数据。对于未恢复的仔猪，我们研究了几种状态变化，这些变化可能解释了为什么一些MRS和NIRS信号在HI侮辱后没有恢复到基线值。我们发现，当我们考虑到线粒体分离和脑血流恢复不良等其他因素时，该模型可以更好地解释这种失败，其中约有40%的脑组织死亡。
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.