新生儿颅脑亚低温治疗中脑热传输机制的量化研究

Mild hypothermia has been demonstrated to be the effective treatment for neonates with hypoxic-ischemic encephalopathy (HIE). It shows good performance in reducing overall mortality and neurodevelopmental disability. The key to this treatment is the precise control of brain temperature. It may be the immaturity of neonatal brain structure, e.g. unclosed fontanel that leads to the vulnerability of regional brain in traditional uniform cooling on the surface. Currently, the noninvasive method for directly measuring the brain temperature distribution is lacking. In addition, it remains unclear about the mechanism of heat transport regarding the mild hypothermia acting on the human brain. All these indeed restrict the development of targeted therapeutic strategy. With the aid of MRI techniques allied with bioheat transfer theory, this project aims to quantitatively investigate the thermal transport mechanism during the mild hypothermia: we would firstly reconstruct the brain structures and estimate the cerebral blood flow (CBF) and metabolic rate of oxygenation by MRI and then construct the computational model for brain temperature distribution by bioheat transfer theory; based on the above model, this project would numerically predict the brain temperature changes during different mild hypothermia conditions, and then investigate the relations of skull structure with the heterogeneous temperature distribution within the brain; further we would explore the thermal transport mechanisms of respiration and cerebral vascular network during the different hypothermia conditions. In the end, through measuring the temperature changes in regional brain before and during the hypothermia (24~36h) by magnetic resonance spectroscopy, we would validate the above simulations, and then explore the characteristics of temperature and CBF within the HIE lesions and factors that affecting these parameters. Through the above investigations, this project would make good progress in both aspects of thermal physiology and clinical application of neonatal mild hypothermia.

亚低温治疗已被证实是治疗新生儿缺氧缺血性脑病（HIE）的有效手段，可提高存活率并改善预后。其实施关键在于颅脑温度的精准控制。新生儿颅脑结构发育不成熟（囟门未闭合），传统头皮表面均匀制冷易造成局部损伤。目前尚缺乏治疗中全脑温度监测方法，且亚低温作用人脑热传输机理不明晰，严重制约靶向调控治疗方案的发展。本项目拟基于生物传热理论和MRI技术，开展亚低温治疗中脑热传输量化研究：借助MRI重构颅脑结构，估算脑血流与氧耗参量，基于生物传热理论建立颅脑温度计算模型；基于上述模型，预测不同亚低温治疗模式颅脑温度变化，分析颅骨结构与脑内温度异质分布关联，探究呼吸与脑血管网的热传输机制；通过波谱MRI测量治疗前与治疗中（24~36h）HIE患儿局部脑区温度变化，验证理论预测准确性，分析HIE病灶区温度、血流变化特征及其影响因素。通过上述研究，本项目可望在新生儿亚低温治疗脑热生理基础与临床应用方面取得重要进展。

亚低温治疗已被证实是治疗新生儿缺氧缺血性脑病的有效手段，其实施关键在于颅脑温度的精准控制。针对亚低温作用人脑传输机制量化的关键问题，本课题依项目计划开展以下几方面的工作：（1）借助颅脑CT与结构MRI成像技术，发展了基于卷积神经网络的新生儿颅脑结构分割算法，重构新生儿颅骨结构与脑灰白质结构，进一步确认新生儿囟门结构随发育成熟体积逐渐降低的演变特征；（2）基于动脉自旋标记成像技术重构脑血流CBF参量，联合生物传热理论与高效对称半隐式差分算法，发展了基于脑CBF的颅脑温度量化计算模型，实现了高稳定性与精准性的颅脑温度计算；（3）针对脑血管网络热学效应量化，采用VaPor（github.com/sblowers/VaPor）三维颅脑几何模型（包含头皮、颅骨、脑脊液、脑灰白质与动静脉血管网络），对不同亚低温治疗条件、不同制冷边界条件以及不同血管网络特征对颅脑温度降温的热学效应进行仿真分析，发现脑血管网对颅脑降温效率影响的空间异质性特征。. 在原研究计划基础上，本课题研究增加了（1）基于磁敏感加权成像（SWI）的脑动态氧摄取分数（OEF）量化计算，并对健康成人在吸氧状态下的OEF变化进行监测，初步揭示了吸氧状态下人脑深部核团（苍白球与尾状核）OEF的“正弦式波动”变化特征；（2）基于快速多回波非对称自旋回波序列（MASE）实现静息态OEF参量计算，相较血液氧饱和水平检测序列产生的OEF，MASE序列计算的OEF对于缺血缺氧相关病变的量化更为敏感；（3）借助SWI重构颅脑静脉网，对轻度HIE新生儿脑缺血缺氧状态进行定量分析，发现HIE导致脑深部髓静脉可见度广泛增加。. 综上，通过本项目研究，实现了新生儿颅脑结构模型、颅脑血氧参量以及颅脑三维温度计算模型的构建，并一定程度揭示脑血管网络热传输对亚低温治疗中的热学效应，为设计个体精准的靶向亚低温治疗方案提供参考。