Monash Newborn, Monash Children's Hospital, Melbourne, Australia; Department of Paediatrics, Monash University, Melbourne, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia.
Monash Biomedical Imaging, Monash University, Melbourne, Australia.
Neuroimage Clin. 2019;24:101991. doi: 10.1016/j.nicl.2019.101991. Epub 2019 Aug 23.
Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased risk of adverse neurodevelopment and neuromorbidity. Current imaging techniques, including conventional magnetic resonance imaging (MRI), are not sensitive enough to detect subtle structural abnormalities in the FGR brain. We examined whether advanced MRI analysis techniques have the capacity to detect brain injury (particularly white matter injury) caused by chronic hypoxia-induced fetal growth restriction in newborn preterm lambs.
Surgery was undertaken in twin bearing pregnant ewes at 88-90 days gestation (term = 150 days) to induce FGR in one fetus. At 127 days gestation (~32 weeks human brain development), FGR and control (appropriate for gestational age, AGA) lambs were delivered by caesarean section, intubated and ventilated. Conventional and advanced brain imaging was conducted within the first two hours of life using a 3T MRI scanner. T1-weighted (T1w) and T2-weighted (T2w) structural imaging, magnetic resonance spectroscopy (MRS), and diffusion MRI (dMRI) data were acquired. Diffusion tensor imaging (DTI) modelling and analysis of dMRI data included the following regions of interest (ROIs): subcortical white matter, periventricular white matter, cerebellum, hippocampus, corpus callosum and thalamus. Fixel-based analysis of 3-tissue constrained spherical deconvolution (CSD) of the dMRI data was performed and compared between FGR and AGA lambs. Lambs were euthanised immediately after the scans and brain histology performed in the regions of interest to correlate with imaging.
FGR and AGA lamb (body weight, mean (SD): 2.2(0.5) vs. 3.3(0.3) kg, p = .002) MRI brain scans were analysed. There were no statistically significant differences observed between the groups in conventional T1w, T2w or MRS brain data. Mean, axial and radial diffusivity, and fractional anisotropy indices obtained from DTI modelling also did not show any statistically significant differences between groups in the ROIs. Fixel-based analysis of 3-tissue CSD, however, did reveal a decrease in fibre cross-section (FC, p < .05) but not in fibre density (FD) or combined fibre density and cross-section (FDC) in FGR vs. AGA lamb brains. The specific tracts that showed a decrease in FC were in the regions of the periventricular white matter, hippocampus and cerebellar white matter, and were supported by histological evidence of white matter hypomyelination and disorganisation in corresponding FGR lamb brain regions.
The neuropathology associated with FGR in neonatal preterm lambs is subtle and imaging detection may require advanced MRI and tract-based analysis techniques. Fixel-based analysis of 3-tissue CSD demonstrates that the preterm neonatal FGR brain shows evidence of macrostructural (cross-sectional) deficits in white matter subsequent to altered antenatal development. These findings can inform analysis of similar brain pathology in neonatal infants.
胎儿生长受限（FGR）是一种严重的妊娠并发症，与不良神经发育和神经病变的风险增加有关。目前的成像技术，包括常规磁共振成像（MRI），不足以检测到 FGR 大脑中的细微结构异常。我们研究了先进的 MRI 分析技术是否有能力检测到由慢性缺氧诱导的胎儿生长受限引起的新生早产儿的脑损伤（特别是白质损伤）。
在妊娠 88-90 天（足月= 150 天）的双胎妊娠母羊中进行手术，以诱导一只胎儿的 FGR。在妊娠 127 天（约 32 周人类大脑发育）时，通过剖宫产分娩 FGR 和对照（胎龄适当，AGA）羔羊，进行气管插管和通气。在生命的头两个小时内，使用 3T MRI 扫描仪进行常规和先进的脑成像。采集 T1 加权（T1w）和 T2 加权（T2w）结构成像、磁共振波谱（MRS）和弥散 MRI（dMRI）数据。弥散张量成像（DTI）建模和 dMRI 数据分析包括以下感兴趣区（ROI）：皮质下白质、脑室周围白质、小脑、海马体、胼胝体和丘脑。对 dMRI 数据进行基于体素的三组织约束球形解卷积（CSD）分析，并在 FGR 和 AGA 羔羊之间进行比较。扫描后立即对羔羊进行安乐死，并在感兴趣的区域进行脑组织学检查，以与成像结果相关联。
对 FGR 和 AGA 羔羊（体重，平均值（SD）：2.2（0.5）vs. 3.3（0.3）kg，p=0.002）的 MRI 脑扫描进行了分析。在常规 T1w、T2w 或 MRS 脑数据方面，两组之间没有观察到统计学上的显著差异。DTI 建模获得的平均、轴向和径向扩散系数以及各向异性指数在 ROI 中也没有显示出两组之间的统计学差异。然而，基于体素的三组织 CSD 分析显示，FGR 与 AGA 羔羊脑相比，纤维交叉面积（FC，p<0.05）减少，但纤维密度（FD）或纤维密度和交叉面积的综合（FDC）没有减少。在脑室周围白质、海马体和小脑白质中观察到 FC 减少的特定束，这些束的变化得到了相应的 FGR 羔羊脑区髓鞘减少和组织紊乱的组织学证据的支持。
新生儿早产儿 FGR 相关的神经病理学是微妙的，成像检测可能需要先进的 MRI 和基于束的分析技术。基于体素的三组织 CSD 分析表明，FGR 早产儿的大脑在经历了产前发育改变后，表现出白质的宏观结构（横截面积）缺陷的证据。这些发现可以为新生儿婴儿的类似脑病理学分析提供信息。
