Development, Health and Disease Research Program, University of California, 92697, Irvine, CA, USA; Department of Pediatrics, University of California, 92697, Irvine, CA, USA.
Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States.
Neuroimage. 2019 Jan 15;185:825-835. doi: 10.1016/j.neuroimage.2018.04.020. Epub 2018 Apr 11.
Maternal inflammation during pregnancy can alter the trajectory of fetal brain development and increase risk for offspring psychiatric disorders. However, the majority of relevant research to date has been conducted in animal models. Here, in humans, we focus on the structural connectivity of frontolimbic circuitry as it is both critical for socioemotional and cognitive development, and commonly altered in a range of psychiatric disorders associated with intrauterine inflammation. Specifically, we test the hypothesis that elevated maternal concentration of the proinflammatory cytokine interleukin-6 (IL-6) during pregnancy will be associated with variation in microstructural properties of this circuitry in the neonatal period and across the first year of life. Pregnant mothers were recruited in early pregnancy and maternal blood samples were obtained for assessment of maternal IL-6 concentrations in early (12.6 ± 2.8 weeks [S.D.]), mid (20.4 ± 1.5 weeks [S.D.]) and late (30.3 ± 1.3 weeks [S.D.]) gestation. Offspring brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ± 1.7 weeks [S.D.]) and again at 12-mo age (N = 32, scan age = 54.0 ± 3.1 weeks [S.D.]). Diffusion Tensor Imaging (DTI) was used to characterize fractional anisotropy (FA) along the left and right uncinate fasciculus (UF), representing the main frontolimbic fiber tract. In N = 30 of the infants with serial MRI data at birth and 12-mo age, cognitive and socioemotional developmental status was characterized using the Bayley Scales of Infant Development. All analyses tested for potentially confounding influences of household income, prepregnancy Body-Mass-Index, obstetric risk, smoking during pregnancy, and infant sex, and outcomes at 12-mo age were additionally adjusted for the quality of the postnatal caregiving environment. Maternal IL-6 concentration (averaged across pregnancy) was prospectively and inversely associated with FA (suggestive of reduced integrity under high inflammatory conditions) in the newborn offspring (bi-lateral, p < 0.01) in the central portion of the UF proximal to the amygdala. Furthermore, maternal IL-6 concentration was positively associated with rate of FA increase across the first year of life (bi-lateral, p < 0.05), resulting in a null association between maternal IL-6 and UF FA at 12-mo age. Maternal IL-6 was also inversely associated with offspring cognition at 12-mo age, and this association was mediated by FA growth across the first year of postnatal life. Findings from the current study support the premise that susceptibility for cognitive impairment and potentially psychiatric disorders may be affected in utero, and that maternal inflammation may constitute an intrauterine condition of particular importance in this context.
孕期母体炎症可能改变胎儿大脑发育轨迹，并增加后代精神疾病的风险。然而，迄今为止，大多数相关研究都是在动物模型中进行的。在这里，我们关注的是额-边缘回路的结构连接，因为它对社会情感和认知发展都至关重要，并且在与宫内炎症相关的一系列精神疾病中通常会发生改变。具体来说，我们假设在怀孕期间，母体白细胞介素-6（IL-6）浓度升高与新生儿期和生命第一年该回路的微观结构特性的变化有关。在妊娠早期招募孕妇，并获取孕妇血样以评估妊娠早期（12.6±2.8 周 [标准差]）、中期（20.4±1.5 周 [标准差]）和晚期（30.3±1.3 周 [标准差]）的母体 IL-6 浓度。新生儿出生后不久（N=86，扫描年龄=3.7±1.7 周 [标准差]）和 12 个月龄时（N=32，扫描年龄=54.0±3.1 周 [标准差]）进行了婴儿脑 MRI 扫描。扩散张量成像（DTI）用于描述左、右钩束（UF）的分数各向异性（FA），代表主要的额-边缘纤维束。在具有出生和 12 个月龄时的系列 MRI 数据的 N=30 名婴儿中，使用贝利婴幼儿发展量表评估认知和社会情感发育状况。所有分析均测试了家庭收入、孕前体重指数、产科风险、孕期吸烟以及婴儿性别等潜在混杂因素的影响，并且 12 个月龄时的结果还考虑了产后照护环境的质量。母体 IL-6 浓度（整个孕期的平均值）与新生儿后代 UF 中部靠近杏仁核的区域的 FA（提示在高炎症状态下完整性降低）呈负相关（双侧，p<0.01）。此外，母体 IL-6 浓度与生命第一年的 FA 增加速度呈正相关（双侧，p<0.05），导致 12 个月龄时母体 IL-6 与 UF FA 之间呈零关联。母体 IL-6 还与 12 个月龄时的后代认知能力呈负相关，这种关联是由出生后第一年的 FA 增长介导的。本研究的结果支持这样的前提，即认知障碍和潜在精神疾病的易感性可能在子宫内受到影响，并且母体炎症可能是这种情况下特别重要的宫内状况。
