Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
New York State Psychiatric Institute, New York, New York 10032.
J Neurosci. 2018 Mar 14;38(11):2877-2886. doi: 10.1523/JNEUROSCI.2272-17.2018. Epub 2018 Feb 27.
Prenatal maternal immune activation (MIA) is associated with altered brain development and risk of psychiatric disorders in offspring. Translational human studies of MIA are few in number. Alterations of the salience network have been implicated in the pathogenesis of the same psychiatric disorders associated with MIA. If MIA is pathogenic, then associated abnormalities in the salience network should be detectable in neonates immediately after birth. We tested the hypothesis that third trimester MIA of adolescent women who are at risk for high stress and inflammation is associated with the strength of functional connectivity in the salience network of their neonate. Thirty-six women underwent blood draws to measure interleukin-6 (IL-6) and C-reactive protein (CRP) and electrocardiograms to measure fetal heart rate variability (FHRV) at 34-37 weeks gestation. Resting-state imaging data were acquired in the infants at 40-44 weeks postmenstrual age (PMA). Functional connectivity was measured from seeds placed in the anterior cingulate cortex and insula. Measures of cognitive development were obtained at 14 months PMA using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Both sexes were studied. Regions in which the strength of the salience network correlated with maternal IL-6 or CRP levels included the medial prefrontal cortex, temporoparietal junction, and basal ganglia. Maternal CRP level correlated inversely with FHRV acquired at the same gestational age. Maternal CRP and IL-6 levels correlated positively with measures of cognitive development on the BSID-III. These results suggest that MIA is associated with short- and long-term influences on offspring brain and behavior. Preclinical studies in rodents and nonhuman primates and epidemiological studies in humans suggest that maternal immune activation (MIA) alters the development of brain circuitry and associated behaviors, placing offspring at risk for psychiatric illness. Consistent with preclinical findings, we show that maternal third trimester interleukin-6 and C-reactive protein levels are associated with neonatal functional connectivity and with both fetal and toddler behavior. MIA-related functional connectivity was localized to the salience, default mode, and frontoparietal networks, which have been implicated in the pathogenesis of psychiatric disorders. Our results suggest that MIA alters functional connectivity in the neonatal brain, that those alterations have consequences for cognition, and that these findings may provide pathogenetic links between preclinical and epidemiological studies associating MIA with psychiatric risk in offspring.
产前母体免疫激活（MIA）与后代大脑发育异常和精神疾病风险增加有关。将 MIA 转化为人类研究的数量很少。突显网络的改变与与 MIA 相关的相同精神疾病的发病机制有关。如果 MIA 是致病的，那么出生后新生儿的突显网络中的相关异常应该是可以检测到的。我们测试了这样一个假设，即处于高压力和炎症风险中的青春期女性的第三个孕期 MIA 与新生儿突显网络功能连接的强度有关。36 名女性在妊娠 34-37 周时进行了采血以测量白细胞介素-6（IL-6）和 C 反应蛋白（CRP），并进行了心电图以测量胎儿心率变异性（FHRV）。在婴儿出生后 40-44 周时，采集了静息状态成像数据。从置于前扣带皮层和脑岛的种子中测量功能连接。使用贝利婴幼儿发展量表第三版（BSID-III）在 14 个月的胎龄时获得认知发展的测量值。对两种性别进行了研究。与母体 IL-6 或 CRP 水平呈正相关的突显网络强度的区域包括内侧前额叶皮层、颞顶联合区和基底节。母体 CRP 水平与在相同胎龄时获得的 FHRV 呈负相关。母体 CRP 和 IL-6 水平与 BSID-III 上的认知发展测量值呈正相关。这些结果表明，MIA 与后代大脑和行为的短期和长期影响有关。在啮齿动物和非人类灵长类动物的临床前研究以及人类的流行病学研究表明，母体免疫激活（MIA）改变了大脑回路的发育，并使后代易患精神疾病。与临床前研究结果一致，我们发现母体第三个孕期白细胞介素-6 和 C 反应蛋白水平与新生儿功能连接以及胎儿和幼儿行为有关。与 MIA 相关的功能连接定位于突显、默认模式和额顶叶网络，这些网络与精神疾病的发病机制有关。我们的研究结果表明，MIA 改变了新生儿大脑的功能连接，这些改变对认知有影响，并且这些发现可能为将 MIA 与后代的精神疾病风险联系起来的临床前和流行病学研究提供发病机制联系。
