Early life exposure to metal mixtures and neuroimaging of internalizing behaviors in childhood

项目总结 儿童内化性疾病，包括焦虑和抑郁，导致相当大的公共卫生负担。 我们对内在化障碍的理解落后于我们对其他 儿科精神变态。内化行为的神经回路，包括前额叶 皮质、外侧眶前叶皮质、前扣带回皮质、杏仁核和海马体早期发育。 发育过程。与相对稳定的成人神经网络不同，婴儿和儿童神经网络 网络是动态的，需要被视为脆弱的发展轨迹。即使是次要的 生命早期的环境破坏可能会引发偏离标准轨迹的运动，而不是 多年来临床上都很明显。在这些过程中，环境化学物质，如金属，会产生神经毒性作用。 易受攻击的关键窗口。神经成像(即磁共振成像；MRI)的进步使我们能够 无创性检测环境暴露对儿童神经回路的影响。这个 产前和儿童早期接触金属对这些内化症状的影响及其潜在的 神经回路尚未被检查，尽管早期接触金属已被证明 对同一回路所支持的认知域产生不利影响。在拟议的研究中，我们将利用 正在进行的预期出生队列研究集中于检查早期接触金属之间的关系 和儿童认知。我们将推出新的后续措施，包括核磁共振和行为测试，以评估 对300名年龄在10-11岁之间的不同暴露儿童的样本进行症状内化。使用创新的 牙齿生物标记物，重建整个孕期和早期金属暴露的综合测量 童年，我们专注于3种神经活性金属，包括：铅(铅)，一种已知的毒物；锰(锰)和 基本营养素，作为一种神经毒物得到越来越多的认可；以及锌(锌)，一种有潜力的基本营养素 以调节神经毒物的不良反应。使用数据驱动统计模型，旨在利用 牙齿数据的暂时性，我们建议识别和定义易感性的关键发育窗口 到单个金属和金属混合物。此外，探索性分析将考察 MRI表现和行为表型，进一步了解金属神经毒性的机制。这 这项研究将情感神经科学和神经成像领域与环境流行病学联系起来。一些 环境健康研究已经将这三个领域集中在一个旨在测试风险的大型队列中 儿童神经发育的因素；因此，我们的研究将有助于形成我们对长期 早期生命金属暴露的影响，并为制定有效的公共卫生干预措施奠定了基础 可以改善儿童的情绪、行为和认知功能。

PROJECT SUMMARY Pediatric internalizing disorders, including anxiety and depression, lead to considerable public health burden. Our understanding of internalizing disorders has lagged behind advances in our understanding of other pediatric psychopathologies. The neural circuitry underlying internalizing behaviors, including the prefrontal cortex, lateral orbitofrontal cortex, anterior cingulate cortex, amygdala and hippocampus develop early during developmental processes. Unlike adult neural networks, which are relatively stable, infant and child neural networks are dynamic, and need to be considered as vulnerable developmental trajectories. Even minor environmental disruptions early in life can set in motion deviations from normative trajectories that are not clinically evident for years. Environmental chemicals, such as metals, can exert neurotoxic effects during these critical windows of vulnerability. Advances in neuroimaging (i.e., magnetic resonance imaging; MRI) allow us to non-invasively test the influence of the environmental exposures on the neural circuitry in children. The influence of prenatal and early childhood metal exposure on these internalizing symptoms and the underlying neural circuitry has not yet been examined, even though early exposures to metals has been shown to adversely affect cognitive domains supported by the same circuitry. In the proposed study, we will leverage an ongoing prospective birth cohort study focused on examining associations between early life metal exposure and child cognition. We will introduce new follow-up measures including MRI and behavioral testing to assess internalizing symptoms in a sample of 300 variably exposed children at age 10-11 years. Using an innovative tooth biomarker that reconstructs integrated measures of metal exposure throughout gestation and early childhood, we focus on 3 neuroactive metals including: lead (Pb), a known toxicant; manganese (Mn) an essential nutrient with growing recognition as a neurotoxicant; and zinc (Zn) an essential nutrient with potential to mediate adverse effects of neurotoxicants. Using data-driven statistical models designed to leverage the temporality of the tooth data, we propose to identify and define critical developmental windows of susceptibility to individual metals and to the metal mixture. In addition, exploratory analyses will examine the link between MRI findings and behavioral phenotypes to further understand the mechanisms of metal neurotoxicity. This study bridges the fields of affective neuroscience and neuroimaging with environmental epidemiology. Few environmental health studies have brought together these three fields within a large cohort designed to test risk factors of child neurodevelopment; thus our study will help shape our overall understanding of the long-term effects of early life metal exposure and set the stage for developing effective public health interventions that can improve emotional, behavioral and cognitive functioning in children.