Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders

生命早期的逆境、生物嵌入和精神障碍发育先兆的风险

• 批准号: 10744627
• 负责人: JOAN L. LUBY
• 金额: $ 246万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-22 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744627
• 关键词: 2 year old; 3 year old; Adverse effects; Affect; Age; Behavior; Behavioral; Biological; Birth; Brain; Caregiver support; Caregivers; Child; Childhood; Chronic; Clinical; Cognitive; Collection; Communities; Crime; Data; Data Collection; Development; Diagnosis; Diffusion; Disadvantaged; Environment; Exposure to; Extended Family; Family; Frequencies; Functional Magnetic Resonance Imaging; Immune; Immunologic Markers; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Investigation; Language; Life; Link; Lipopolysaccharides; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Mediator; Meditation; Memory; Mental disorders; Metabolic Pathway; Neighborhoods; Neonatal; Neurons; Parents; Pathway interactions; Phase; Pregnancy; Prevalence; Prevention; Psychopathology; Reporting; Risk; Role; Sampling; School-Age Population; Schools; Social support; Structure; Supportive care; Surface; Symptoms; TNF gene; Testing; Time; Variant; brain volume; caregiving; circulating biomarkers; clinical risk; cognitive development; cytokine; data repository; early childhood; early life adversity; effector T cell; experience; gut microbiome; in utero; inflammatory marker; inflammatory milieu; mental disorder prevention; microbiome; microbiome alteration; middle childhood; monocyte; multimodality; neighborhood safety; neurodevelopment; neuroinflammation; novel; peer; peer support; prenatal; preventive intervention; prospective; repository; resilience; resilience factor; response; risk minimization; school environment; social; social disparities; social influence; social relationships; social structure; spectrograph; systemic inflammatory response; translational potential

PROJECT SUMMARY Early exposure to social disadvantage, specifically family and neighborhood financial disadvantage in utero and through the first 3 years of life, is a powerful and potentially modifiable environmental determinant of risk for childhood psychopathology. The ongoing Early Life Adversity and Biological Embedding (eLABE) study launched in 2017 has aimed to elucidate mechanisms of this risk trajectory and guide preventive interventions. To date, eLABE has detected powerful associations between prenatal social disadvantage and structural and functional brain development at birth which are mediated through elevations in maternal cytokines and alterations in the gut microbiome. These neonatal neurodevelopmental variations have been linked to elevations in markers of psychopathology risk at age 2 years. Further, decreased caregiver nurturance mediated some aspects of this relationship, with supportive caregiving mitigating child psychopathology risk. Our central hypothesis is that pro- inflammatory immune and gut microbiome profiles evident in children exposed to prenatal and early life social disadvantage induce neuronal effects that negatively impact structural and functional brain development leading to increased risk for psychopathology. This renewal proposes to build upon the existing data to continue following our unique and well-characterized sample of 377 children for whom we have assembled a rich, unparalleled repository including comprehensive measures of social disadvantage (in utero and ages 1, 2, and 3 years) with early life measures of inflammation, the gut microbiome, and brain development (structural, microstructural, and functional MRI at birth and ages 2 and 3). In the next phase of eLABE, we propose to follow this sample into school entry (age 6) and middle childhood (age 8), adding assessments of social disadvantage, developmental/behavioral, inflammatory marker, multimodal MRI, and caregiver and social support measures at both timepoints and one additional wave of the gut microbiome at age 6. We will utilize these data to test specific hypotheses about mechanistic pathways to mental disorders that begin to clearly emerge in early childhood and school age, and will utilize novel brain metrics to more directly examine the roles of neuroinflammation and plasticity in this risk pathway. We will also examine the effects of caregiver and family, peer, and school supports on this risk trajectory, including their role as possible resilience factors, and explore whether there are sensitive periods for these effects. The results will provide the first systematic and intensive prospective examination of the relationship of social disadvantage to chronic systemic inflammation, the gut microbiome, and their links to brain development and behavior related to risk for clinical mental disorders. Critically, by targeting caregiving, inflammation, and the gut microbiome as key mechanistic pathways, these data will also have tremendous clinical and translational potential as they investigate potential mediators of risk and provide modifiable targets for prevention of mental disorders.

项目总结 早期暴露于社会劣势，特别是家庭和邻里的经济劣势 在生命的前3年，是一个强大的和潜在的可改变的环境风险决定因素 儿童期精神变态学。正在进行的早期生活逆境和生物嵌入(ELABE)研究启动 2017年旨在阐明这一风险轨迹的机制并指导预防性干预。到目前为止， Elabe发现了产前社会劣势与结构和功能之间的强大联系 出生时的大脑发育是通过母体细胞因子的升高和母体细胞的改变来调节的 肠道微生物群。这些新生儿神经发育的变化与血清标志物的升高有关 2岁时有精神病理风险。此外，照顾者养育力的降低在某些方面起到了中介作用 关系，辅助性照料可以减轻儿童的精神疾病风险。我们的中心假设是支持- 暴露于产前和早期社会生活的儿童明显的炎性免疫和肠道微生物组特征 劣势导致神经元效应，对大脑结构和功能发育产生负面影响 增加了患精神病的风险。这一更新建议在现有数据的基础上继续进行以下工作 我们独一无二的377名儿童样本，我们为他们收集了一个丰富的、无与伦比的 存储库，包括社会劣势的全面测量(在子宫内以及1、2和3岁)，以及 早期生命测量炎症、肠道微生物群和脑发育(结构、微结构和 出生时和2岁和3岁时的功能磁共振成像)。在下一阶段的Elabe中，我们建议遵循此样本进入 入学(6岁)和童年中期(8岁)，增加了对社会劣势的评估， 发展/行为、炎症标记物、多模式核磁共振、照顾者和社会支持措施 两个时间点和一个额外的肠道微生物组的波动。我们将利用这些数据来测试特定的 关于精神障碍的机械途径的假说，这些假说明显出现在儿童早期和 并将利用新的大脑测量方法更直接地检查神经炎症和 这一风险途径中的可塑性。我们还将研究照顾者和家庭、同伴和学校支持的影响。 关于这一风险轨迹，包括它们作为可能的复原力因素的作用，并探讨是否存在敏感性 这些影响的时间段。这些结果将提供第一次系统和深入的前瞻性检查 社会劣势与慢性全身炎症、肠道微生物群的关系及其与 与临床精神障碍风险相关的大脑发育和行为。最重要的是，通过以照顾为目标， 炎症和肠道微生物群作为关键的机制途径，这些数据也将产生巨大的影响 临床和翻译潜力，因为他们调查潜在的风险介体并提供可修改的目标 用于预防精神障碍。

项目成果

Disentangling Socioeconomic Status and Race in Infant Brain, Birth Weight, and Gestational Age at Birth: A Neural Network Analysis.

• DOI: 10.1016/j.bpsgos.2023.05.001
• 发表时间: 2024-01
• 期刊: Biological psychiatry global open science

Environmental Conditions to Promote Healthy Childhood Brain/Behavioral Development: Informing Early Preventive Interventions for Delivery in Routine Care.

• DOI: 10.1016/j.bpsgos.2021.10.003
• 发表时间: 2022-07
• 期刊: Biological psychiatry global open science

SSRI use during pregnancy and risk of stillbirth and neonatal mortality.

怀孕期间使用 SSRI 会增加死产和新生儿死亡的风险。

• DOI: 10.1176/appi.ajp.2012.11081251
• 发表时间: 2013
• 期刊: The American journal of psychiatry
• 作者: Jimenez-Solem,Espen;Andersen,JonTrærup;Petersen,Morten;Broedbaek,Kasper;Lander,AndersRune;Afzal,Shoaib;Torp-Pedersen,Christian;Poulsen,HenrikE
• 通讯作者: Poulsen,HenrikE

Translating RDoC to Real-World Impact in Developmental Psychopathology: A Neurodevelopmental Framework for Application of Mental Health Risk Calculators.

• DOI: 10.1017/s0954579421000651
• 发表时间: 2021-12
• 期刊: Development and psychopathology
• 影响因子: 3.3
• 作者: MacNeill LA;Allen NB;Poleon RB;Vargas T;Osborne KJ;Damme KSF;Barch DM;Krogh-Jespersen S;Nielsen AN;Norton ES;Smyser CD;Rogers CE;Luby JL;Mittal VA;Wakschlag LS
• 通讯作者: Wakschlag LS

The Infant Brain: A Critical Antecedent of Psychiatric Risk.

婴儿大脑：精神病风险的关键前因。

• DOI: 10.1016/j.biopsych.2023.03.005
• 发表时间: 2023
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Spann,MarisaN;Rogers,Cynthia
• 通讯作者: Rogers,Cynthia