Establishing Early Brain Signatures associated with Maternal Immune Activation Exposure

建立与母体免疫激活暴露相关的早期大脑特征

• 批准号: 10570905
• 负责人: Christoph Juchem
• 金额: $ 107.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570905
• 关键词: 2019-nCoV; Age; Age Months; Anterior; Area; Astrocytes; Behavior; Behavioral; Behavioral Paradigm; Biochemical; Biological; Biomedical Engineering; Blood; Brain; Brain Mapping; Brain region; Cells; Child; Clinical; Cross-Sectional Studies; Data; Data Collection; Data Science; Development; Diagnosis; Discipline of obstetrics; Dorsal; Exposure to; Fetus; Functional Imaging; Future; Goals; Growth; Gynecology; Head circumference; Health; Human; IL17 gene; IL8 gene; Immune; Immunoglobulin G; Immunologic Markers; Infant; Infection; Inflammation; Inflammatory; Influenza; Insula of Reil; Interleukin-1 beta; Interleukin-6; Knowledge; Learning Disabilities; Left; Level of Evidence; Life; Link; MRI Scans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Maternal-fetal medicine; Measures; Medical; Mental Health Services; Mental disorders; Metabolic; Modification; Motor; National Institute of Mental Health; Neonatal; Neurosciences; Newborn Infant; Normal Statistical Distribution; Pathway interactions; Perinatal; Physiological; Pilot Projects; Placenta; Population; Pregnancy; Pregnant Women; Premature Infant; Process; Property; Psychoneuroimmunology; Psychosocial Stress; Public Health; Reporting; Research; Research Domain Criteria; Risk; Rodent; Schizophrenia; School-Age Population; Science; Signal Transduction; Spottings; Stimulus; Stress; Structure; System; TNF gene; Temperament; Third Pregnancy Trimester; Time; Training; Umbilical Cord Blood; Variant; Work; autism spectrum disorder; behavioral health; behavioral phenotyping; behavioral response; brain behavior; cognitive control; cohort; early childhood; early detection biomarkers; emotion regulation; endophenotype; epidemiology study; experience; fetal; fetal reactivity; imaging science; immune activation; in vivo; indexing; individual variation; infancy; interest; longitudinal, prospective study; metabolic profile; myoinositol; neonatal period; neonate; neural; neurobehavior; neuron development; offspring; pathogen; postnatal; preclinical study; prenatal; prenatal exposure; psychiatric symptom; psychologic; public health relevance; recruit; response

While 1 in 5 children are at risk for psychiatric disorders, only 1 in 20 young children receive mental health care. There remains a gap in knowledge of early causes and precursor symptoms of psychiatric disorders; therefore, many children are not identified as at risk until school age, when a diagnosis can reliably be made. Prenatal maternal immune activation (MIA) from infection, stress, medical conditions, and environmental pathogens has been associated with offspring risk of psychiatric disorders. There remains a gap in our knowledge of the early brain and behavioral antecedents of this risk. Preclinical studies suggest that MIA may lead to biochemical changes in the developing brain that disrupt brain-behavior functional associations. We propose to examine whether prenatal exposure to MIA leads to metabolic and functional modifications in the developing brain and analogous behavioral phenotypes in human offspring. Our prior work demonstrated that MIA (interleukin-6; IL- 6) was associated with functional connectivity of the salience network (SAN), a network integral for emotion regulation, in neonates. Extending this, we will conduct longitudinal magnetic resonance imaging (MRI) scans in fetuses, neonates, and infants to determine if the alterations in the SAN originate in the fetal period and map developmental trajectories of the SAN in early life. In tandem, we plan to collect longitudinal magnetic resonance spectroscopy (MRS), which provides mechanistic information about the metabolic and cellular properties that may correspond to disruptions of SAN functional activity. Our pilot data suggests that MIA is associated with myo-inositol, an indicator of astroglial cell activation, in the newborn brain. Our central hypothesis is that MIA, evidenced by levels of inflammation (primary: IL-6) and infection (primary: Total immunoglobulin G), is associated with brain connectivity and metabolites in the SAN and behavioral reactivity from the fetal to infancy periods. One hundred and seventy-five pregnant women-fetal dyads will participate in this study from 12 weeks gestation to 9 months postnatal life. The pregnant women will have blood draws and psychological assessments at three timepoints and fetal physiologic assessment and MRI at 33-36 weeks. The infants will participate in MRI (2-6 weeks and 4 months postnatally) and observer-based behavioral paradigms at 4- and 9-months of age. Our proposal uses a collaborative science approach, bringing together perinatal-developmental neuroscience (Marisa Spann), psychoneuroimmunology (Staci Bilbo), maternal-fetal medicine (Mirella Mourad), and quantitatively trained biomedical engineers in the areas of developmental functional imaging and data science (Dustin Scheinost) and MRS (Christoph Juchem). This proposal is significant because it will provide mechanistic and system levels information about the rapidly developing brain that map on to an important behavioral system, emotion regulation. This research has the potential to reveal trajectories of behavioral health in early childhood and present approaches to detect early markers of psychiatric risk.

虽然五分之一的儿童有患精神疾病的风险，但只有二十分之一的幼儿接受精神卫生保健。 在对精神疾病的早期原因和前兆症状的了解方面仍然存在差距;因此， 许多儿童直到学龄时才被确定为有风险，而学龄时才能可靠地作出诊断。产前 来自感染、压力、医疗条件和环境病原体的母体免疫激活（MIA）， 与后代患精神疾病的风险有关。在我们对早期的知识中仍然存在着空白。 这种风险的大脑和行为前因。临床前研究表明，MIA可能导致生化 发育中的大脑发生改变，破坏大脑行为功能关联。我们建议研究 产前暴露于MIA是否会导致发育中大脑的代谢和功能改变， 人类后代的类似行为表型。我们先前的工作表明，MIA（白细胞介素-6; IL-10）， 6)与显著性网络（SAN）的功能连接有关，SAN是情绪的网络整合 监管，在新生儿。扩展这一点，我们将进行纵向磁共振成像（MRI）扫描， 胎儿、新生儿和婴儿，以确定SAN中的改变是否起源于胎儿期， SAN在生命早期的发展轨迹。同时，我们计划收集纵向磁共振 波谱分析（MRS），其提供关于代谢和细胞特性的机械信息， 可能对应于SAN功能活动的中断。我们的试验数据表明，MIA与 肌醇，星形胶质细胞活化的指标，在新生儿的大脑。我们的核心假设是失踪， 通过炎症（原发性：IL-6）和感染（原发性：总免疫球蛋白G）水平证明， 从胎儿期到婴儿期，SAN中的大脑连接和代谢物以及行为反应性。 175例妊娠12周以上的孕妇-胎儿二联体将参与本研究 到产后9个月。孕妇将在三点抽血和心理评估 在33-36周的时间点和胎儿生理评估和MRI。婴儿将参加MRI（2-6 出生后4周和4个月）和4个月和9个月时基于行为范式的行为。我们 该提案采用协作科学方法，将围产期发育神经科学 （玛丽莎·斯潘），心理神经免疫学（斯塔奇·比尔博），母胎医学（米雷拉·穆拉德），和 在发育功能成像和数据科学领域接受定量培训的生物医学工程师 （Dustin Scheinost）和MRS（Christoph Juchem）这一建议意义重大，因为它将提供机械 和系统水平的信息，这些信息是关于快速发育的大脑的，这些大脑映射到一个重要的行为系统， emotion regulation.这项研究有可能揭示儿童早期行为健康的轨迹 并提出了检测精神病风险早期标志物的方法。