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精神疾病的风险，但只有20个年幼的儿童中只有1个患有精神卫生保健。 关于早期原因和精神疾病的前体症状的知识仍然存在差距；所以， 在可以可靠地进行诊断的时候，许多孩子直到学龄前才被确定为风险。产前 孕产妇免疫激活（MIA）感染，压力，医疗状况和环境病原体具有 与精神疾病的后代风险有关。我们对早期的了解仍然存在差距 这种风险的大脑和行为前提。临床前研究表明，MIA可能导致生化 破坏大脑行为功能关联的发展大脑的变化。我们建议检查 产前暴露于MIA是否会导致发育中的大脑的代谢和功能修饰 人后代中的类似行为表型。我们先前的工作证明了MIA（白介素-6; il-- 6）与显着性网络（SAN）的功能连通性有关，这是情绪不可或缺的网络 调节，在新生儿中。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时期和地图 早期的SAN的发展轨迹。在同时，我们计划收集纵向磁共振 光谱法（MRS），提供有关代谢和细胞特性的机械信息 可能对应于圣功能活动的中断。我们的飞行员数据表明​​MIA与 新生儿大脑中星形胶质细胞活化的指标肌醇。我们的中心假设是MIA， 炎症水平（主要：IL-6）和感染（主要：总免疫球蛋白G）证明了 从胎儿到婴儿期的SAN和行为反应性的大脑连通性和代谢产物。 一百七十五名孕妇 - 狂欢二元组将从12周的妊娠开始参加这项研究 到9个月后生活。孕妇将在三个时进行血液抽血和心理评估 时间点和胎儿生理评估以及33-36周的MRI。婴儿将参加MRI（2-6 产后几周和4个月）和基于观察者的行为范例在4个月和9个月的年龄。我们的 建议使用协作科学方法，将围产期开发神经科学汇总在一起 （Marisa Spann），Psychoneuromummumumanology（Staci Bilbo），母亲医学（Mirella Mourad）和 在发育功能成像和数据科学领域的定量训练的生物医学工程师 （Dustin Scheinost）和太太（Christoph Juchem）。该提议很重要，因为它将提供机械 以及有关快速发展的大脑的系统级信息，该信息映射到重要的行为系统， 情绪调节。这项研究有可能在童年时期揭示行为健康的轨迹 并目前的方法来检测精神病风险的早期标记。