White Matter and Working Memory Development in Typical and High-Risk Children

典型和高危儿童的白质和工作记忆发育

• 批准号: 8962171
• 负责人: SARAH J SHORT
• 金额: $ 15.35万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962171
• 关键词: 6 year old; 8 year old; Address; Adolescence; Adolescent; Adult; Affect; Age; Area; Behavioral; Biological Markers; Biological Neural Networks; Biostatistical Methods; Birth; Brain; Brain region; Child; Childhood; Clinical; Cognitive; Data; Data Set; Development; Diffuse; Diffusion Magnetic Resonance Imaging; Disease; Feasibility Studies; Genetic; Goals; Health; Human; Image; Impaired cognition; Impairment; Individual; Instruction; Interdisciplinary Study; Intervention; Joints; Knowledge; Life; Location; Longitudinal Studies; Measures; Memory impairment; Mentored Research Scientist Development Award; Mentors; Mothers; Multivariate Analysis; National Institute of Mental Health; Neurocognitive; Neurodevelopmental Disorder; North Carolina; Outcome; Parietal; Participant; Pathologic; Patients; Performance; Pilot Projects; Prevention; Preventive Intervention; Psychotic Disorders; Randomized; Reading; Research; Research Personnel; Research Project Grants; Research Training; Risk; Sampling; Schizophrenia; Scientist; Short-Term Memory; Staging; Structure; Structure-Activity Relationship; Symptoms; Techniques; Time; Training; Training Programs; Universities; Work; base; career; career development; cognitive ability; cognitive capacity; cognitive function; cognitive process; cognitive skill; cognitive testing; cohort; critical period; density; design; executive function; experience; gray matter; high risk; improved; infancy; innovation; knowledge base; lateral ventricle; memory process; multidisciplinary; neural circuit; neuroimaging; neuropsychiatric disorder; novel; prevent; programs; relating to nervous system; research and development; skills; social; support network; white matter

DESCRIPTION (provided by applicant): This application for an NIMH Mentored Research Scientist Career Development (K01) award seeks support to develop a program of research focused on characterizing the development of white matter and working memory in children who are typically developing and in children who are at genetic high-risk for schizophrenia from 1 to 8 years of age. An additional aim of this program is to conduct a pilot study with typical children to determine the feasibility of measuring experience-dependent structural plasticity in white matter, following training with a standardized adaptive working memory program. The candidate seeks career development training in three areas to support her long-term career goals: 1) Advance her neuroimaging background with novel instruction in joint analysis of structural (sMRI) and diffusion tensor imaging (DTI) across multiple stages of early brain development, 2) Develop a strong knowledge base for the biostatistical methods used in longitudinal and multivariate analyses important for examining developmental trajectories, structure-function relationships, and subtle brain changes over time, and 3) Gain experience in the design, planning and implementation of neurocognitive interventions in young children. This program of training and research will improve current understanding of early brain development in typical and high-risk children in relation to an early emerging and formative cognitive skill, working memory. Results from the proposed research will be used to identify early biomarkers of risk, which can be used to inform the design of targeted preventive intervention strategies for high-risk children. Schizophrenia is a debilitating disease with early neurodevelopmental origins that impact the structure, function and connectivity of the brain. Impairments in network connectivity are likely responsible for many of the core features of schizophrenia, including poor working memory. By the time clinical symptoms present, in late adolescence or adulthood, the underlying pathologic brain development has already occurred and is most likely irreversible. Neuroimaging studies have consistently shown that patients had reduced gray matter (GM) volumes and increased lateral ventricles, prior to the onset of psychosis. Likewise, DTI studies suggest that white matter (WM) integrity is also reduced early in schizophrenia. Therefore the importance of identifying early indicators or biomarkers of risk is critical for determining who is at-risk and how to design targeted preventive interventions. Relatively little is known about how the brain develops during one of the most dynamic and critical periods of maturation, from birth to 6 years of age. As a consequence, our understanding of structure-function relationships during this developmental period is limited as well. Working memory emerges in infancy and serves as a cognitive building block for the formation of other executive functions. Poor working memory is a core feature of schizophrenia that is typically present in childhood, long before the onset of psychosis. Therefore, improving our understanding of brain development in relation to cognitive functions is critical for advancing our ability to identify individuals at-risk early in development and for promoting healthy long-term outcomes. Until recently, technological and methodological limitations prevented researchers from non- invasively characterizing these early periods of human brain development. Our multidisciplinary research team at the University of North Carolina, Chapel Hill has pioneered recent advances in noninvasive neuroimaging (sMRI and DTI), and has also developed innovative analysis techniques to characterize microstructural features of white matter in children. Our research team at UNC has generated the only longitudinal dataset available, with neuroimaging and cognitive measures, collected from birth through 6 years of age, from large cohorts of children who are typically developing and at genetic high-risk for schizophrenia. This existing data will serve as the basis for the proposed research and career development training. The importance of identifying early indicators or biomarkers of risk is critical for determining who is at-risk and how to design targeted preventive interventions. The proposed research will help identify white matter connections that are important for the development of working memory and will determine whether they are altered in children at risk for schizophrenia. In addition, the feasibility study f working memory training in typical children will provide valuable information about the capacity to measure experience-dependent structural changes in white matter tracts. Strengthening neural networks associated with early foundational cognitive processes may help to ameliorate later impairments in other cognitive, social and developmental capacities that depend on working memory.

描述（由申请人提供）：NIMH指导研究科学家职业发展（K01）奖的申请寻求支持，以开发一项研究计划，旨在表征通常正在发展的儿童和在1至8岁之间为精神分裂症的基因高风险的儿童中的白质和工作记忆。该计划的另一个目的是与典型的儿童进行试点研究 在使用标准化的自适应工作记忆程序进行训练之后，确定在白质中测量与经验相关的结构可塑性的可行性。候选人在三个领域寻求职业发展培训，以支持她的长期职业目标：1）通过在结构性分析（SMRI）和扩散张量成像（DTI）中的新指导中提高她的神经影像的背景，并在早期大脑发展的多个阶段跨越多个阶段，开发了较强的知识基础，用于在远程和多个跨性别的脑海中使用的脑海中使用的良好相关方法，并构建了多个跨性别的发展。时间和3）在幼儿的神经认知干预措施的设计，计划和实施方面获得经验。该培训和研究计划将提高对早期新兴和形成性认知技能（工作记忆）的典型和高风险儿童早期大脑发展的理解。拟议研究的结果将用于识别早期的风险生物标志物，可用于为高危儿童的有针对性预防干预策略的设计提供信息。精神分裂症是一种令人衰弱的疾病，具有早期神经发育起源，会影响大脑的结构，功能和连通性。网络连通性的障碍可能导致精神分裂症的许多核心特征，包括工作记忆不佳。到存在临床症状时，在青春期或成年期，潜在的病理脑发育已经发生，并且很可能是不可逆的。神经影像学研究一直表明，在精神病发作之前，患者的灰质（GM）体积减少（GM）和侧心增加。同样，DTI研究表明，在精神分裂症早期，白质（WM）的完整性也降低了。因此，确定早期指标或风险生物标志物的重要性对于确定谁是 高危以及如何设计目标预防干预措施。从出生到6岁的最动态和关键时期之一，大脑在成熟的最活跃和关键时期之一中的发展知之甚少。结果，我们对在此发展时期内对结构功能关系的理解也受到限制。工作记忆在婴儿期出现，并作为形成其他行政职能的认知基础。工作记忆不佳是精神分裂症的核心特征，通常在精神病发作之前就存在。因此，提高我们对认知功能有关的大脑发展的理解对于提高我们在发育早期识别危险和促进健康的长期结局的能力至关重要。直到最近，技术和方法论上的局限性仍阻止了研究人员非侵入性地表征人类脑发育的这些早期时期。我们位于北卡罗来纳大学的多学科研究团队，教堂山（Chapel Hill）开创了非侵入性神经影像学（SMRI和DTI）的最新进展，并且还开发了创新的分析技术来表征儿童白质的微观结构特征。 UNC的研究团队生成了唯一可用的纵向数据集，从出生到6岁的大批儿童中，他们从出生到6岁都收集了神经影像学和认知措施，这些儿童通常正在发展，并且患有精神分裂症的遗传高风险。这些现有数据将作为拟议的研究和职业发展培训的基础。识别早期指标或风险生物标志物的重要性对于确定谁是风险和如何设计有针对性的预防干预措施至关重要。拟议的研究将有助于确定对工作记忆发展至关重要的白质连接，并确定他们是否会改变有精神分裂症风险的儿童。此外，在典型儿童中的可行性研究F工作记忆训练将提供有关衡量与经验依赖的白质结构变化能力的有价值的信息。加强与早期基础认知过程相关的神经网络可能有助于改善依赖工作记忆的其他认知，社会和发育能力的后来损害。