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: 8425776
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425776
• 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; 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; Process; 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 function; 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; neuropsychiatry; novel; prevent; programs; public health relevance; relating to nervous system; research and development; skills; social; 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）：此 NIMH 指导研究科学家职业发展 (K01) 奖申请寻求支持，以制定一项研究计划，重点关注典型发育儿童和低龄儿童的白质和工作记忆的发育特征。 1至8岁是精神分裂症的遗传高危人群。该计划的另一个目的是对典型儿童进行试点研究 在使用标准化自适应工作记忆程序进行训练后，确定测量白质中依赖于经验的结构可塑性的可行性。候选人寻求三个领域的职业发展培训，以支持她的长期职业目标：1) 通过跨早期大脑发育多个阶段的结构 (sMRI) 和扩散张量成像 (DTI) 联合分析的新颖指导，提升她的神经影像学背景， 2) 为纵向和多变量分析中使用的生物统计方法建立强大的知识基础，这对于检查发育轨迹、结构功能关系和大脑随时间的微妙变化非常重要，以及 3) 获得设计、规划和实施的经验对幼儿进行神经认知干预。该培训和研究计划将提高目前对典型和高危儿童早期大脑发育与早期出现和形成的认知技能（工作记忆）相关的理解。拟议研究的结果将用于识别风险的早期生物标志物，这可用于为高危儿童设计有针对性的预防干预策略。精神分裂症是一种使人衰弱的疾病，其起源于早期神经发育，会影响大脑的结构、功能和连通性。网络连接受损可能是精神分裂症许多核心特征的原因，包括工作记忆不佳。当临床症状出现时，在青春期后期或成年期，潜在的病理性大脑发育已经发生，并且很可能是不可逆转的。神经影像学研究一致表明，在精神病发作之前，患者的灰质 (GM) 体积减少，侧脑室增加。同样，DTI 研究表明，精神分裂症早期白质 (WM) 完整性也会降低。因此，识别风险的早期指标或生物标志物对于确定谁是关键人群至关重要。 面临风险以及如何设计有针对性的预防干预措施。对于大脑在最活跃和最关键的成熟时期之一（从出生到 6 岁）如何发育的了解相对较少。因此，我们对这一发展时期结构与功能关系的理解也很有限。工作记忆出现在婴儿期，是形成其他执行功能的认知基础。工作记忆差是精神分裂症的一个核心特征，通常出现在童年时期，早在精神病发作之前。因此，提高我们对大脑发育与认知功能相关的理解对于提高我们在发育早期识别高危个体的能力以及促进健康的长期结果至关重要。直到最近，技术和方法上的限制还阻止研究人员以非侵入性的方式描述人类大脑发育的这些早期阶段。我们位于北卡罗来纳大学教堂山分校的多学科研究团队引领了无创神经影像（sMRI 和 DTI）的最新进展，并开发了创新的分析技术来表征儿童白质的微观结构特征。我们北卡罗来纳大学的研究团队生成了唯一可用的纵向数据集，其中包括从出生到 6 岁的神经影像学和认知测量数据，这些数据集是从大量通常处于发育阶段且具有精神分裂症遗传高风险的儿童中收集的。这些现有数据将作为拟议研究和职业发展培训的基础。识别风险的早期指标或生物标志物对于确定谁有风险以及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识别对工作记忆发展很重要的白质连接，并将确定这些连接是否在有精神分裂症风险的儿童中发生改变。此外，典型儿童工作记忆训练的可行性研究将为测量白质束中经验依赖性结构变化的能力提供有价值的信息。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于工作记忆的其他认知、社交和发展能力的后期损伤。