Brain iron as a neurodevelopmental mechanism for transdianostic executive dysfunction

项目摘要 执行功能是一个多方面的结构，包括高阶认知过程，例如反应 抑制、工作记忆和目标选择。执行能力在整个青春期都会得到提高，并且 执行功能缺陷或执行功能障碍是许多精神病学的跨诊断特征 在此发育时期出现的疾病。了解潜在的神经发育 导致执行功能障碍的机制是有针对性的干预措施的关键先决条件。铁 缺乏症是世界上最常见的营养缺乏症，也是执行功能障碍的已知根源 在幼儿期和青春期的脆弱时期。然而，尽管其盛行且 影响，潜在的神经生物学机制尚未完全了解。该提案的重点是 将缺铁与跨诊断执行联系起来的潜在关键但尚未充分探索的机制 功能障碍：脑缺铁。目标 1 将定义青春期脑缺铁如何介导 外周铁缺乏对执行功能障碍的影响。我们首先要在大范围内调查这种关系 基于社区的样本（n=9,500 人进行外周铁和认知评估，n=1,601 人进行神经影像学评估） 然后将模型复制并扩展到针对患有精神疾病的个体进行富集的样本。 目标 2 将使用前瞻性收集的有或没有缺铁史的青少年样本 在 9-18 个月大时进行常规筛查，以确定儿童期和青春期缺铁的情况 影响青春期的大脑缺铁和执行功能障碍。至关重要的是，这个目标将告知多重打击 模型表明，儿童期和青春期缺铁与脑铁含量增加有关 缺铁，因此执行功能比仅在两次中的一次缺铁更严重 期间。最后，目标 3 将研究外周铁缺乏的性别差异如何影响 青春期开始后脑铁。这些目标将共同确定脆弱性发生的时间和 执行功能障碍的神经生物学机制，从而为目标转化模型提供信息 治疗和干预。 K99/R00 独立之路奖的支持将提供 申请人接受过实现这些目标所需的培训，包括发展方面的培训 神经精神病学、认知评估、定量磁共振成像和高级生物统计学。 这些培训目标将在杰出的导师团队 Drs. 的支持下完成。 Satterthwaite、Gur、Witschey、Shinohara、Wehrli 和 Georgieff 以及世界一流的技术和知识分子 宾夕法尼亚大学的资源。拟议的科学目标和培训目标将共同实现 为旨在揭示神经发育的独立研究项目奠定了基础 患有精神疾病的青少年执行功能障碍的机制。

PROJECT ABSTRACT Executive function is a multifaceted construct that includes higher-order cognitive processes such as response inhibition, working memory, and goal selection. Executive abilities improve throughout adolescence, and deficits of executive function, or executive dysfunction, are a transdiagnostic feature of many psychiatric disorders that emerge during this period of development. Understanding the underlying neurodevelopmental mechanisms that contribute to executive dysfunction is a critical prerequisite for targeted interventions. Iron deficiency is the most common nutrient deficiency in the world and is a known source of executive dysfunction during the vulnerable windows of early childhood and adolescence. However, despite its prevalence and impact, the underlying neurobiological mechanisms are not fully understood. This proposal focuses on a potentially critical but under-explored mechanism linking iron deficiency to transdiagnostic executive dysfunction: brain iron deficiency. Aim 1 will define how brain iron deficiency during adolescence mediates the effect of peripheral iron deficiency on executive dysfunction. We will first investigate this relationship in a large community-based sample (n=9,500 with peripheral iron and cognitive assessment, n=1,601 with neuroimaging) and then replicate and extend the model to a sample that is enriched for individuals with psychiatric disorders. Aim 2 will use a prospectively collected sample of adolescents with and without a history of iron deficiency in routine screenings at 9-18monts of age to determine how iron deficiency across childhood and adolescence impacts brain iron deficiency and executive dysfunction in adolescence. Critically, this aim will inform a multi-hit model whereby iron deficiency across childhood and adolescence will be associated with greater brain iron deficiency and thus more severe executive function than having iron deficiency in only one of the two time periods. Finally, Aim 3 will examine how sex differences in peripheral iron deficiency impact sex differences in brain iron after the onset of puberty. Together, these aims will identify both the timing of vulnerability and the neurobiological mechanisms underlying executive dysfunction, thus informing translational models for targeted treatments and interventions. The support of this K99/R00 Pathway to Independence award will provide the applicant with the training necessary to achieve these aims, including training in developmental neuropsychiatry, cognitive assessment, quantitative magnetic resonance imaging, and advanced biostatistics. These training objectives will be accomplished with the support of an outstanding mentorship team, Drs. Satterthwaite, Gur, Witschey, Shinohara, Wehrli, and Georgieff, and the world class technical and intellectual resources of the University of Pennsylvania. Together, the proposed scientific aims and training objectives will form the foundation for an independent research program aimed at uncovering the neurodevelopmental mechanisms for executive dysfunction in youth with mental illness.