Brain iron as a neurodevelopmental mechanism for transdianostic executive dysfunction

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.