Depressive and anxiety (referred to internalizing) disorders are increasing in prevalence in adolescents; yet, no specific etiology has been clearly demonstrated. This is quite concerning given that these disorders are associated with substantial distress and impairment, jeopardize one's trajectory towards a productive adulthood, and increase suicide risk; the latter being the 2nd leading cause of death in adolescents, with worsening recent trends. Iron deficiency (ID) has been associated with neuropsychiatric impairment, including depressive and anxiety symptoms. This is not surprising, given iron's role in dendritic mitochondrial motility during hippocampal neuron development, monoaminergic signaling, and myelination. In fact, across two independent samples of medically-healthy adolescents, we have found prevalent ID and an inverse association between iron stores and the severity of internalizing symptoms. Moreover, our preliminary evidence suggests that body iron stores are associated with brain morphometry and connectivity, as captured by magnetic resonance imaging (MRI). Building on these novel findings, the current research application seeks to enroll unmedicated 10 to 17 year- old participants with and without internalizing disorders to examine the association between peripheral iron stores, as captured by serum ferritin, and brain iron content, as measured by quantitative susceptibility mapping (QSM), a state-of-the-art MRI-based technique (Aim 1). Moreover, in order to establish the impact of ID on brain development, we will examine the association between brain and body iron stores, on the one hand, and brain structure, brain connectivity, and white matter integrity, on the other (Aim 2). Finally, in order to establish the clinical significance of the findings, we will examine the association between brain and body iron stores and psychiatric symptom severity (Aim 3). The proposed work will be the first to investigate the effect of ID on brain development and clinical symptoms in late childhood and adolescence, a developmental period characterized by increased risk for ID as well as rapid brain structural and functional changes. The ultimate goal is to determine the clinical significance of ID, in the absence of anemia, informing future therapeutic interventions.
Building on findings from animal studies and on preliminary data, from our laboratory, in adolescents with depression and anxiety, this project will be the first to investigate the impact of iron deficiency on brain iron content, brain structural and functional development, and psychiatric symptom severity. This information is necessary to guide future preventive interventions during a period of rapid brain maturation.