PROJECT SUMMARY Pediatric internalizing disorders, including anxiety and depression, lead to considerable public health burden. Our understanding of internalizing disorders has lagged behind advances in our understanding of other pediatric psychopathologies. The neural circuitry underlying internalizing behaviors, including the prefrontal cortex, lateral orbitofrontal cortex, anterior cingulate cortex, amygdala and hippocampus develop early during developmental processes. Unlike adult neural networks, which are relatively stable, infant and child neural networks are dynamic, and need to be considered as vulnerable developmental trajectories. Even minor environmental disruptions early in life can set in motion deviations from normative trajectories that are not clinically evident for years. Environmental chemicals, such as metals, can exert neurotoxic effects during these critical windows of vulnerability. Advances in neuroimaging (i.e., magnetic resonance imaging; MRI) allow us to non-invasively test the influence of the environmental exposures on the neural circuitry in children. The influence of prenatal and early childhood metal exposure on these internalizing symptoms and the underlying neural circuitry has not yet been examined, even though early exposures to metals has been shown to adversely affect cognitive domains supported by the same circuitry. In the proposed study, we will leverage an ongoing prospective birth cohort study focused on examining associations between early life metal exposure and child cognition. We will introduce new follow-up measures including MRI and behavioral testing to assess internalizing symptoms in a sample of 300 variably exposed children at age 10-11 years. Using an innovative tooth biomarker that reconstructs integrated measures of metal exposure throughout gestation and early childhood, we focus on 3 neuroactive metals including: lead (Pb), a known toxicant; manganese (Mn) an essential nutrient with growing recognition as a neurotoxicant; and zinc (Zn) an essential nutrient with potential to mediate adverse effects of neurotoxicants. Using data-driven statistical models designed to leverage the temporality of the tooth data, we propose to identify and define critical developmental windows of susceptibility to individual metals and to the metal mixture. In addition, exploratory analyses will examine the link between MRI findings and behavioral phenotypes to further understand the mechanisms of metal neurotoxicity. This study bridges the fields of affective neuroscience and neuroimaging with environmental epidemiology. Few environmental health studies have brought together these three fields within a large cohort designed to test risk factors of child neurodevelopment; thus our study will help shape our overall understanding of the long-term effects of early life metal exposure and set the stage for developing effective public health interventions that can improve emotional, behavioral and cognitive functioning in children.

PROJECT NARRATIVE Internalizing disorders, including anxiety and depression are the most prevalent category of mental illness in childhood with a median onset at age 11 years and a lifetime prevalence of 28%. Early life exposure to environmental chemicals such as neurotoxic metals may disrupt the development of the neural circuitry subserving internalizing disorders, setting in motion maladaptive trajectories later in life. The proposed research uses neuroimaging to inform our understanding of the influence of early life exposure to neurotoxic metals on the neural circuitry supporting internalizing behaviors among young children and supports public health interventions to improve the long term emotional, behavioral and cognitive functioning in children.