Clinically normal children exposed to Zika-virus (ZIKV) in utero may evidence abnormal neurodevelopment during the first few years of life even in the absence of the severe phenotype of congenital Zika syndrome (CZS). This is an important problem because the majority of children with in utero ZIKV exposure do not develop CZS but are at risk for neurodevelopmental abnormalities as they mature. The risk for neurodevelopmental impairments at school age in children with in utero ZIKV exposure, who do not have CZS, is not known because children have neither reached nor been studied at this critical age. The long-term goal is to recognize the spectrum of neurologic outcomes for children exposed to ZIKV in utero, which will enable appropriate follow-up guidelines, educational interventions, and therapies to support all children exposed to ZIKV. The objective of this application is to identify school age abnormalities in neurodevelopment and the domains affected and to evaluate for brain structural and functional differences among children in Colombia and in the US with ZIKV exposure in utero who do not have CZS. Guided by strong preliminary data, we will test two specific hypotheses: 1) that executive and motor function will be negatively impacted in ZIKV-exposed children compared to controls; and 2) that quantitative imaging will find structural and functional brain differences between ZIKV-exposed children and controls. The children will be followed at age 5 and 7 years using a specifically designed set of neurodevelopmental assessment tools and quantitative structural and functional neuroimaging. Neurodevelopment will be assessed by an approach utilizing validated questionnaires and child assessments that measure executive function, behavior, motor function, and intellectual ability. The advanced brain MRI will provide a multimodal assessment of brain structure and function. The approach is innovative because of access to two uniquely well characterized cohorts, one from the Caribbean coast of Colombia who had sequential fetal and neonatal neuroimaging and had early neurodevelopmental evaluations and a cohort from a congenital Zika program in the United States with exposure by travel or emigration. The proposed research is significant, because it will address a key question in child health by focusing on neurodevelopmental abnormalities in children following in utero ZIKV exposure that can manifest at school age. Ultimately, such knowledge has the potential to immediately inform the development of guidelines for neuropsychological and imaging assessment at school age for children with in utero exposure to ZIKV. Completion of the aims will improve identification of abnormal neurologic outcomes in children who had exposure to ZIKV in utero. The knowledge to be gained from this work is essential to be done now and is important to families, care providers, public health policy authorities, and federal agencies. It may be also applicable to future congenital infectious epidemics and potentially other perinatal exposures.
The proposed research is relevant to public health because the spectrum of neurodevelopmental outcomes for children exposed to Zika-virus in utero is not known at school age and this knowledge is necessary to inform primary and sub-specialty medical providers, educational systems, and public health policy. This knowledge can also improve preparedness for future infectious outbreaks that can affect the developing brain. The proposed research is relevant to NIH's mission because it aims to enhance the lives of children and optimize abilities for all.