One of the most significant consequences of the Zika virus (ZIKV) epidemic is the increased risk of adverse neurodevelopmental outcomes in the children of ZIKV infected mothers. ZIKV exposed children (ZEC) are at high risk for neurodevelopmental disorders due to the direct impact of ZIKV on neural progenitor cells, immature neurons and the neurovasculature of the developing brain. This suggests a causal link between human ZIKV exposure and malformations of cortical development (MCD) beyond microcephaly. Imaging findings in Brazilian children from Pernambuco state with microcephaly and presumed ZIKV-associated congenital infection revealed a range of additional central nervous system (CNS) abnormalities. These included abnormal calcifications at the gray and white matter junction in all cases, MCDs occurring predominantly in the frontal lobes, ventriculomegaly, and hypoplasia of the cerebellum and brain stem. These CNS malformations are in turn associated with cognitive dysfunction and seizures. The main clinical manifestations of CNS malformations are chronic epilepsy, intellectual disability, and learning disabilities. Environmental Enrichment (EE) can attenuate cognitive deficits associated with neonatal teratogens and MCD, and has been shown to facilitate recovery from behavioral abnormalities and cognitive disabilities in several neurological disease models. EE effects have been demonstrated in microcephalic rates, mice with MCDs, and mice exposed to prenatal maternal infection. However, investigation of EE effects in humans with MCDs is lacking. Specifically, there are currently no known interventions that can mitigate adverse neurodevelopmental outcomes in ZEC. This study will provide valuable data on whether EE can rescue neurodevelopmental outcomes in humans with ZIKV, with and without evidence of microcephaly or MCDs. Investigators on this project have already successfully implemented an EE program called ?Saving Brains Grenada?, in which community workers interacted with caregiver-child dyads biweekly and helped parents implement enjoyable `brain smart' methods that foster neurodevelopment in young children by focusing on safety, attachment, and self-regulation, in addition to stimulation. Differences in neuropsychological outcomes between children who received the EE and children in the waitlist control group were measured using a sensitive, internationally normed assessment tool called the INTER-NDA. Results demonstrated improvements in cognition as early as two years of age in neurotypical children whose caregivers participated in the full EE program, compared to waitlist control parents and children. The current proposal will use a randomized controlled-trial design to test whether this evidence-based and culturally adapted EE program can attenuate adverse neuropsychological outcomes at 2 years of age in Grenadian ZEC. !

Public Health Relevance

One of the most significant consequences of the Zika virus (ZIKV) epidemic is the increased risk of adverse neurodevelopmental outcomes in the children of ZIKV infected mothers. Structurally, these include central nervous system malformations, and functionally, these are associated with an increased risk of cognitive impairment. This project will implement a randomized controlled study design and a culturally adapted and evidence-based community intervention with toddlers who have been exposed to ZIKV to determine whether environmental enrichment can rescue cognitive dysfunction in ZIKV exposed children.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZHD1)
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Chakhtoura, Nahida Abdo
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Windward Islands Research & Ed Fdn
Great River
United States
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