Prenatal cocaine exposure (PCE) is related to deficits in cognitive function in infants, children and adolescents, however little is known about the effects of in utero cocaine exposure on early brain development that may contribute to these deficits. The long term goal is to better understand neural mechanisms underlying the cognitive impairments attributable to PCE. The objective of this proposal is to quantify the effects of PCE on functional connectivity networks in a pre-existing dataset from 148 infants, tested at 2-6 weeks of age, in which cocaine-related prefrontal and frontal cortical gray matter (GM) loss has already been determined. The central hypothesis is that effects of PCE will entail reductions in patterns of functional connectivity that are related to GM loss in prefrontal and frontal cortex, and that greater in utero exposure will be related to more widespread reductions in connectivity. This hypothesis has been formulated on the basis of preliminary data produced by the applicants that: 1) describes the presence of functional networks in typically developing infants as early as 2 weeks of age;2) shows that infants exposed to cocaine in utero display reduced prefrontal and frontal gray matter volumes compared to drug-free controls and to infants exposed to other drugs (nicotine, alcohol, marijuana, opiates). The rationale for the proposed research is that measurement of functional connectivity in infants with PCE in the first weeks of life will lay the foundation for study of developmental changes in neural circuitry that underlie cognitive deficits, suggest factors that bolster resilience against these deficits, and reveal targets for early intervention. This hypothesis will be tested by pursuit of two specific aims: 1) Quantify the effects of PCE on multi-level functional connectivity using pre-existing data from 46 infants exposed to cocaine and other drugs (PCE), 58 drug-free controls (CTL) and 44 exposed to the same drugs experienced by the PCE group (nicotine, alcohol, marijuana and/or opiates) but without cocaine;2) Determine the relationship of frontal and prefrontal connectivity to cognitive, behavioral and biological markers of infant development. Under the first aim, a proven approach of seed-based analysis, independent components analysis (ICA) and graph theoretic analysis, which is well-established as feasible in the applicants'hands, will be used to describe strength and density of prefrontal and frontal neonatal functional networks anchored by structural deficits. Under the second aim regional, network level and whole brain functional connectivity at 2-6 weeks will be related to measures of infant cognitive, behavioral and physiological development measured at 3 months. The approach is innovative because it will be first to apply these well-developed analyses methods to characterize early abnormalities in brain activity in early infancy in this at-risk group. The proposed research is significant because it is expected to identify a neurophenotype of cocaine's effects on early brain function prior to exposure to the damaging environmental influences that accompany maternal drug abuse, and provide support for more detailed longitudinal study of PCE's effects on developing trajectories of brain structure and function.
The proposed research is relevant to public health because it will provide currently unavailable knowledge of the effects of prenatal cocaine exposure on developing functional brain networks in the first weeks of life. This knowledge will directly improve our understanding of the impaired cognitive, behavioral and physiological developmental trajectories reported in this vulnerable group, and provide the foundation for future studies of developmental deficits related to prenatal exposure. The proposed research is relevant to the parts of NIH's mission that pertain to 'advancing the Nation's capacity to protect and improve health,''conducting and supporting research in the processes of human growth and development,'and 'understanding the addictive disorders'.
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