Prenatal cocaine exposure (PCE) is consistently related to impaired attention and behavioral and physiological self-regulation in infants and young children, suggesting persistent negative impact on skills essential for optimal learning and social competence. Gestational exposure to cocaine occurs during a time of extraordinary brain growth and organization, which is immediately followed by massive expansion and refinement of brain structure, functional connections and network organization in the first year of life. However, little is known about the effects of PCE on early human brain development that may contribute to reported deficits in cognition and neurobehavior. The objectives of this proposal are to quantify the effects of PCE on the developmental trajectory of infant brain functional connectivity in postnatal months 0-12, to determine associations with neurobehavioral and cognitive outcomes, and to examine how specific maternal caregiving characteristics (Sensitivity, Harshness) moderate these effects. Our central hypothesis is that fetal brain development and organization are altered by PCE; deficits in developing functional connections mediate the negative effects of PCE on simultaneously developing neurobehavior and early cognition; postnatal maternal behaviors and environment interact with PCE to influence growth trajectories of developing connections and networks that subserve emerging abilities. This hypothesis is based on the Co-PIs'strong preliminary data describing normative development of functional networks from birth to 2 years (Gao), disruptions in functional connectivity due to prenatal cocaine and other drugs in neonates (Grewen, Gao), and on Co-investigator Eiden's longitudinal studies of the behavioral effects of PCE and its moderation by maternal behaviors in infants, toddlers and children. We propose to study infant resting state functional connectivity and behavioral development at 2 weeks, 6 months and 12 months in 3 groups of infants: 120 with PCE with or without exposure to other drugs (nicotine, alcohol, marijuana, and/or opiates), 100 exposed to the same other drugs but without cocaine (OD), 100 drug-free (CTL). We will measure Maternal Sensitivity (primary), Maternal Harshness (secondary) and an index of cumulative environmental risk to determine postnatal moderation of PCE effects on developing connectivity. The rationale is that longitudinal study will reveal prenatal drug effects, determine whether the postnatal trajectory of brain functional connections is merely delayed or permanently altered by initial PCE insult, and ascertain postnatal factors contributing to greater risk or resilience in func- tional network development. This innovative approach will quantify direct and interactive effects of initial neural deficit and postnatal environmental influences on patterns of brain and cognitive development, and will apply hypothesis-driven and data-driven analytic methods, including machine learning, to characterize mechanisms underlying PCE effects on trajectory of brain development. Knowledge gleaned has potential to inform earlier, more effective interventions to prevent or reduce learning and behavioral impairments in this at-risk population.
The proposed research will provide currently unavailable knowledge of the effects of prenatal cocaine and other drug exposures on developing brain functional connections and networks that subserve emerging behaviors and cognition in the first year of life, and will shed light on modifiable postnatal factors that may enhance or further impair early brain development. It is relevant to public health because discovery of mechanisms by which prenatal cocaine exposure influences development of brain and cognition in infancy will lead to earlier, more effective interventions to prevent or reduce later disabilities, as opposed to treatment in later childhood. This research is relevant to the mission of NIDA because it seeks to identify the physiological and social substrates and mechanisms involved in the cognitive and behavioral effects produced by drugs of abuse in an exceptionally vulnerable population? infants exposed in utero.
