Opioid use during pregnancy has increased dramatically in the past decade, and may pose significant health challenges for the rapidly growing number of exposed infants born to mothers using illicit and/or prescribed opioids. Prenatal opioid exposure (OE) is inconsistently related to impaired neurobehavior, attention, and cognition in infancy and childhood, suggesting persistent, potentially life-long, consequences. This fetal exposure occurs during a time of extraordinary brain growth and organization, making it a critical period of vulnerability to environmental insult. However, little is known about the effects of OE on early human brain development that may contribute to reported deficits. The objectives of this proposal are to quantify the effects of OE on the development of infant brain functional connectivity in postnatal months 1-12, to determine associations with neurobehavioral and cognitive outcomes, and to examine how gender, other prenatal drug exposures, and postnatal environmental factors moderate these effects. Our central hypothesis is that fetal brain development and organization are altered by OE; deficits in developing connections and networks mediate the negative effects of OE on simultaneously developing neurobehavior and early cognition; gender, other drugs and postnatal environment interact with OE to influence growth trajectories of rapidly developing connections and networks that subserve emerging abilities. This hypothesis is based on the study team?s substantial research experience with mother-infant dyads with prenatal opioid and other drug exposures (Jones, Grewen), and on strong preliminary data showing normative development of functional networks from birth to 2 years (Gao), disruptions in neonatal functional connectivity due to prenatal opioids and other drugs (Grewen, Gao), and on associations between functional connections and behavioral effects (Grewen, Gao). The rationale for the proposed research is that longitudinal study will quantify direct and interactive effects of initial neural insult, infant gender and postnatal environment on developing functional connections. The hypotheses will be tested with 3 Specific Aims: 1) Quantify the extent to which OE impairs developing functional connections at 2 weeks and again at 12 months; 2) Determine the extent to which the effects of OE on neurobehavior, attention, self-regulation and cognition are related to developmental trajectories of functional connections; 3) Determine how infant gender, other prenatal drug exposures, and a Cumulative Environmental Risk Index moderate the effects of OE on developing connectivity. This approach is innovative because it will employ hypothesis-driven analyses as well as novel, exploratory data-driven and machine learning methods to quantify direct and interactive effects of OE and other drug exposures on functional circuitry. The proposed research is significant because rates of prenatal OE and NAS have increased 5-fold since 2000, in parallel with the opioid epidemic, and because knowledge gleaned has potential to identify factors that may protect or further harm growing functional networks underlying nascent cognitive abilities in this at-risk group.
The proposed research will provide currently unavailable knowledge of the effects of prenatal opioid 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. At a broader level, this work is relevant to understanding brain mechanisms underlying developing attention/arousal systems and how these brain-behavior connections may be altered by biological or environmental challenges. It is relevant to public health because the number of women using opioids during pregnancy is rapidly growing, in parallel with the current opioid epidemic. This research is relevant to NIDA?s mission 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.
