Karen M. Grewen, Ph.D. - US grants

We propose to investigate the relationship of cognitive factors, specially pessimistic attributional style, to cardiovascular and neuroendocrine reactivity at rest, in response to and during recovery from laboratory and natural life stressors. A bi-racial sample of 80 postmenopausal women (age 40-69) and 40 aged-matched men will be recruited to participate. Blood pressure and its hemodynamic components (stroke volume, total peripheral resistance) will be measured during a laboratory protocol consisting of resting baseline, three stressor tasks (speech, mental arithmetic, and cold pressor ice tasks) and recovery periods. Plasma catecholamines and cortisol will also be measured at baseline and during stressors. The relationship of attributional style to blood pressure and neuroendocrine parameters will be assessed, controlling for variables quantifying demographic information and known risk factors for hypertension (socioeconomic status, parental history of hypertension). The association of attributional style with 24-hour ambulatory blood pressure and urinary cortisol measurements will also be assessed.

[unreadable] DESCRIPTION (provided by applicant): This K01 Mentored Research Scientist Development Award application proposes a 5-year program of training and research designed to promote the Candidate's growth as an independent investigator, and to facilitate a shift of focus to a new area of translational research. This new line of inquiry is based on animal studies that identify the neuropeptide, oxytocin (OT) as essential for establishment of normal maternal behaviors in mammals, and that describe the disruptions in both OT activity and maternal behavior resulting from perinatal cocaine exposure. The short-term objective is to examine links between oxytocin, mother infant attachment and prenatal cocaine use in humans. The training goals are to provide the Candidate with new knowledge and measurement skills in: 1) the development of human mother-infant attachment, and aberrations associated with prenatal cocaine, 2) the neurobiology of cocaine addiction and perinatal abuse with a focus on dysregulation of OT activity, 3) training in the design and implementation of studies utilizing functional magnetic resonance imaging (fMRI) to identify maternal brain circuitry involved in reward, attachment, and responses to infant cues. This training will complement the Candidate's strong background in cardiovascular and neuroendocrine stress reactivity research, and in psychophysiological study of the role of OT in human social interactions. The specific aims of the research component are: 1) to examine, in 48 mothers of infants (12 cocaine only, 12 cocaine + smoking, 12 smoking only, 12 no drug), how prenatal exposure to cocaine and/or smoking is linked to maternal behavioral and physiological responses to structured mother-infant contact and experimental stressors in the laboratory, and to behavioral and physiological activity in the home environment using ambulatory monitors and diaries; 2) to determine the role of OT in these responses; and 3) to conduct a supervised pilot study, using fMRI to determine whether prenatal cocaine use is related to differential activation of brain regions of interest involved in maternal attachment and reward, and to relate these responses to OT levels. Findings from this MRSDA will be used as the basis of an R01 application in Years 04-05 of the award. The proposed research, acquisition of new skills, and expanded interdisciplinary scope will promote the Candidate's long-term goal of building an independent research career examining the biological basis of human social attachments and their alteration by drugs of abuse. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This K01 Mentored Research Scientist Development Award application proposes a 5-year program of training and research designed to promote the Candidate's growth as an independent investigator, and to facilitate a shift of focus to a new area of translational research. This new line of inquiry is based on animal studies that identify the neuropeptide, oxytocin (OT) as essential for establishment of normal maternal behaviors in mammals, and that describe the disruptions in both OT activity and maternal behavior resulting from perinatal cocaine exposure. The short-term objective is to examine links between oxytocin, mother infant attachment and prenatal cocaine use in humans. The training goals are to provide the Candidate with new knowledge and measurement skills in: 1) the development of human mother-infant attachment, and aberrations associated with prenatal cocaine, 2) the neurobiology of cocaine addiction and perinatal abuse with a focus on dysregulation of OT activity, 3) training in the design and implementation of studies utilizing functional magnetic resonance imaging (fMRI) to identify maternal brain circuitry involved in reward, attachment, and responses to infant cues. This training will complement the Candidate's strong background in cardiovascular and neuroendocrine stress reactivity research, and in psychophysiological study of the role of OT in human social interactions. The specific aims of the research component are: 1) to examine, in 48 mothers of infants (12 cocaine only, 12 cocaine + smoking, 12 smoking only, 12 no drug), how prenatal exposure to cocaine and/or smoking is linked to maternal behavioral and physiological responses to structured mother-infant contact and experimental stressors in the laboratory, and to behavioral and physiological activity in the home environment using ambulatory monitors and diaries;2) to determine the role of OT in these responses;and 3) to conduct a supervised pilot study, using fMRI to determine whether prenatal cocaine use is related to differential activation of brain regions of interest involved in maternal attachment and reward, and to relate these responses to OT levels. Findings from this MRSDA will be used as the basis of an R01 application in Years 04-05 of the award. The proposed research, acquisition of new skills, and expanded interdisciplinary scope will promote the Candidate's long-term goal of building an independent research career examining the biological basis of human social attachments and their alteration by drugs of abuse.

Use of cocaine has been linked to increased risk of child abuse and neglect. Research in rats by Johns et al. (1) has shown that cocaine exposure during pregnancy decreases maternal behavior while enhancing aggression, effects linked to decreased activity of oxytocin (OT), a neuropeptide known to enhance maternal behavior and bonding. Light et al. (2) showed that mothers with prenatal exposure to cocaine tend to hold their babies less often at home, have greater stress and negative affect based on physiological and selfreport measures, and show lower OT levels before and after baby holding than mothers with no substance exposure. Thus, we hypothesize that: 1. decreased maternal OT activity, greater maternal stress and negative affect, and fewer and poorer quality mother-infant interactions are consequences of prenatal cocaine; 2. in addition to cocaine's effects on the mother, these outcomes may be related to differences in the infant's signals (cries, behavior during social interaction). The present investigation will examine these translational neurobehavioral patterns by studying 180 mother-infant dyads at 1 month postpartum, including 75 with prenatal cocaine exposure, 30 with prenatal drug exposure other than cocaine, and 75 non-exposed dyads. Infants will undergo MRI to assess maturation of brain structures. Acoustice analysis of their cry characteristics which might influence maternal response will be performed. Mothers will undergo 24-hour home monitoring of their mood, stress, and frequency of baby holding using diary data recorded 4 times per hour together with ambulatory blood pressure (BP) and heart rate (HR). Maternal plasma OT, vasopressin (VP), prolactin, stress hormones and mood ratings, along with BP and HR variability, will also be assessed during multiple lab events designed to elicit maternal biobehavioral responses: 1. mother-infant face-to-face interaction (videotaped for blinded ratings of maternal touch, co-regulation /mutuality, and emotional quality); 2. brief (8 min) mother-infant separation followed by reunion; 3. a speech stressor; 4. listening to and rating tape-recorded infant cries that vary in frequency and temporal characteristics; 5. viewing photos of babies in safe and happy vs. unhappy or dangerous contexts. Maternal ratings of positive and negative affect to these events will be examined and related to physiological responses. In a pilot feasibility component, mother and infant salivary and urinary measures (OT, VP, alpha-amylase and cortisol) will also be obtained. This research will provide insights into the effect of prenatal exposure to cocaine on the quality of the motherinfant relationship and neurobehavioral pathways influencing maternal stress, affect and behavior, which may have profound implications for the health and well-being of both mother and child.

DESCRIPTION (provided by applicant): Prenatal nicotine exposure (PNE) caused by maternal cigarette-smoking is linked to defects in auditory and visual sensory processing, behavior, memory, language, and generalized intelligence. Exposure to environmental tobacco smoke (ETS), in utero and early life is also related to neurocognitive deficits, behavioral disorders, and lower IQ measured in childhood and adolescence. The human brain undergoes massive growth, differentiation and maturation in utero and the first year of life, making it especially vulnerable to neurotoxic insult. Nicotine, a well-documented neural teratogen, crosses the placental and blood brain barriers to bind to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity and function of developing fetal and infant neural circuits. Thus PNE or ETS may have long term impact on neurochemical, neural circuitry, and behavioral development. Nicotine exposure from breast milk of smoking mothers or from breast milk of non-smoking mothers living with a smoker, may also contribute added nicotine exposure during early brain development. Quantification of infant nicotine levels from these multiple sources has been done in few studies, and fewer still have studied nicotine in association with very early brain and neurocognitive function. Methods: We propose to use auditory event-related potentials (ERP) in young infants with and without perinatal nicotine exposure, to study biological markers of neural aberration that may herald future neurocognitive deficits. We will examine sensory and higher order auditory cognitive processing in 3 groups of infants: 50 infants of mothers who smoke (PNE), 50 infants of non-smoking mothers living with a smoker (ETS), and 50 infants from smoke-free homes (CTL). We will measure biomarkers of nicotine exposure in maternal hair, urine and expired air, and in infant urine. We will use well- validated tools to estimate age-appropriate development focusing on items dependent upon auditory processing. A long term goal is to identify and refine a neurophenotype of nicotine's detrimental effects on the developing brain, in order to inform early interventions in this important at-risk population. We plan to use acquired findings to support an application for more detailed, longitudinal study.

DESCRIPTION (provided by applicant): Mothers who do not breastfeed their infants and those who wean early are at increased risk of cardiovascular disease (CVD) compared with mothers who practice exclusive or prolonged lactation. Mechanisms underlying this association remain to be determined. The long-term goal of this research is to identify biological mechanisms through which lactation reduces cardiovascular risk, thereby revealing targets for early intervention. The objective of this application is to determine the effect of lactation on vascular endothelial dysfunction, which is an early causal factor in the pathogenesis of atherogenic and hypertensive disease. The transition from pregnancy to early postpartum is characterized by marked increase in potent contributors to endothelial damage, including increased systemic and local inflammatory mediators, circulating lipids and visceral fat. The postpartum period, like the perimenopause, may therefore be a critical period of enhanced risk for inflammatory damage to vascular endothelium. The central hypothesis is that lactation reduces cardiovascular risk through its salutary effects on endothelial function during the critica 1st year postpartum. This hypothesis is based on preliminary data collected in the applicant's laboratory and is further supported by published literature. The rationale for the proposed research is that determining mechanisms through which lactation reduces endothelial dysfunction will identify new therapeutic targets for reduction of CVD risk among parous women. This hypothesis will be tested using three specific aims: 1) Determine the effect of lactation on endothelial function, indexed by brachial artery flow-mediated dilation (FMD) assessed at 2, 6 and 12 months postpartum; 2) Quantify the effect of lactation on systemic and vascular inflammatory mediators that contribute to endothelial dysfunction; 3) Measure the effect of lactation on metabolic risk factors that impair endothelial function. These aims will be achieved through a longitudinal study of 120 primiparous women recruited in the third trimester of pregnancy, with oversampling of low SES, overweight, and African-American women, who are at increased risk for future CVD. Infant feeding intention will be assessed at 3rd trimester. Pro-inflammatory and metabolic biomarkers will be assessed at 3rd trimester, and at 2, 6 and 12 months postpartum. Acute endothelial effects of breast- or bottle-feeding will be measured by FMD assessed before and after infant feeding at 2 months postpartum. FMD % change during the first year will be used to test the cumulative effects of feeding method and lactation characteristics (duration, intensity, lactation hormones) on endothelial function. The approach is innovative because no studies to date have examined effects of lactation on endothelial function, inflammation and metabolism during the first postpartum year, when vascular endothelium may be most susceptible to injury, and when acute effects of lactation may be observed. The proposed research is significant because it is expected to advance understanding of early mechanisms of CVD, the #1 cause of death for women in the U.S, and has potential for widespread positive impact on women's health.

DESCRIPTION (provided by applicant): 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.

? DESCRIPTION (provided by applicant): Prenatal cocaine exposure (PCE) is related to cognitive and behavioral deficits in infancy, childhood and adolescence, however findings are diverse and inconsistent across studies, and the postnatal environment plays a powerful role in such developmental outcomes. MRI studies in childhood and adolescence report similarly inconsistent effects of PCE on brain structure, activation and links to behavior. Although gestational exposure occurs during a time of extraordinary brain growth and organization, and the months following birth are marked by massive expansion of brain structure and connectivity, little is known about the effects of PCE on early human brain development that may contribute to reported deficits in cognitive function. The long term goal is to understand prenatal effects of cocaine exposure on early development of brain structure and function, and to discern how postnatal factors may protect or further harm growth and connectivity of structures underlying nascent cognitive abilities. The objectives of this proposal are to quantify the effects of PCE on the developmental trajectory of infant brain structure in postnatal months 1-9, to determine the extent to which gray and white matter (GM, WM) growth trajectories contribute to the effects of PCE on early cognitive function, and to identify maternal factors that moderate these effects. The central hypothesis is that fetal brain development is impaired by PCE; deficits in GM and WM growth and connectivity mediate the effect of PCE on simultaneously developing early cognitive skills; and postnatal maternal behaviors interact with PCE to influence growth of brain structure and function. This hypothesis is based on the applicant's strong preliminary data showing reduced cortical prefrontal and frontal GM volume and connectivity in cocaine-exposed neonates compared with drug-free infants and infants exposed to other drugs (nicotine, marijuana, alcohol, opiates), and inverse association between prefrontal GM volume and duration of gestational cocaine exposure. The rationale for this research is that longitudinal study will determine whether the postnatal trajectory of brain growth is merely delayed or permanently altered by PCE, ascertain postnatal factors that contribute to greater risk or resilience in developing brain, and suggest new mechanisms and targets for earlier intervention. The hypothesis will be tested with three Specific Aims: 1) Determine effects of PCE on developmental trajectories of infant brain structure; 2) Determine the extent to which the effects of PCE on early cognitive functions are predicted by GM and WM developmental trajectories; 3) Determine the moderating effects of maternal behavior on brain development. The approach is innovative because it will integrate maternal behavioral and physiological responses to infant with neonatal brain imaging proximal to in utero exposure, in order to quantify the direct and interactive effects of initial neural deficit and postnatal environment on subsequent patterns of brain and cognitive development. The proposed research is significant because knowledge gleaned has potential to inform earlier interventions to prevent or reduce cognitive disabilities i this vulnerable population.

ABSTRACT 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.

PROJECT SUMMARY Despite efforts of prevention and education programs, licit and illicit drug use among pregnant women remains prevalent1. Most drugs of abuse easily cross the placenta and can alter the intricate balance among fetal neurotransmitters and receptors, which critically dictate in utero development of the brain's functional wiring system2-5. Therefore prenatal drug exposures (PDE) have long-lasting implications for brain and behavioral development since a small perturbation to the immature brain circuits may cascade into substantial deviations during long-term growth6. Existing behavioral studies provide converging evidence on the detrimental effects of PDE throughout development 1,6,7 but mechanistic studies of the brain basis of PDE remains scarce, especially during the infancy period. Nevertheless, studying the brain mechanisms of PDE during infancy is critical and urgently needed given that: 1) the infancy period immediately follows PDE insults and features the most dynamic postnatal brain development; 2) the infancy period is least confounded by postnatal environmental adversities that frequently accompany PDE; 3) identification of brain alterations associated with PDE during this stage has the best potential to guide early preventive intervention before behavioral problems onset. Our previous results8,9 demonstrated significant and widespread functional connectivity alterations in neonates prenatally exposed to cocaine and marijuana, respectively. However, three major areas need to be better delineated: 1) an overall picture of PDE effects on whole brain functional organization is lacking; 2) a more systematic delineation of the potential differential drug effects and their interactions is needed given the multi- drug exposure for most of the drug-abusing mothers; 3) the prediction power of detected neonatal functional alterations for later behavioral outcomes remains to be determined. Our long-term goal is to derive early functional-connectivity-based brain biomarkers for different PDEs that will reliably predict long-term behavioral outcomes. Our goal in this project is to derive neonate-based functional connectivity signatures for different PDEs and test their prediction power for 3-month behavioral outcomes. This project is significant because it is expected to be the first to identify drug-specific neurophenotypes for different PDEs on early brain functional and behavioral development, prior to the damaging postnatal influences that may accompany parental drug abuse. It is innovative because: 1) It will integrate resting-state brain functional connectivity and cognitive and behavioral function to quantify the potential drug-specific and drug-common effects on brain and behavior development in neonates; 2) It will apply detailed multi-level whole brain survey to discern differential drug-effect profiles and leverage advanced machine learning algorithms to better characterize their link with later behavioral outcomes. It is relevant to public health because it will provide currently unavailable knowledge of PDE effects on developing brain functional networks in neonates and inform earlier interventions that are documented to be most effective before symptom onset.

ABSTRACT 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.

PROJECT SUMMARY/ABSTRACT Brain development occurs at a rapid pace prenatally and throughout childhood, impacted by dynamic genetic and environmental influences. Studies using advanced neuroimaging have provided significant insights into brain development but have been limited by small sample size, especially for high-risk populations. Substance- exposed infants are at particularly high risk for adverse outcomes; however, findings are inconsistent, making it difficult to disentangle prenatal exposure effects from other adverse influences. The objectives of our HEALthy Brain and Child Development (HBCD) Prenatal Experiences and Longitudinal Development (PRELUDE) consortium are to characterize typical trajectories of brain development from birth through childhood, measuring the influence of key biologic and environmental factors and their interactions on child social, cognitive, and emotional development. We will assess how children prenatally exposed to opioids and other substances, as well as environmental adversity, differ in those brain trajectories and outcomes. Our consortium consists of six centers (Arkansas Children?s Research Institute, Case Western Reserve University, Cincinnati Children?s Hospital, Children?s National Medical Center, University of North Carolina at Chapel Hill, and Vanderbilt University) which have collaborated previously and have complementary expertise in neuroimaging, neurophysiology, longitudinal clinical research, child development, substance exposure and addiction, ethical/legal issues, and clinical care of high-risk infants/children. The PRELUDE consortium will recruit 680 pregnant women with substance use, 680 at-risk pregnant women without substance use, and 1360 comparison pregnant women representative of the general population to contribute to the overall HBCD study. We will work closely with the other sites, the HBCD Consortium Administrative Core, and the HBCD Data Coordinating Center to develop a comprehensive study protocol and ensure compliance of study workflow and data transfer. Our consortium has an optimized research protocol and 4 specific aims: 1) Employ ethical and evidence-based best practices to enroll and retain a diverse cohort of pregnant women into a longitudinal study of infant/child brain development, oversampling mothers from high-risk backgrounds and those using substances during pregnancy; 2) Engage a comprehensive array of maternal- and child-oriented community stakeholders to identify community concerns and priorities regarding this research, minimize risks, and promote long-term engagement of the recruited child-mother dyads; 3) Collect rich data to examine how maternal health context and broader environmental factors may affect the maternal-fetal dyad and neurodevelopment of children; 4) Capture key developmental windows during which maternal and environmental factors may interact with brain and behavioral development of children. The insights from these data will provide greater understanding of factors affecting early childhood brain development, allowing targeted interventions and improved outcomes for mother-child dyads.