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1.  Risk for Neurobehavioral Disinhibition in Prenatal Methamphetamine-Exposed Young Children with Positive Hair Toxicology Results 
Therapeutic drug monitoring  2014;36(4):535-543.
The objective was to evaluate effects of prenatal methamphetamine exposure (PME) and postnatal drug exposures identified by child hair analysis on neurobehavioral disinhibition at 6.5 years of age.
Mother-infant pairs were enrolled in the Infant Development, Environment, and Lifestyle (IDEAL) Study in Los Angeles, Honolulu, Tulsa and Des Moines. PME was determined by maternal self-report and/or positive meconium results. At the 6.5-year follow-up visit, hair was collected and analyzed for methamphetamine, tobacco, cocaine, and cannabinoid markers. Child behavioral and executive function test scores were aggregated to evaluate child neurobehavioral disinhibition. Hierarchical linear regression models assessed the impact of PME, postnatal substances, and combined PME with postnatal drug exposures on the child’s neurobehavioral disinhibition aggregate score. Past year caregiver substance use was compared to child hair results.
A total of 264 children were evaluated. Significantly more PME children (n=133) had hair positive for methamphetamine/amphetamine (27.1% versus 8.4%) and nicotine/cotinine (38.3% versus 25.2%) than children without PME (n=131). Overall, no significant differences in analyte hair concentrations were noted between groups. Significant differences in behavioral and executive function were observed between children with and without PME. No independent effects of postnatal methamphetamine or tobacco exposure, identified by positive hair test, were noted and no additional neurobehavioral disinhibition was observed in PME children with postnatal drug exposures, as compared to PME children without postnatal exposure.
Child hair testing offered a non-invasive means to evaluate postnatal environmental drug exposure, although no effects from postnatal drug exposure alone were seen. PME, alone and in combination with postnatal drug exposures, was associated with behavioral and executive function deficits at 6.5 years.
PMCID: PMC4101149  PMID: 24518561
methamphetamine; hair; children; prenatal drug exposure; toxicology
2.  Physiological Correlates of Neurobehavioral Disinhibition that Relate to Drug Use and Risky Sexual Behavior in Adolescents with Prenatal Substance Exposure 
Developmental neuroscience  2014;36(0):306-315.
Physiological correlates of behavioral and emotional problems, substance use onset and initiation of risky sexual behavior have not been studied in adolescents with prenatal drug exposure. We studied the concordance between baseline respiratory sinus arrhythmia (RSA) at age 3 and baseline Cortisol levels at age 11. We hypothesized that children who showed concordance between RSA and Cortisol would have lower neurobehavioral disinhibition scores which would in turn predict age of substance use onset and first sexual intercourse. The sample included 860 children aged 16 years participating in the Maternal Lifestyle Study, a multisite longitudinal study of children with prenatal exposure to cocaine and other substances. Structural equation modeling was used to test pathways between prenatal substance exposure, early adversity, baseline RSA, baseline Cortisol, neurobehavioral disinhibition, drug use, and sexual behavior outcomes. Concordance was studied by examining separate male and female models in which there were statistically significant interactions between baseline RSA and Cortisol. Prenatal substance exposure was operationalized as the number of substances to which the child was exposed. An adversity score was computed based on caregiver postnatal substance use, depression and psychological distress, number of caregiver changes, socioeconomic and poverty status, quality of the home environment, and child history of protective service involvement, abuse and neglect. RSA and Cortisol were measured during a baseline period prior to the beginning of a task. Neurobehavioral disinhibition, based on composite scores of behavioral dysregulation and executive dysfunction, substance use and sexual behavior were derived from questionnaires and cognitive tests administered to the child. Findings were sex specific. In females, those with discordance between RSA and Cortisol (high RSA and low Cortisol or low RSA and high Cortisol) had the most executive dysfunction which, in turn, predicted earlier initiation of alcohol by age 16. Among boys, there also existed a significant baseline RSA by baseline Cortisol interaction. Boys with low baseline RSA and high baseline Cortisol had the highest levels of behavioral dysregulation. This increase in behavioral dysregulation was in turn related to initiation of alcohol use by age 16 and lower age of first sexual intercourse. We found sex-specific pathways to the initiation of alcohol use and risky sexual behavior through the combined activity of parasympathetic and neuroendocrine functioning. The study of multiple physiological systems may suggest new pathways to the study of age of onset of substance use and engagement in risky sexual behavior in adolescents.
PMCID: PMC4476628  PMID: 25033835
Cortisol; Heart rate variability; Adversity; Sex differences; Teenage substance use onset; Behavioral problems; Executive function
3.  Structural Brain Imaging in Children and Adolescents Following Prenatal Cocaine Exposure 
Developmental neuroscience  2014;36(0):316-328.
Brain morphometry of 21 children, who were followed from birth and underwent structural brain magnetic resonance imaging (MRI) at 8–10 years, were studied. This cohort included 11 children with prenatal cocaine exposure (CE) and 10 non-cocaine exposed children (NCE). We compared the CE versus NCE groups using FreeSurfer to automatically segment and quantify the volume of individual brain structures. In addition, we created a pediatric atlas specifically for this population and demonstrate the enhanced accuracy of this approach. We found an overall trend towards smaller brain volumes among CE children. The volume differences were significant for cortical gray matter, thalamus and putamen. Here, reductions in thalamic and putaminal volumes showed a robust inverse-correlation with exposure levels, thus highlighting effects on dopamine rich brain regions that form key components of brain circuitry known to play important roles in behavior and attention. Interestingly, head circumferences (HCs) at birth as well as at the time of imaging showed a tendency for smaller size among CE children. HCs at the time of imaging correlated well with the cortical volumes, for all subjects. In contrast, HCs at birth were predictive of the cortical volume only for the CE group.
A subgroup of these subjects (6 CE and 4 NCE) was also scanned at 13–15 years old. In subjects who were scanned twice, we found that the trend for smaller structures continues into 13–15 years of age. We found that the differences in structural volumes between CE and NCE groups are largely diminished when the HCs are matched by study design or controlled for. Participants in this study were drawn from a unique longitudinal cohort, and while the small sample size precludes strong conclusions, the results point to reductions in HCs and in specific brain structures that persist through teenage years in children who were exposed to cocaine in utero.
PMCID: PMC4125447  PMID: 24994509
structural brain imaging; prenatal cocaine exposure; Developing brain; Magnetic resonance imaging; Prenatal cocaine
4.  Placental DNA Methylation Related to Both Infant Toenail Mercury and Adverse Neurobehavioral Outcomes 
Environmental Health Perspectives  2015;123(7):723-729.
Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. Because Hg can interfere with placental functioning and cross the placenta to target the fetal brain, prenatal Hg exposure can inhibit fetal growth and development directly and indirectly.
We examined potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes.
The methylation status of > 485,000 CpG loci was interrogated in 192 placental samples using Illumina’s Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU Network Neurobehavioral Scales (NNNS) in an independent subset of 151 infants.
We identified 339 loci with an average methylation difference > 0.125 between any two toenail Hg tertiles. Variation among these loci was subsequently found to be associated with a high-risk neurodevelopmental profile (omnibus p-value = 0.007) characterized by the NNNS. Ten loci had p < 0.01 for the association between methylation and the high-risk NNNS profile. Six of 10 loci reside in the EMID2 gene and were hypomethylated in the 16 high-risk profile infants’ placentas. Methylation at these loci was moderately correlated (correlation coefficients range, –0.33 to –0.45) with EMID2 expression.
EMID2 hypomethylation may represent a novel mechanism linking in utero Hg exposure and adverse infant neurobehavioral outcomes.
Maccani JZ, Koestler DC, Lester B, Houseman EA, Armstrong DA, Kelsey KT, Marsit CJ. 2015. Placental DNA methylation related to both infant toenail mercury and adverse neurobehavioral outcomes. Environ Health Perspect 123:723–729;
PMCID: PMC4492267  PMID: 25748564
5.  Regional Brain Morphometry and Impulsivity in Adolescents Following Prenatal Exposure to Cocaine and Tobacco 
JAMA pediatrics  2013;167(4):348-354.
Animal studies have suggested that prenatal cocaine exposure (PCE) deleteriously influences the developing nervous system, in part attributable to its site of action in blocking the function of monoamine reuptake transporters, increasing synaptic levels of serotonin and dopamine.
To examine the brain morphologic features and associated impulsive behaviors in adolescents following prenatal exposure to cocaine and/or tobacco.
Magnetic resonance imaging data and behavioral measures were collected from adolescents followed up longitudinally in the Maternal Lifestyle Study.
A hospital-based research center.
A total of 40 adolescent participants aged 13 to 15 years were recruited, 20 without PCE and 20 with PCE; a subset of each group additionally had tobacco exposure. Participants were selected and matched based on head circumference at birth, gestational age, maternal alcohol use, age, sex, race/ethnicity, IQ, family poverty, and socioeconomic status.
Main Outcome Measures
Subcortical volumetric measures of the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens; cortical thickness measures of the dorsolateral prefrontal cortex and ventral medial prefrontal cortex; and impulsivity assessed by Conners' Continuous Performance Test and the Sensation Seeking Scale for Children.
After controlling for covariates, cortical thickness of the right dorsolateral prefrontal cortex was significantly thinner in adolescents following PCE (P=.03), whereas the pallidum volume was smaller in adolescents following prenatal tobacco exposure (P=.03). Impulsivity was correlated with thalamic volume following either PCE (P=.05) or prenatal tobacco exposure (P=.04).
Conclusions and Relevance
Prenatal cocaine or tobacco exposure can differentially affect structural brain maturation during adolescence and underlie enhanced susceptibility to impulsivity. Additional studies with larger sample sizes are warranted.
PMCID: PMC4467165  PMID: 23400239
6.  Children of Addicted Women 
Journal of addictive diseases  2010;29(2):259-276.
The purpose of this article was to review follow up studies of children with prenatal drug exposure from preschool through adolescence. Specifically, the authors focus on the effects of prenatal exposure to cocaine, methamphetamine, and opiates on behavior and development. The largest number of studies have examined cocaine-exposed children. The authors identified 42 studies that suggest that there are unique effects of prenatal cocaine exposure on 4- to 13-year-old children, particularly in the areas of behavior problems, attention, language, and cognition. In addition, studies make reasonable attempts to control for possible confounding factors. Systematic research on the long-term effects of prenatal methamphetamine exposure is just beginning but seems to be showing similar effects to that of cocaine. The literature on the on the long-term effects of children with prenatal opiate exposure is more substantial than the methamphetamine literature but it is still relatively sparse and surprising in that there is little recent work. Thus, there are no studies on the current concerns with opiates used for prescription mediation. There is a growing literature using neuroimaging techniques to study the effects of prenatal drug exposure that holds promise for understanding brain/behavior relationships. In addition to pharmacological and teratogenic effects, drugs can also be viewed from a prenatal stressor model. The author discuss this “fetal origins” approach that involves fetal programming and the neuroendocrine system and the potential implications for adolescent brain and behavioral development.
PMCID: PMC4451952  PMID: 20407981
Prenatal drug exposure; follow-up; fetal origins
The Journal of pediatrics  2014;164(6):1333-1338.
To examine child behavioral and cognitive outcomes after prenatal exposure to methamphetamine.
Study design
412 mother-infant pairs (204 methamphetamine-exposed and 208 unexposed matched comparisons) were enrolled in the Infant Development, Environment and Lifestyle (IDEAL) study. The 151 children exposed to methamphetamine and 147 comparisons who attended the 7.5 year visit were included. Exposure was determined by maternal self-report and/or positive meconium toxicology. Maternal interviews assessed behavioral and cognitive outcomes using the Conner’s Parent Rating Scale – Revised: Short Form (CPRS-R:S).
After adjusting for covariates, children exposed to methamphetamine had significantly higher cognitive problems subscale scores than comparisons and were 2.8 times more likely to have cognitive problems scores that were above average on the CPRS-R:S No association between prenatal methamphetamine exposure and behavioral problems, measured by the oppositional, hyperactivity and ADHD Index subscales, were found.
Prenatal methamphetamine exposure was associated with increased cognitive problems which may impact academic achievement and lead to increased negative behavioral outcomes.
PMCID: PMC4035384  PMID: 24630350
amphetamine; ADHD; Conner’s
8.  The contributions of early adverse experiences and trajectories of respiratory sinus arrhythmia on the development of neurobehavioral disinhibition among children with prenatal substance exposure 
Development and psychopathology  2014;26(4 0 1):901-916.
Neurobehavioral disinhibition (ND) is a complex condition reflecting a wide range of problems involving difficulties with emotion regulation and behavior control. Respiratory sinus arrhythmia (RSA) is a physiological correlate of emotion regulation that has been studied in a variety of at-risk populations; however, there are no studies of RSA in children with ND. Data were drawn from a prospective longitudinal study of prenatal substance exposure that included 1,073 participants. Baseline RSA and RSA reactivity to an attention-demanding task were assessed at 3, 4, 5, and 6 years. ND was assessed at ages 8/9, 11, and 13/14 years via behavioral dysregulation and executive dysfunction composite measures. Greater exposure to early adversity was related to less RSA reactivity at 3 years, increases in RSA reactivity from ages 3 to 6 years, and increased behavioral dysregulation from ages 8/9 to 13/14. RSA reactivity was examined as a moderator of the association between early adversity and changes in ND. A significant Early Adversity × RSA Reactivity quadratic interaction revealed that children with decelerations in RSA reactivity exhibited increases in behavioral dysregulation, regardless of their exposure to early adversity. However, greater exposure to early adversity was related to greater increases in behavioral dysregulation, but only if children exhibited accelerations in RSA reactivity from ages 3 to 6 years. The results contribute to our understanding of how interactions across multiple levels of analysis contribute to the development of ND.
PMCID: PMC4447302  PMID: 24909973
9.  Reactivity and Regulation of Motor Responses in Cocaine-Exposed Infants 
Effects of prenatal exposure to cocaine on the reactivity and regulation of the motor system of 825 four-month-old infants enrolled in the Maternal Lifestyle Study were examined. Videotaped assessments of 338 cocaine-exposed (CE) infants and 487 non-exposed comparison infants were coded by examiners masked to exposure status. Exposure status was determined by meconium assay and maternal self-report of prenatal cocaine use. Infants were presented with a series of 17 visual, auditory and tactile stimuli for 30-second each. Intensity and latency of limb movement responses on a subset of items were analyzed to test the following hypotheses: CE infants are more active in general; CE infants exhibit increased movement levels for a larger proportion of time in response to stimulation; the motor systems of CE infants are more reactive to stimulation (e.g., shorter latencies to respond); and CE infants are poorer regulators of the motor system. Results CE infants were not more active in general and data do not indicate a more highly reactive motor system. However, CE infants exhibited increased movement levels for a larger proportion of time in response to stimulation. Additional analysis of movement exhibited during three tactile items found increased movement lability in CE infants and different patterns of responding, suggesting that the effects of prenatal cocaine exposure on the motor system may vary by context. Covariate effects for tobacco, alcohol, and marijuana are also reported.
PMCID: PMC4337232  PMID: 24583252
cocaine; prenatal exposure; motor activity; reactivity; regulation
10.  Are epigenetic changes in the intrauterine environment related to newborn neurobehavior? 
Epigenomics  2014;6(2):175-178.
PMCID: PMC4407197  PMID: 24811786
human behavioral epigenetics; intrauterine environment; NNNS; newborn neurobehavior; placenta
11.  Prenatal methamphetamine exposure and neurodevelopmental outcomes in children from 1 to 3 years 
Despite the evidence that women world-wide are using methamphetamine (MA) during pregnancy little is known about the neurodevelopment of their children.
The controlled, prospective longitudinal New Zealand (NZ) Infant Development, Environment and Lifestyle (IDEAL) study was carried out in Auckland, NZ. Participants were 103 children exposed to MA prenatally and 107 not exposed. The Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development, Second Edition (BSID-II) measured cognitive and motor performance at ages 1, 2 and 3, and the Peabody Developmental Motor Scale, Second Edition (PDMS-II) measured gross and fine motor performance at 1 and 3. Measures of the child’s environment included the Home Observation of Measurement of the Environment and the Maternal Lifestyle Interview. The Substance Use Inventory measured maternal drug use.
After controlling for other drug use and contextual factors, prenatal MA exposure was associated with poorer motor performance at 1 and 2 years on the BSID-II. No differences were observed for cognitive development (MDI). Relative to non-MA exposed children, longitudinal scores on the PDI and the gross motor scale of the PDMS-2 were 4.3 and 3.2 points lower, respectively. Being male and of Maori descent predicted lower cognitive scores (MDI) and being male predicted lower fine motor scores (PDMS-2)
Prenatal exposure to MA was associated with delayed gross motor development over the first 3 years, but not cognitive development. However, being male and of Maori descent were both associated with poorer cognitive outcomes. Males in general did more poorly on tasks related to fine motor development.
PMCID: PMC3997367  PMID: 24566524
Prenatal exposure; Methamphetamine; Neurodevelopment; Longitudinal
12.  Neonatal Neurobehavior Effects following Buprenorphine versus Methadone Exposure 
Addiction (Abingdon, England)  2012;107(0 1):63-73.
To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior.
Three sites from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial participated in this sub-study.
Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore, MD, Providence, RI, and Vienna, Austria.
39 full-term infants.
The NICU Network Neurobehavioral Scale (NNNS) was administered to a subgroup of infants on postpartum days 3, 5, 7, 10, 14-15 and 28-30.
While neurobehavior improved for both medication conditions over time, infants exposed in utero to buprenorphine exhibited fewer Stress-Abstinence signs (P<0.001), were less Excitable (P<0.001) and less Over-Aroused (P<0.01), exhibited less Hypertonia (P<0.007), and had better Self-Regulation (P<0.04) and required less Handling (P<0.001) to maintain a quiet alert state relative to in utero methadone-exposed infants. Infants who were older when they began morphine treatment for withdrawal had higher Self-Regulation scores (P<0.01), and demonstrated the least amount of Excitability (P<0.02) and Hypertonia (P<0.02) on average. Quality of Movement was negatively correlated with peak NAS score (P<0.01), number of days treated with morphine for NAS (P<0.01) and total amount of morphine received (P<0.03). Excitability scores were positively related to total morphine dose (P<0.03).
While neurobehavior improves during the first month of postnatal life for in utero agonist-medication-exposed neonates, buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure.
PMCID: PMC4337995  PMID: 23106928
neonatal abstinence syndrome; NICU Network Neurobehavioral Scale (NNNS); neurobehavior
13.  Prenatal Methamphetamine Exposure and Neonatal and Infant Neurobehavioral Outcome: Results from the IDEAL Study 
Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. How MA use during pregnancy affects neonatal and infant neurobehavior is unknown.
The Infant Development, Environment, and Lifestyle (IDEAL) study screened 34,833 subjects at 4 clinical centers. 17,961 were eligible and 3,705 were consented, among which 412 were enrolled for longitudinal follow-up. Exposed subjects were identified by self-report and/or GC/MS confirmation of amphetamine and metabolites in meconium. Comparison subjects were matched (race, birth weight, maternal education, insurance), denied amphetamine use and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, or phencyclidine. The NICU Network Neurobehavioral Scale (NNNS) was administered within the first 5 days of life and again at one month to 380 enrollees (185 exposed, 195 comparison). ANOVA tested exposure effects on NNNS summary scores at birth and one month. GLM repeated measures analysis assessed the effect of MA exposure over time on the NNNS scores with and without covariates.
By one month of age, both groups demonstrated higher quality of movement (P=.029), less lethargy (P=.001), and fewer asymmetric reflexes (P=.012), with no significant differences in NNNS scores between the exposed and comparison groups. Over the first month of life, arousal increased in exposed infants but decreased in comparison infants (p=.031) and total stress was decreased in exposed infants with no change in comparison infants (p=.026).
Improvement in total stress and arousal were observed in MA-exposed newborns by one month of age relative to the newborn period.
PMCID: PMC3942806  PMID: 24588296
14.  Prenatal predictors of infant self-regulation: the contributions of placental DNA methylation of NR3C1 and neuroendocrine activity 
We examined whether placental DNA methylation of the glucocorticoid receptor gene, NR3C1 was associated with self-regulation and neuroendocrine responses to a social stressor in infancy. Placenta samples were obtained at birth and mothers and their infants (n = 128) participated in the still-face paradigm when infants were 5 months old. Infant self-regulation following the still-face episode was coded and pre-stress cortisol and cortisol reactivity was assessed in response to the still-face paradigm. A factor analysis of NR3C1 CpG sites revealed two factors: one for CpG sites 1–4 and the other for sites 5–13. DNA methylation of the factor comprising NR3C1 CpG sites 5–13 was related to greater cortisol reactivity and infant self-regulation, but cortisol reactivity was not associated with infant self-regulation. The results reveal that prenatal epigenetic processes may explain part of the development of infant self-regulation.
PMCID: PMC4448036  PMID: 26074794
DNA methylation; prenatal origins; glucocorticoid receptor gene; self-regulation; infancy
15.  Emotional Expression and Heart Rate in High-Risk Infants during the Face-To-Face/Still-Face 
Infant behavior & development  2013;36(4):10.1016/j.infbeh.2012.11.009.
In infants, eye constriction—the Duchenne marker—and mouth opening appear to index the intensity of both positive and negative facial expressions. We combined eye constriction and mouth opening that co-occurred with smiles and cry-faces (respectively, the prototypic expressions of infant joy and distress) to measure emotional expression intensity. Expression intensity and heart rate were measured throughout the Face-to-Face/Still Face (FFSF) in a sample of infants with prenatal cocaine exposure who were at risk for developmental difficulties. Smiles declined and cry-faces increased in the still-face episode, but the distribution of eye constriction and mouth opening in smiles and cry-faces did not differ across episodes of the FFSF. As time elapsed in the still face episode potential indices of intensity increased, cry-faces were more likely to be accompanied by eye constriction and mouth opening. During cry-faces there were also moderately stable individual differences in the quantity of eye constriction and mouth opening. Infant heart rate was higher during cry-faces and lower during smiles, but did not vary with intensity of expression or by episode. In sum, infants express more intense negative affect as the still-face progresses, but do not show clear differences in expressive intensity between episodes of the FFSF.
PMCID: PMC3874324  PMID: 24095807
Facial Expression; Affect; Heart Rate; Prenatal Cocaine Exposure; Still-Face; Facial Action Coding System
16.  The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior 
Epigenetics  2013;8(12):1321-1329.
Exposure to maternal mood disorder in utero may program infant neurobehavior via DNA methylation of the glucocorticoid receptor (NR3C1) and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), two placental genes that have been implicated in perturbations of the hypothalamic pituitary adrenocortical (HPA) axis. We tested the relations among prenatal exposure to maternal depression or anxiety, methylation of exon 1F of NR3C1 and 11β-HSD-2, and newborn neurobehavior. Controlling for relevant covariates, infants whose mothers reported depression during pregnancy and showed greater methylation of placental NR3C1 CpG2 had poorer self-regulation, more hypotonia, and more lethargy than infants whose mothers did not report depression. On the other hand, infants whose mothers reported anxiety during pregnancy and showed greater methylation of placental 11β-HSD-2 CpG4 were more hypotonic compared with infants of mothers who did not report anxiety during pregnancy. Our results support the fetal programming hypothesis and suggest that fetal adjustments to cues from the intrauterine environment, in this case an environment that could be characterized by increased exposure to maternal cortisol, may lead to poor neurodevelopmental outcomes.
PMCID: PMC3933492  PMID: 24135662
DNA methylation; maternal depression; maternal anxiety; newborn neurobehavior
17.  Genetic and Epigenetic Variation of the Glucocorticoid Receptor (NR3C1) in Placenta and Infant Neurobehavior 
Developmental psychobiology  2012;55(7):673-683.
The intrauterine environment can impact the developing infant by altering the function of the placenta through changes to the epigenetic regulatory features of this tissue. Genetic variation, too, may impact infant development or may modify the relationship between epigenetic alterations and infant outcomes. To examine the association of this variation with early life infant neurodevelopment, we examined the extent of DNA methylation of the glucocorticoid receptor gene (NR3C1) promoter and a common SNP in the promoter region in a series of 186 placentas from healthy newborn infants. We associated these molecular features with specific summary measures from the NICU Network Neurobehavioral Scales. After controlling for genotype and confounders, we identified significant associations of NR3C1 methylation with infant quality of movement (P=0.05) and with infant attention (P=0.05), and a potential interaction between methylation and genotype on infant attention score. These results suggest that epigenetic alteration of the NR3C1 gene in the placentas of genetically susceptible infants can have impacts on neurodevelopment which may have lifelong impact on neurobehavioral and mental health outcomes. Further research is needed to more precisely define these relationships and the interaction between epigenetic alterations and genetic variations on infant health.
PMCID: PMC3458180  PMID: 22714792
Epigenetic; glucocorticoid receptor; placenta; neurodevelopment; human; attention; quality of movement
18.  Prenatal Substance Exposure: Neurobiological Organization at One Month 
The Journal of pediatrics  2013;163(4):989-994.e1.
To examine the autonomic nervous system and neurobehavioral response to a sustained visual attention challenge among 1-month old infants with prenatal substance exposure.
Study design
We measured heart rate (HR), respiratory sinus arrhythmia (RSA), and neurobehavior during sustained visual orientation tasks included in the NICU Network Neurobehavioral Scale (NNNS) in 1,129, 1-month infants with prenatal substance exposure. Four groups were compared: infants with prenatal cocaine and opiate exposure, infants with cocaine exposure, infants with opiate exposure, and infants with exposure to other substances (i.e. alcohol, marijuana, and tobacco).
Infants with prenatal cocaine and opiate exposure had the highest HRs and lowest levels of RSA during a sustained visual attention procedure compared with the other three groups. Infants with prenatal cocaine and opiate exposure had poorer quality of movement and more hypertonicity during the NNNS exam compared with the other three exposure groups. Infants with prenatal cocaine and opiate exposure had more nonoptimal reflexes and stress/abstinence signs compared with infants with prenatal cocaine exposure only and infants with prenatal exposure to alcohol, tobacco, and marijuana.
Problems with arousal regulation were identified among infants with prenatal substance exposure. Autonomic dysregulation has been implicated as a mechanism by which these difficulties occur. Our results suggest that infants with both prenatal cocaine and opiate exposure have the greatest autonomic response to the challenge of a sustained visual attention task, which may place these infants at risk for developing problems associated with physiological and behavioral regulation, a necessary prerequisite for early learning.
PMCID: PMC3773295  PMID: 23743094
in utero drug exposure; physiology; neurobehavioral
19.  Epigenetic Basis for the Development of Depression in Children 
The growing field of epigenetics and human behavior affords an unprecedented opportunity to discover molecular underpinnings of mental health disorders and pave the way for the development of preventive intervention programs. Maternal depression during pregnancy is a serious public health issue and leads to a fourfold increase in the likelihood that the child will develop depression. We describe how mood disorders, particularly depression, may be shaped by early life stress, programming, and epigenetic processes and pathways showing how these processes could lead to depression in childhood. Implications of this approach to the study of mental health disorders for preventive interventions are discussed.
PMCID: PMC3780987  PMID: 23751878
maternal depression; childhood depression; programming; epigenetics; stress; developmental origins
20.  Examining the Relationships Between Prenatal Methamphetamine Exposure, Early Adversity, and Child Neurobehavioral Disinhibition 
Methamphetamine use is a growing problem among pregnant women in the United States. Many negative consequences of methamphetamine use have been documented for the users, but little research has examined the long-term association between prenatal methamphetamine exposure (PME) and childhood outcomes. The current study examined the extent to which PME was predictive of childhood neurobehavioral disinhibition (ND), as well as the extent to which early adversity mediated this relationship. A sample of 320 mother–infant dyads (162 PME) was followed from birth through 6.5 years of age. ND was conceptualized as a two factor model consisting of deficits in (a) behavioral and emotional control, and (b) executive function. PME was associated with behavioral and emotional control at 5 years, which was associated with executive function deficits at 6.5 years. Early adversity (birth through year 3) significantly mediated the relationship between PME and ND. Associations with previous research and implications for prevention are discussed.
PMCID: PMC3842232  PMID: 23067308
methamphetamine; prenatal; adversity; disinhibition
21.  Prenatal Cocaine Exposure and Motor Performance at 4 Months 
The relation between prenatal cocaine exposure and quality of movement was studied at 4 mo using the Posture and Fine Motor Assessment of Infants (PFMAI–I).
Posture and fine motor scores of 4-month-old infants exposed to cocaine in utero (n = 370) were compared with an unexposed group (n = 533) within the context of gestational age, medical and demographic characteristics, and level of prenatal substance exposure using the PFMAI–I.
Infants prenatally exposed to cocaine had significantly lower posture scores than infants in the unexposed group. There was no main effect of cocaine exposure on fine motor scores; however, there were independent effects of gestational age at birth on both posture and fine motor scores at 4-mo corrected age.
These findings demonstrate independent contributions of prenatal cocaine exposure and prematurity to risk of motor delay and support the validity of the PFMAI–I as a measure of motor competence in early infancy.
PMCID: PMC4144172  PMID: 25170184
child development; cocaine-related disorders; motor skills; posture; prenatal exposure delayed effects
22.  Risk-Taking Behavior among Adolescents with Prenatal Drug Exposure and Extrauterine Environmental Adversity 
High-risk environments characterized by familial substance use, poverty, inadequate parental monitoring, and violence exposure are associated with an increased propensity for adolescents to engage in risk-taking behaviors (e.g., substance use, sexual behavior, and delinquency). However, additional factors such as drug exposure in utero and deficits in inhibitory control among drug-exposed youth may further influence the likelihood that adolescents in high-risk environments will engage in risk-taking behavior. This study examined the influence of prenatal substance exposure, inhibitory control, and sociodemographic/environmental risk factors on risk-taking behaviors in a large cohort of adolescents with and without prenatal cocaine exposure (PCE).
Risk-taking behavior (delinquency, substance use, and sexual activity) was assessed in 963 adolescents (433 cocaine-exposed, 530 nonexposed) at 15 years of age.
PCE predicted later arrests and early onset of sexual behavior in controlled analyses. Associations were partially mediated, however, by adolescent inhibitory control problems. PCE was not associated with substance use at this age. In addition, male gender, low parental involvement, and violence exposure were associated with greater odds of engaging in risk-taking behavior across the observed domains.
Study findings substantiate concern regarding the association between prenatal substance exposure and related risk factors and the long-term outcomes of exposed youth. Access to the appropriate social, educational, and medical services are essential in preventing and intervening with risk-taking behaviors and the potential consequences (e.g., adverse health outcomes, incarceration), especially among high-risk adolescent youth and their families.
PMCID: PMC4139145  PMID: 24220515
prenatal drug exposure; cocaine; adolescence; risk-taking behavior
23.  The Role of Prenatal Substance Exposure and Early Adversity on Parasympathetic Functioning from 3 to 6 Years of Age 
Developmental psychobiology  2013;56(4):821-835.
We employed latent growth curve analysis to examine trajectories of respiratory sinus arrhythmia (RSA) from 3 to 6 years among children with varying levels of prenatal substance exposure and early adversity. Data were drawn from a prospective longitudinal study of prenatal substance exposure that included 1,121 participants. Baseline RSA and RSA reactivity to an attention-demanding task were assessed at 3, 4, 5, and 6 years. Overall, there were significant individual differences in the trajectories of RSA reactivity, but not baseline RSA, across development. Greater levels of prenatal substance exposure, and less exposure to early adversity, were associated with increased RSA reactivity at 3 years, but by 6 years, both were associated with greater RSA reactivity. Prenatal substance exposure had an indirect influence through early adversity on growth in RSA reactivity. Results are in support of and contribute to the framework of allostatic load.
PMCID: PMC4132658  PMID: 24002807
allostatic load; prenatal substance exposure; early adversity; respiratory sinus arrhythmia
24.  Placental FKBP5 Genetic and Epigenetic Variation Is Associated with Infant Neurobehavioral Outcomes in the RICHS Cohort 
PLoS ONE  2014;9(8):e104913.
Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = −0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = −0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07–4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92–4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta’s ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.
PMCID: PMC4130612  PMID: 25115650
25.  Neurobehavioral Integrity of Chimpanzee Newborns: Comparisons across groups and across species reveal gene-environment interaction effects 
Infant and child development  2010;20(1):47-93.
The aims of this article are to describe the neurobehavioral integrity of chimpanzee newborns, to investigate how early experiences affect the neurobehavioral organization of chimpanzees, and to explore species differences by comparing chimpanzee newborns to a group of typically developing human newborns. Neurobehavioral integrity related to orientation, motor performance, arousal, and state regulation of 55 chimpanzee (raised in four different settings) and 42 human newborns was measured with the Neonatal Behavioral Assessment Scale (NBAS) a semi-structured 25-minute interactive assessment. Thirty-eight chimpanzees were tested every other day from birth, and analyses revealed significant developmental changes in 19 of 27 NBAS scores. The cross-group and cross-species comparisons were conducted at 2 and 30 days of age. Among the 4 chimpanzee groups, significant differences were found in 23 of 24 NBAS scores. Surprisingly, the cross-species comparisons revealed that the human group was distinct in only 1 of 25 NBAS scores (the human group had significantly less muscle tone than all the chimpanzee groups). The human group was indistinguishable from at least one of the chimpanzee groups in the remaining 24 of 25 NBAS scores. The results of this study support the conclusion that the interplay between genes and environment, rather than genes alone or environment alone, accounts for phenotypic expressions of newborn neurobehavioral integrity in hominids.
PMCID: PMC4125135  PMID: 25110465
ape; infant; epigenesis; social cognition; early development; NBAS; Brazelton test; emotion

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