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"Lester, Barry"
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Evidence for neurobehavioral risk phenotypes at birth
Observations of newborn behavior provide clinicians and researchers with a first description of the neurobehavioral organization of the newborn that is largely independent of the postnatal environment. The Neonatal Network Neurobehavioral Scale (NNNS) was developed in 2004 to evaluate how prenatal exposure to substances such as cocaine is related to neurobehavioral outcomes. There are now 156 empirical articles published using the NNNS, which we review and summarize. Z-scores from published studies using the NNNS were compiled and aggregated supporting the replicability of three newborn neurobehavioral phenotypes: one typical and two that are predictive of later cognitive and behavioral delay; hyper- and hypo-dysregulated newborns. These phenotypes emerged from independent samples and research groups and were identified in a variety of populations, including infants with prenatal substance exposure, preterm infants, and healthy term infants. Our findings show that newborn neurobehavior can be measured in a reliable and valid manner and that certain behavioral phenotypes, identifiable at birth, can predict neurodevelopmental challenges. These findings have important clinical utility. Intervening early with infants exhibiting these risk phenotypes may prevent later neurodevelopmental delay.
Impact
We reviewed all empirical studies published using the Neonatal Network Neurobehavioral Scale and found evidence for two replicable stress phenotypes that predict later behavioral outcomes.
This study highlights the utility of the Neonatal Network Neurobehavioral Scale for early identification of newborn neurodevelopmental risk phenotypes.
Early identification of neurodevelopmental risk, when neuroplasticity is high, may ultimately reduce the burden of subsequent neurobehavioral problems through early intervention.
Journal Article
Introduction to the Special Section on Epigenetics
Epigenetics provides the opportunity to revolutionize our understanding of the role of genetics and the environment in explaining human behavior, although the use of epigenetics to study human behavior is just beginning. In this introduction, the authors present the basics of epigenetics in a way that is designed to make this exciting field accessible to a wide readership. The authors describe the history of human behavioral epigenetic research in the context of other disciplines and graphically illustrate the burgeoning of research in the application of epigenetic methods and principles to the study of human behavior. The role of epigenetics in normal embryonic development and the influence of biological and environmental factors altering behavior through epigenetic mechanisms and developmental programming are discussed. Some basic approaches to the study of epigenetics are reviewed. The authors conclude with a discussion of challenges and opportunities, including intervention, as the field of human behavioral epigenetics continue to grow.
Journal Article
Patterning in Placental 11-B Hydroxysteroid Dehydrogenase Methylation According to Prenatal Socioeconomic Adversity
Prenatal socioeconomic adversity as an intrauterine exposure is associated with a range of perinatal outcomes although the explanatory mechanisms are not well understood. The development of the fetus can be shaped by the intrauterine environment through alterations in the function of the placenta. In the placenta, the HSD11B2 gene encodes the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol thereby protecting the developing fetus from this exposure. This gene is regulated by DNA methylation, and this methylation and the expression it controls has been shown to be susceptible to a variety of stressors from the maternal environment. The association of prenatal socioeconomic adversity and placental HSD11B2 methylation has not been examined. Following a developmental origins of disease framework, prenatal socioeconomic adversity may alter fetal response to the postnatal environment through functional epigenetic alterations in the placenta. Therefore, we hypothesized that prenatal socioeconomic adversity would be associated with less HSD11B2 methylation.
We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 444 healthy term newborn infants and several markers of prenatal socioeconomic adversity: maternal education, poverty, dwelling crowding, tobacco use and cumulative risk. We also examined whether such associations were sex-specific. We found that infants whose mothers experienced the greatest levels of socioeconomic adversity during pregnancy had the lowest extent of placental HSD11B2 methylation, particularly for males. Associations were maintained for maternal education when adjusting for confounders (p<0.05).
Patterns of HSD11B2 methylation suggest that environmental cues transmitted from the mother during gestation may program the developing fetus's response to an adverse postnatal environment, potentially via less exposure to cortisol during development. Less methylation of placental HSD11B2 may therefore be adaptive and promote the effective management of stress associated with social adversity in a postnatal environment.
Journal Article
Placental 11-Beta Hydroxysteroid Dehydrogenase Methylation Is Associated with Newborn Growth and a Measure of Neurobehavioral Outcome
There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment.
We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P = 0.04), and this increasing methylation was associated with reduced scores of quality of movement (P = 0.04).
These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for the developmental origins of infant neurological health.
Journal Article
Placental FKBP5 Genetic and Epigenetic Variation Is Associated with Infant Neurobehavioral Outcomes in the RICHS Cohort
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.
Journal Article
A protocol for enhancing the diagnostic accuracy and predictive validity of neonatal opioid withdrawal syndrome: The utility of non-invasive clinical markers
Every 15 minutes in the US, an infant exposed to opioids is born. Approximately 50% of these newborns will develop Neonatal Opioid Withdrawal Syndrome (NOWS) within 5 days of birth. It is not known which infants will develop NOWS, therefore, the current hospital standard-of-care dictates a 96-hour observational hold. Understanding which infants will develop NOWS soon after birth could reduce hospital stays for infants who do not develop NOWS and decrease burdens on hospitals and clinicians. We propose noninvasive clinical indicators of NOWS, including newborn neurobehavior, autonomic biomarkers, prenatal substance exposures, and socioeconomic environments. The goals of this protocol are to use these indicators shortly after birth to differentiate newborns who will be diagnosed with NOWS from those who will have mild/no withdrawal, to determine if the indicators predict development at 6 and 18 months of age, and to increase NOWS diagnostic sensitivity for earlier, more accurate diagnoses.
Journal Article
Epigenetic Regulation of Placental NR3C1: Mechanism Underlying Prenatal Programming of Infant Neurobehavior by Maternal Smoking?
Epigenetic regulation of the placental glucocorticoid receptor gene (NR3C1) was investigated as a mechanism underlying links between maternal smoking during pregnancy (MSDP) and infant neurobehavior in 45 mother–infant pairs (49% MSDP-exposed; 52% minorities; ages 18–35). The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale was administered 7 times over the 1st postnatal month; methylation of placental NR3C1 was assessed via bisulfite pyrosequencing. Increased placental NR3C1 methylation was associated with increased infant attention and self-regulation, and decreased lethargy and need for examiner soothing over the 1st postnatal month. A causal steps approach revealed that NR3C1 methylation and MSDP were independently associated with lethargic behavior. Although preliminary, results highlight the importance of epigenetic mechanisms in elucidating pathways to neurobehavioral alterations from MSDP.
Journal Article
The Contributions of Maternal Sensitivity and Maternal Depressive Symptoms to Epigenetic Processes and Neuroendocrine Functioning
This study tested whether maternal responsiveness may buffer the child to the effects of maternal depressive symptoms on DNA methylation of NR3C1, 11β-HSD2, and neuroendocrine functioning. DNA was derived from buccal epithelial cells and prestress cortisol was obtained from the saliva of 128 infants. Mothers with depressive symptoms who were more responsive and who engaged in more appropriate touch during face-to-face play had infants with less DNA methylation of NR3C1 and 11β-HSD2 compared to mothers with depressive symptoms who were also insensitive. The combination of exposure to maternal depressive symptoms and maternal sensitivity was related to the highest prestress cortisol levels, whereas exposure to maternal depressive symptoms and maternal insensitivity was related to the lowest prestress cortisol levels.
Journal Article