Developmental trajectories of autonomic functioning in autism from birth to early childhood.

Deficits in social engagement emerge in autism during the infant and toddler period and may be related to emotion regulation and stress response systems. This study examined patterns of growth in autonomic functioning related to autism diagnosis and addresses the hypothesis that there are differences in autonomic functioning related to autism in infancy. Heart rate (HR) and respiratory sinus arrhythmia (RSA) were measured at 8 time points from 1 to 72 months of age in infants later diagnosed with autism (n = 12) and a non-autistic comparison group (n = 106). Multilevel models were used to describe the developmental course of HR and RSA and to test the effect of autism diagnosis on growth trajectories. Both groups showed an expected age-related decrease in HR and increase in RSA. Groups did not differ in the rate of decrease of HR over time. However, infants with autism demonstrated a smaller linear increase in RSA, indicating slower growth in RSA over time in comparison to controls. These results suggest that differences in physiological regulation may develop with age in autism. The slowed RSA growth in autism was most evident after 18 months of age, at a time when behavioral symptoms become prominent. This is consistent with the view that RSA is a marker of functional status in autism rather than a cause of social deficits in autism.

A developmental origins perspective on the emergence of violent behavior in males with prenatal substance exposure.

Children with prenatal substance exposure are at increased risk for externalizing behavior problems and violence. However, the contribution of early life experiences for placing these individuals at risk is not well understood. Utilizing a sample of 1,388 children with prenatal substance exposure from the Maternal Lifestyle Study, we attempt to shed light on these contributing factors by examining the impact of infant temperament, maternal sensitivity, and early life stress on the expression of violent behavior at ages 12 through 14 years. Males may be more at risk for increases in violent behavior in early adolescence through a number of early life experiences, such as variability in responses to maternal flexibility and engagement related to individual differences in temperament, as well as exposure to early adversity. Comparing two prevailing developmental theoretical frameworks, deficit models and differential susceptibility, we aim to understand the developmental origins of violent behavior in males by identifying children who may be most susceptible to early caregiving experiences.

Epigenetic Programming by Maternal Behavior in the Human Infant.

: media-1vid110.1542/5804912859001PEDS-VA_2017-1890Video Abstract OBJECTIVES: We sought to determine if variations in maternal care alter DNA methylation in term, healthy, 5-month-old infants. This work was based on landmark studies in animal models demonstrating that nurturing care by dams would alter their newborns' stress responses through epigenetic mechanisms. We used breastfeeding as a proxy for animal maternal behavior. We hypothesized alterations in DNA methylation of the glucocorticoid receptor gene and less hypothalamic stress response in infants of mothers who breastfed their infants versus infants of mothers who did not breastfeed. METHODS: A cohort study of term, healthy infants and their mothers who did (n = 21) or did not (n = 21) breastfeed for the first 5 months was used in this analysis. Cortisol stress reactivity was measured in infant saliva by using a mother-infant interaction procedure and DNA methylation of an important regulatory region of the glucocorticoid receptor gene. Changes in DNA methylation of this gene in humans were compared to homologous regions of the rat gene. DNA samples were prepared from cheek swabs and subjected to quantitative analysis of the extent of methylation by using sensitive sequencing techniques. RESULTS: Breastfeeding was associated with decreased DNA methylation of the glucocorticoid receptor promoter and decreased cortisol reactivity in 5-month-old infants. Decreased DNA methylation occurred in the promoter region involved in regulation of the hypothalamic-pituitary-adrenal and immune system responses. CONCLUSIONS: Maternal care in humans may impact the hypothalamic-pituitary-adrenal stress response through behavioral programming and manifest as offspring epigenetic change. These results explain, in part, some of the positive effects observed in children who are breastfed.

Testing the programming of temperament and psychopathology in two independent samples of children with prenatal substance exposure.

Prenatal programming models have rarely been applied to research on children with prenatal substance exposure, despite evidence suggesting that prenatal drug exposure is a form of stress that impacts neurodevelopmental outcomes and risk for psychopathology. Utilizing data from two longitudinal multisite studies comprising children prenatally exposed to substances as well as a nonexposed comparison group (Maternal Lifestyle Study, n = 1,388; Infant Development, Environment, and Lifestyle study, n = 412), we tested whether early phenotypic indicators of hypothesized programming effects, indexed by growth parameters at birth and infant temperament, served as a link between prenatal substance exposure and internalizing and externalizing behavior at age 5. Latent profile analysis indicated that individual differences in reactivity and regulation for infants prenatally exposed to substances was best characterized by four temperament profiles. These profiles were virtually identical across two independent samples, and demonstrated unique associations with adjustment difficulties nearly 5 years later. Results of path analysis using structural equation modeling also showed that increased prenatal substance exposure was linked to poorer growth parameters at birth, profiles of temperamental reactivity in infancy, and internalizing and externalizing behavior at age 5. This pathway was partially replicated across samples. This study was among the first to link known individual-level correlates of prenatal substance exposure into a specific pathway to childhood problem behavior. Implications for the developmental origins of a child's susceptibility to psychopathology as a result of intrauterine substance exposure are discussed.

Diminished respiratory sinus arrhythmia response in infants later diagnosed with autism spectrum disorder.

Indicators of risk for developing Autism Spectrum Disorder (ASD) are difficult to detect within the first year of life. In this study, infants who were originally followed prospectively to examine general developmental risks due to substance exposure interacted with their mother and an unfamiliar experimenter for 2-min episodes at 4 months of age. Electrocardiogram was collected to measure respiratory sinus arrhythmia (RSA) and the session was video recorded for behavioral coding. Two groups of infants were compared: infants with a diagnosed ASD outcome (N = 8) and matched controls (N = 186). Infants were compared on mean RSA and infant behavioral codes for each 2-min episode. No significant group differences were revealed on RSA or behavior during interactions between the infants and mothers. However, in response to play with a stranger, infants with an ASD outcome had lower RSA (M = 2.49, 95% CI [2.30, 2.98]) than controls (M = 3.12, 95% CI [3.06, 3.18]). During the interaction with a stranger, lower RSA response was associated with more protesting behaviors (P < 0.01), whereas higher RSA response was associated with more social monitoring (P = 0.001). Lower RSA suggests that 4-month-old infants later diagnosed with ASD exhibited poorer autonomic regulation during interaction with an unfamiliar adult than did controls. Physiological regulation during interactions with a new social partner may be disrupted early in infancy in children with ASD, as indicated here by lower RSA, and therefore be a potential target for developing early risk screening tools for ASD. Autism Res 2018, 11: 726-731. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism Spectrum Disorder (ASD) emerges within the first years of life; however, it is difficult to identify children who will develop autism before 12 months of age based on behavioral measures. In a study of infants who were followed from birth, infants who were later diagnosed with ASD had poorer physiological regulation during play with a new adult. With additional evidence, poorer physiological regulation may function as an early sign of ASD risk.

Global motion perception is related to motor function in 4.5-year-old children born at risk of abnormal development.

Global motion perception is often used as an index of dorsal visual stream function in neurodevelopmental studies. However, the relationship between global motion perception and visuomotor control, a primary function of the dorsal stream, is unclear. We measured global motion perception (motion coherence threshold; MCT) and performance on standardized measures of motor function in 606 4.5-year-old children born at risk of abnormal neurodevelopment. Visual acuity, stereoacuity and verbal IQ were also assessed. After adjustment for verbal IQ or both visual acuity and stereoacuity, MCT was modestly, but significantly, associated with all components of motor function with the exception of fine motor scores. In a separate analysis, stereoacuity, but not visual acuity, was significantly associated with both gross and fine motor scores. These results indicate that the development of motion perception and stereoacuity are associated with motor function in pre-school children.

Perinatal substance use, residential instability, and negative behavioral outcomes among adolescents: Lessons from the maternal lifestyle study.

PROBLEM: Both housing instability and prenatal substance use are known risk factors for behavioral problems among adolescents. METHODS: The purpose of this study was to investigate the association between residential instability (residential mobility and homelessness) and delinquent behaviors among adolescents enrolled in the maternal lifestyle study (MLS), a 16-year research study that explored short-term and long-term effects of in-utero exposure to cocaine and/or opiates (N = 736). Logistic regression was used to measure the association between housing problems with youth crimes, school delinquency, and substance use at 11, 15, and 16 years of age. FINDINGS: Both high-frequency residential mobility and homelessness were associated with deviant behaviors across the entire sample of children born with in-utero cocaine/opiate exposure and those without. CONCLUSIONS: Psychiatric nursing care of youth should include a comprehensive assessment of residential instability to identify risk and target potential interventions.

Maternal and infant affect at 4 months predicts performance and verbal IQ at 4 and 7 years in a diverse population.

Using existing longitudinal data from 570 infants in the Maternal Lifestyle Study, we explored the predictive value of maternal and infant affect and maternal vocalizations during 2 minutes of face-to-face interactions at 4 months on IQ scores at 4.5 and 7 years. After controlling for demographic factors, maternal depression, and prenatal drug exposure, maternal positive affect and maternal positive vocalizations emerged as predictors of both verbal and performance IQ at 4.5 and 7 years. Although infant positive affect during the interaction with the mother was not predictive of these outcome measures, infant positive affect towards an examiner predicted verbal but not performance IQ at 4.5 years. These results suggest that maternal positive affect may index emotional engagement in interaction that facilitates both verbal and nonverbal cognitive development, while infant social positive affect is specifically related to the acquisition of verbal reasoning abilities. These findings are significant because they are based on a discrete snapshot of observable behavior in infancy (just 2 minutes of interaction), because they extend the range of maternal behaviors and characteristics known to support positive developmental outcomes, and because they are derived from high-risk infants where prevention efforts may be beneficial. Potential mechanisms for these associations are discussed, as are the clinical implications for identifying dyads most in need of targeted interventions.

Infants' early visual attention and social engagement as developmental precursors to joint attention.

This study examined infants' early visual attention (at 1 month of age) and social engagement (4 months) as predictors of their later joint attention (12 and 18 months). The sample (n = 325), drawn from the Maternal Lifestyle Study, a longitudinal multicenter project conducted at 4 centers of the National Institute of Child Health and Human Development Neonatal Research Network, included high-risk (cocaine-exposed) and matched noncocaine-exposed infants. Hierarchical regressions revealed that infants' attention orienting at 1 month significantly predicted more frequent initiating joint attention at 12 (but not 18) months of age. Social engagement at 4 months predicted initiating joint attention at 18 months. Results provide the first empirical evidence for the role of visual attention and social engagement behaviors as developmental precursors for later joint attention outcome. (PsycINFO Database Record

18-Month Follow-Up of Infants Cared for in a Single-Family Room Neonatal Intensive Care Unit.

OBJECTIVES: To determine whether the single-family room (SFR)-neonatal intensive care unit (NICU) is associated with improved 18-month neurodevelopmental outcome, especially in infants of mothers with high maternal involvement. STUDY DESIGN: An 18-month follow-up was undertaken that compared infants born <30 weeks gestational age; 123 from a SFR-NICU vs 93 from an open-bay NICU. Infants were divided into high vs low maternal involvement based on days/week of kangaroo care, breast/bottle feeding, and maternal care. Infants with high vs low maternal involvement in the SFR and open-bay NICUs were compared on the Bayley Cognitive, Language, and Motor scores and Pervasive Developmental Disorders autism screen. RESULTS: There were more mothers in the high maternal involvement SFR than in the high maternal involvement open-bay group (P = .002). Infants with high maternal involvement in both NICUs had greater Cognitive (P = .029) and Language (P < .000) scores than infants with low maternal involvement. Effect sizes within NICU were moderate to large in the SFR-NICU for Language scores and moderate for the Language composite in the open-bay NICU. The number of days of maternal involvement was greater in the SFR than open-bay NICU (P < .000), and length of stay was shorter in the high maternal involvement SFR than high maternal involvement open-bay NICU (P = .024). Kangaroo and maternal care predicted Cognitive (kangaroo, P = .003) and Language scores (P = .015, P = .032, respectively). Infants with ≥1 symptom of autism were more likely to be in the open-bay low maternal involvement group vs the SFR high maternal involvement group (OR = 4.91, 95% CI = 2.2-11.1). CONCLUSIONS: High maternal involvement is associated with improved 18-month neurodevelopmental outcome, especially in infants cared for in a SFR-NICU.

Transactional relations between caregiving stress, executive functioning, and problem behavior from early childhood to early adolescence.

Developmental psychopathologists face the difficult task of identifying the environmental conditions that may contribute to early childhood behavior problems. Highly stressed caregivers can exacerbate behavior problems, while children with behavior problems may make parenting more difficult and increase caregiver stress. Unknown is: (a) how these transactions originate, (b) whether they persist over time to contribute to the development of problem behavior and (c) what role resilience factors, such as child executive functioning, may play in mitigating the development of problem behavior. In the present study, transactional relations between caregiving stress, executive functioning, and behavior problems were examined in a sample of 1,388 children with prenatal drug exposures at three developmental time points: early childhood (birth to age 5), middle childhood (ages 6 to 9), and early adolescence (ages 10 to 13). Transactional relations differed between caregiving stress and internalizing versus externalizing behavior. Targeting executive functioning in evidence-based interventions for children with prenatal substance exposure who present with internalizing problems and treating caregiving psychopathology, depression, and parenting stress in early childhood may be particularly important for children presenting with internalizing behavior.

Fine Motor Differences and Prenatal Serotonin Reuptake Inhibitors Exposure.

OBJECTIVE: To examine fine motor differences between preschoolers with prenatal exposure to serotonin reuptake inhibitor (SRI) and children of mothers with major depressive disorder. STUDY DESIGN: A subset of children (N = 40) from a larger study on the effects of prenatal SRI and untreated major depressive disorder participated in a kinematic task of visual motor and fine motor functions at ages 4-5 years: exposure to SRI (n = 15), untreated major depressive disorder exposure (n = 10), and the control group (n = 15). The task was to reach and secure a peg, then drop it in a small hole near the start position in the light condition with full visibility or in the glow condition in which a phosphorescent peg glows in the dark. Movement-tracking software measured the positioning of the moving hand and fingers. RESULTS: In the glow condition, the group exposed to SRIs had a greater proportion of maximum aperture than the group with major depressive disorder, and the group exposed to SRIs was slower than the group with major depressive disorder to drop the peg into the hole. In the glow condition, the trajectory of the group exposed to SRI was less straight than the group with major depressive disorder, and the group with major depressive disorder had a straighter trajectory than the control group. CONCLUSION: This study provides evidence that preschool aged children with prenatal SRI exposure have poorer fine motor and visual-motor control compared with those with prenatal untreated major depressive disorder.

School-Aged Outcomes following Prenatal Methamphetamine Exposure: 7.5-Year Follow-Up from the Infant Development, Environment, and Lifestyle Study.

OBJECTIVE: To assess the relationship between prenatal methamphetamine exposure (PME) and behavior problems at age 7.5 years and the extent to which early adversity mediated this relationship. STUDY DESIGN: The multicenter, longitudinal Infant Development, Environment, and Lifestyle study enrolled 412 mother-infant pairs at 4 sites. Methamphetamine-exposed participants (n = 204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched participants (n = 208) denied methamphetamine use and had a negative meconium screen. At the 7.5-year follow-up, 290 children with complete Child Behavior Checklist data and an early adversity index score were available for analysis (n = 146 exposed). RESULTS: PME was significantly associated with an increased early adversity index score (P < .001) and with increased externalizing, rule-breaking behavior, and aggressive behavior (P < .05). Early adversity was also associated with higher externalizing behavior scores. Early adversity significantly mediated the relationship between PME and behavioral problems. After adjusting the mediation model for sex, prenatal tobacco, alcohol, and marijuana exposures, and study site, the association of PME with early adversity remained significant. CONCLUSIONS: Though PME is associated with behavioral problems, early adversity may be a strong determinant of behavioral outcome for children exposed to methamphetamine in utero. Early adversity significantly mediated the relationship between PME and behavioral problems.

Early caregiving stress exposure moderates the relation between respiratory sinus arrhythmia reactivity at 1 month and biobehavioral outcomes at age 3.

There is a growing scientific interest in the psychophysiological functioning of children living in low-socioeconomic status (SES) contexts, though this research is complicated by knowledge that physiology-behavior relations often operate differently in these environments among adults. Importantly, such research is made more difficult because SES may be a proxy for a wide range of risk factors including poor caregiving and exposure to parental substance use. We used factor analysis to organize risk-exposure data collected from 827 children-many of whom were raised in low-SES contexts and exposed to substances prenatally-into dissociable components including economic stress, caregiving stress (e.g., stress the caregiver may experience, including parental psychopathology), and postnatal substance exposure. These factors, along with respiratory sinus arrhythmia (RSA) reactivity at age 1 month, were used to predict behavior dysregulation and resting RSA at age 3 years. A significant RSA Reactivity × Caregiving Stress interaction indicated that infants who exhibited high RSA reactivity at 1 month experienced the greatest behavior dysregulation at 3 years, but only when they were exposed to high levels of caregiving stress. Among African Americans, the highest resting RSA at 3 years was found in infants with less RSA reactivity, but only if they also experienced less caregiving stress. Our work is consistent with biological sensitivity to context, adaptive calibration, and allostatic load models, and highlights the importance of studying Physiology × Environment interactions in low-SES contexts for predicting behavior and resting RSA.

Effects of prenatal substance exposure on infant temperament vary by context.

This was a prospective longitudinal multisite study of the effects of prenatal cocaine and/or opiate exposure on temperament in 4-month-olds of the Maternal Lifestyle Study (N = 958: 366 cocaine exposed, 37 opiate exposed, 33 exposed to both drugs, 522 matched comparison). The study evaluated positivity and negativity during The Behavior Assessment of Infant Temperament (Garcia Coll et al., 1988). Parents rated temperament (Infant Behavior Questionnaire; Rothbart, 1981). Cocaine-exposed infants showed less positivity overall, mainly during activity and threshold items, more negativity during sociability items, and less negativity during irritability and threshold items. Latent profile analysis indicated individual temperament patterns were best described by three groups: low/moderate overall reactivity, high social negative reactivity, and high nonsocial negative reactivity. Infants with heavy cocaine exposure were more likely in high social negative reactivity profile, were less negative during threshold items, and required longer soothing intervention. Cocaine- and opiate-exposed infants scored lower on Infant Behavior Questionnaire smiling and laughter and duration of orienting scales. Opiate-exposed infants were rated as less respondent to soothing. By including a multitask measure of temperament we were able to show context-specific behavioral dysregulation in prenatally cocaine-exposed infants. The findings indicate flatter temperament may be specific to nonsocial contexts, whereas social interactions may be more distressing for cocaine-exposed infants.

Neurobehavior related to epigenetic differences in preterm infants.

UNLABELLED: Preterm birth is associated with medical problems affecting the neuroendocrine system, altering cortisol levels resulting in negative effects on newborn neurobehavior. Newborn neurobehavior is regulated by DNA methylation of NR3C1 and HSD11B2. AIM: Determine if methylation of HSD11B2 and NR3C1 is associated with neurobehavioral profiles in preterm infants. PATIENTS & METHODS: Neurobehavior was measured before discharge from the hospital in 67 preterm infants. Cheek swabs were collected for DNA extraction. RESULTS: Infants with the high-risk neurobehavioral profile showed more methylation than infants with the low-risk neurobehavioral profile at CpG3 for NR3C1 and less methylation of CpG3 for HSD11B2. Infants with these profiles were more likely to have increased methylation of NR3C1 and decreased methylation of HSD11B2 at these CpG sites. CONCLUSION: Preterm birth is associated with epigenetic differences in genes that regulate cortisol levels related to high-risk neurobehavioral profiles.

Prenatal exposure to recreational drugs affects global motion perception in preschool children.

Prenatal exposure to recreational drugs impairs motor and cognitive development; however it is currently unknown whether visual brain areas are affected. To address this question, we investigated the effect of prenatal drug exposure on global motion perception, a behavioural measure of processing within the dorsal extrastriate visual cortex that is thought to be particularly vulnerable to abnormal neurodevelopment. Global motion perception was measured in one hundred and forty-five 4.5-year-old children who had been exposed to different combinations of methamphetamine, alcohol, nicotine and marijuana prior to birth and 25 unexposed children. Self-reported drug use by the mothers was verified by meconium analysis. We found that global motion perception was impaired by prenatal exposure to alcohol and improved significantly by exposure to marijuana. Exposure to both drugs prenatally had no effect. Other visual functions such as habitual visual acuity and stereoacuity were not affected by drug exposure. Prenatal exposure to methamphetamine did not influence visual function. Our results demonstrate that prenatal drug exposure can influence a behavioural measure of visual development, but that the effects are dependent on the specific drugs used during pregnancy.

Global motion perception is independent from contrast sensitivity for coherent motion direction discrimination and visual acuity in 4.5-year-old children.

Global motion processing depends on a network of brain regions that includes extrastriate area V5 in the dorsal visual stream. For this reason, psychophysical measures of global motion perception have been used to provide a behavioral measure of dorsal stream function. This approach assumes that global motion is relatively independent of visual functions that arise earlier in the visual processing hierarchy such as contrast sensitivity and visual acuity. We tested this assumption by assessing the relationships between global motion perception, contrast sensitivity for coherent motion direction discrimination (henceforth referred to as contrast sensitivity) and habitual visual acuity in a large group of 4.5-year-old children (n=117). The children were born at risk of abnormal neurodevelopment because of prenatal drug exposure or risk factors for neonatal hypoglycemia. Motion coherence thresholds, a measure of global motion perception, were assessed using random dot kinematograms. The contrast of the stimuli was fixed at 100% and coherence was varied. Contrast sensitivity was measured using the same stimuli by fixing motion coherence at 100% and varying dot contrast. Stereoacuity was also measured. Motion coherence thresholds were not correlated with contrast sensitivity or visual acuity. However, lower (better) motion coherence thresholds were correlated with finer stereoacuity (ρ=0.38, p=0.004). Contrast sensitivity and visual acuity were also correlated (ρ=-0.26, p=0.004) with each other. These results indicate that global motion perception for high contrast stimuli is independent of contrast sensitivity and visual acuity and can be used to assess motion integration mechanisms in children.

Developmental and behavioral consequences of prenatal methamphetamine exposure: A review of the Infant Development, Environment, and Lifestyle (IDEAL) study.

This study reviews the findings from the Infant Development, Environment, and Lifestyle (IDEAL) study, a multisite, longitudinal, prospective study designed to determine maternal outcome and child growth and developmental findings following prenatal methamphetamine exposure from birth up to age 7.5 years. These findings are presented in the context of the home environment and caregiver characteristics to determine how the drug and the environment interact to affect the outcome of these children. No neonatal abstinence syndrome requiring pharmacologic intervention was observed but heavy drug exposure was associated with increased stress responses in the neonatal period. Poorer inhibitory control was also observed in heavy methamphetamine exposed children placing them at high risk for impaired executive function. Independent of methamphetamine exposure, children with more responsive home environments to developmental and emotional needs demonstrated lower risks for internalizing and externalizing behavior.

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.