Sylvana M. Côté

The Signature of Maternal Rearing in the Methylome in Rhesus Macaque Prefrontal Cortex and T Cells

Early-life adversity is associated with a broad scope of life-long health and behavioral disorders. Particularly critical is the role of the mother. A possible mechanism is that these effects are mediated by “epigenetic” mechanisms. Studies in rodents suggest a causal relationship between early-life adversity and changes in DNA methylation in several “candidate genes” in the brain. This study examines whether randomized differential rearing (maternal vs surrogate–peer rearing) of rhesus macaques is associated with differential methylation in early adulthood. The data presented here show that differential rearing leads to differential DNA methylation in both prefrontal cortex and T cells. These differentially methylated promoters tend to cluster by both chromosomal region and gene function. The broad impact of maternal rearing on DNA methylation in both the brain and T cells supports the hypothesis that the response to early-life adversity is system-wide and genome-wide and persists to adulthood. Our data also point to the feasibility of studying the impact of the social environment in peripheral T-cell DNA methylation.

The joint development of physical and indirect aggression: Predictors of continuity and change during childhood

A person-oriented approach was adopted to examine joint developmental trajectories of physical and indirect aggression. Participants were 1183 children aged 2 years at the initial assessment and followed over 6 years. Most children followed either low or declining trajectories of physical aggression (PA), but 14.6% followed high stable trajectories. Approximately two-thirds of participants followed low indirect aggression (IA) trajectories (67.9%), and one-third (32.1%) followed high rising trajectories. The results combining both PA and IA group memberships indicate that most children (62.1%) exhibit desisting levels of PA and low levels of IA. A significant proportion followed a trajectory of moderately desisting PA and rising IA (14.2%), and 13.5% followed high level trajectories of both forms of aggression. Virtually no children were high on one type and low on the other. Multinomial regressions analyses were used to predict joint trajectory group membership from selected child and family variables measured at 2 years. Young motherhood and low income predicted membership in the high PA-high IA trajectory, but only hostile parenting remained significant after family processes variables were entered in the model. Being a boy, young motherhood, and hostile parenting were generally associated with higher levels of PA. Girls were more likely than boys to follow a trajectory of desisting PA and rising IA. The results suggest that some children, mostly girls, reduce their use of PA and tend to increase their use of IA, and that highly physically aggressive children also tend to be highly indirectly aggressive. Early family risk characteristics and hostile parenting interfere with the socialization of aggression.

Depression and anxiety symptoms: onset, developmental course and risk factors during early childhood

BACKGROUND Depressive and anxiety disorders are among the top ten leading causes of disabilities. We know little, however, about the onset, developmental course and early risk factors for depressive and anxiety symptoms (DAS). OBJECTIVE Model the developmental trajectories of DAS during early childhood and to identify risk factors for atypically high DAS. METHOD Group-based developmental trajectories of DAS conditional on risk factors were estimated from annual maternal ratings (1(1/2) to 5 years) in a large population sample (n = 1759). RESULTS DAS increased substantially in two of the three distinct trajectory groups identified: High-Rising (14.7%); Moderate-Rising (55.4%); and Low (29.9%). Two factors distinguished the High-Rising group from the other two: Difficult temperament at 5 months (High-Rising vs Moderate-Rising: OR = 1.32; 95% CI = 1.13-1.55; High-Rising vs Low: OR = 1.31, CI = 1.12-1.54) and maternal lifetime major depression (High-Rising vs Moderate-Rising: OR = 1.10; CI = 1.01-1.20; High-Rising vs Low: OR = 1.19; CI = 1.08-1.31). Two factors distinguished the High-Rising group from the Low group: High family dysfunction (OR = 1.24; CI = 1.03-1.5) and Low parental self-efficacy (OR = .71; CI = .54-.94). CONCLUSIONS DAS tend to increase in frequency over the first 5 years of life. Atypically high level can be predicted from mother and child characteristics present before 6 months of age. Preventive interventions should be experimented with at risk infants and parents.

Early Risk Factors for Hyperactivity-Impulsivity and Inattention Trajectories From Age 17 Months to 8 Years

CONTEXT Attention-deficit/hyperactivity disorder is an etiologically heterogeneous neurodevelopmental condition with long-term negative outcomes. However, the early developmental course of hyperactivity-impulsivity and inattention symptoms and their association with previous environmental risk factors are still poorly understood OBJECTIVES To describe the developmental trajectories of hyperactivity-impulsivity and inattention symptoms and to identify their prenatal, perinatal, and postnatal risk factors. DESIGN Birth cohort from the general population. SETTING Quebec Longitudinal Study of Child Development. PARTICIPANTS The sample consisted of 2057 individuals, followed up from age 5 months to 8 years. MAIN OUTCOME MEASURES Prenatal, perinatal, and postnatal risk factors assessed at age 5 months were considered predictors of group membership in high hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years. RESULTS The frequency of hyperactivity-impulsivity symptoms tended to slightly decrease with age, whereas the frequency of inattention symptoms substantially increased up to age 6 years. However, trajectories of hyperactivity-impulsivity and inattention symptoms were significantly associated with each other. Risk factors for high trajectories of both types of symptoms were premature birth (adjusted odds ratio [aOR], 1.93; 95% CI, 1.07-3.50), low birth weight (2.11; 1.12-3.98), prenatal tobacco exposure (1.41; 1.03-1.93), nonintact family (1.85; 1.26-2.70), young maternal age at birth of the target child (1.78; 1.17-2.69), paternal history of antisocial behavior (1.78; 1.28-2.47), and maternal depression (1.35; 1.18-1.54). CONCLUSIONS A large range of early risk factors, including prenatal, perinatal social, and parental psychopathology variables, act independently to heighten the likelihood of having persistently high levels of hyperactivity-impulsivity and inattention symptoms from infancy to middle childhood. Early interventions should be experimented with to provide effective tools for attention-deficit/hyperactivity disorder prevention.

Gender Differences in Physical Aggression: A Prospective Population-Based Survey of Children Before and After 2 Years of Age

There has been much controversy over the past decades on the origins of gender differences in childrens aggressive behavior. A widely held view is that gender differences emerge sometime after 2 years of age and increase in magnitude thereafter because of gender-differentiated socialization practices. The objective of this study was to test for (a) gender differences in the prevalence of physical aggression in the general population of 17-month-old children and (b) change in the magnitude of these differences between 17 and 29 months of age. Contrary to the differential socialization hypothesis, the results showed substantial gender differences in the prevalence of physical aggression at 17 months of age, with 5% of boys but only 1% of girls manifesting physically aggressive behaviors on a frequent basis. The results suggest that there is no change in the magnitude of these differences between 17 and 29 months of age.

Peripheral SLC6A4 DNA Methylation Is Associated with In Vivo Measures of Human Brain Serotonin Synthesis and Childhood Physical Aggression

The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

Childhood Trajectories of Inattention and Hyperactivity and Prediction of Educational Attainment in Early Adulthood: A 16-Year Longitudinal Population-Based Study

OBJECTIVE Literature clearly documents the association between mental health problems, particularly attention deficit hyperactivity disorder (ADHD), and educational attainment. However, inattention and hyperactivity are generally not considered independently from each other in prospective studies. The aim of the present study was to differentiate the unique, additive, or interactive contributions of inattention and hyperactivity symptoms to educational attainment. METHOD The authors randomly selected 2,000 participants from a representative sample of Canadian children and estimated developmental trajectories of inattention and hyperactivity between the ages of 6 and 12 years using yearly assessments. High school graduation status, at age 22-23 years, was obtained from official records. RESULTS Four trajectories of inattention and four trajectories of hyperactivity were observed between the ages of 6 and 12 years. After controlling for hyperactivity and other confounding variables, a high inattention trajectory (compared with low inattention) strongly predicted not having a high school diploma at 22-23 years of age (odds ratio=7.66, 95% confidence interval [CI]=5.06-11.58). To a lesser extent, a declining or rising trajectory of inattention also made a significant contribution (odds ratios of 2.67 [95% CI=1.90-3.75] and 3.87 [95% CI=2.75-5.45], respectively). Hyperactivity was not a significant predictor once inattention was taken into account. CONCLUSIONS Inattention rather than hyperactivity during elementary school significantly predicts long-term educational attainment. Children with attention problems, regardless of hyperactivity, need preventive intervention early in their development.

Developmental trajectories of body mass index in early childhood and their risk factors: an 8-year longitudinal study.

OBJECTIVES To identify groups of children with distinct developmental trajectories of body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, between the ages of 5 months and 8 years and identify early-life risk factors that distinguish children in an atypically elevated BMI trajectory group. DESIGN Prospective cohort study. SETTING Families with a child born between October 1997 and July 1998 in the province of Quebec, Canada. PARTICIPANTS A representative sample of children (N = 2120) selected through birth registries for the Quebec Longitudinal Study of Child Development. Children for whom BMI data were available for at least 5 time points were retained in the present study (n = 1957). MAIN EXPOSURES Early-life factors putatively associated with BMI, assessed by maternal report. OUTCOME MEASURE Group-based trajectories of childrens BMI, identified with a semiparametric modeling method from raw BMI values at each age. RESULTS Three trajectories of BMI were identified: low-stable (54.5% of children), moderate (41.0%), and high-rising (4.5%). The high-rising group was characterized by an increasing average BMI, which exceeded international cutoff values for obesity by age 8 years. Two maternal risk factors were associated with the high-rising group as compared with the low-stable and moderate groups combined: maternal BMI (odds ratio, 2.38; 95% confidence interval, 1.38-4.54 for maternal overweight and 6.33; 3.82-11.85 for maternal obesity) and maternal smoking during pregnancy (2.28; 1.49-4.04). CONCLUSIONS Children continuing on an elevated BMI trajectory leading to obesity in middle childhood can be distinguished from children on a normative BMI trajectory as early as age 3.5 years. Important and preventable risk factors for childhood obesity are in place before birth.

Development and Prediction of Hyperactive Symptoms From 2 to 7 Years in a Population-Based Sample

OBJECTIVES. Children with hyperactive symptoms are often referred to mental health services. Given the frequency and persistent nature of hyperactivity, it is important to better understand its developmental course. This study identified the different developmental trajectories of hyperactive symptoms from 2 to 7 years and tested early predictors of high-level and persistent hyperactivity. These data may lead to earlier detection of at-risk children and to more effective interventions that take into account developmental considerations. PARTICIPANTS. Four data-collection cycles of a nationwide survey of Canadian children were used to track the early development of hyperactivity. Children were 0 to 23 months at the first cycle in 1994 and 6 to 7 years at the fourth cycle in 2000. OUTCOME MEASURES. Hyperactivity data were gathered from mothers on a biennial basis beginning when children were 24 months old. Information on potential prenatal and postnatal predictors was gathered from mothers at the first cycle. DESIGN. Group-based semiparametric mixture modeling was used to estimate developmental trajectories, and logistic-regression analysis identified predictors of hyperactivity. RESULTS. Four trajectories of hyperactive symptoms were identified: very low, low, moderate, and high. Statistically significant predictors for high and persistent hyperactivity, after controlling for all other factors, were maternal prenatal smoking, child male gender, maternal depression, and hostile parenting. CONCLUSIONS. For the majority of children, the frequency of hyperactive symptoms decreased or remained low from 2 to 7 years. However, 7 children in 100 were classified as having high initial levels of hyperactive symptoms that persisted over time. Several prenatal and early postnatal risk factors identified these children, although additional variables will need to be identified to accurately predict high and persistent hyperactivity. Findings suggest that preventive interventions could target high-risk families during pregnancy and early childhood.

Closing the gap in academic readiness and achievement: the role of early childcare

BACKGROUND Socially disadvantaged children with academic difficulties at school entry are at increased risk for poor health and psychosocial outcomes. Our objective is to test the possibility that participation in childcare--at the population level--could attenuate the gap in academic readiness and achievement between children with and without a social disadvantage (indexed by low levels of maternal education). METHODS A cohort of infants born in the Canadian province of Quebec in 1997/1998 was selected through birth registries and followed annually until 7 years of age (n = 1,863). Children receiving formal childcare (i.e., center-based or non-relative out-of-home) were distinguished from those receiving informal childcare (i.e., relative or nanny). Measures from 4 standardized tests that assessed cognitive school readiness (Lollipop Test for School Readiness), receptive vocabulary (Peabody Picture Vocabulary Test Revised), mathematics (Number Knowledge Test), and reading performance (Kaufman Assessment Battery for children) were administered at 6 and 7 years. RESULTS Children of mothers with low levels of education showed a consistent pattern of lower scores on academic readiness and achievement tests at 6 and 7 years than those of highly educated mothers, unless they received formal childcare. Specifically, among children of mothers with low levels of education, those who received formal childcare obtained higher school readiness (d = 0.87), receptive vocabulary (d = 0.36), reading(d = 0.48) and math achievement scores (d = 0.38; although not significant at 5%) in comparison with those who were cared for by their parents. Childcare participation was not associated with cognitive outcomes among children of mothers with higher levels of education. CONCLUSIONS Public investments in early childcare are increasing in many countries with the intention of reducing cognitive inequalities between disadvantaged and advantaged children. Our findings provide further evidence suggesting that formal childcare could represent a preventative means of attenuating effects of disadvantage on childrens early academic trajectory.