A Standardized Protocol for Efficient and Reliable Quality Control of Brain Registration in Functional MRI Studies.

Automatic alignment of brain anatomy in a standard space is a key step when processing magnetic resonance imaging for group analyses. Such brain registration is prone to failure, and the results are therefore typically reviewed visually to ensure quality. There is however no standard, validated protocol available to perform this visual quality control (QC). We propose here a standardized QC protocol for brain registration, with minimal training overhead and no required knowledge of brain anatomy. We validated the reliability of three-level QC ratings (OK, Maybe, Fail) across different raters. Nine experts each rated N = 100 validation images, and reached moderate to good agreement (kappa from 0.4 to 0.68, average of 0.54 ± 0.08), with the highest agreement for "Fail" images (Dice from 0.67 to 0.93, average of 0.8 ± 0.06). We then recruited volunteers through the Zooniverse crowdsourcing platform, and extracted a consensus panel rating for both the Zooniverse raters (N = 41) and the expert raters. The agreement between expert and Zooniverse panels was high (kappa = 0.76). Overall, our protocol achieved a good reliability when performing a two level assessment (Fail vs. OK/Maybe) by an individual rater, or aggregating multiple three-level ratings (OK, Maybe, Fail) from a panel of experts (3 minimum) or non-experts (15 minimum). Our brain registration QC protocol will help standardize QC practices across laboratories, improve the consistency of reporting of QC in publications, and will open the way for QC assessment of large datasets which could be used to train automated QC systems.

The Quebec Newborn Twin Study at 21.

This paper is a revised and updated edition of a previous description of the Quebec Newborn Twin Study (QNTS), an ongoing prospective longitudinal follow-up of a birth cohort of twins born between 1995 and 1998 in the greater Montreal area, Québec, Canada. The goal of QNTS is to document individual differences in the cognitive, behavioral, and social-emotional aspects of developmental health across childhood, their early genetic and environmental determinants, as well as their putative role in later social-emotional adjustment, school, health, and occupational outcomes. A total of 662 families of twins were initially assessed when the twins were aged 6 months. These twins and their family were then followed regularly. QNTS now has 16 waves of data collected or planned, including 5 in preschool. Over the last 24 years, a broad range of physiological, cognitive, behavioral, school, and health phenotypes were documented longitudinally through multi-informant and multimethod measurements. QNTS also entails extended and detailed multilevel assessments of proximal (e.g., parenting behaviors, peer relationships) and distal (e.g., family income) features of the child's environment. QNTS children and a subset of their parents have been genotyped, allowing for the computation of a variety of polygenic scores. This detailed longitudinal information makes QNTS uniquely suited for the study of the role of the early years and gene-environment transactions in development.

Identifying craniofacial features associated with prenatal exposure to androgens and testing their relationship with brain development.

We used magnetic resonance (MR) images obtained in same-sex and opposite-sex dizygotic twins (n = 119, 8 years of age) to study possible effects of prenatal androgens on craniofacial features. Using a principal component analysis of 19 craniofacial landmarks placed on the MR images, we identified a principal component capturing craniofacial features that distinguished females with a presumed differential exposure to prenatal androgens by virtue of having a male (vs. a female) co-twin (Cohen's d = 0.76). Subsequently, we tested the possibility that this craniofacial "signature" of prenatal exposure to androgens predicts brain size, a known sexually dimorphic trait. In an independent sample of female adolescents (singletons; n = 462), we found that the facial signature predicts up to 8% of variance in brain size. These findings are consistent with the organizational effects of androgens on brain development and suggest that the facial signature derived in this study could complement other indirect measures of prenatal exposure to androgens.

A methodological comparison of the Porges algorithm, fast Fourier transform, and autoregressive spectral analysis for the estimation of heart rate variability in 5-month-old infants.

Little empirical evidence exists on the comparability of heart rate variability (HRV) quantification methods commonly used in infants. The aim was to compare three methods of HRV estimation: (1) fast Fourier transform (FFT), (2) autoregressive (AR), and (3) the Porges methods. HRV was estimated in 63 healthy 5-month-old infants. HRV parameters were strongly correlated across methods (.92-.99) but yielded significantly different mean HRV estimates (Porges method > FFT > AR). There was no systematic bias over the whole range of values between the two spectral approaches, while differences between the Porges method and the spectral estimates were systematically greater for larger values. Additional comparative studies are needed to explore the between-method agreement across a range of physiological conditions.

Gene-environment processes linking peer victimization and physical health problems: a longitudinal twin study.

OBJECTIVE: This study examined whether (a) a genetic disposition for physical health problems increases the risk of peer victimization and (b) peer victimization interacts with genetic vulnerability in explaining physical health problems. METHODS: Participants were 167 monozygotic and 119 dizyogtic twin pairs. Physical symptoms were assessed in early childhood and early adolescence. Peer victimization was assessed in middle childhood. RESULTS: Genetic vulnerability for physical health problems in early childhood was unrelated to later peer victimization, but genetic vulnerability for physical health problems during early adolescence increased the risk of victimization. Victimization did not interact with genetic factors in predicting physical symptoms. Environmental, not genetic, factors had the greatest influence on the development of physical symptoms in victims. CONCLUSION: Genetic vulnerability for physical health problems in early adolescence increases the risk of peer victimization. Whether victims suffer a further increase in physical symptoms depends on the presence of protective environmental factors.

Genetic and environmental influences on eating behaviors in 2.5- and 9-year-old children: a longitudinal twin study.

BACKGROUND: Eating behaviors during childhood are related both to children's diet quality and to their weight status. A better understanding of the determinants of eating behavior during childhood is essential for carrying out effective dietary interventions. METHODS: We assessed the contribution of genetic and environmental factors to variations in selected eating behaviors in early and late childhood. Information on eating behaviors came from questionnaires administered to parents of children participating in the Quebec Newborn Twin Study when the twins were 2.5 and 9 years old (n = 692 children). Dichotomous variables were derived and analyzed using structural equation modeling, as part of a classic twin study design. We performed univariate and bivariate longitudinal analyses to quantify sources of variation and covariation across ages, for several eating behavior traits. RESULTS: We found moderate to strong heritability for traits related to appetite such as eating too much, not eating enough and eating too fast. Univariate analysis estimates varied from 0.71 (95% CI: 0.49, 0.87) to 0.89 (0.75, 0.96) in younger children and from 0.44 (0.18, 0.66) to 0.56 (0.28, 0.78) in older children. Bivariate longitudinal analyses indicated modest to moderate genetic correlations across ages (r(A) varying from 0.34 to 0.58). Common genetic influences explained 17% to 43% of the phenotypic correlation between 2.5 and 9 years for these appetite-related behaviors. In 9-year-old children, food acceptance traits, such as refusing to eat and being fussy about food, had high heritability estimates, 0.84 (0.63, 0.94) and 0.85 (0.59, 0.96) respectively, while in younger children, the shared environment (i.e., common to both twins) contributed most to phenotypic variance. Variances in meal-pattern-related behaviors were mostly explained by shared environmental influences. CONCLUSIONS: Genetic predispositions explain a large part of the variations in traits related to appetite during childhood, though our results suggest that as children get older, appetite-related behaviors become more sensitive to environmental influences outside the home. Still, for several traits environmental influences shared by twins appear to have the largest relative importance. This finding supports the notion that familial context has considerable potential to influence the development of healthy eating habits throughout childhood.

Gene-environment contributions to energy and macronutrient intakes in 9-year-old children: results from the Quebec Newborn Twin Study.

BACKGROUND: Few twin studies have examined nutrition-related phenotypes among children, and none has investigated energy and macronutrient intakes. OBJECTIVE: The objective was to quantify genetic and environmental influences on variations in energy and macronutrient intakes among children aged 9 years. DESIGN: We conducted a nutrition study among children participating in the Quebec Newborn Twin Study, a population-based birth cohort of twins. We derived dietary data from two multiple-pass 24-hour dietary recalls with a parent and his or her child. The analysis employed a classic twin study design and used data from 379 twin pairs. RESULTS: Univariate analyses indicate that heritability for mean daily energy (kcal) and macronutrient (g) intakes was moderate, ranging from 0.34 (95% CI: 0.22, 0.46) to 0.42 (0.31, 0.53). Genetic effects also accounted for 0.28 (0.16, 0.40) of the variance in percent of energy from lipids, while only environmental (shared and unique) effects accounted for the variance in percent of energy from proteins and carbohydrates. The shared environment did not contribute to variations in daily intakes for most of the nutritional variables under study. Multivariate analyses suggest the presence of macronutrient-specific genetic influences for lipids and carbohydrates, estimated at 0.12 (0.04, 0.19) and 0.20 (0.11, 0.29) respectively. CONCLUSIONS: The unique environment (i.e., not shared by family members) has the largest influence on variances in daily energy and macronutrient intakes in 9-year-old children. This finding underscores the need to take obesogenic environments into account when planning dietary interventions for younger populations.

Genetic and environmental influences on daytime and nighttime sleep duration in early childhood.

OBJECTIVES: To determine the relative contributions of genetic and environmental factors on daytime and nighttime continuous sleep duration at 6, 18, 30, and 48 months of age, and to identify different subgroups of children who followed different daytime and nighttime sleep duration trajectories and to investigate their etiology. METHODS: The current study included 995 twins (405 monozygotic and 586 dizygotic) of the Quebec Newborn Twin Study recruited from the birth records of the Quebec Statistics Institute. Daytime and nighttime sleep was assessed through maternal reports at 6, 18, 30, and 48 months of age. A semiparametric modeling strategy was used to estimate daytime and nighttime sleep duration trajectories. Quantitative genetic models were used to examine to what extent genetic and environmental factors influenced daytime and nighttime continuous sleep duration. RESULTS: Genetic modeling analyses revealed environmental influences for all daytime sleep duration trajectories. In contrast, strong genetic influences were found for consolidated nighttime sleep duration (except at 18 months and for the short-increasing sleep duration trajectory). CONCLUSIONS: This is the first indication that early childhood daytime sleep duration may be driven by environmental settings, whereas the variance in consolidated nighttime sleep duration is largely influenced by genetic factors with a critical environmental time-window influence at ∼18 months.

The Quebec Newborn Twin Study into adolescence: 15 years later.

The Quebec Newborn Twin Study (QNTS) is an ongoing prospective longitudinal follow-up of a birth cohort of twins born between 1995 and 1998 in the greater Montreal area, Québec, Canada. The goal of QNTS is to document individual differences in the cognitive, behavioral, and social-emotional aspects of developmental health across childhood, their early bio-social determinants, as well as their putative role in later social-emotional adjustment, school and health outcomes. A total of 662 families of twins were initially assessed when the twins were aged 6 months. These twins and their family were then followed regularly. QNTS has 14 waves of data collected or planned, including 5 in preschool. Over the past 15 years, a broad range of physiological, cognitive, behavioral, school, and health phenotypes were documented longitudinally through multi-informant and multi-method measurements. QNTS also entails extended and detailed multi-level assessments of proximal (e.g., parenting behaviors, peer relationships) and distal (e.g., family income) features of the child's environment. This detailed longitudinal information makes QNTS uniquely suited for the study of the role of the early years and gene-environment transactions in development.

Strong genetic contribution to peer relationship difficulties at school entry: findings from a longitudinal twin study.

This study assessed the genetic and environmental contributions to peer difficulties in the early school years. Twins' peer difficulties were assessed longitudinally in kindergarten (796 twins, Mage = 6.1 years), Grade 1 (948 twins, Mage = 7.1 years), and Grade 4 (868 twins, Mage = 10 years) through multiple informants. The multivariate results revealed that genetic factors accounted for a strong part of both yearly and stable peer difficulties. At the univariate level, the genetic contributions emerged progressively, as did a growing consensus among informants with respect to those who experienced peer difficulties. These results underline the need to intervene early and persistently, and to target the child and the peer context to prevent peer difficulties and their consequences.

Genetic and environmental contributions to weight, height, and BMI from birth to 19 years of age: an international study of over 12,000 twin pairs.

OBJECTIVE: To examine the genetic and environmental influences on variances in weight, height, and BMI, from birth through 19 years of age, in boys and girls from three continents. DESIGN AND SETTINGS: Cross-sectional twin study. Data obtained from a total of 23 twin birth-cohorts from four countries: Canada, Sweden, Denmark, and Australia. Participants were Monozygotic (MZ) and dizygotic (DZ) (same- and opposite-sex) twin pairs with data available for both height and weight at a given age, from birth through 19 years of age. Approximately 24,036 children were included in the analyses. RESULTS: Heritability for body weight, height, and BMI was low at birth (between 6.4 and 8.7% for boys, and between 4.8 and 7.9% for girls) but increased over time, accounting for close to half or more of the variance in body weight and BMI after 5 months of age in both sexes. Common environmental influences on all body measures were high at birth (between 74.1-85.9% in all measures for boys, and between 74.2 and 87.3% in all measures for girls) and markedly reduced over time. For body height, the effect of the common environment remained significant for a longer period during early childhood (up through 12 years of age). Sex-limitation of genetic and shared environmental effects was observed. CONCLUSION: Genetics appear to play an increasingly important role in explaining the variation in weight, height, and BMI from early childhood to late adolescence, particularly in boys. Common environmental factors exert their strongest and most independent influence specifically in pre-adolescent years and more significantly in girls. These findings emphasize the need to target family and social environmental interventions in early childhood years, especially for females. As gene-environment correlation and interaction is likely, it is also necessary to identify the genetic variants that may predispose individuals to obesity.

Gene-environment processes linking aggression, peer victimization, and the teacher-child relationship.

Aggressive behavior in middle childhood is at least partly explained by genetic factors. Nevertheless, estimations of simple effects ignore possible gene-environment interactions (G × E) or gene-environment correlations (rGE) in the etiology of aggression. The present study aimed to simultaneously test for G × E and rGE processes between aggression, on the one hand, and peer victimization and the teacher-child relationship in school, on the other hand. The sample comprised 124 MZ pairs and 93 DZ pairs assessed in Grade 1 (mean age = 84.7 months). Consistent with rGE, children with a presumed genetic disposition for aggression were at an increased risk of peer victimization, whereas in line with G × E, a positive relationship with the teacher mitigated the genetically mediated expression of aggression.

Altered patterns of brain activity during transient sadness in children at familial risk for major depression.

INTRODUCTION: We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of sadness, the prevailing mood in major depression (MD), in a prospective, well-documented community sample followed since birth. METHODS: The children, comprising 136 children (65 boys and 71 girls) of mothers with varying levels of depressive symptomatology, were scanned - using a 1.5-Tesla system - while they watched 5 blocks of both sad and neutral film excerpts. Following scanning, they rated the emotions they experienced, and if they identified sadness, they were also asked to rate its intensity. RESULTS: In children whose mothers exhibited higher depressive symptomatology, compared to children whose mothers displayed lower depressive symptomatology, altered neural responses to sad film excerpts were noted in brain regions known to be involved in sadness and MD, notably the insula, anterior cingulate cortex and caudate nucleus, even though the children did not differ in current mood. LIMITATIONS: Whether this represents genetic vulnerability or a consequence of exposure to maternal depressive symptoms at a young age is unknown. DISCUSSION: The results are consistent with the results of studies in healthy adults and MD patients. The present study suggests that an altered pattern of regional brain responses to sad stimuli, is already present in childhood and might represent vulnerability for MD later in life.

Early influence of the rs4675690 on the neural substrates of sadness.

BACKGROUND: CREB1 has previously been implicated in mood disorders, suicide, and antidepressant response. There is some evidence that the T allele in rs4675690, a single-nucleotide polymorphism near the CREB1 gene, is involved in the modulation of neural responses to negative stimuli. It is not known whether differential brain activity during negative mood state appears early in life in T allele carriers. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure brain activity, during a transient state of sadness, in children homozygous for the T allele or the C allele. This primary emotion was selected given that it is the prevailing mood in major depressive disorder (MDD). Blood-oxygen-level dependent (BOLD) signal changes were measured while subjects viewed blocks of neutral film excerpts and blocks of sad film excerpts. RESULTS: There was significantly greater BOLD activation in the TT group, compared to the CC group, in the right dorsal anterior cingulate cortex (Brodmann area [BA 24]), right putamen, right caudate nucleus and left anterior temporal pole (BA 21), when the brain activity associated with the viewing of the emotionally neutral film excerpts was subtracted from that associated with the viewing of the sad film excerpts. LIMITATIONS: A replication study using larger samples may be required for more definitive conclusions. CONCLUSIONS: The different pattern of regional brain activation found here during transient sadness - in children carrying the T allele, compared to those carrying the C allele - might increase later in life susceptibility to emotional dysregulation and depressive symptoms.

Neuroanatomy of childhood disruptive behavior disorders.

Our aims were to (1) examine possible neuroanatomical abnormalities associated with the Disruptive Behavior Disorders (DBDs) as a group and (2) assess neuroanatomical anomalies specific to each DBD (i.e., conduct disorder [CD] and oppositional defiant disorder). Cortical thickness analysis and voxel-based morphometry were analyzed in 47 8-year-old boys (22 DBDs with and without CD and/or ODD and 25 healthy controls) from Magnetic Resonance Imaging brain scans. DBD symptoms were assessed using the Dominic-R. In DBD subjects relative to controls, we found (1) a decreased overall mean cortical thickness; (2) thinning of the cingulate, prefrontal and insular cortices; and (3) decreased gray matter density (GMd) in the same brain regions. We also found that scores on the Dominic-R were negatively correlated with GMd in the prefrontal and precuneus/superior temporal regions. There was a subdiagnostic main effect for CD, related to thinning of the middle/medial frontal, and for ODD in the left rectal/orbitofrontal. Findings suggest that thinning and decreased GMd of the insula disorganizes prefrontal circuits, diminishing the inhibitory influence of the prefrontal cortex on anger, aggression, cruelty, and impulsivity, and increasing a person's likelihood of aggressive behavior. These findings have implications for pathophysiologic models of the DBDs, their diagnostic classification system, and for designing more effective intervention programs.

Salivary cortisol levels are associated with resource control in a competitive situation in 19 month-old boys.

Glucocorticoids (GCs) have been related to social rank in many studies across species, a particular rank giving rise to a particular stress-related physiological profile. Our aim was to examine the hypothesis that GCs levels in toddlers would be related to social dominance in a competitive resource situation. Subjects were 376 toddlers from the Quebec Newborn Twin Study. At 19 months of age, each subject was exposed to 2 unfamiliar situations known to be moderately stressful at that age. Saliva was collected before and after the unfamiliar situations, to assess pre-test and reactive cortisol. Then the toddler reaction to a competitive situation for a toy with an unfamiliar peer was assessed and we measured the proportion of time the child controlled the resource. In girls, no association between cortisol levels and the proportion of time the child got the toy was found. On the other hand, in boys, increased cortisol levels before the unfamiliar situation were significantly related to a decreased proportion of time they got the toy in the competitive situation (r(174) = -0.17, P = 0.02). These results show that even in toddlers with limited social experience, association between GCs levels and social dominance can be found, an association that is specific to boys.

A monozygotic twin difference study of friends' aggression and children's adjustment problems.

This study used the monozygotic (MZ) twin difference method to examine whether differences in friends' aggression increased the differences in MZ twins' aggression and depressive symptoms from kindergarten to Grade 1 and whether perceived victimization by the friend played a mediating role in this context. Participants were 223 MZ twin pairs. Results showed that differences in kindergarten friends' aggression significantly predicted an increased difference in MZ twins' aggression from kindergarten (mean age = 6.7 years) to Grade 1 (mean age = 7.5 years) for both boys and girls. Differences in perceived victimization by the friend mediated this association, albeit only in boys. Differences in perceived victimization by the friend also predicted an increase in MZ twins' differences in depressive symptoms. These results support the importance of friendship experiences during early childhood.

Genetic and environmental influences on structural variability of the brain in pediatric twin: deformation based morphometry.

Twin studies are one of the most powerful study designs for estimating the relative contribution of genetic and environmental influences on phenotypic variation inhuman brain morphology. In this study, we applied deformation based morphometry, a technique that provides a voxel-wise index of local tissue growth or atrophy relative to a template brain, combined with univariate ACE model, to investigate the genetic and environmental effects on the human brain structural variations in a cohort of homogeneously aged healthy pediatric twins. In addition, anatomical regions of interest (ROIs) were defined in order to explore global and regional genetic effects. ROI results showed that the influence of genetic factors on cerebrum (h(2)=0.70), total gray matter (0.67), and total white matter (0.73) volumes were significant. In particular, structural variability of left-side lobar volumes showed a significant heritability. Several subcortical structures such as putamen (h(ROI)(2)=0.79/0.77(L/R),h(MAX)(2)=0.82/0.79) and globus pallidus (0.81/0.76, 0.88/0.82) were also significantly heritable in both voxel-wise and ROI-based results. In the voxel-wise results, lateral parts of right cerebellum (c(2)=0.68) and the posterior portion of the corpus callosum (0.63) were rather environmentally determined, but it failed to reach statistical significance. Pediatric twin studies are important because they can discriminate several influences on developmental brain trajectories and identify relationships between gene and behavior. Several brain structures showed significant genetic effects and might therefore serve as biological markers for inherited traits, or as targets for genetic linkage and association studies.

Genetic and environmental etiology of disregard for rules.

Disregard for rules, a key component of oppositional defiant and conduct disorders, is stable during early childhood. This study investigates for the first time the relative importance of genetic and environmental factors underlying this early developmental stability. Maternal reports of child disregard for rules were obtained at four time points from 20 to 64 months of age in a population-based twin sample (N = 597 twin pairs, including 238 monozygotic and 359 dizygotic pairs). Structural equation modeling was conducted using both variance-covariance and latent growth curve approaches. Genetic factors accounted for most of the stability in disregard for rules throughout early childhood. In contrast, most environmental effects were age specific. Developmental stability in early symptoms of disregard for rules is best explained by the stable action of genetic factors, suggesting that preventive interventions should take an intergenerational approach, targeting at-risk families as early as possible.

Prenatal alcohol exposure and cortisol activity in 19-month-old toddlers: an investigation of the moderating effects of sex and testosterone.

RATIONALE: Early exposure to stress and teratogenic substances have an impact on brain structures involved in cognition and mental health. While moderate-to-high levels of prenatal alcohol exposure (PAE) have repeatedly been associated with long-term neurodevelopmental deficits, no consensus has yet been reached on the detrimental effects of low-to-moderate PAE on the children's functioning, including the limbic-hypothalamic-pituitary-adrenal axis. OBJECTIVES: The study aims to examine the association between low PAE and cortisol response to unfamiliar situations in 19-month-old children and to determine whether this association was moderated by sex and testosterone levels. METHODS: Information regarding PAE, cortisol response to unfamiliar situations, and testosterone activity was available in a total of 130 children participating to the Québec Newborn Twin Study (Montréal, QC, Canada). Mother alcohol consumption during pregnancy was assessed via a semistructured interview conducted when the children were 6 months of age. The contribution of prenatal and postnatal confounds were examined. RESULTS: Disrupted patterns of cortisol activity were observed only in PAE males. Testosterone tended to be negatively associated with the cortisol response, but not for PAE males, suggesting an altered sensitivity to the inhibitory effects of testosterone in these participants. CONCLUSIONS: Low levels of PAE were associated with disrupted cortisol activity, and males may be at higher risk. These findings challenge the existence of a "safe level" of alcohol consumption during pregnancy and have public health implications.