Decomposing Neural Representational Patterns of Discriminatory and Hedonic Information during Somatosensory Stimulation.

The ability to interrogate specific representations in the brain, determining how, and where, difference sources of information are instantiated can provide invaluable insight into neural functioning. Pattern component modeling (PCM) is a recent analytic technique for human neuroimaging that allows the decomposition of representational patterns in brain into contributing subcomponents. In the current study, we present a novel PCM variant that tracks the contribution of prespecified representational patterns to brain representation across areas, thus allowing hypothesis-guided employment of the technique. We apply this technique to investigate the contributions of hedonic and nonhedonic information to the neural representation of tactile experience. We applied aversive pressure (AP) and appetitive brush (AB) to stimulate distinct peripheral nerve pathways for tactile information (C-/CT-fibers, respectively) while patients underwent functional magnetic resonance imaging (fMRI) scanning. We performed representational similarity analyses (RSAs) with pattern component modeling to dissociate how discriminatory versus hedonic tactile information contributes to population code representations in the human brain. Results demonstrated that information about appetitive and aversive tactile sensation is represented separately from nonhedonic tactile information across cortical structures. This also demonstrates the potential of new hypothesis-guided PCM variants to help delineate how information is instantiated in the brain.

Associations of peripheral blood DNA methylation and estimated monocyte proportion differences during infancy with toddler attachment style.

Attachment is a motivational system promoting felt security to a caregiver resulting in a persistent internal working model of interpersonal behavior. Attachment styles are developed in early social environments and predict future health and development outcomes with potential biological signatures, such as epigenetic modifications like DNA methylation (DNAm). Thus, we hypothesized infant DNAm would associate with toddler attachment styles. An epigenome-wide association study (EWAS) of blood DNAm from 3-month-old infants was regressed onto children's attachment style from the Strange Situation Procedure at 22-months at multiple DNAm Cytosine-phosphate-Guanine (CpG) sites. The 26 identified CpGs associated with proinflammatory immune phenotypes and cognitive development. In post-hoc analyses, only maternal cognitive-growth fostering, encouraging intellectual exploration, contributed. For disorganized children, DNAm-derived cell-type proportions estimated higher monocytes -cells in immune responses hypothesized to increase with early adversity. Collectively, these findings suggested the potential biological embedding of both adverse and advantageous social environments as early as 3-months-old.

Prenatal exposure to phthalates and peripheral blood and buccal epithelial DNA methylation in infants: An epigenome-wide association study.

BACKGROUND: Prenatal exposure to phthalates has been associated with adverse health and neurodevelopmental outcomes. DNA methylation (DNAm) alterations may be a mechanism underlying these effects, but prior investigations of prenatal exposure to phthalates and neonatal DNAm profiles are limited to placental tissue and umbilical cord blood. OBJECTIVE: Conduct an epigenome-wide association study (EWAS) of the associations between prenatal exposure to phthalates and DNAm in two accessible infant tissues, venous buffy coat blood and buccal epithelial cells (BECs). METHODS: Participants included 152 maternal-infant pairs from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Maternal second trimester urine samples were analyzed for nine phthalate metabolites. Blood (n = 74) or BECs (n = 78) were collected from 3-month-old infants and profiled for DNAm using the Infinium HumanMethylation450 (450K) BeadChip. Robust linear regressions were used to investigate the associations between high (HMWPs) and low molecular weight phthalates (LMWPs) and change in methylation levels at variable Cytosine-phosphate-Guanine (CpG) sites in infant tissues, as well as the sensitivity of associations to potential confounders. RESULTS: One candidate CpG in gene RNF39 reported by a previous study examining prenatal exposure to phthalates and cord blood DNAm was replicated. The EWAS identified 12 high-confidence CpGs in blood and another 12 in BECs associated with HMWPs and/or LMWPs. Prenatal exposure to bisphenol A (BPA) associated with two of the CpGs associated with HMWPs in BECs. DISCUSSION: Prenatal exposure to phthalates was associated with DNAm variation at CpGs annotated to genes associated with endocrine hormone activity (i.e., SLCO4A1, TPO), immune pathways and DNA damage (i.e., RASGEF1B, KAZN, HLA-A, MYO18A, DIP2C, C1or109), and neurodevelopment (i.e., AMPH, NOTCH3, DNAJC5). Future studies that characterize the stability of these associations in larger samples, multiple cohorts, across tissues, and investigate the potential associations between these biomarkers and relevant health and neurodevelopmental outcomes are needed.

Infant DNA methylation: an early indicator of intergenerational trauma?

Exposure to adverse childhood experiences (ACEs) increases risk for mental and physical health problems. Intergenerationally, mothers' ACEs predict children's health problems including neurodevelopmental and behavioural problems and poorer physical health. Theories of intergenerational trauma suggest that ACEs experienced in one generation negatively affect the health and well-being of future generations, with DNA methylation (DNAm) being one of several potential biological explanations. To begin exploring this hypothesis, we tested whether infant DNA methylation associated with intergenerational trauma. Secondary analysis employed data from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Subsample data were collected from mothers during pregnancy and postpartum on measures of distress, stress and ACEs and from infants at 3 months of age on DNAm from blood (n = 92) and buccal epithelial cells (BECs; n = 124; primarily nonoverlapping individuals between tissues). Blood and BECs were examined in separate analyses. Preliminary associations identified in blood and BECs suggest that infant DNAm patterns may relate to maternal ACEs. For the majority of ACE-related DNAm sites, neither maternal perinatal distress, nor maternal cortisol awakening response (CAR; a measure of hypothalamic-pituitary-adrenocortical axis function), substantially reduced associations between maternal ACEs and infant DNAm. However, accounting for maternal perinatal distress and cortisol substantially changed the effect of ACEs in a greater proportion of blood DNAm sites than BEC DNAm sites in the top ACEs-associated correlated methylated regions (CMRs), as well as across all CMRs and all remaining CpGs (that did not fall into CMRs). Possible DNAm patterns in infants, thus, might capture a signature of maternal intergenerational trauma, and this effect appears to be more dependent on maternal perinatal distress and CAR in blood relative to BECs.

Sex differences in the genetic regulation of the blood transcriptome response to glucocorticoid receptor activation.

Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. Here, we explore the genomic variants in 93 females and 196 males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation. Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation. Sex stratified analyses revealed that while the transcripts responsive to GR-stimulation were mostly overlapping between males and females, the quantitative trait loci (eQTLs) regulation differential transcription to GR-stimulation was distinct. Sex-stratified eQTL SNPs (eSNPs) were located in different functional genomic elements and sex-stratified transcripts were enriched within postmortem brain transcriptional profiles associated with Major Depressive Disorder (MDD) specifically in males and females in the cingulate cortex. Female eSNPs were enriched among SNPs linked to MDD in genome-wide association studies. Finally, transcriptional sensitive genetic profile scores derived from sex-stratified eSNPS regulating differential transcription to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). These results suggest the potential of eQTLs regulating differential transcription to GR-stimulation as biomarkers of sex-specific biological risk for stress-related psychiatric disorders.

Paternal adverse childhood experiences: Associations with infant DNA methylation.

Adverse childhood experiences (ACEs), or cumulative childhood stress exposures, such as abuse, neglect, and household dysfunction, predict later health problems in both the exposed individuals and their offspring. One potential explanation suggests exposure to early adversity predicts epigenetic modification, especially DNA methylation (DNAm), linked to later health. Stress experienced preconception by mothers may associate with DNAm in the next generation. We hypothesized that fathers' exposure to ACEs also associates with their offspring DNAm, which, to our knowledge, has not been previously explored. An epigenome-wide association study (EWAS) of blood DNAm (n = 45) from 3-month-old infants was regressed onto fathers' retrospective ACEs at multiple Cytosine-phosphate-Guanosine (CpG) sites to discover associations. This accounted for infants' sex, age, ethnicity, cell type proportion, and genetic variability. Higher ACE scores associated with methylation values at eight CpGs. Post-hoc analysis found no contribution of paternal education, income, marital status, and parental postpartum depression, but did with paternal smoking and BMI along with infant sleep latency. These same CpGs also contributed to the association between paternal ACEs and offspring attention problems at 3 years. Collectively, these findings suggested there were biological associations with paternal early life adversity and offspring DNAm in infancy, potentially affecting offspring later childhood outcomes.

DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis.

The stress response system is disrupted in individuals with major depressive disorder (MDD) as well as in those at elevated risk for developing MDD. We examined whether DNA methylation (DNAm) levels of CpG sites within HPA-axis genes predict the onset of MDD. Seventy-seven girls, approximately half (n = 37) of whom were at familial risk for MDD, were followed longitudinally. Saliva samples were taken in adolescence (M age = 13.06 years [SD = 1.52]) when participants had no current or past MDD diagnosis. Diagnostic interviews were administered approximately every 18 months until the first onset of MDD or early adulthood (M age of last follow-up = 19.23 years [SD = 2.69]). We quantified DNAm in saliva samples using the Illumina EPIC chip and examined CpG sites within six key HPA-axis genes (NR3C1, NR3C2, CRH, CRHR1, CRHR2, FKBP5) alongside 59 genotypes for tagging SNPs capturing cis genetic variability. DNAm levels within CpG sites in NR3C1, CRH, CRHR1, and CRHR2 were associated with risk for MDD across adolescence and young adulthood. To rule out the possibility that findings were merely due to the contribution of genetic variability, we re-analyzed the data controlling for cis genetic variation within these candidate genes. Importantly, methylation levels in these CpG sites continued to significantly predict the onset of MDD, suggesting that variation in the epigenome, independent of proximal genetic variants, prospectively predicts the onset of MDD. These findings suggest that variation in the HPA axis at the level of the methylome may predict the development of MDD.

Touch-induced face conditioning is mediated by genetic variation in opioid but not oxytocin receptors.

Soft touch possesses strong prosocial effects that facilitate social bonding and group cohesion in animals. Touch activates opioids (OP) and oxytocin (OXT), two neuromodulators involved in affiliative behaviors and social bonding. We examined whether touch serves as an unconditioned reward in affective conditioning of human faces, a basic process in social bonding, and whether this process is mediated by variation in mu-OP (OPRM1) and OXT (rs53576) receptor genes. Participants viewed affectively-neutral human faces, half of which were paired with a brief soft brushing on the forearm as an unconditioned stimulus (US). Paired and unpaired faces were rated for positive affective and sensory features of touch. Variation in OPRM1 but not rs53576 significantly modulated strength and development of conditioning, indicating that touch-induced mu-OP but not OXT activity provides rewarding properties of a US in conditioning. Implications for touch-induced mu-OP activity in normal and disordered conditioned social bonding are discussed.

Principles and Challenges of Applying Epigenetic Epidemiology to Psychology.

The interplay of genetically driven biological processes and environmental factors is a key driver of research questions spanning multiple areas of psychology. A nascent area of research focuses on the utility of epigenetic marks in capturing this intersection of genes and environment, as epigenetic mechanisms are both tightly linked to the genome and environmentally responsive. Advances over the past 10 years have allowed large-scale assessment of one epigenetic mark in particular, DNA methylation, in human populations, and the examination of DNA methylation is becoming increasingly common in psychological studies. In this review, we briefly outline some principles of epigenetics, focusing on highlighting important considerations unique to DNA methylation studies to guide psychologists in incorporating DNA methylation into a project. We discuss study design and biological and analytical considerations and conclude by discussing interpretability of epigenetic findings and how these important factors are currently being applied across areas of psychology.

Epigenetic correlates of neonatal contact in humans.

Animal models of early postnatal mother-infant interactions have highlighted the importance of tactile contact for biobehavioral outcomes via the modification of DNA methylation (DNAm). The role of normative variation in contact in early human development has yet to be explored. In an effort to translate the animal work on tactile contact to humans, we applied a naturalistic daily diary strategy to assess the link between maternal contact with infants and epigenetic signatures in children 4-5 years later, with respect to multiple levels of child-level factors, including genetic variation and infant distress. We first investigated DNAm at four candidate genes: the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), µ-opioid receptor M1 (OPRM1) and oxytocin receptor (OXTR; related to the neurobiology of social bonds), and brain-derived neurotrophic factor (BDNF; involved in postnatal plasticity). Although no candidate gene DNAm sites significantly associated with early postnatal contact, when we next examined DNAm across the genome, differentially methylated regions were identified between high and low contact groups. Using a different application of epigenomic information, we also quantified epigenetic age, and report that for infants who received low contact from caregivers, greater infant distress was associated with younger epigenetic age. These results suggested that early postnatal contact has lasting associations with child biology.

Commentary: What is the case for candidate gene approaches in the era of high-throughput genomics? A response to Border and Keller (2017).

Border and Keller argue that candidate gene approaches are outdated and out-of-touch with the current understanding of the genetic architecture of complex behavioral traits and should be abandoned in favor of unbiased, genome-wide approaches. Border and Keller further suggest that a candidate gene should not be selected for in-depth investigation unless identified by a well-powered genome-wide association study (GWAS). An alternative perspective is offered that candidate approaches can be sensible for developmental and deep-phenotyping studies aimed at elucidating particular biological pathways responsible for the emergence of psychological phenotypes, and that candidates should not necessarily be expected to be confirmed by, or solely selected based on, GWAS. Both candidate and whole genome strategies have limitations, and each approach is useful and valid in the quest to identify the elusive genetic architecture of complex behavioral phenotypes.

Recollections of puberty and disordered eating in young women.

Puberty begins a period of vulnerability for disordered eating that is maintained and amplified through adolescence and early adulthood. In the present study, we test the association between young women's recollections of physical maturation and disordered eating outcomes in early adulthood. Participants comprised N = 421 female undergraduate students at a large, northeastern university in the United States (Mage = 19.7 years). Three models assessed the relative contributions of recollected puberty (perceptions of changes and preparedness, and timing of puberty), current contextual (social support, romantic bond, sorority or sport participation), and demographic (race, socioeconomic status, family structure) variables to three eating-disorder outcomes. Recollections of feeling unprepared and disliking the physical changes of puberty predicted eating disorder symptoms more than any other demographic or current contextual factor. Results indicate that how young women experience the pubertal transition is related to eating disorder symptoms many years later.

What is the biological reality of gene-environment interaction estimates? An assessment of bias in developmental models.

BACKGROUND: Standard models used to test gene-environment interaction (G × E) hypotheses make the causal assumption that there are no unobserved variables that could be biasing the interaction estimate. Whether this assumption can be met in nonexperimental studies is unclear because the interactive biological pathways from genetic polymorphisms and environments to behavior, and the confounders that can be introduced along these pathways, are often not delineated. This is problematic in the context of studies focused on caregiver-child dyads, in which common genes and environments induce gene-environment correlation. To address the impact of sources of bias in G × E models specifically assessing the interaction between child genotype and caregiver behavior, we provide a causal framework that integrates biological and statistical concepts of G × E, and assess the magnitude of bias introduced by various confounding pathways in different causal circumstances. METHODS: A simulation assessed the magnitude of bias introduced by four types of confounding pathways in different causal models. Unadjusted and adjusted statistical models were then applied to the simulated data to assess the efficacy of these procedures to capture unbiased G × E estimates. Finally, the simulation was run under null effects of the genotype to assess the impact of biasing sources on the false-positive rate. RESULTS: Common environmental pathways between caregiver and child inflated G × E estimates and raised the false-positive rate. Evocative effects of the child also inflated G × E estimates. CONCLUSIONS: Gene-environment interaction studies should be approached with consideration to the causal pathways at play and the confounding opportunities along these pathways to facilitate the inclusion of adequate statistical controls and correct inferences from study findings. Bridging biological and statistical concepts of G × E can significantly improve research design and the communication of how a G × E process fits into a broader developmental framework.

Puberty, Socioeconomic Status, and Depression in Girls: Evidence for Gene × Environment Interactions.

In the current study, we tested for Gene × Environment interactions in the association between pubertal timing and adolescent depression by examining how socioeconomic factors might moderate age at menarche's relation with depressive symptoms. Participants comprised 630 female twin and sibling pairs from the National Longitudinal Study of Adolescent Health. Consistent with previous studies, results showed that genetic predispositions toward later menarche were associated with fewer depressive symptoms and that genetic predispositions toward earlier menarche were associated with more depressive symptoms. However, this pattern was subtle and evident only in girls from higher socioeconomic backgrounds. Although girls from lower socioeconomic families showed the highest overall levels of depression, their symptoms appeared unrelated to timing of physical development through either a genetic or an environmental path.

Neurobehavioral foundation of environmental reactivity.

Sensitivity to environmental context has been of interest for many years, but the nature of individual differences in environmental sensitivity has become of particular focus over the past 2 decades. What is particularly uncertain are the neural variables and processes that mediate the effects of environment on developmental outcomes. Accordingly, we provide a neurobehavioral foundation of reactivity to the environment in several steps. First, the different patterns of environmental sensitivity are defined to identify the significant factors involved in the manifestation of these patterns. Second, we focus on neurobiological reactivity as the construct underlying variation in sensitivity to the environment by (a) providing an organizing threshold model of elicitation of neurobiology by environmental context; and (b) integrating the literature on 2 sets of neuromodulators in terms of each modulator's (a) contribution to neural and behavioral reactivity to stimulation, and (b) relation to emotional-motivational systems (dopamine, opiates and oxytocin, corticotropin-releasing hormone) or the general modulation of those systems (serotonin, norepinephrine, and GABA). Discussion concludes with (a) a comprehensive neurobehavioral framework of environmental reactivity based on a combinatorial model of a supertrait, (b) methodological implications of the model, and (c) a developmental perspective on environmental reactivity.

Social traits modulate attention to affiliative cues.

Neurobehavioral models of personality suggest that the salience assigned to particular classes of stimuli vary as a function of traits that reflect both the activity of neurobiological encoding and relevant social experience. In turn, this joint influence modulates the extent that salience influences attentional processes, and hence learning about and responding to those stimuli. Applying this model to the domain of social valuation, we assessed the differential effects on attentional guidance by affiliative cues of (i) a higher-order temperament trait (Social Closeness), and (ii) attachment style in a sample of 57 women. Attention to affiliative pictures paired with either incentive or neutral pictures was assessed using camera eye-tracking. Trait social closeness and attachment avoidance interacted to modulate fixation frequency on affiliative but not on incentive pictures, suggesting that both traits influence the salience assigned to affiliative cues specifically.

Descriptive review: hormonal influences on risk for eating disorder symptoms during puberty and adolescence.

OBJECTIVE: Puberty is an important period of risk for the onset of eating pathology in adolescent females. This review focuses on changes in reproductive hormones during puberty as one specific psychopathogenic mechanism. METHOD: Studies of puberty and eating disorder-related phenotypes were identified using search databases and the reference sections of previous literature. RESULTS: Correlational studies of adult women and experimental studies of animals provide evidence for the effects of reproductive hormones on eating disorder symptoms. Very few studies of puberty, however, have directly measured or tested the effects of hormonal change in samples of human adolescents. Commonly used measures of pubertal development, such as menarche or self-reported pubertal status, are relatively poor indicators of individual differences in hormones. The extent to which puberty-related hormonal change accounts for elevated risk for disordered eating remains unclear. DISCUSSION: Future research is necessary to elucidate the specific relations between hormonal change during puberty and risk for disordered eating. In particular, there is a need for longitudinal studies with multivariate measurement of pubertal development, including direct measures of change in reproductive hormones.

Pubertal timing and adolescent sexual behavior in girls.

Girls who experience earlier pubertal timing relative to peers also exhibit earlier timing of sexual intercourse and more unstable sexual relationships. Although pubertal development initiates feelings of physical desire, the transition into romantic and sexual relationships involves complex biological and social processes contributing both to physical maturation and to individual interpretations of pubertal experiences. Using a sample of female sibling pairs (n = 923 pairs) from the National Longitudinal Study of Adolescent Health, the present study investigated associations among menarche and perceived pubertal timing, age of first sexual intercourse (AFI), and adolescent dating and sexual behavior using a behavioral genetic approach. Genetic factors influencing age at menarche and perceived pubertal timing predicted AFI through shared genetic pathways, whereas genetic factors related only to perceived pubertal timing predicted engagement in dating, romantic sex, and nonromantic sex in the previous 18 months. These results suggest that a girl's interpretation of her pubertal timing beyond objective timing is important to consider for the timing and the contexts of romantic and reproductive behavior.

Connectedness and suicide prevention in adolescents: pathways and implications.

Adolescent suicide is a major public health concern. Stressing the need for public health-based solutions, the Centers for Disease Control and Prevention identified "connectedness" as one means of pursuing this agenda. To advance this effort in suicide prevention with adolescents, (1) consistencies and variation in the literature overtly linking connectedness to suicide thoughts and behaviors (STB) are reviewed, (2) three more specific mechanistic pathways are proposed whereby connectedness may influence STB, and (3) several implications related to use of connectedness as a public health framework for adolescent suicide prevention and intervention are outlined.