Structural architecture and brain network efficiency link polygenic scores to intelligence.

Intelligence is highly heritable. Genome-wide association studies (GWAS) have shown that thousands of alleles contribute to variation in intelligence with small effect sizes. Polygenic scores (PGS), which combine these effects into one genetic summary measure, are increasingly used to investigate polygenic effects in independent samples. Whereas PGS explain a considerable amount of variance in intelligence, it is largely unknown how brain structure and function mediate this relationship. Here, we show that individuals with higher PGS for educational attainment and intelligence had higher scores on cognitive tests, larger surface area, and more efficient fiber connectivity derived by graph theory. Fiber network efficiency as well as the surface of brain areas partly located in parieto-frontal regions were found to mediate the relationship between PGS and cognitive performance. These findings are a crucial step forward in decoding the neurogenetic underpinnings of intelligence, as they identify specific regional networks that link polygenic predisposition to intelligence.

Early childhood deprivation is associated with alterations in adult brain structure despite subsequent environmental enrichment.

Early childhood deprivation is associated with higher rates of neurodevelopmental and mental disorders in adulthood. The impact of childhood deprivation on the adult brain and the extent to which structural changes underpin these effects are currently unknown. To investigate these questions, we utilized MRI data collected from young adults who were exposed to severe deprivation in early childhood in the Romanian orphanages of the Ceaușescu era and then, subsequently adopted by UK families; 67 Romanian adoptees (with between 3 and 41 mo of deprivation) were compared with 21 nondeprived UK adoptees. Romanian adoptees had substantially smaller total brain volumes (TBVs) than nondeprived adoptees (8.6% reduction), and TBV was strongly negatively associated with deprivation duration. This effect persisted after covarying for potential environmental and genetic confounds. In whole-brain analyses, deprived adoptees showed lower right inferior frontal surface area and volume but greater right inferior temporal lobe thickness, surface area, and volume than the nondeprived adoptees. Right medial prefrontal volume and surface area were positively associated with deprivation duration. No deprivation-related effects were observed in limbic regions. Global reductions in TBV statistically mediated the observed relationship between institutionalization and both lower intelligence quotient (IQ) and higher levels of attention deficit/hyperactivity disorder symptoms. The deprivation-related increase in right inferior temporal volume seemed to be compensatory, as it was associated with lower levels of attention deficit/hyperactivity disorder symptoms. We provide compelling evidence that time-limited severe deprivation in the first years of life is related to alterations in adult brain structure, despite extended enrichment in adoptive homes in the intervening years.

Exploring hair steroid concentrations in asylum seekers, internally displaced refugees, and immigrants.

The study of physiology in response to war and forced displacement can yield insight into the origin of stress-related mental health disorders. Previous studies found alterations in hair cortisol concentrations (HCC) in refugees. However, the direction of this alteration in HCC, as well as the association between HCC and psychological stress, remain unclear. Mixed findings can potentially be explained by the lack of contextual factors that have been taken into account. In this explorative study, we investigated HCCs in three female refugee samples (N = 89) in different contexts. Samples were i) asylum seekers from Syria, who sought protection in Germany two years ago (n = 37), ii) internally displaced persons (IDPs), who fled a genocide and lived in conditions of onging insecurity in Iraq (n = 14), and iii) Kurdish immigrants and former asylum seekers, who resettled to Germany 18 years ago and were used as reference group (n = 38). HCC was assessed in the scalp-nearest 6 cm of hair (2*3 cm segments). Data on mental and physical health, exposure to traumatic events, and time between immigration and HCC assessments were collected. Syrian asylum seekers had lower HCC than immigrant controls (η2 = .06). PTSD symptoms and perceived stress were associated with elevated cortisol levels in IDPs (r = .66 and r = .56), while time since immigration was associated with cortisol levels only in immigrant controls (r = .38). We discuss our findings with regard to the importance of contextual factors, particularly time since displacement and on-going insecurity, when studying physiological reactions in refugees.Lay summaryFemale Syrian asylum seekers had lower levels of hair cortisol concentration than Kurdish immigrants in Germany. Hair cortisol concentration was associated with post-traumatic stress symptoms only in internally displaced women who were exposed to ongoing stress and insecurity in Iraq.

Why does early childhood deprivation increase the risk for depression and anxiety in adulthood? A developmental cascade model.

BACKGROUND: Using data from the English & Romanian Adoptees (ERA) study, we recently reported that early time-limited exposure to severe institutional deprivation is associated with early-onset and persistent neurodevelopmental problems and later-onset emotional problems. Here, we examine possible reasons for the late emergence of emotional problems in this cohort. Our main focus is on testing a developmental cascade mediated via the functional impact of early-appearing neurodevelopmental problems on late adolescent functioning. We also explore a second putative pathway via sensitization to stress. METHODS: The ERA study includes 165 Romanian individuals who spent their early lives in grossly depriving institutions and were subsequently adopted into UK families, along with 52 UK adoptees with no history of deprivation. Age six years symptoms of neurodevelopmental problems and age 15 anxiety/depression symptoms were assessed via parental reports. Young adult symptoms of depression and anxiety were assessed by both parent and self-reports; young adults also completed measures of stress reactivity, exposure to adverse life events, and functioning in work and interpersonal relationships. RESULTS: The path between early institutional deprivation and adult emotional problems was mediated via the impact of early neurodevelopmental problems on unemployment and poor friendship functioning during the transition to adulthood. The findings with regard to early deprivation, later life stress reactivity, and emotional problems were inconclusive. CONCLUSIONS: Our analysis suggests that the risk for adult depression and anxiety following extreme institutional deprivation is explained through the effects of early neurodevelopmental problems on later social and vocational functioning. Future research should more fully examine the role of stress susceptibility in this model.

Adoptees' responses to separation from, and reunion with, their adoptive parent at age 4 years is associated with long-term persistence of autism symptoms following early severe institutional deprivation.

Institutionally deprived young children often display distinctive patterns of attachment, classified as insecure/other (INS/OTH), with their adoptive parents. The associations between INS/OTH and developmental trajectories of mental health and neurodevelopmental symptoms were examined. Age 4 attachment status was determined for 97 Romanian adoptees exposed to up to 24 months of deprivation in Romanian orphanages and 49 nondeprived UK adoptees. Autism, inattention/overactivity and disinhibited-social-engagement symptoms, emotional problems, and IQ were measured at 4, 6, 11, and 15 years and in young adulthood. Romanian adoptees with over 6 months deprivation (Rom>6) were more often classified as INS/OTH than UK and Romanian adoptees with less than 6 months deprivation combined. INS/OTH was associated with cognitive impairment at age 4 years. The interaction between deprivation, attachment status, and age for autism spectrum disorder assessment was significant, with greater symptom persistence in Rom>6 INS/OTH(+) than other groups. This effect was reduced when IQ at age 4 was controlled for. Age 4 INS/OTH in Rom>6 was associated with worse autism spectrum disorder outcomes up to two decades later. Its association with cognitive impairment at age 4 is consistent with INS/OTH being an early marker of this negative developmental trajectory, rather than its cause.

Child-to-adult neurodevelopmental and mental health trajectories after early life deprivation: the young adult follow-up of the longitudinal English and Romanian Adoptees study.

BACKGROUND: Time-limited, early-life exposures to institutional deprivation are associated with disorders in childhood, but it is unknown whether effects persist into adulthood. We used data from the English and Romanian Adoptees study to assess whether deprivation-associated adverse neurodevelopmental and mental health outcomes persist into young adulthood. METHODS: The English and Romanian Adoptees study is a longitudinal, natural experiment investigation into the long-term outcomes of individuals who spent from soon after birth to up to 43 months in severe deprivation in Romanian institutions before being adopted into the UK. We used developmentally appropriate standard questionnaires, interviews completed by parents and adoptees, and direct measures of IQ to measure symptoms of autism spectrum disorder, inattention and overactivity, disinhibited social engagement, conduct or emotional problems, and cognitive impairment (IQ score <80) during childhood (ages 6, 11, and 15 years) and in young adulthood (22-25 years). For analysis, Romanian adoptees were split into those who spent less than 6 months in an institution and those who spent more than 6 months in an institution. We used a comparison group of UK adoptees who did not experience deprivation. We used mixed-effects regression models for ordered-categorical outcome variables to compare symptom levels and trends between groups. FINDINGS: Romanian adoptees who experienced less than 6 months in an institution (n=67 at ages 6 years; n=50 at young adulthood) and UK controls (n=52 at age 6 years; n=39 at young adulthood) had similarly low levels of symptoms across most ages and outcomes. By contrast, Romanian adoptees exposed to more than 6 months in an institution (n=98 at ages 6 years; n=72 at young adulthood) had persistently higher rates than UK controls of symptoms of autism spectrum disorder, disinhibited social engagement, and inattention and overactivity through to young adulthood (pooled p<0·0001 for all). Cognitive impairment in the group who spent more than 6 months in an institution remitted from markedly higher rates at ages 6 years (p=0·0001) and 11 years (p=0·0016) compared with UK controls, to normal rates at young adulthood (p=0·76). By contrast, self-rated emotional symptoms showed a late-onset pattern with minimal differences versus UK controls at ages 11 years (p=0·0449) and 15 years (p=0·17), and then marked increases by young adulthood (p=0·0005), with similar effects seen for parent ratings. The high deprivation group also had a higher proportion of people with low educational achievement (p=0·0195), unemployment (p=0·0124), and mental health service use (p=0·0120, p=0·0032, and p=0·0003 for use when aged <11 years, 11-14 years, and 15-23 years, respectively) than the UK control group. A fifth (n=15) of individuals who spent more than 6 months in an institution were problem-free at all assessments. INTERPRETATION: Notwithstanding the resilience shown by some adoptees and the adult remission of cognitive impairment, extended early deprivation was associated with long-term deleterious effects on wellbeing that seem insusceptible to years of nurturance and support in adoptive families. FUNDING: Economic and Social Research Council, Medical Research Council, Department of Health, Jacobs Foundation, Nuffield Foundation.

The Return of Fear: Variation of the Serotonin Transporter Gene Predicts Outcome of a Highly Standardized Exposure-Based One-Session Fear Treatment.

BACKGROUND: Methodological problems of existing research, such as the application of unstandardized treatments in heterogeneous samples, has hampered clear conclusions about the extent and direction to which allelic variation of the serotonin transporter gene-linked polymorphic region (5- HTTLPR) is associated with a differential response to psychological treatment. The present study aimed to investigate the effects of the 5-HTTLPR genotype on treatment outcome under highly standardized environmental conditions. METHODS: We treated 222 medication-free adults highly fearful of spiders, dental surgeries or blood, injuries and injections with a highly standardized exposure-based 1-session treatment and genotyped them for the 5-HTTLPR. Participants' subjective fear was assessed before, immediately after treatment and at 7 months of follow-up. RESULTS: There were no differences between 5-HTTLPR genotypes in treatment outcome effects at the immediate posttreatment assessment. However, we observed a highly significant genotype × treatment effect (p = 0.004) at the 7-month follow-up. Fear levels of homozygous S allele carriers differed from those heterozygous (p = 0.026) and homozygous (p = 0.012) for the L allele. Compared to posttreatment assessment, LL allele carriers exhibited a further fear decrease at the follow-up assessment. In contrast, SS allele carriers displayed a strong return of fear. CONCLUSIONS: Results suggest that genetic variation of the serotonin transporter is associated with differential stability of inhibitory learning processes, potentially reflecting heightened susceptibility for context-related processes that facilitate a return of fear in S allele carriers. If replicated, results suggest the 5-HTTLPR might represent a biomarker for the long-term outcome of brief exposure-based fear treatments and might inform genotype-based selection of psychotherapeutic interventions.

DNA methylation in candidate genes for handedness predicts handedness direction.

Handedness is a complex trait influenced by both genetic and non-genetic factors. Asymmetries of DNA methylation and gene expression in the developing foetus are thought to underlie its development. However, its molecular epigenetics are not well understood. We collected buccal cells from adult left- and right-handers (n = 60) to investigate whether epigenetic biomarkers of handedness can be identified in non-neuronal tissue. We associated DNA methylation in promoter regions of candidate genes with handedness direction. Results indicate that DNA methylation of genes asymmetrically expressed in the foetal brain or spinal cord might play a role within such a multifactorial model. Moreover, we provide tentative evidence that birth stress might be a factor that affects DNA methylation in NEUROD6, a gene that is asymmetrically expressed in foetal brains.

Serotonin transporter gene (SLC6A4) polymorphism and susceptibility to a home-visiting maternal-infant attachment intervention delivered by community health workers in South Africa: Reanalysis of a randomized controlled trial.

BACKGROUND: Clear recognition of the damaging effects of poverty on early childhood development has fueled an interest in interventions aimed at mitigating these harmful consequences. Psychosocial interventions aimed at alleviating the negative impacts of poverty on children are frequently shown to be of benefit, but effect sizes are typically small to moderate. However, averaging outcomes over an entire sample, as is typically done, could underestimate efficacy because weaker effects on less susceptible individuals would dilute estimation of effects on those more disposed to respond. This study investigates whether a genetic polymorphism of the serotonin transporter gene moderates susceptibility to a psychosocial intervention. METHODS AND FINDINGS: We reanalyzed data from a randomized controlled trial of a home-visiting program delivered by community health workers in a black, isiXhosa-speaking population in Khayelitsha, South Africa. The intervention, designed to enhance maternal-infant attachment, began in the third trimester and continued until 6 mo postpartum. Implemented between April 1999 and February 2003, the intervention comprised 16 home visits delivered to 220 mother-infant dyads by specially trained community health workers. A control group of 229 mother-infant dyads did not receive the intervention. Security of maternal-infant attachment was the main outcome measured at infant age 18 mo. Compared to controls, infants in the intervention group were significantly more likely to be securely attached to their primary caregiver (odds ratio [OR] = 1.7, p = 0.029, 95% CI [1.06, 2.76], d = 0.29). After the trial, 162 intervention and 172 control group children were reenrolled in a follow-up study at 13 y of age (December 2012-June 2014). At this time, DNA collected from 279 children (134 intervention and 145 control) was genotyped for a common serotonin transporter polymorphism. There were both genetic data and attachment security data for 220 children (110 intervention and 110 control), of whom 40% (44 intervention and 45 control) carried at least one short allele of the serotonin transporter gene. For these 220 individuals, carrying at least one short allele of the serotonin transporter gene was associated with a 26% higher rate of attachment security relative to controls (OR = 3.86, p = 0.008, 95% CI [1.42, 10.51], d = 0.75), whereas there was a negligible (1%) difference in security between intervention and control group individuals carrying only the long allele (OR = 0.95, p = 0.89, 95% CI [0.45, 2.01], d = 0.03). Expressed in terms of absolute risk, for those with the short allele, the probability of secure attachment being observed in the intervention group was 84% (95% CI [73%, 95%]), compared to 58% (95% CI [43%, 72%]) in the control group. For those with two copies of the long allele, 70% (95% CI [59%, 81%]) were secure in the intervention group, compared to 71% (95% CI [60%, 82%]) of infants in the control group. Controlling for sex, maternal genotype, and indices of socioeconomic adversity (housing, employment, education, electricity, water) did not change these results. A limitation of this study is that we were only able to reenroll 49% of the original sample randomized to the intervention and control conditions. Attribution of the primary outcome to causal effects of intervention in the present subsample should therefore be treated with caution. CONCLUSIONS: When infant genotype for serotonin transporter polymorphism was taken into account, the effect size of a maternal-infant attachment intervention targeting impoverished pregnant women increased more than 2.5-fold when only short allele carriers were considered (from d = 0.29 for all individuals irrespective of genotype to d = 0.75) and decreased 10-fold when only those carrying two copies of the long allele were considered (from d = 0.29 for all individuals to d = 0.03). Genetic differential susceptibility means that averaging across all participants is a misleading index of efficacy. The study raises questions about how policy-makers deal with the challenge of balancing equity (equal treatment for all) and efficacy (treating only those whose genes render them likely to benefit) when implementing psychosocial interventions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN25664149.

Adult disinhibited social engagement in adoptees exposed to extreme institutional deprivation: examination of its clinical status and functional impact.

BackgroundEarly-life institutional deprivation produces disinhibited social engagement (DSE). Portrayed as a childhood condition, little is known about the persistence of DSE-type behaviours into, presentation during, and their impact on, functioning in adulthood.AimsWe examine these issues in the young adult follow-up of the English and Romanian Adoptees study.MethodA total of 122 of the original 165 Romanian adoptees who had spent up to 43 months as children in Ceausescu's Romanian orphanages and 42 UK adoptees were assessed for DSE behaviours, neurodevelopmental and mental health problems, and impairment between ages 2 and 25 years.ResultsYoung adult DSE behaviour was strongly associated with early childhood deprivation, with a sixfold increase for those who spent more than 6 months in institutions. However, although DSE overlapped with autism spectrum disorder and attention-deficit hyperactivity disorder symptoms it was not, in itself, related to broader patterns of mental health problems or impairments in daily functioning in young adulthood.ConclusionsDSE behaviour remained a prominent, but largely clinically benign, young adult feature of some adoptees who experienced early deprivation.

Testosterone and androgen receptor gene polymorphism are associated with confidence and competitiveness in men.

A contribution to a special issue on Hormones and Human Competition. Studies in non-human animals and humans have demonstrated the important role of testosterone in competitive interactions. Here, we investigated whether endogenous testosterone levels predict the decision to compete, in a design excluding spite as a motive underlying competitiveness. In a laboratory experiment with real monetary incentives, 181 men solved arithmetic problems, first under a noncompetitive piece rate, followed by a competition incentive scheme. We also assessed several parameters relevant to competition, such as risk taking, performance, and confidence in one's own performance. Salivary testosterone levels were measured before and 20min after the competition task using mass spectrometry. Participants were also genotyped for the CAG repeat polymorphism of the androgen receptor gene, known to influence the efficacy of testosterone signaling in a reciprocal relationship to the number of CAG repeats. We observed a significant positive association between basal testosterone levels and the decision to compete, and that higher testosterone levels were related to greater confidence in one's own performance. Whereas the number of CAG repeats was not associated with the choice to compete, a lower number of CAG repeats was related to greater confidence in those who chose to compete, but this effect was attributable to the polymorphism's effect on actual performance. An increase in testosterone levels was observed following the experiment, and this increase varied with self-reported high-school math grades. We expand upon the latest research by documenting effects of the androgen system in confidence in one's own ability, and conclude that testosterone promotes competitiveness without spite.

Poverty, early care, and stress reactivity in adolescence: Findings from a prospective, longitudinal study in South Africa.

A considerable body of evidence suggests that early caregiving may affect the short-term functioning and longer term development of the hypothalamic-pituitary-adrenocortical axis. Despite this, most research to date has been cross-sectional in nature or restricted to relatively short-term longitudinal follow-ups. More important, there is a paucity of research on the role of caregiving in low- and middle-income countries, where the protective effects of high-quality care in buffering the child's developing stress regulation systems may be crucial. In this paper, we report findings from a longitudinal study (N = 232) conducted in an impoverished periurban settlement in Cape Town, South Africa. We measured caregiving sensitivity and security of attachment in infancy and followed children up at age 13 years, when we conducted assessments of hypothalamus-pituitary-adrenocortical axis reactivity, as indexed by salivary cortisol during the Trier Social Stress Test. The findings indicated that insecure attachment was predictive of reduced cortisol responses to social stress, particularly in boys, and that attachment status moderated the impact of contextual adversity on stress responses: secure children in highly adverse circumstances did not show the blunted cortisol response shown by their insecure counterparts. Some evidence was found that sensitivity of care in infancy was also associated with cortisol reactivity, but in this case, insensitivity was associated with heightened cortisol reactivity, and only for girls. The discussion focuses on the potentially important role of caregiving in the long-term calibration of the stress system and the need to better understand the social and biological mechanisms shaping the stress response across development in low- and middle-income countries.

Early severe institutional deprivation is associated with a persistent variant of adult attention-deficit/hyperactivity disorder: clinical presentation, developmental continuities and life circumstances in the English and Romanian Adoptees study.

BACKGROUND: Early-life institutional deprivation is associated with attention-deficit/hyperactivity disorder (ADHD) later in childhood and adolescence. In this article, we examine, for the first time, the persistence of deprivation-related ADHD into young adulthood in a sample of individuals adopted as young children by UK families after periods in extremely depriving Romanian orphanages. METHODS: We estimated rates of ADHD at age 15 years and in young adulthood (ages 22-25 years) in individuals at low (LoDep; nondeprived UK adoptees and Romanian adoptees with less than 6-month institutional exposure) and high deprivation-related risk (HiDep; Romanian adoptees with more than 6-month exposure). Estimates were based on parent report using DSM-5 childhood symptom and impairment criteria. At age 15, data were available for 108 LoDep and 86 HiDep cases, while in young adulthood, the numbers were 83 and 60, respectively. Data on education and employment status, IQ, co-occurring symptoms of young adult disinhibited social engagement (DSE), autism spectrum disorder (ASD), cognitive impairment, conduct disorder (CD), callous-unemotional (CU) traits, anxiety, depression and quality of life (QoL) were also collected. RESULTS: ADHD rates in the LoDep group were similar to the general population in adolescence (5.6%) and adulthood (3.8%). HiDep individuals were, respectively, nearly four (19%) and over seven (29.3%) times more likely to meet criteria, than LoDep. Nine 'onset' young adult cases emerged, but these had a prior childhood history of elevated ADHD behaviours at ages 6, 11 and 15 years. Young adult ADHD was equally common in males and females, was predominantly inattentive in presentation and co-occurred with high levels of ASD, DSE and CU features. ADHD was associated with high unemployment and low educational attainment. CONCLUSION: We provide the first evidence of a strong persistence into adulthood of a distinctively complex and impairing deprivation-related variant of ADHD. Our results confirm the powerful association of early experience with later development in a way that suggests a role for deep-seated alterations to brain structure and function.

Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans.

The neuropeptide oxytocin has played an essential role in the regulation of social behavior and attachment throughout mammalian evolution. Because recent studies in humans have shown that oxytocin administration reduces stress responses and increases prosocial behavior, we investigated whether a common single nucleotide polymorphism (rs53576) in the oxytocin receptor gene (OXTR) might interact with stress-protective effects of social support. Salivary cortisol samples and subjective stress ratings were obtained from 194 healthy male participants before, during, and after a standardized psychosocial laboratory stress procedure. Participants were randomly assigned either to prepare alone or to receive social support from their female partner or close female friend while preparing for the stressful task. Differential stress responses between the genotype groups were observed depending on the presence or absence of social support. Only individuals with one or two copies of the G allele of rs53576 showed lower cortisol responses to stress after social support, compared with individuals with the same genotype receiving no social support. These results indicate that genetic variation of the oxytocin system modulates the effectiveness of positive social interaction as a protective buffer against a stressful experience.

Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood.

Leukocyte telomere length (LTL) is a predictor of age-related disease onset and mortality. The association in adults of psychosocial stress or stress biomarkers with LTL suggests telomere biology may represent a possible underlying mechanism linking stress and health outcomes. It is, however, unknown whether stress exposure in intrauterine life can produce variations in LTL, thereby potentially setting up a long-term trajectory for disease susceptibility. We, therefore, as a first step, tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life after accounting for the effects of other factors on LTL. LTL was assessed in 94 healthy young adults. Forty-five subjects were offspring of mothers who had experienced a severe stressor in the index pregnancy (prenatal stress group; PSG), and 49 subjects were offspring of mothers who had a healthy, uneventful index pregnancy (comparison group; CG). Prenatal stress exposure was a significant predictor of subsequent adult telomere length in the offspring (178-bp difference between prenatal stress and CG; d = 0.41 SD units; P < 0.05). The effect was substantially unchanged after adjusting for potential confounders (subject characteristics, birth weight percentile, and early-life and concurrent stress level), and was more pronounced in women (295-bp difference; d = 0.68 SD units; P < 0.01). To the best of our knowledge, this study provides the first evidence in humans of an association between prenatal stress exposure and subsequent shorter telomere length. This observation may help shed light on an important biological pathway underlying the developmental origins of adult health and disease risk.

DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment.

Epigenetic alterations are regarded as a potential mechanism mediating the effects of environmental risk factors on vulnerability for a range of mental health problems. Recent studies have addressed the question whether DNA methylation patterns predict the outcome of psychological interventions and whether treatment effects might be associated with changes of DNA methylation. We assessed phobic fear symptoms, treatment-relevant traits and treatment response in 308 adults free of psychotropic medication - highly fearful of either spiders, blood-injury-injections, dental-treatments or heights - all subjected to highly standardized exposure-based one-session fear treatment. DNA methylation level of the promotor region of the serotonin transporter gene (SLC6A4) was assessed in either saliva samples (spider and dental treatment fear cohorts) or oral mucosa (BII, heights) to check whether possible effects are independent of the surrogate tissue examined. Moreover, in order to examine possible DNA methylation by genotype effects, patients were assessed for genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR). DNA methylation levels were neither associated with pre-treatment fear levels, treatment relevant traits or treatment outcome data even when allelic variation of the 5HTTLPR was considered. Overall DNA methylation levels were higher in saliva samples compared to buccal samples. In saliva samples there was a small pre- to post-treatment increase in DNA methylation, which, however, was also not associated with the investigated phenotypes. We conclude that DNA methylation of SLC6A4 is no suitable biomarker for response efficacy to highly standardized one-session exposure-based fear treatments.

The role of stress in the biological embedding of experience.

Exposure to early adversity is one of the most important and pervasive risk factors for the development of nearly all major mental disorders across the lifespan. In the search for the mediating mechanisms and processes that underlie long-term stability of these effects, changes to stress-associated hormonal and cellular signalling have emerged as prime candidates. This review summarises evidence showing that experience of early adversity in the form of childhood abuse or neglect and exposure to severe institutional deprivation influences multiple interconnected bio-behavioural, physiological and cellular processes. This paper focusses on dysregulations of hormonal stress regulation, altered DNA methylation pattern, changes to transcriptomic profiles in the context of stress-immune interplay, and mitochondrial biology. Consistent findings that have emerged include a relative cortisol hypoactivity and hyporeactivity in response to challenge, increased activity of pro-inflammatory genes, and altered mitochondrial function. The majority of investigations have focussed on single outcomes, but there is a clear rationale of conceiving the implicated physiological processes as interconnected parts of a wider stress-associated regulatory network, which in turn is connected to behaviour and mental disorders. This calls for integrated and longitudinal investigations to come to a more comprehensive understanding of the role of stress in the biological embedding of experience. The review concludes with considerations of how stress research can contribute to translational efforts through characterising subtypes of mental disorders which arise as a function of early adversity, and have distinct features of behavioral and biological stress processing.

A matter of habit? Stressful life events and cognitive flexibility in 15-month-olds.

Exposure to chronic stress is associated with habitual learning in adults. We studied the origins of this association by examining the link between stressful life events and infant cognitive flexibility. The final sample consisted of N = 72 fifteen-month-old infants and their mothers. Mothers completed a survey on pre- and postnatal negative life events. To assess chronic stress physiologically, infant and maternal hair cortisol concentrations were determined for cortisol accumulation during the past 3 months. Each infant participated in two cognitive tasks in the laboratory. An instrumental learning task tested infants' ability to disengage from a habituated action when this action became ineffective (Seehagen et al., 2015). An age-adequate version of the A-not-B task tested infants' ability to find a toy at location B after repeatedly finding it at location A. Correlations between cortisol concentrations and postnatal negative life events (number, perceived impact) did not yield significance. Infant and maternal hair cortisol concentrations were not correlated. Infants' ability to shift to a new action in either task, controlled for acute stress, correlated neither with pre- and postnatal negative life events nor with cortisol concentrations. Taken together, these results indicate that the potential link between long-term stress exposure and cognitive flexibility might not be present in samples with low levels of psychosocial stress.

No association between war-related trauma or PTSD symptom severity and epigenome-wide DNA methylation in Burundian refugees.

Background: War-related trauma is associated with varying posttraumatic stress disorder (PTSD) prevalence rates in refugees. In PTSD development, differential DNA methylation (DNAm) levels associated with trauma exposure might be involved in risk versus resilience processes. Studies investigating DNAm profiles related to trauma exposure and PTSD among refugees remain sparse.Objective: The present epigenome-wide association study investigated associations between war-related trauma, PTSD, and altered DNAm patterns in Burundian refugee families with 110 children and their 207 female and male caregivers.Method: War-related trauma load and PTSD symptom severity were assessed in structured clinical interviews with standardised instruments. Epigenome-wide DNAm levels were quantified from buccal epithelia using the Illumina EPIC beadchip.Results: Controlling for biological confounders, no significant epigenome-wide DNAm alterations associated with trauma exposure or PTSD were identified in children or caregivers (FDRs > .05). Co-methylated positions derived as modules from weighted gene correlation network analyses were not significantly associated with either war-related trauma experience in children or caregivers or with PTSD.Conclusions: These results do not provide evidence for altered DNAm patterns associated with exposure to war-related trauma or PTSD.

The study examines an understudied population in epigenome-wide association studies.Burundian refugees' war-trauma, PTSD, and DNA methylation were studied.Epigenome-wide DNA methylation was not significantly associated with war-trauma or PTSD in the conflict-affected sample.

Risk and protective factors of mental health in children in residential care: A nationwide study from Luxembourg.

BACKGROUND: Children who grow up in residential care are at high risk for mental health problems. Existing studies have focused on negative mental health indicators and risk factors. There has been less emphasis on identifying protective factors, particularly those associated with positive mental health outcomes. OBJECTIVE: This study explores positive and negative dimensions of mental health and their links to risk and protective factors in children who have experienced early adversity and trauma and have been placed in residential care. PARTICIPANTS AND SETTINGS: Children aged 11 to 18 (N = 264) were recruited from residential care homes in Luxembourg, a small, high-income European country. METHODS: The children completed self-report questionnaires on mental health, perceived stress, school pressure, and participation. Residential care workers provided information on demographic factors, developmental and care history, and pre-care experiences of early adversity and trauma. RESULTS: Confirmatory factor analysis indicated that subjective well-being, internalising problems, and externalising problems are separate yet interconnected components of mental health. Multiple Indicators Multiple Causes models showed that individual, contextual, and psychosocial predictors contribute differentially to positive and negative mental health outcomes. CONCLUSIONS: Using a national sample of children in residential care in Luxembourg, this research indicates that subjective well-being, internalising problems, and externalising problems are distinct but related aspects of mental health. 'Child participation' and 'school pressure' displayed strong links with positive mental health outcomes and may serve as a potential path for improving public health interventions for children in care.