Stacy S. Drury

Telomere length and early severe social deprivation: linking early adversity and cellular aging

Accelerated telomere length attrition has been associated with psychological stress and early adversity in adults; however, no studies have examined whether telomere length in childhood is associated with early experiences. The Bucharest Early Intervention Project is a unique randomized controlled trial of foster care placement compared with continued care in institutions. As a result of the study design, participants were exposed to a quantified range of time in institutional care, and represented an ideal population in which to examine the association between a specific early adversity, institutional care and telomere length. We examined the association between average relative telomere length, telomere repeat copy number to single gene copy number (T/S) ratio and exposure to institutional care quantified as the percent of time at baseline (mean age 22 months) and at 54 months of age that each child lived in the institution. A significant negative correlation between T/S ratio and percentage of time was observed. Children with greater exposure to institutional care had significantly shorter relative telomere length in middle childhood. Gender modified this main effect. The percentage of time in institutional care at baseline significantly predicted telomere length in females, whereas the percentage of institutional care at 54 months was strongly predictive of telomere length in males. This is the first study to demonstrate an association between telomere length and institutionalization, the first study to find an association between adversity and telomere length in children, and contributes to the growing literature linking telomere length and early adversity.

Validity of evidence-derived criteria for reactive attachment disorder: indiscriminately social/disinhibited and emotionally withdrawn/inhibited types.

OBJECTIVE This study examined the validity of criteria for indiscriminately social/disinhibited and emotionally withdrawn/inhibited reactive attachment disorder (RAD). METHOD As part of a longitudinal intervention trial of previously institutionalized children, caregiver interviews and direct observational measurements provided continuous and categorical data used to examine the internal consistency, criterion validity, construct validity, convergent and discriminant validity, association with functional impairment, and stability of these disorders over time. RESULTS As in other studies, the findings showed distinctions between the two types of RAD. Evidence-derived criteria for both types of RAD showed acceptable internal consistency and criterion validity. In this study, rates of indiscriminately social/disinhibited RAD at baseline and at 30, 42, and 54 months were 41/129 (31.8%), 22/122 (17.9%), 22/122 (18.0%), and 22/125 (17.6%), respectively. Signs of indiscriminately social/disinhibited RAD showed little association with caregiving quality. Nearly half of children with indiscriminately social/disinhibited RAD had organized attachment classifications. Signs of indiscriminately social/disinhibited RAD were associated with signs of activity/impulsivity and of attention-deficit/hyperactivity disorder and modestly with inhibitory control but were distinct from the diagnosis of attention-deficit/hyperactivity disorder. At baseline, 30, 42, and 54 months, 6/130 (4.6%), 4/123 (3.3%), 2/125 (1.6%), and 5/122 (4.1%) of children met criteria for emotionally withdrawn/inhibited RAD. Emotionally withdrawn/inhibited RAD was moderately associated with caregiving at the first three time points and strongly associated with attachment security. Signs of this type of RAD were associated with depressive symptoms, although two of the five children with this type of RAD at 54 months did not meet criteria for major depressive disorder. Signs of both types of RAD contributed independently to functional impairment and were stable over time. CONCLUSIONS Evidence-derived criteria for indiscriminately social/disinhibited and emotionally withdrawn/inhibited RAD define two statistically and clinically cohesive syndromes that are distinct from each other, shows stability over 2 years, have predictable associations with risk factors and attachment, can be distinguished from other psychiatric disorders, and cause functional impairment.

Psychiatric Outcomes in Young Children with a History of Institutionalization

&NA; Children raised in institutions, considered an extreme example of social deprivation, are one group through which we can better understand the impact of neglect on child health and development. The Bucharest Early Intervention Project (BEIP) is the first randomized, controlled trial of foster care as an intervention for institutionalized children. In this review we describe the mental health outcomes from the BEIP. Specifically, we report findings on attachment styles, attachment disorders, emotional reactivity, and psychiatric symptomatology for children in the BEIP. We describe the impact of the foster care intervention on these outcomes and also describe how outcomes differ by gender and by length of time spent in the institution. In addition, we explore the influence of genetic variation on individual outcomes and recovery from early severe social deprivation, as well as the role of differences in brain development in mediating later psychiatric morbidity. The results from the BEIP confirm and extend the previous findings on the negative sequelae of early institutional care on mental health. The results also underscore the benefit of early family placement for children living in institutions.

Genetic sensitivity to the caregiving context: The influence of 5httlpr and BDNF val66met on indiscriminate social behavior

Evidence that gene×environment interactions can reflect differential sensitivity to the environmental context, rather than risk or resilience, is increasing. To test this model, we examined the genetic contribution to indiscriminate social behavior, in the setting of a randomized controlled trial of foster care compared to institutional rearing. Children enrolled in the Bucharest Early Intervention Project (BEIP) were assessed comprehensively before the age of 30 months and subsequently randomized to either care as usual (CAUG) or high quality foster care (FCG). Indiscriminate social behavior was assessed at four time points, baseline, 30 months, 42 months and 54 months of age, using caregiver report with the Disturbances of Attachment Interview (DAI). General linear mixed-effects models were used to examine the effect of the interaction between group status and functional polymorphisms in Brain Derived Neurotrophic Factor (BDNF) and the Serotonin Transporter (5htt) on levels of indiscriminate behavior over time. Differential susceptibility, relative to levels of indiscriminate behavior, was demonstrated in children with either the s/s 5httlpr genotype or met 66 BDNF allele carriers. Specifically children with either the s/s 5httlpr genotype or met66 carriers in BDNF demonstrated the lowest levels of indiscriminate behavior in the FCG and the highest levels in the CAUG. Children with either the long allele of the 5httlpr or val/val genotype of BDNF demonstrated little difference in levels of indiscriminate behaviors over time and no group×genotype interaction. Children with both plasticity genotypes had the most signs of indiscriminate behavior at 54 months if they were randomized to the CAUG in the institution, while those with both plasticity genotypes randomized to the FCG intervention had the fewest signs at 54 months. Strikingly children with no plasticity alleles demonstrated no intervention effect on levels of indiscriminate behavior at 54 months. These findings represent the first genetic associations reported with indiscriminate social behavior, replicate previous gene×gene×environment findings with these polymorphisms, and add to the growing body of literature supporting a differential susceptibility model of gene×environment interactions in developmental psychopathology.

Neighborhood disorder and telomeres: connecting children's exposure to community level stress and cellular response.

Our objective was to explore the utility of salivary telomere length (sTL) as an early indicator of neighborhood-level social environmental risk during child development. We therefore tested the hypothesis that sTL would be associated with markers of social stress exposure in children. Children age 4-14 from 87 neighborhoods were recruited through five urban schools in New Orleans, Louisiana, U.S. Data were collected at the level of the child, family/household, and neighborhood. DNA was obtained from saliva using commercially available kits and sTL was determined for 104 children using quantitative PCR. Analysis was performed on 99 children who had complete data including sTL, social environmental stress, and additional covariates. The mean sTL value was 7.4 T/S (telomere signal/single-copy signal) ratio units (±2.4, range = 2.5-18.0), and 4.7% of the variance in sTL was attributed to differences across neighborhoods. Children living in neighborhoods characterized by high disorder had an sTL value 3.2 units lower than children not living in high disordered environments (p < 0.05) and their odds of having low relative sTL (defined as <1 standard deviation below standardized Z-score mean) values was 3.43 times that of children not living in high disorder environments (adjusted OR = 3.43, 95% CI = 1.22, 9.62). Our findings are consistent with previous studies in adults demonstrating a strong link between psychosocial stress and sTL obtained from peripheral blood, consistent with previous studies in youth demonstrating an association between early life stress and sTL obtained from buccal cell DNA and offer increased support for the hypothesis that sTL represents a non-invasive biological indicator of psychosocial stress exposure (i.e., neighborhood disorder) able to reflect differences in stress exposure levels even in young children.

The association of telomere length with family violence and disruption

BACKGROUND: To enhance the understanding of biological mechanisms connecting early adversity and negative health, we examine the association between family interpersonal violence and disruption and telomere length in youth. These specific exposures were selected because of their established links with negative health consequences across the life-course. METHODS: Children, age 5 to 15, were recruited from the greater New Orleans area, and exposure to family disruption and violence was assessed through caregiver report. Telomere length, from buccal cell DNA (buccal telomere length [bTL]), was determined by using monochrome multiplex quantitative real-time polymerase chain reaction. The association between bTL and adversity exposure was tested (n = 80). RESULTS: Cumulative exposure to interpersonal violence and family disruption was correlated with bTL. Controlling for other sociodemographic factors, bTL was significantly shorter in children with higher exposure to family violence and disruption. Witnessing family violence exerted a particularly potent impact. A significant gender interaction was found (β = −0.0086, SE = 0.0031, z test= −2.79, P = .0053) and analysis revealed the effect only in girls. CONCLUSIONS: bTL is a molecular biomarker of adversity and allostatic load that is detectable in childhood. The present results extend previous studies by demonstrating that telomeres are sensitive to adversity within the overarching family domain. These findings suggest that the family ecology may be an important target for interventions to reduce the biological impact of adversity in the lives of children.

Cumulative Neighborhood Risk of Psychosocial Stress and Allostatic Load in Adolescents

The authors examined the impact of cumulative neighborhood risk of psychosocial stress on allostatic load (AL) among adolescents as a mechanism through which life stress, including neighborhood conditions, may affect health and health inequities. They conducted multilevel analyses, weighted for sampling and propensity score-matched, among adolescents aged 12-20 years in the National Health and Nutrition Examination Survey (1999-2006). Individuals (first level, n = 11,886) were nested within families/households (second level, n = 6,696) and then census tracts (third level, n = 2,191) for examination of the contextual effect of cumulative neighborhood risk environment on AL. Approximately 35% of adolescents had 2 or more biomarkers of AL. A significant amount of variance in AL was explained at the neighborhood level. The likelihood of having a high AL was approximately 10% higher for adolescents living in medium-cumulative-risk neighborhoods (adjusted odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.08, 1.09), 28% higher for those living in high-risk neighborhoods (adjusted OR = 1.28, 95% CI: 1.27, 1.30), and 69% higher for those living in very-high-risk neighborhoods (adjusted OR = 1.69, 95% CI: 1.68, 1.70) as compared with adolescents living in low-risk areas. Effect modification was observed by both individual- and neighborhood-level sociodemographic factors. These findings offer support for the hypothesis that neighborhood risks may culminate in a range of biologically mediated negative health outcomes detectable in adolescents.

Recovering From Early Deprivation: Attachment Mediates Effects of Caregiving on Psychopathology

OBJECTIVE Children exposed to early institutional rearing are at risk for developing psychopathology. The present investigation examines caregiving quality and the role of attachment security as they relate to symptoms of psychopathology in young children exposed to early institutionalization. METHOD Participants were enrolled in the Bucharest Early Intervention Project (BEIP), a longitudinal intervention study of children abandoned and placed in institutions at or shortly after birth. Measures included observed caregiving when children were 30 months of age, observed attachment security at 42 months, and caregiver reports of childrens psychopathology at 54 months. At 54 months, some children remained in institutions, others were in foster care, others had been adopted domestically, and still others had been returned to their biological families. Thus, the children had experienced varying amounts of institutional rearing. RESULTS After controlling for gender, quality of caregiving when children were 30 months old was associated with symptoms of multiple domains of psychopathology at 54 months of age. Ratings of security of attachment at 42 months mediated the associations between quality caregiving at 30 months and fewer symptoms of psychopathology at 54 months. CONCLUSIONS Among deprived young children, high-quality caregiving at 30 months predicted reduced psychopathology and functional impairment at 54 months. Security of attachment mediated this relationship. Interventions for young children who have experienced deprivation may benefit from explicitly targeting caregiver-child attachment relationships.

Effects of institutional rearing and foster care on psychopathology at age 12 years in Romania: follow-up of an open, randomised controlled trial

BACKGROUND Early social deprivation can negatively affect domains of functioning. We examined psychopathology at age 12 years in a cohort of Romanian children who had been abandoned at birth and placed into institutional care, then assigned either to be placed in foster care or to care as usual. METHODS We used follow-up data from the Bucharest Early Intervention Project (BEIP), a randomised controlled trial of abandoned children in all six institutions for young children in Bucharest, Romania. In the initial trial, 136 children, enrolled between ages 6-31 months, were randomly assigned to either care as usual or placement in foster care. In this study we followed up these children at age 12 years to assess psychiatric symptoms using the Diagnostic Interview Schedule for Children (4th edition; DISC-IV). We also recruited Romanian children who had never been placed in an institution from paediatric clinics and schools in Bucharest as a comparator group who had never been placed in an institution. The primary outcome measure was symptom counts assessed through DISC-IV scores for three domains of psychopathology: internalising symptoms, externalising symptoms, and attention-deficit hyperactivity disorder (ADHD). We compared mean DISC-IV scores between trial participants and comparators who had never been placed in an institution, and those assigned to care as usual or foster care. Analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747396. FINDINGS We followed up 110 children from the BEIP trial between Jan 27, 2011, and April 11, 2014, and 49 children as comparators who had never been placed in an institution. The 110 children who had ever been placed in an institution had higher symptom counts for internalising disorders (mean 0·93 [SD 1·68] vs 0·45 [0·84], difference 0·48 [95% CI 0·14-0·82]; p=0·0127), externalising disorders (2·31 [2·86] vs 0·65 [1·33], difference 1·66 [1·06-2·25]; p<0·0001), and ADHD (4·00 [5·01] vs 0·71 [1·85], difference 3·29 [95% CI 2·39-4·18]; p<0·0001) than did children who had never been placed in an institution. Compared with 55 children randomly assigned to receive care as usual, the 55 children in the foster-care group had fewer externalising symptoms (mean 2·89 [SD 3·00] for care as usual vs 1·73 [2·61] for foster care, difference 1·16 [95% CI 0·11 to 2·22]; p=0·0255), but symptom counts for internalising disorders (mean 1·00 [1·59] for care as usual vs 0·85 [1·78] for foster care, difference 0·15 [-0·35 to 0·65]; p=0·5681) and ADHD (mean 3·76 [4·61] for care as usual vs 4·24 [5·41] for foster care, difference -0·47 [-2·15 to 1·20; p=0·5790) did not differ. In further analyses, symptom scores substantially differed by stability of foster-care placement. INTERPRETATION Early foster care slightly reduced the risk of psychopathology in children who had been living in institutions, but long-term stability of foster-care placements is an important predictor of psychopathology in early adolescence. FUNDING National Institute of Mental Health and the John D and Catherine T MacArthur Foundation.

Modification of depression by COMT val158met polymorphism in children exposed to early severe psychosocial deprivation.

OBJECTIVE To examine the impact of the catechol-O-methyltransferase (COMT) val(158)met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions. METHODS One hundred thirty six children from the Bucharest Early Intervention Project (BEIP) were randomized before 31 months of age to either care as usual (CAU) in institutions or placement in newly created foster care (FCG). At 54 months of age, a psychiatric assessment using the Preschool Age Psychiatric Assessment (PAPA) was completed. DNA was collected and genotyped for the COMT val(158)met polymorphism. Multivariate analysis examined the relationship between COMT alleles and depressive symptoms. RESULTS Mean level of depressive symptoms was lower among participants with the met allele compared to those with two copies of the val allele (P<0.05). Controlling for group and gender, the rate of depressive symptoms was significantly lower among participants with the met/met or the met/val genotype [adjusted relative risk (aRR)=0.67, 95% CI=0.45, 0.99] compared to participants with the val/val genotype, indicating an intermediate impact for heterozygotes consistent with the biological impact of this polymorphism. The impact of genotype within groups differed significantly. There was a significant protective effect of the met allele on depressive symptoms within the CAU group, however there was no relationship seen within the FCG group. CONCLUSIONS This is the first study, to our knowledge, to find evidence of a genexenvironment interaction in the setting of early social deprivation. These results support the hypothesis that individual genetic differences may explain some of the variability in recovery amongst children exposed to early severe social deprivation.