Determine if epigenetic markers predict dimensional ratings of depression in maltreated children.
A Genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 non-traumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible.
Methylation in three genes emerged as genomewide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (ID3); Glutamate Receptor, Ionotropic NMDA 1 (GRIN1); and Tubulin Polymerization Promoting Protein (TPPP) (p<5.0 × 10−7, all analyses). These genes are all biologically relevant–with ID3 involved in the stress response, GRIN1 involved in neural plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different beta values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5).
This study suggests epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. It adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. While epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed.
Child Abuse; Depression; Methylation; Epigenetics
The goal of this paper is to synthesize available data to help guide policy and programmatic initiatives for families with substance abuse problems that are involved with the child welfare system, and identify gaps in the research base needed to further refine practices in this area. To date, Family Treatment Drug Court and newly developed home-based substance abuse treatment interventions appear the most effective at improving substance abuse treatment initiation and completion in child welfare populations. Research is needed to compare the efficacy of these two approaches, and examine cost and child well-being indicators in addition to substance abuse treatment and child welfare outcomes.
Substance Abuse; Child Welfare; Treatment
Posttraumatic stress disorder (PTSD) is frequently under-diagnosed in maltreated samples. Protective services information is critical for obtaining complete trauma histories and determining whether to survey PTSD symptoms in maltreated children. In the current study, without protective services information to supplement parent and child report, the diagnosis of PTSD was missed in a significant proportion of the cases. Collaboration between mental health professionals and protective service workers is critical in determining psychiatric diagnoses and treatment needs of children involved with the child welfare system.
Posttraumatic Stress Disorder; Children; Assessment; Child Maltreatment
Alcohol use disorders in adolescents are associated with significant morbidity and mortality. Over the past decade, there has been a burgeoning of research on adolescent alcohol use disorders.
A summary of the alcohol assessment tools is provided, and randomized studies reviewed and synthesized to provide an overview of state of the art knowledge of treatment of adolescent alcohol use disorders. Animal models of addiction are also briefly reviewed, and the value of translational research approaches, using findings from basic studies to guide the design of clinical investigations, is also highlighted.
Comorbidity is the rule, not the exception in adolescent alcohol use disorders. Comprehensive assessment of psychiatric and other substance use disorders, trauma experiences, and suicidality is indicated in this population to optimize selection of appropriate clinical interventions. In terms of available investigated treatments for adolescents with alcohol use disorders, Multidimensional Family Therapy and group administered Cognitive Behavioral Therapies have received the most empirical support to date. There is a paucity of research on pharmacological interventions in this patient population, and no firm treatment recommendations can be made in this area.
Given the high rate of relapse after treatment, evaluation of combined psychosocial and pharmacological interventions, and the development of novel intervention strategies are indi cated.
Adolescents; alcohol abuse; alcohol dependence; assessment; treatment
Purpose of review
To summarize research on the emotional and behavioral consequences of childhood maltreatment published between January 2009 and April 2010.
Many studies published during this time frame replicated prior research studies that have shown that childhood maltreatment is a nonspecific risk factor for a range of different emotional and behavioral problems. Two research groups highlighted the high revictimization rate among abused girls, with more than one in five abused girls found to have subsequent experiences of rape by young adulthood. The association between physical and sexual abuse and subsequent perpetration of violence toward self and other was also demonstrated, with one study noting the particular vulnerability of sexually abused boys to these negative outcomes. In this study, sexually abused boys had a 15-fold increased risk of making a suicide attempt, and a 45-fold increased risk of perpetrating domestic violence. A three-generation longitudinal study of the intergenerational transmission of abuse is also highlighted in the review, together with emerging findings on genetic and environmental risk and protective factors associated with variability in child outcomes.
Maltreated children are at-risk for a host of negative outcomes. Although marked gains have been made in treating trauma-related psychopathology, these recent studies highlight the need to examine long-term outcomes of youths who have received state-of-the-art evidence-based interventions, and determine if there is a need for more comprehensive and sustained intervention approaches.
child abuse; childhood maltreatment; emotional and behavioral problems; sequelae
Male bonnet monkeys (Macaca radiata) were subjected to the Variable Foraging Demand (VFD) early stress paradigm as infants, MRI scans were completed an average of four years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of Interest (ROI) hippocampus and whole brain voxel- based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. Animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.
stress; monkeys; corpus callosum; hippocampus; brain abnormalities; 5-HTTLPR
Child abuse is highly prevalent and associated with increased risk for a range of health problems including: cancer, cardiovascular disease, diabetes, psychiatric disorders, and other health problems. Little is currently known about the mechanism by which early adversity confers risk for health problems later in life.
To determine if there are epigenetic differences associated with child maltreatment that may help explain association between adverse childhood experiences and later health problems.
As part of a study examining genetic and environmental factors associated with depression, saliva DNA specimens were collected on 96 maltreated children removed from their parents due to abuse or neglect and 96 demographically-matched control children between 2003 and 2010. In 2011, the Illumina 450K BeadChip was used on stored DNA specimens and analyzed to examine whole-genome methylation differences between maltreated and control children.
After controlling for multiple comparisons, maltreated and control children had significantly different methylation values at 2868 CpG sites (p< 5.0 × 10−7, all sites; average methylation difference per site=17%; range 1%–62%). The gene set contained numerous markers of diseases and biological processes related to the health problems associated with early childhood adversity.
While replication is required, this study suggests that epigenetic mechanisms may be associated with risk for health problems later in life in maltreated children. This study lays the groundwork for future studies examining health and methylation measures to further characterize the role of epigenetic mechanisms in conferring risk for medical problems in individuals with histories of early adversity.
Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.
Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).
Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: “high” cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.
Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.
amygdala; early life stress; non-human primates; MRI; stress; serotonin transporter gene
Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).
Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].
Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.
Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.
variable foraging demand; MRI; cisternal tap; serotonin metabolite; monoamine metabolites
Childhood adversity has been shown to interact with monoamine
oxidase-A (MAOA) genotype to confer risk for antisocial
behavior. Studies examining this gene-by-environment (G×E)
association, however, have produced mixed results.
Relevant research is reviewed, and results of a study with 114
children (73 maltreated and 41 control subjects) are presented. The
maltreated children represent the extreme on a continuum of adversity and
were assessed at a time of extreme stress—shortly after removal from
their parents’ care due to abuse. Measures of aggressive behavior
were obtained using standard research instruments, and monoamine oxidase-A
MAOA genotypes were obtained from saliva-derived DNA
specimens. Population structure was controlled for using ancestral
proportion scores computed on the basis of genotypes of ancestry informative
Many prior investigations appear to have had reduced power to detect
the predicted G×E interaction because of low base rates of
maltreatment and antisocial behavior in their samples and failure to use
optimal procedures to control for population structure in ethnically diverse
cohorts. In this investigation, a significant interaction was detected
between exposure to moderate trauma and the “low-activity”
MAOA genotype in conferring risk for aggression.
Children with exposure to extreme levels of trauma, however, had high
aggression scores regardless of genotype.
Our study suggests that problems in aggressive behavior in maltreated
children are moderated by MAOA genotype, but only up to
moderate levels of trauma exposure. Extreme levels of trauma appear to
overshadow the effect of MAOA genotype, especially in
children assessed at time of acute crisis.
Aggression; antisocial; child abuse; gene–environment interaction; maltreatment; MAOA
Contrary to expectations derived from preclinical studies of the effects of stress, and imaging studies of adults with PTSD, there is no evidence of hippocampus atrophy in children with PTSD. Multiple pediatric studies have reported reductions in the corpus callosum – the primary white matter tract in the brain. Consequently, in the present study, Diffusion Tensor Imaging was used to assess corpus callosum white matter integrity in 17 maltreated children with PTSD and 15 demographically matched normal controls. Children with PTSD had reduced fractional anisotropy in the medial and posterior corpus, a region which contains interhemispheric projections from brain structures involved in circuits that mediate the processing of emotional stimuli and various memory functions --- core disturbances associated with a history of trauma. Further exploration of the effects of stress on corpus callosum and white matter development appears a promising strategy to better understanding the pathophysiology of PTSD in children.
Posttraumatic Stress Disorder; Imaging; DTI; children
The Harvard University Asia Center hosted a symposium in October 2010 focused on sex work and sexually transmitted infections in Asia, engaging a biosocial approach to promote sexual health in this region. Asia has an estimated 151 million cases of curable sexually transmitted infections (STIs; eg, syphilis, gonorrhea, chlamydia) each year, with commercial sex interactions playing a large role in ongoing transmission. Substantial human movement and migration, gender inequalities, and incipient medical and legal systems in many states stymie effective STI control in Asia. The articles in this supplement provide theoretical and empirical pathways to improving the sexual health of those who sell and purchase commercial sex in Asia. The unintended health consequences of various forms of regulating commercial sex are also reviewed, emphasizing the need to carefully consider the medical and public health consequences of new and existing policies and laws.
Dialectical Behaviour Therapy (DBT) has been used to treat adults and adolescents with suicidal and non-suicidal self-injury. This article describes initial progress in modifying DBT for affected pre-adolescent children.
Eleven children from regular education classes participated in a 6-week pilot DBT skills training program for children. Self-report measures of children’s emotional and behavioural difficulties, social skills and coping strategies were administered at pre- and post-intervention, and indicated that the children had mild to moderate symptoms of depression, anxiety and suicidal ideation at baseline.
Subjects were able to understand and utilise DBT skills for children and believed that the skills were important and engaging. Parents also regarded skills as important, child friendly, comprehensible and beneficial. At post-treatment, children reported a significant increase in adaptive coping skills and significant decreases in depressive symptoms, suicidal ideation and problematic internalising behaviours.
These promising preliminary results suggest that continued development of DBT for children with more severe clinical impairment is warranted. Progress on adapting child individual DBT and developing a caregiver training component in behavioural modification and validation techniques is discussed.
Children; Dialectical Behaviour Therapy; self-harm; self-injury; suicide
Recent studies have indicated a gene by environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques (Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one “s” allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A “juvenile” CSF sample was obtained at approximately three years of age. CSF CRF concentrations were elevated specifically in the VFD “s/s” and “s/l” allele group in comparison to each of the remaining three groups, indicating a gene by environment (GxE) interaction.
Nonhuman primates; corticotropin-releasing hormone; early-life stress; serotonin transporter gene; major depression; anxiety disorders; gene by environment interaction
Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC.
We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter.
VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter.
Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.
Diffusion tensor imaging; fractional anisotropy; white matter integrity; variable foraging demand
To report results of the clinical reappraisal study of lifetime DSM-IV diagnoses based on the fully-structured lay-administered WHO Composite International Diagnostic Interview Version 3.0 (CIDI) in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A).
Blinded clinical reappraisal interviews with a probability sub-sample of 347 NCS-A respondents were administered using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) as the gold standard. DSM-IV/CIDI cases were over-sampled and the clinical reappraisal sample was weighted to adjust for this over-sampling.
Good aggregate consistency was found between CIDI and K-SADS prevalence estimates, although CIDI estimates were meaningfully higher than K-SADS estimates for specific phobia (51.2%) and oppositional-defiant disorder (38.7%). Estimated prevalence of any disorder, in comparison, was only slightly higher in the CIDI than K-SADS (8.3%). Strong individual-level CIDI vs. K-SADS concordance was found for most diagnoses. Area under the ROC curve (AUC, a measure of classification accuracy not influenced by prevalence) was .88 for any anxiety disorder, .89 for any mood disorder, .84 for any disruptive behavior disorder, .94 for any substance disorder, and .87 for any disorder. Although AUC was unacceptably low for alcohol dependence and bipolar I and II disorders, these problems were resolved by aggregation with alcohol abuse and bipolar I disorder, respectively. Logistic regression analysis documented that consideration of CIDI symptom-level data significantly improved prediction of some K-SADS diagnoses.
These results document that the diagnoses made in the NCS-A based on the CIDI have generally good concordance with blinded clinical diagnoses.
National Comorbidity Survey Adolescent Supplement (NCS-A); Composite International Diagnostic Interview (CIDI); mental disorders; epidemiology; validity
The purpose of this study is to examine processing of facial emotions in a sample of maltreated children showing high rates of post-traumatic stress disorder (PTSD). Maltreatment during childhood has been associated independently with both atypical processing of emotion and the development of PTSD. However, research has provided little evidence indicating how high rates of PTSD might relate to maltreated children’s processing of emotions.
Participants’ reaction time and labeling of emotions were measured using a morphed facial emotion identification task. Participants included a diverse sample of maltreated children with and without PTSD and controls ranging in age from 8 to 15 years. Maltreated children had been removed from their homes and placed in state custody following experiences of maltreatment. Diagnoses of PTSD and other disorders were determined through combination of parent, child, and teacher reports.
Maltreated children displayed faster reaction times than controls when labeling emotional facial expressions, and this result was most pronounced for fearful faces. Relative to children who were not maltreated, maltreated children both with and without PTSD showed enhanced response times when identifying fearful faces. There was no group difference in labeling of emotions when identifying different facial emotions.
Maltreated children show heightened ability to identify fearful faces, evidenced by faster reaction times relative to controls. This association between maltreatment and atypical processing of emotion is independent of PTSD diagnosis.
Maltreatment; Emotional processing; PTSD; Children
There is increasing debate about whether the scaled-up investment in HIV/AIDS programs is strengthening or weakening the fragile health systems of many developing countries. This article examines and assesses the evidence and proposes ways forward.
Considerably increased resources have been brought into countries for HIV/AIDS programs by major Global Health Initiatives. Among the positive impacts are the increased awareness of and priority given to public health by governments. In addition, services to people living with HIV/AIDS have rapidly expanded. In many countries infrastructure and laboratories have been strengthened, and in some, primary health care services have been improved. The effect of AIDS on the health work force has been lessened by the provision of antiretroviral treatment to HIV-infected health care workers, by training, and, to an extent, by task-shifting. However, there are reports of concerns, too – among them, a temporal association between increasing AIDS funding and stagnant reproductive health funding, and accusations that scarce personnel are siphoned off from other health care services by offers of better-paying jobs in HIV/AIDS programs. Unfortunately, there is limited hard evidence of these health system impacts.
Because service delivery for AIDS has not yet reached a level that could conceivably be considered "as close to Universal Access as possible," countries and development partners must maintain the momentum of investment in HIV/AIDS programs. At the same time, it should be recognized that global action for health is even more underfunded than is the response to the HIV epidemic. The real issue is therefore not whether to fund AIDS or health systems, but how to increase funding for both.
The evidence is mixed – mostly positive but some negative – as to the impact on health systems of the scaled-up responses to HIV/AIDS driven primarily by global health partnerships. Current scaled-up responses to HIV/AIDS must be maintained and strengthened. Instead of endless debate about the comparative advantages of vertical and horizontal approaches, partners should focus on the best ways for investments in response to HIV to also broadly strengthen the primary health care systems.