A multi-method and multi-informant approach to assessing post-traumatic stress disorder (PTSD) in children.

Trauma exposure is highly prevalent among children globally, and is associated with elevated rates of PTSD. The goal of this study was to systematically evaluate the effects of multiple informants and multiple screening measures on the identification of specific PTSD symptoms and rates of PTSD diagnoses. Participants in this study included 350 maltreated children from two cohorts, one recruited from Connecticut (n = 130), and the other from Vermont (n = 220). Both cohorts completed the Screen for Child Anxiety-Related Emotional Disorders (SCARED) before a PTSD self-report measure. The KSADS psychiatric interview was also completed with the Connecticut cohort, with best-estimate ratings generated using parent and child interview, child self-report, and teacher questionnaire data. In addition to the SCARED and PTSD self-report scale, parents of the Vermont cohort completed the Child Behavioural Checklist. Significant differences emerged between parent and child report of sleep, nightmares, concentration, and irritability problems, suggesting the need for multiple informants in PTSD screening. Children also under-reported nightmares when asked in the context of a trauma-specific screening tool. As child trauma is associated with a broad range of psychiatric sequelae, comprehensive assessment using both general symptomatology and trauma-specific measures is recommended, since children often shut down when completing trauma measures.

Adverse Childhood Experiences, Epigenetic Measures, and Obesity in Youth.

OBJECTIVE: To determine if measures of adverse childhood experiences and DNA methylation relate to indices of obesity in youth. STUDY DESIGN: Participants were derived from a cohort of 321 8 to 15-year-old children recruited for an investigation examining risk and resilience and psychiatric outcomes in maltreated children. Assessments of obesity were collected as an add-on for a subset of 234 participants (56% female; 52% maltreated). Illumina arrays were used to examine whole genome epigenetic predictors of obesity in saliva DNA. For analytic purposes, the cohort analyzed in the first batch comprised the discovery sample (n = 160), and the cohort analyzed in the second batch the replication sample (n = 74). RESULTS: After controlling for race, sex, age, cell heterogeneity, 3 principal components, and whole genome testing, 10 methylation sites were found to interact with adverse childhood experiences to predict cross-sectional measures of body mass index, and an additional 6 sites were found to exert a main effect in predicting body mass index (P < 5.0 × 10-7, all comparisons). Eight of the methylation sites were in genes previously associated with obesity risk (eg, PCK2, CxCl10, BCAT1, HID1, PRDM16, MADD, PXDN, GALE), with several of the findings from the discovery data set replicated in the second cohort. CONCLUSIONS: This study lays the groundwork for future longitudinal studies to elucidate these mechanisms further and identify novel interventions to alleviate the health burdens associated with early adversity.

Risk factors that predict longitudinal patterns of substantiated and unsubstantiated maltreatment reports.

BACKGROUND: Substantiated and unsubstantiated reports of maltreatment are associated with similar risk of emotional and behavioral problems. However, substantiation status often determines service provision. OBJECTIVE: We examined substantiated and unsubstantiated reports to identify patterns of recurrence over a five-year period and identified family risk factors that predicted recurrence patterns. PARTICIPANTS AND SETTING: We studied a subsample (N = 246,021) of the National Child Abuse and Neglect Data System from 2011-2015. METHODS: Measures included child, caregiver, and child protective services case characteristics obtained in 2011. We used latent class analysis to identify heterogeneous classes, then entered class membership as the outcome variable in a multinomial logistic regression to identify risk factors. RESULTS: Four latent classes emerged: (1) initial unsubstantiation and moderate recurrence, (2) initial unsubstantiation and low recurrence, (3) initial substantiation and moderate recurrence, and (4) initial substantiation and low recurrence. Domestic violence (relative risk ratio (RRR) = 2.56, ß = 0.94, SE = .02, p < .001), caregiver substance abuse (RRR=2.23, ß=0.80, SE=.02, p < .001), and Native Hawaiian/Pacific Islander race (RRR=1.67, ß=0.52, SE=.11, p < .001), predicted initial substantiation status but were not meaningful predictors of long-term recurrence. Prior substantiated report and poverty predicted initial substantiation status (report RRR=1.50, ß=0.41, SE=.02, p < .001; poverty RRR=1.50, ß=0.41, SE=.02, p < .001) and long-term recurrence (report RRR=2.60, ß=0.96, SE=.02, p < .001; poverty RRR = 1.35, ß=0.30, SE=.02, p < .001). Asian American race predicted low recurrence rates (RRR=2.09, ß=0.74, SE=.12, p < .001). CONCLUSIONS: Similar recurrence patterns between substantiated and unsubstantiated reports emphasize the importance of providing services regardless of substantiation status. Integrating administrative databases may reveal more variables that predict long-term recurrence.

Sport participation moderates association between bullying and depressive symptoms in Italian adolescents.

BACKGROUND: A high rate of bullying episodes has been reported in Italian schools, as well as its association with psychopathology in adolescents. However, information regarding moderators of this interaction are still lacking. This study explored whether gender, exercise frequency, and sport participation exerted a protective effect on the association between bullying and depressive symptoms in Italian students. METHODS: Researchers obtained data from 4,829 Italian youth ages 13 to 21 using the self-report Epidemiologia dell'Infortunistica Stradale survey (EDIT) developed by the Regional Health Agency of Tuscany, Italy. Three structural equation models were run to assess moderators of the association between bullying and depressive symptoms. Moderators examined in the models included gender, exercise frequency, and sport participation. RESULTS: The association between bullying and depressive symptoms was stronger for females (B=0.95, SE=0.04, p< .001) than for males (B=0.45, SE=0.00, p< .001) and for students who did not play sports (B=0.74, SE=0.09, p< .001) than for those who played sports (B=0.61, SE=0.06, p< .001). Females may be more affected by the depressive effects of bullying than males. CONCLUSIONS: Participation in sports buffers against the effects of bullying and may prove a helpful strategy for increasing exercise, positive peer interactions, and mood in adolescents. LIMITATIONS: The cross-sectional nature of the study, the possible role of BMI as a confounding factor and the use of a not widely used measure of depression.

Social supports moderate the effects of child adversity on neural correlates of threat processing.

BACKGROUND: Child abuse and other forms of adversity are associated with alterations in threat processing and emotion regulation brain circuits. OBJECTIVE: The goal of the current investigation is to determine if the availability of positive social support can ameliorate the negative impact of adversity on these brain systems. PARTICIPANTS AND SETTING: Subjects included 55 children ages 7-16 (X = 11.8, SD = 2.0). Approximately one-third of the cohort had no significant history of adversity, one-third had a history of moderate adversity, and one-third had a history of severe adversity. Brain imaging was conducted at the University of Vermont using a 3.0 T Philips scanner. METHODS: The Emotional Go-NoGo task with fearful and calm facial stimuli was used to assess the neural correlates of threat processing and emotion regulation in children during functional magnetic resonance imaging (fMRI). Dimensional measures of anxiety, social supports, and children's adverse experiences were also obtained. RESULTS: A conjunction analysis was used to test if trauma-related brain activation in responding to fearful vs. calm targets was impacted by social support. This approach identified multiple activation foci, including a cluster extending from the left amygdala to several other key brain regions involved in emotion regulation, including the orbitofrontal cortex, anterior cingulate cortex (ACC), anterior insula, nucleus accumbens, and frontal pole (Family Wise Error (FWE) correction, p < 0.05). CONCLUSIONS: Greater social support may reduce the effect that adversity has on neural processing of threat stimuli, consistent with the protective role of positive supports in promoting resilience and recovery demonstrated in the literature.

Tubulin Polymerization Promoting Protein (TPPP) gene methylation and corpus callosum measures in maltreated children.

The goal of the current study was to evaluate the impact of Tubulin Polymerization Promoting Protein (TPPP) methylation on structural and fractional anisotropy (FA) corpus callosum (CC) measures. TPPP is involved in the development of white matter tracts in the brain and was implicated in stress-related psychiatric disorders in an unbiased whole epigenome methylation study. The cohort included 63 participants (11.73 y/o ±1.91) from a larger study investigating risk and resilience in maltreated children. Voxel-based morphometry (VBM) was used to process the structural data, fractional anisotropy (FA) was determined using an atlas-based approach, and DNA specimens were derived from saliva in two batches using the 450 K (N = 39) and 850 K (N = 24) Illumina arrays, with the data from each batch analyzed separately. After controlling for multiple comparisons and relevant covariates (e.g., demographics, brain volume, cell composition, 3 PCs), 850 K derived TPPP methylation values, in interaction with a dimensional measure of children's trauma experiences, predicted left and right CC body volumes and genu, body and splenium FA (p < .007, all comparisons). The findings in the splenium replicated in subjects with the 450 K data. The results extend prior investigations and suggest a role for TPPP in brain changes associated with stress-related psychiatric disorders.

Methylation in OTX2 and related genes, maltreatment, and depression in children.

Through unbiased transcriptomics and multiple molecular tools, transient downregulation of the Orthodenticle homeobox 2 (OTX2) gene was recently causatively associated with the development of depressive-like behaviors in a mouse model of early life stress. The analyses presented in this manuscript test the translational applicability of these findings by examining peripheral markers of methylation of OTX2 and OTX2-regulated genes in relation to measures of depression and resting-state functional connectivity data collected as part of a larger study examining risk and resilience in maltreated children. The sample included 157 children between the ages of 8 and 15 years (χ = 11.4, SD = 1.9). DNA specimens were derived from saliva samples and processed using the Illumina 450 K beadchip. A subset of children (N = 47) with DNA specimens also had resting-state functional MRI data. After controlling for demographic factors, cell heterogeneity, and three principal components, maltreatment history and methylation in OTX2 significantly predicted depression in the children. In terms of the imaging data, increased OTX2 methylation was found to be associated with increased functional connectivity between the right vmPFC and bilateral regions of the medial frontal cortex and the cingulate, including the subcallosal gyrus, frontal pole, and paracingulate gyrus-key structures implicated in depression. Mouse models of early stress hold significant promise in helping to unravel the mechanisms by which child adversity confers risk for psychopathology, with data presented in this manuscript supporting a potential role for OTX2 and OTX2-related (e.g., WNT1, PAX6) genes in the pathophysiology of stress-related depressive disorders in children.

Impaired memory consolidation in children with obstructive sleep disordered breathing.

Memory consolidation is stabilized and even enhanced by sleep (and particularly by 12-15 Hz sleep spindles in NREM stage 2 sleep) in healthy children but it is unclear what happens to these processes when sleep is disturbed by obstructive sleep disordered breathing. This cross-sectional study investigates differences in declarative memory consolidation among children with primary snoring (PS) and obstructive sleep apnea (OSA) compared to controls. We further investigate whether memory consolidation group differences are associated with NREM stage 2 (N2) sigma (12-15 Hz) or NREM slow oscillation (0.5-1 Hz) spectral power bands. In this study, we trained and tested participants on a spatial declarative memory task with cued recall. Retest occurred after a period of daytime wake (Wake) or a night of sleep (Sleep) with in-lab polysomnography. 36 participants ages 5-9 years completed the protocol: 14 with OSA as defined by respiratory disturbance index (RDI) > 1/hour, 12 with primary snoring (PS) and 10 controls. OSA participants had poorer overall memory consolidation than controls across Wake and Sleep conditions [OSA: mean = -18.7% (5.8), controls: mean = 1.9% (7.2), t = -2.20, P = 0.04]. In contrast, PS participants and controls had comparable memory consolidation across conditions (t = 0.41; P = 0.38). We did not detect a main effect for condition (Sleep, Wake) or group x condition interaction on memory consolidation. OSA participants had lower N2 sigma power than PS (P = 0.03) and controls (P = 0.004) and N2 sigma power inversely correlated with percentage of time snoring on the study night (r = -0.33, P<0.05). Across all participants, N2 sigma power modestly correlated with memory consolidation in both Sleep (r = 0.37, P = 0.03) and Wake conditions (r = 0.44, P = 0.009). Further observed variable path analysis showed that N2 sigma power mediated the relationship between group and mean memory consolidation across Sleep and Wake states [Bindirect = 6.76(3.5), z = 2.03, P = 0.04]. NREM slow oscillation power did not correlate with memory consolidation. All results retained significance after controlling for age and BMI. In sum, participants with mild OSA had impaired memory consolidation and results were mediated by N2 sigma power. These results suggest that N2 sigma power could serve as biomarker of risk for cognitive dysfunction in children with sleep disordered breathing.

Sleep Dependent Memory Consolidation in Children with Autism Spectrum Disorder.

STUDY OBJECTIVES: Examine the role of sleep in the consolidation of declarative memory in children with autism spectrum disorder (ASD). DESIGN: Case-control study. SETTING: Home-based study with sleep and wake conditions. PARTICIPANTS: Twenty-two participants with ASD and 20 control participants between 9 and 16 y of age. MEASUREMENTS AND RESULTS: Participants were trained to criterion on a spatial declarative memory task and then given a cued recall test. Retest occurred after a period of daytime wake (Wake) or a night of sleep (Sleep) with home-based polysomnography; Wake and Sleep conditions were counterbalanced. Children with ASD had poorer sleep efficiency than controls, but other sleep macroarchitectural and microarchitectural measures were comparable after controlling for age and medication use. Both groups demonstrated better memory consolidation across Sleep than Wake, although participants with ASD had poorer overall memory consolidation than controls. There was no interaction between group and condition. The change in performance across sleep, independent of medication and age, showed no significant relationships with any specific sleep parameters other than total sleep time and showed a trend toward less forgetting in the control group. CONCLUSION: This study shows that despite their more disturbed sleep quality, children with autism spectrum disorder (ASD) still demonstrate more stable memory consolidation across sleep than in wake conditions. The findings support the importance of sleep for stabilizing memory in children with and without neurodevelopmental disabilities. Our results suggest that improving sleep quality in children with ASD could have direct benefits to improving their overall cognitive functioning.