Connecting the dots: social networks in the classroom and white matter connections in the brain.

BACKGROUND: Peer connections in school classrooms play an important role in social-emotional development and mental health. However, research on the association between children's peer relationships and white matter connections in the brain is scarce. We studied associations between peer relationships in the classroom and white matter structural connectivity in a pediatric population-based sample. METHODS: Bullying and victimization, as well as rejection and acceptance, were assessed in classrooms in 634 children at age 7. White matter microstructure (fractional anisotropy (FA), mean diffusivity (MD)) was measured with diffusion tensor imaging at age 10. We examined global metrics of white matter microstructure and used Tract-Based Spatial Statistics (TBSS) for voxel-wise associations. RESULTS: Peer victimization was associated with higher global FA and lower global MD and peer rejection was associated with lower global MD; however, these associations did not remain after multiple testing correction. Voxel-wise TBSS results for peer victimization and rejection were in line with global metrics both in terms of direction and spatial extent of the associations, with associated voxels (pFWE <.05) observed throughout the brain (including corpus callosum, corona radiata, sagittal stratum and superior longitudinal fasciculi). CONCLUSIONS: Although based only on cross-sectional data, the findings could indicate accelerated white matter microstructure maturation in certain brain areas of children who are victimized or rejected more often. However, repeated measurements are essential to unravel this complex interplay of peer connections, maturation and brain development over time.

Schizophrenia polygenic risk is associated with child mental health problems through early childhood adversity: evidence for a gene-environment correlation.

Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene-environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02-1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01-1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5-23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene-environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities.

Predicting persistence of hallucinations from childhood to adolescence.

BACKGROUND: Psychotic experiences predict adverse health outcomes, particularly if they are persistent. However, it is unclear what distinguishes persistent from transient psychotic experiences. AIMS: In a large population-based cohort, we aimed to (a) describe the course of hallucinatory experiences from childhood to adolescence, (b) compare characteristics of youth with persistent and remittent hallucinatory experiences, and (c) examine prediction models for persistence. METHOD: Youth were assessed longitudinally for hallucinatory experiences at mean ages of 10 and 14 years (n = 3473). Multi-informant-rated mental health problems, stressful life events, self-esteem, non-verbal IQ and parental psychopathology were examined in relation to absent, persistent, remittent and incident hallucinatory experiences. We evaluated two prediction models for persistence with logistic regression and assessed discrimination using the area under the curve (AUC). RESULTS: The persistence rate of hallucinatory experiences was 20.5%. Adolescents with persistent hallucinatory experiences had higher baseline levels of hallucinatory experiences, emotional and behavioural problems, as well as lower self-esteem and non-verbal IQ scores than youth with remittent hallucinatory experiences. Although the prediction model for persistence versus absence of hallucinatory experiences demonstrated excellent discriminatory power (AUC-corrected = 0.80), the prediction model for persistence versus remittance demonstrated poor accuracy (AUC-corrected = 0.61). CONCLUSIONS: This study provides support for the dynamic expression of childhood hallucinatory experiences and suggests increased neurodevelopmental vulnerability in youth with persistent hallucinatory experiences. Despite the inclusion of a wide array of psychosocial parameters, a prediction model discriminated poorly between youth with persistent versus remittent hallucinatory experiences, confirming that persistent hallucinatory experiences are a complex multifactorial trait.

Psychotic experiences and future school performance in childhood: a population-based cohort study.

BACKGROUND: Psychotic experiences are common in childhood and an important risk indicator of adverse mental health outcomes. However, little is known about the association of psychotic experiences with functional outcomes in childhood, particularly regarding school performance. The aim of the present study was to examine whether psychotic experiences were prospectively related to school performance in childhood. METHODS: This study was embedded in the population-based Generation R Study (N = 2,362). Psychotic experiences were assessed using self-reports on hallucinations at age 10 years. School performance was assessed using a standardized national school performance test at age 12 years. We considered the total school performance score, as well as language and mathematics subscales. Analyses were adjusted for sociodemographic characteristics, maternal nonverbal IQ, nonverbal IQ at age 6 years and co-occurring psychopathology at age 10 years. RESULTS: Psychotic experiences were prospectively associated with poorer school performance scores (B = -0.61, 95% CI [-0.98;-0.25], p = .001), as well as poorer language (Bpercentile rank score  = -2.00, 95% CI [-3.20;-0.79], p = .001) and mathematical ability (Bpercentile rank score  = -1.75, 95% CI [-2.99;-0.51], p = .006). These associations remained after additional adjustment for nonverbal IQ at age 6 years (B = -0.51, 95% CI [-0.86;-0.16], p = .005), and co-occurring internalizing (B = -0.40, 95% CI [-0.77;-0.03], p = .036) and externalizing problems (B = -0.40, 95% CI [-0.75;-0.04], p = .029), but not attention problems (B = -0.10, 95% CI [-0.47;0.26], p = .57). CONCLUSIONS: Children with psychotic experiences had lower school performance scores than their nonaffected peers. The finding was independent of sociodemographic characteristics, intelligence and co-occurring internalizing and externalizing problems, but not attention problems. This study suggests that psychotic experiences are associated with childhood functional impairments, although the relatively small effects and the role of attention problems warrant further exploration.

Peer-reported bullying, rejection and hallucinatory experiences in childhood.

OBJECTIVE: Psychotic experiences, such as hallucinations, occur commonly in children and have been related to bullying victimization. However, whether bullying perpetration, peer rejection, or peer acceptance are related to hallucinatory experiences has remained under-examined. We used a novel peer nomination method to examine whether (i) bullying perpetration and (ii) social positions within peer networks were associated with future hallucinatory experiences. METHODS: This prospective study was embedded in the population-based Generation R Study. Bullying perpetration, peer rejection, and peer acceptance were assessed using peer nominations at age 7 years (N = 925). Using a social network analysis, we estimated social positions within peer rejection and acceptance networks. Bullying victimization was assessed using self-reports. Self-reported hallucinatory experiences were assessed at age 10 years. Analyses were adjusted for sociodemographic covariates. RESULTS: Higher levels of bullying perpetration were prospectively associated with an increased burden of hallucinatory experiences (OR = 1.22, 95% CI 1.05-1.43, p = 0.011). Bullies had a 50% higher, and bully-victims had a 89% higher odds, of endorsing hallucinatory experiences three years later than children who were not involved in bullying (ORbully = 1.50, 95% CI 1.01-2.24, p = 0.045; ORbully-victim = 1.89, 95% CI 1.15-3.10, p = 0.012). Unfavorable positions within peer rejection networks, but not peer acceptance networks, were associated with an increased risk for hallucinatory experiences (ORpeer rejection = 1.24, 95% CI 1.07-1.44, pFDR-corrected = 0.024). CONCLUSION: Using peer reports, we observed that bullies and socially rejected children have a higher likelihood to report hallucinatory experiences in pre-adolescence. Children who are both a bully and a victim of bullying (ie, bully-victims) may be particularly vulnerable for psychotic experiences.

A Prospective Cohort Study on the Intergenerational Transmission of Childhood Adversity and Subsequent Risk of Psychotic Experiences in Adolescence.

BACKGROUND AND HYPOTHESIS: Previous studies have shown a robust relationship between childhood adversity and subsequent psychotic symptoms. However, the role of familial risk factors underlying this relationship remains largely unclear. Here, we tested whether offspring childhood adversity and postnatal maternal psychopathology mediated the relationship between maternal childhood adversity and offspring psychotic experiences. STUDY DESIGN: N = 3068 mother-offspring dyads were included. Maternal history of childhood adversity was retrospectively assessed using the Childhood Trauma Questionnaire during pregnancy. Maternal psychopathology was assessed during and after pregnancy. Twenty-four offspring childhood adversities were assessed by maternal interview when the child was 10 years old. Offspring psychotic experiences were examined using self-report at 14 years. Structural equation mediation models were conducted to explore whether maternal postnatal psychopathology and offspring childhood adversities sequentially mediated the relationship between maternal childhood adversity and offspring psychotic experiences. Analyses were adjusted for sociodemographic confounders. STUDY RESULTS: Maternal history of childhood adversity was associated with offspring childhood adversities (ß = 0.12, 95% CI: 0.09 to 0.16). Offspring childhood adversity mediated the association of maternal childhood adversity with offspring hallucinations (ßindirect effect = 0.008, 95% CI: 0.002 to 0.014, proportion mediated = 16.3%) and delusions (ßindirect effect = 0.006, 95% CI: 0.000 to 0.012, proportion mediated = 13.1%). CONCLUSIONS: Intergenerational transmission of childhood adversity can be considered of relevance in the etiology of psychosis vulnerability and can potentially serve as a modifiable risk factor.

Childhood trauma and real-world social experiences in psychosis.

BACKGROUND: Childhood trauma is associated with a variety of negative outcomes in psychosis, but it is unclear clear if childhood trauma affects day-to-day social experiences. We aimed to examine the association between childhood trauma and functional and structural characteristics of real-world social relationships in psychosis. METHODS: Participants with psychotic disorders or affective disorders with psychosis completed ecological momentary assessments (EMAs) over ten days (N = 209). Childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire. Associations between childhood trauma and EMA-assessed social behavior and perceptions were examined using linear mixed models. Analyses were adjusted for sociodemographic characteristics and psychotic and depressive symptom severity. RESULTS: Higher levels of childhood trauma were associated with more perceived threat (B = -0.19, 95 % CI [-0.33, -0.04]) and negative self-perception (B = -0.18, 95 % CI [-0.34, -0.01]) during recent social interactions, as well as reduced social motivation (B = -0.29, 95 % CI [-0.47, -0.10]), higher desire for social avoidance (B = 0.34, 95 % CI [0.14, 0.55]), and lower sense of belongingness (B = -0.24, 95 % CI [-0.42, -0.06]). These negative social perceptions were mainly linked with emotional abuse and emotional neglect. In addition, paranoia was more strongly associated with negative social perceptions in individuals with high versus low levels of trauma. Childhood trauma was not associated with frequency (i.e., time spent alone) or type of social interactions. CONCLUSION: Childhood trauma - particularly emotional abuse and neglect - is associated with negative social perceptions but not frequency of real-world social interactions. Our findings suggest that childhood trauma may affect day-to-day social experiences beyond its association with psychosis.

Psychotic experiences, suicidality and non-suicidal self-injury in adolescents: Independent findings from two cohorts.

BACKGROUND: Prior studies have shown that psychotic experiences are prospectively associated with an increased risk of suicidality. However, it is unclear whether this association is causal or arises from shared risk factors. Furthermore, little is known about the association between psychotic experiences and non-suicidal self-injury (NSSI). METHODS: We used data from two independent samples of young adolescents, which we analyzed separately. In a population-based cohort, data on hallucinatory experiences and suicidality were collected at ages 10 and 14 years (N = 3435). In a cross-sectional study of a population oversampled for elevated psychopathology levels, psychotic experiences, suicidality, and NSSI were assessed at age 15 years (N = 910). Analyses were adjusted for sociodemographic covariates, maternal psychopathology, intelligence, childhood adversity, and mental health problems. RESULTS: Psychotic experiences were prospectively associated with an increased risk of suicidality, even when considering self-harm ideation at baseline. Furthermore, persistent and incident, but not remittent, patterns of psychotic experiences were related to an increased burden of suicidality. Self-harm ideation was also prospectively associated with the risk for psychotic experiences, although of smaller magnitude and only by self-report. Among at-risk adolescents, psychotic experiences were cross-sectionally associated with a greater burden of suicidality and a higher frequency of NSSI events, with more extensive tissue damage. CONCLUSION: Psychotic experiences are longitudinally associated with suicidality beyond the effects of shared risk factors. We also found modest support for reverse temporality, which warrants further investigation. Overall, our findings highlight the importance of assessing psychotic experiences as an index of risk for suicidality and NSSI.

Hallucinations and Brain Morphology Across Early Adolescence: A Longitudinal Neuroimaging Study.

BACKGROUND: Psychotic disorders have been widely associated with structural brain abnormalities. However, it is unclear whether brain structure predicts psychotic experiences in youth from the general population, owing to an overall paucity of studies and predominantly cross-sectional designs. Here, the authors investigated longitudinal associations between brain morphology and hallucinations from childhood to early adolescence. METHODS: This study was embedded in the population-based Generation R Study. Children underwent structural neuroimaging at age 10 years (N = 2042); a subsample received a second scan at age 14 years (n = 964). Hallucinations were assessed at ages 10 and 14 years and studied as a binary variable. Cross-lagged panel models and generalized linear mixed-effects models were fitted to examine longitudinal associations between brain morphology and hallucinations. RESULTS: Smaller total gray and white matter volumes and total cortical surface area at baseline were associated with a higher occurrence of hallucinations between ages 10 and 14 years. The regions associated with hallucinations were widespread, including the frontal, parietal, temporal, and occipital lobes, as well as the insula and cingulate cortex. Analyses of subcortical structures revealed that smaller baseline hippocampal volumes were longitudinally associated with hallucinations, although this association was no longer significant following adjustment for intracranial volume. No evidence for reverse temporality was observed (i.e., hallucinations predicting brain differences). CONCLUSIONS: The findings from this longitudinal study suggest that global structural brain differences are associated with the development of hallucinations. These results extend findings from clinical populations and provide evidence for a neurodevelopmental vulnerability across the psychosis continuum.

Severity of anxiety- but not depression- is associated with oxidative stress in Major Depressive Disorder.

BACKGROUND: Oxidative stress is implicated in both depression and anxiety, but it is currently unclear whether this relates to syndromal diagnoses or trans-diagnostic dimensional symptoms. We examined the relationship between oxidative stress and severity of depression and anxiety symptoms in individuals with Major Depressive Disorder (MDD). METHODS: Plasma oxidative stress markers F2-isoprostanes and oxidized glutathione (GSSG), and the antioxidant reduced glutathione (GSH), were assessed in 69 physically healthy, medication-free MDD subjects. Symptoms of anxiety and depression were assessed using the Hamilton Anxiety (HAM-A) and Hamilton Depression (HAM-D) Rating Scales. Total HAM-A and HAM-D scores, along with "core" anxiety and depression subscales, and individual HAM-D items "psychic anxiety" and "depressed mood," were related to oxidative stress markers. Analyses controlled for age, sex, BMI, and smoking. RESULTS: Total HAM-A ratings were positively associated with F2-isoprostanes (ß=.26, p=.042) and GSSG (ß=.25, p=.049), but not GSH (ß=.05, p=.711). Core anxiety severity was positively associated with F2-isoprostanes (ß=.34, p=.012) and GSSG, although this did not reach significance (ß=.24, p=.074). None of the biological markers were significantly associated with total HAM-D or core depression ratings (all p>.13). Subjects scoring high on "psychic anxiety" had elevated F2-isoprostanes (p=.030) and GSSG (p=.020). This was not seen with "depressed mood" scores (all p>.12). LIMITATIONS: We assessed peripheral oxidative markers, but their relationship to the brain is unclear. CONCLUSIONS: Oxidative stress is more closely related to anxiety than depression symptoms in MDD. This highlights the importance of relating oxidative stress to specific symptoms and could provide new insights into the biological correlates of affective disorders.