Presence of Natural Killer B Cells in Simian Immunodeficiency Virus-Infected Colon That Have Properties and Functions Similar to Those of Natural Killer Cells and B Cells but Are a Distinct Cell Population.

Here, we report the appearance of natural killer B (NKB) cells within the colon during simian immunodeficiency virus (SIV) infection of susceptible monkeys. Using RNA sequencing (RNAseq) and flow cytometry, we show that NKB cells are unique cells with features and functions of both NK and B cells. NKB cells express receptors and ligands found on B cells that are important for (i) antigen presentation; (ii) activities associated with class switching, affinity maturation, and B-cell memory formation in secondary lymphoid follicles; and (iii) antigen recognition. The predominant immunoglobulins (Igs) expressed on NKB cells are IgA, although NKB cells can express surface IgM and IgG. There is dominant lambda expression over the kappa light chain characteristic of mucosal B cells. In addition to B-cell aspects, NKB cells express NK cell activation receptors and Fas ligand. We show in this study that NKB cells express perforin and granzymes and lyse cells in a lytic assay. In addition to NK cell cytolytic function, NKB cells also produce the inflammatory cytokines interferon gamma, tumor necrosis factor alpha, and interleukin-18 (IL-18). Finally, we noted the increased capacity of NKB cells to proliferate compared to NK cells and CD8+ T cells from the SIV-infected colon. The increased proliferation and inflammatory cytokine production may be related to the relatively high expression levels of IL-15 receptor beta, IL-7 receptor, IL-18 receptor, and 41BB relative to the same receptors on CD8 and NK cells. The properties of NKB cells may point to their role in the enhanced inflammation observed in the SIV-infected gut. IMPORTANCE There is low-level but significant mucosal inflammation in the gastrointestinal tract secondary to human immunodeficiency virus (HIV) infection that has long-term consequences for the infected host. This inflammation most likely originates from the immune response that appears as a consequence of HIV. Here, we show in an animal model of HIV that the chronically SIV-infected gut contains cytotoxic natural killer B cells that produce inflammatory cytokines and proliferate during infection.

Mother and father depression symptoms and child emotional difficulties: a network model.

BACKGROUND: Mother and father depression symptoms often co-occur, and together can have a substantial impact on child emotional well-being. Little is understood about symptom-level mechanisms underlying the co-occurrence of depression symptoms within families. AIMS: The objective was to use network analysis to examine depression symptoms in mothers and fathers after having a baby, and emotional symptoms in children in early adolescence. METHOD: We examined data from 4492 mother-father-child trios taken from a prospective, population-based cohort in the UK. Symptoms were examined using two unregularised partial correlation network models. The initial model was used to examine the pattern of associations, i.e. the overall network structure, for mother and father depression symptoms, and then to identify bridge symptoms that reinforce depression symptoms between parents during offspring infancy. The second model examined associations between the parent symptom network, including bridge symptoms, with later child emotional difficulties. RESULTS: The study included 4492 mother-father-child trios; 2204 (49.1%) children were female. Bridge symptoms reinforcing mother and father depression symptoms were feeling guilty and self-harm ideation. For mothers, the bridge symptom of feeling guilty, and symptoms of anhedonia, panic and sadness were highly connected with child emotional difficulties. For fathers, the symptom of feeling overwhelmed associated with child emotional difficulties. Guilt and anhedonia in fathers appeared to indirectly associate with child emotional difficulties through the same symptom in mothers. CONCLUSIONS: Our findings suggest that specific symptom cascades are central for co-occurring depression in parents and increased vulnerability in children, providing potential therapeutic targets.

Epilepsy severity mediates association between mutation type and ADHD symptoms in tuberous sclerosis complex.

The association between attention-deficit/hyperactivity disorder (ADHD) and tuberous sclerosis complex (TSC) is widely reported, with support for the role of epilepsy, yet the mechanisms underlying the association across development are unclear. The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of TSC. In Phase 1 of the study, baseline measures of epilepsy, cortical tuber load, and mutation were obtained with 125 children ages 0-16 years. In Phase 2, at an average of 8 years later, ADHD symptoms were measured for 81 of the participants. Structural equation modeling revealed an indirect pathway from genetic mutation, to cortical tuber load, to epileptic spasm severity in infancy, to ADHD symptoms in middle childhood and adolescence, in addition to a pathway linking current seizure severity to ADHD symptoms. Findings were retained when intelligence quotient (IQ) was entered as a correlated factor. The findings support a cascading developmental pathway to ADHD symptoms mediated by early-onset and severe epilepsy in the first 2 years of life. This warrants detailed investigation of seizure characteristics and cognitive and behavioral sequelae associated with ADHD from early in life, to further the understanding of the association between ADHD and early-onset epilepsy across syndromic and non-syndromic populations.

The adult outcome of childhood quasi-autism arising following extreme institutional deprivation.

BACKGROUND: Rutter and colleagues' seminal observation that extended early life exposure to extreme institutional deprivation can result in what he termed quasi-autism (QA), informed both our understanding of the effects of adversity on development and the nature of autism. Here we provide the first detailed analysis of the adult outcomes of the group of institutionally deprived-then-adopted children identified as displaying QA. METHODS: Twenty-six adult adoptees identified with QA in childhood (Childhood QA+) were compared to 75 adoptees who experienced extended institutional deprivation (>6 months) but no QA (Childhood QA-), and 116 adoptees exposed to Low/No institutional deprivation. The outcomes were child-to-adult developmental trajectories of neuro-developmental symptoms (autism, attention-deficit/hyperactivity disorder (ADHD), disinhibited social engagement (DSE) and cognitive impairment), adult functioning, life satisfaction and mental health. RESULTS: Childhood QA+ was associated with elevated and persistent trajectories of broad-based autism-related difficulties, ADHD and DSE symptoms and low IQ, as well as adult mental health difficulties and functional impairment, including high rates of low educational attainment and unemployment. Life satisfaction and self-esteem were unaffected. Autism-related communication problems, in particular, predicted negative adult outcomes. Childhood QA+ was still associated with poor outcomes even when ADHD, DSE and IQ were controlled. CONCLUSIONS: Early and time-limited institutional deprivation has a critical impact on adult functioning, in part via its association with an early established and persistent variant of autism, especially related to communication difficulties. Apparent similarities and differences to non-deprivation related autism are discussed.

Gut Bacteria Induce Granzyme B Expression in Human Colonic ILC3s In Vitro in an IL-15-Dependent Manner.

Group 3 innate lymphoid cells (ILC3s) in the gut mucosa have long been thought to be noncytotoxic lymphocytes that are critical for homeostasis of intestinal epithelial cells through secretion of IL-22. Recent work using human tonsillar cells demonstrated that ILC3s exposed to exogenous inflammatory cytokines for a long period of time acquired expression of granzyme B, suggesting that under pathological conditions ILC3s may become cytotoxic. We hypothesized that inflammation associated with bacterial exposure might trigger granzyme B expression in gut ILC3s. To test this, we exposed human colon lamina propria mononuclear cells to a panel of enteric bacteria. We found that the Gram-negative commensal and pathogenic bacteria induced granzyme B expression in a subset of ILC3s that were distinct from IL-22-producing ILC3s. A fraction of granzyme B+ ILC3s coexpressed the cytolytic protein perforin. Granzyme B expression was mediated, in part, by IL-15 produced upon exposure to bacteria. ILC3s coexpressing all three IL-15R subunits (IL15Rα/ß/γ) increased following bacterial stimulation, potentially allowing for cis presentation of IL-15 during bacterial exposure. Additionally, a large frequency of colonic myeloid dendritic cells expressed IL-15Rα, implicating myeloid dendritic cells in trans presentation of IL-15 to ILC3s. Tonsillar ILC3s minimally expressed granzyme B when exposed to the same bacteria or to rIL-15. Overall, these data establish the novel, to our knowledge, finding that human colonic ILC3s can express granzyme B in response to a subset of enteric bacteria through a process mediated by IL-15. These observations raise new questions about the multifunctional role of human gut ILC3s.

Sensation-seeking-related DNA methylation and the development of delinquency: A longitudinal epigenome-wide study.

Heightened sensation-seeking is related to the development of delinquency. Moreover, sensation-seeking, or biological correlates of sensation-seeking, are suggested as factors linking victimization to delinquency. Here, we focused on epigenetic correlates of sensation-seeking. First, we identified DNA methylation (DNAm) patterns related to sensation-seeking. Second, we investigated the association between sensation-seeking related DNAm and the development of delinquency. Third, we examined whether victimization was related to sensation-seeking related DNAm and the development of delinquency. Participants (N = 905; 49% boys) came from the Avon Longitudinal Study of Parents and Children. DNAm was assessed at birth, age 7 and age 15-17. Sensation-seeking (self-reports) was assessed at age 11 and 14. Delinquency (self-reports) was assessed at age 17-19. Sensation-seeking epigenome-wide association study revealed that no probes reached the critical significance level. However, 20 differential methylated probes reached marginal significance. With these 20 suggestive sites, a sensation-seeking cumulative DNAm risk score was created. Results showed that this DNAm risk score at age 15-17 was related to delinquency at age 17-19. Moreover, an indirect effect of victimization to delinquency via DNAm was found. Sensation-seeking related DNAm is a potential biological correlate that can help to understand the development of delinquency, including how victimization might be associated with adolescent delinquency.

Psychological and Developmental Correlates of Paraphilic and Normophilic Sexual Interests.

The classification of sexual fantasies and behaviors (here referred to as 'sexual interests') has historically been divided into 'paraphilic' and 'normophilic'. However, studies on paraphilic interests are often limited to clinical or forensic samples and normophilic interests are rarely assessed in tandem. Previous research has found mixed results for psychological and other correlates of sexual interests, potentially due to inconsistency in operationalism and measurement of fantasies and behaviors. The aim of the current study was to quantify correlates of sexual interests via the Sexual Fantasies and Behaviors Inventory, containing factors related to general fantasies/behaviors, normophilia, power dynamics, sadomasochism, and courtship paraphilias, using a large (N = 4280) non-clinical sample. Psychological, developmental, sexual, and demographic correlates were investigated via bivariate correlations, mean difference testing, and multiple regression. Sexual interest domains were largely unrelated to psychopathology and developmental factors. Sociosexuality and more accepting attitudes towards sadomasochism was generally related to more arousal to/engagement in normophilic and paraphilic domains. More autism spectrum disorder traits were related to decreased normophilic interests. Psychopathic traits, sexual sensation seeking, and sexual compulsivity were related to paraphilia dimensions, especially courtship paraphilias and domination/sadism; the former was also associated with negative attitudes about establishing consent. Men, non-monogamous, and non-heterosexual participants indicated greater sexual fantasies and behaviors compared to women (except in the case of submission and masochism), monogamous, and heterosexual participants, respectively.

Sex differences in neural correlates of common psychopathological symptoms in early adolescence.

BACKGROUND: Sex-related differences in psychopathology are known phenomena, with externalizing and internalizing symptoms typically more common in boys and girls, respectively. However, the neural correlates of these sex-by-psychopathology interactions are underinvestigated, particularly in adolescence. METHODS: Participants were 14 years of age and part of the IMAGEN study, a large (N = 1526) community-based sample. To test for sex-by-psychopathology interactions in structural grey matter volume (GMV), we used whole-brain, voxel-wise neuroimaging analyses based on robust non-parametric methods. Psychopathological symptom data were derived from the Strengths and Difficulties Questionnaire (SDQ). RESULTS: We found a sex-by-hyperactivity/inattention interaction in four brain clusters: right temporoparietal-opercular region (p < 0.01, Cohen's d = -0.24), bilateral anterior and mid-cingulum (p < 0.05, Cohen's d = -0.18), right cerebellum and fusiform (p < 0.05, Cohen's d = -0.20) and left frontal superior and middle gyri (p < 0.05, Cohen's d = -0.26). Higher symptoms of hyperactivity/inattention were associated with lower GMV in all four brain clusters in boys, and with higher GMV in the temporoparietal-opercular and cerebellar-fusiform clusters in girls. CONCLUSIONS: Using a large, sex-balanced and community-based sample, our study lends support to the idea that externalizing symptoms of hyperactivity/inattention may be associated with different neural structures in male and female adolescents. The brain regions we report have been associated with a myriad of important cognitive functions, in particular, attention, cognitive and motor control, and timing, that are potentially relevant to understand the behavioural manifestations of hyperactive and inattentive symptoms. This study highlights the importance of considering sex in our efforts to uncover mechanisms underlying psychopathology during adolescence.

Do ADHD-impulsivity and BMI have shared polygenic and neural correlates?

There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this overlap. The neural and polygenic correlates of this association have not been thoroughly examined. In participants of the IMAGEN study, we found that impulsivity symptoms and body mass index (BMI) were associated (r = 0.10, n = 874, p = 0.014 FWE corrected), as were their respective polygenic risk scores (PRS) (r = 0.17, n = 874, p = 6.5 × 10-6 FWE corrected). We then examined whether the phenotypes of impulsivity and BMI, and the PRS scores of ADHD and BMI, shared common associations with whole-brain grey matter and the Monetary Incentive Delay fMRI task, which associates with reward-related impulsivity. A sparse partial least squared analysis (sPLS) revealed a shared neural substrate that associated with both the phenotypes and PRS scores. In a last step, we conducted a bias corrected bootstrapped mediation analysis with the neural substrate score from the sPLS as the mediator. The ADHD PRS associated with impulsivity symptoms (b = 0.006, 90% CIs = 0.001, 0.019) and BMI (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. The BMI PRS associated with BMI (b = 0.014, 95% CIs = 0.003, 0.033) and impulsivity symptoms (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. A common neural substrate may (in part) underpin shared genetic liability for ADHD and BMI and the manifestation of their (observable) phenotypic association.

Not in education, employment and training: pathways from toddler difficult temperament.

BACKGROUND: Youths disengaged from the education system and labour force (i.e. 'Not in Education, Employment, or Training' or 'NEET') are often at reduced capacity to flourish and thrive as adults. Developmental precursors to NEET status may extend back to temperamental features, though this - and possible mediators of such associations such as attention deficit hyperactivity (ADHD) symptoms and antisocial behaviours (ASB) - have yet to be directly tested. This study investigates if i) difficult temperament in toddlerhood associates with NEET status in adulthood and ii) different subdomains of ADHD (i.e. hyperactivity-impulsivity vs. inattention) in late childhood and ASB in adolescence partially explain this pathway. METHODS: Participants were 6,240 mother-child dyads (60.7% female) from the Avon Longitudinal Study of Parents and Children. Mothers reported on their child's (a) difficult temperament (i.e. mood, intensity and adaptability) at age 2 and (b) ADHD symptoms at ages 8 and 10. Participants reported their own ASB at age 14 and NEET status in adulthood (ages 18, 20, 22 and 23). RESULTS: First, higher levels of difficult temperament in toddlerhood directly associated with an increased probability of being NEET in adulthood. Second, this effect was carried through hyperactivity-impulsivity, but not inattention, in late childhood, and ASB in adolescence; this demonstrates differential contribution to the pathway between the ADHD dimensions, with symptoms of hyperactivity-impulsivity playing a prominent role. CONCLUSIONS: Early difficult temperament is a vulnerability factor for NEET status in adulthood. Our findings suggest that one developmental pathway for this vulnerability manifests through increased hyperactivity-impulsivity in childhood and ASB in adolescence. Of note, difficult temperament, as measured here, reflects difficulties in emotional and behavioural self-control (e.g. low adaptability and high intensity negative emotional expressions). Our results, therefore, suggest a prominent developmental role for lack of self-control from toddlerhood onwards in increasing risk for NEET.

Editorial: Does the polygenic revolution herald a watershed in the study of GE interplay in developmental psychopathology? Some considerations for the Special Issue reader.

The primary goal motivating the scientific field of Developmental Psychopathology is to discover why some individuals develop mental health and neuro-developmental difficulties while others do not. This is not simply a 'blue skies' preoccupation: the underlying hope, of course, is to translate such discoveries to the benefit of individuals, families and communities, reducing poor outcomes for those at risk and - in the best case scenario - ensuring that they thrive. A core tenet of the bio-psycho-social framework within which this field of enquiry operates is that children's difficulties are determined by the interplay of predisposing genetic risk and resilience factors and the environments and experiences to which individuals are exposed. From this perspective, understanding gene-environment (GE) interplay is a necessary condition for explaining and, as importantly predicting, why one individual is at risk while another is not. If we believe this, then the risk calculators designed to show who will and will not get a particular disorder - all the rage at the moment - are doomed to fail until they can go beyond modelling the main effects of genes and environments, and reliably estimate GE processes too. Despite significant progress, we remain a considerable way off cracking this problem.

Epigenetic profiling of social communication trajectories and co-occurring mental health problems: a prospective, methylome-wide association study.

While previous studies suggest that both genetic and environmental factors play an important role in the development of autism-related traits, little is known about potential biological mechanisms underlying these associations. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined prospective associations between DNA methylation (DNAm: nbirth = 804, nage 7 = 877) and trajectories of social communication deficits at age 8-17 years. Methylomic variation at three loci across the genome (false discovery rate = 0.048) differentiated children following high (n = 80) versus low (n = 724) trajectories of social communication deficits. This differential DNAm was specific to the neonatal period and not observed at 7 years of age. Associations between DNAm and trajectory membership remained robust after controlling for co-occurring mental health problems (i.e., hyperactivity/inattention, conduct problems). The three loci identified at birth were not replicated in the Generation R Study. However, to the best of our knowledge, ALSPAC is the only study to date that is prospective enough to examine DNAm in relation to longitudinal trajectories of social communication deficits from childhood to adolescence. Although the present findings might point to potentially novel sites that differentiate between a high versus low trajectory of social communication deficits, the results should be considered tentative until further replicated.

Nighttime lights, urban features, household poverty, depression, and obesity.

Nighttime Light Emission (NLE) is associated with diminished mental and physical health. The present study examines how NLE and associated urban features (e.g., air pollution, low green space) impact mental and physical wellbeing. We included 200,393 UK Biobank Cohort participants with complete data. The study was carried out in two steps. In Step1, we assessed the relationship between NLE, deprivation, pollution, green space, household poverty and mental and physical symptoms. In Step2, we examined the role of NLE on environment-symptom networks. We stratified participants into high and low NLE and used gaussian graphical model to identify nodes which bridged urban features and mental and physical health problems. We then compared the global strength of these networks in high vs low NLE. We found that higher NLE associated with higher air pollution, less green space, higher economic and neighborhood deprivation, higher household poverty and higher depressed mood, higher tiredness/lethargy and obesity (Rtraining_mean = 0.2624, P training_mean < .001; Rtest_mean = 0.2619, P test_mean < .001). We also found that the interaction between environmental risk factors and mental, physical problems (overall network connectivity) was higher in the high NLE network than in the low NLE network (t = 0.7896, P < .001). In areas with high NLE, economic deprivation, household poverty and waist circumference acted as bridge factors between the key urban features and mental health symptoms. In conclusion, NLE, urban features, household poverty and mental and physical symptoms are all interrelated. In areas with high NLE, urban features associate with mental and physical health problems at a greater magnitude than in areas with low NLE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12144-022-02754-3.

Presence of Inflammatory Group I and III Innate Lymphoid Cells in the Colon of Simian Immunodeficiency Virus-Infected Rhesus Macaques.

Chronic, low-grade, systemic, and mucosal inflammation correlates with increased morbidity and poor clinical outcomes among patients living with human immunodeficiency virus (HIV). These long-term complications are linked to the disruption of gastrointestinal (GI) tract epithelial barrier integrity and subsequent microbial translocation. However, the mechanisms responsible for these downstream effects of infection are unknown. Here, we demonstrate that during the disruption of the GI tract and increased microbial translocation, we find inflammatory cytokines (e.g., interferon gamma [IFN-γ] and tumor necrosis factor alpha [TNF-α]) produced by innate lymphoid cells (ILCs) located in the colon secondary to simian immunodeficiency virus (SIV) infection. To do this, we used viably cryopreserved colon cells from SIV-infected and uninfected rhesus macaque monkeys and determined the make-up of the ILC subpopulations and the cytokines they expressed constitutively. Our studies revealed that the interleukin-22 (IL-22)/IL-17-producing ILCS was not altered during SIV infection. However, the percentage of IFN-γ+ ILCs in infected colons was 5- to 10-fold higher than that in uninfected colons. ILCs from infected tissue that produced IFN-γ also expressed TNF-α and IL-22. The coexpression of inflammatory cytokines with IL-22 is linked to the ability of ILCs to coexpress T-bet and RORγT/Ahr. The expression of IFN-γ/TNF-α by ILCs and NK cells combined likely triggers a pathway that contributes to chronic mucosal inflammation, GI barrier breakdown, and microbial translocation within the context of SIV/HIV infection.IMPORTANCE There is a slow yet significant uptick in systemic inflammation secondary to HIV infection that has long-term consequences for the infected host. The systemic inflammation most likely occurs as a consequence of the disruption of the gut epithelial barrier, leading to the translocation of gut microbial products. This disruption may result from mucosal inflammation. Here, we show in an animal model of HIV that chronic SIV-infected gut contains innate lymphoid cells producing inflammatory cytokines.

Peer victimization and its impact on adolescent brain development and psychopathology.

Chronic peer victimization has long-term impacts on mental health; however, the biological mediators of this adverse relationship are unknown. We sought to determine whether adolescent brain development is involved in mediating the effect of peer victimization on psychopathology. We included participants (n = 682) from the longitudinal IMAGEN study with both peer victimization and neuroimaging data. Latent profile analysis identified groups of adolescents with different experiential patterns of victimization. We then associated the victimization trajectories and brain volume changes with depression, generalized anxiety, and hyperactivity symptoms at age 19. Repeated measures ANOVA revealed time-by-victimization interactions on left putamen volume (F = 4.38, p = 0.037). Changes in left putamen volume were negatively associated with generalized anxiety (t = -2.32, p = 0.020). Notably, peer victimization was indirectly associated with generalized anxiety via decreases in putamen volume (95% CI = 0.004-0.109). This was also true for the left caudate (95% CI = 0.002-0.099). These data suggest that the experience of chronic peer victimization during adolescence might induce psychopathology-relevant deviations from normative brain development. Early peer victimization interventions could prevent such pathological changes.

Promoting better functioning among children exposed to high levels of family adversity: the protective role of childcare attendance.

BACKGROUND: Children exposed to early adversity are vulnerable to cognitive impairments and externalizing behaviors. Attending childcare may, however, partly buffer this detrimental effect by providing social and cognitive stimulation in a secure environment. The aims of this study were (a) to determine whether the association between exposure to adversity and later externalizing behaviors is mediated by children's cognitive abilities, and (b) to examine if childcare attendance moderates this mediation-thereby highlighting a protective function of children's childcare attendance. METHODS: Data come from the Avon Longitudinal Study of Children and Parents (N = 6,149). Exposure to adversity was assessed by maternal reports three times from the second trimester of the mother's pregnancy to the child's fourth year of age. Childcare attendance was assessed on four occasions between eight months and three years of age. Factors explaining differences in childcare attendance were controlled using propensity score weights. Children's cognitive abilities were assessed by the Weschler Intelligence Scale for Children at eight years of age, and externalizing behaviors were reported by mothers using the Development and Well-Being Assessment interview at 10, 13, and 15 years of age. RESULTS: Notably, lower cognitive abilities partly accounted for the higher levels of externalizing behaviors in adolescents exposed to adversity (B indirect effect = 0.02, 95% CI = 0.007-0.03, p < .01). Importantly, childcare attendance moderated this indirect effect. For children exposed to adversity, being in maternal care was associated with lower cognitive abilities which were related to higher levels of externalizing behaviors. On the contrary, for children exposed to adversity, attending childcare was associated with higher cognitive abilities which were linked to lower levels of externalizing behaviors. CONCLUSIONS: Easily accessible community childcare may be a relatively low-cost public health strategy to prevent the emergence of externalizing behavioral problems in adolescence through its positive effects on cognitive abilities.

Neuroimaging Association Scores: reliability and validity of aggregate measures of brain structural features linked to mental disorders in youth.

In genetics, aggregation of many loci with small effect sizes into a single score improved prediction. Nevertheless, studies applying easily replicable weighted scores to neuroimaging data are lacking. Our aim was to assess the reliability and validity of the Neuroimaging Association Score (NAS), which combines information from structural brain features previously linked to mental disorders. Participants were 726 youth (aged 6-14) from two cities in Brazil who underwent MRI and psychopathology assessment at baseline and 387 at 3-year follow-up. Results were replicated in two samples: IMAGEN (n = 1627) and the Healthy Brain Network (n = 843). NAS were derived by summing the product of each standardized brain feature by the effect size of the association of that brain feature with seven psychiatric disorders documented by previous meta-analyses. NAS were calculated for surface area, cortical thickness and subcortical volumes using T1-weighted scans. NAS reliability, temporal stability and psychopathology and cognition prediction were analyzed. NAS for surface area showed high internal consistency and 3-year stability and predicted general psychopathology and cognition with higher replicability than specific symptomatic domains for all samples. They also predicted general psychopathology with higher replicability than single structures alone, accounting for 1-3% of the variance, but without directionality. The NAS for cortical thickness and subcortical volumes showed lower internal consistency and less replicable associations with behavioural phenotypes. These findings indicate the NAS based on surface area might be replicable markers of general psychopathology, but these links are unlikely to be causal or clinically useful yet.

Neonatal DNA methylation and childhood low prosocial behavior: An epigenome-wide association meta-analysis.

Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of "chronic-low" versus "typical" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous "low prosocial" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.

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.

Erotic Target Identity Inversions Among Men and Women in an Internet Sample.

INTRODUCTION: Erotic target identity inversions (ETIIs) are poorly studied paraphilias that involve sexual arousal by the idea or fantasy of being the object of one's sexual desires. AIM: To conduct a large non-clinical online survey to investigate self-reported sexual arousal, behavioral expression, and psychological correlates of 4 proposed ETIIs. METHODS: A total of 736 natal males and 549 natal females responded to items about self-reported sexual arousal to the idea of acting as an animal (autoanthropomorphozoophilia) or the idea of acting as a child or infant (autonepiophilia), natal males reporting arousal to the idea of acting as a woman (autogynephilia), and natal females reporting arousal to the idea of acting as a man (autoandrophilia). Data pertaining to sexual orientation, childhood gender nonconformity, gender identity discomfort, autism, masochism, and humiliation were also collected. MAIN OUTCOME MEASURES: The main outcome was a measure of self-reported arousal and expression of the ETIIs being explored using 4 items: arousal level (-3 to 3) when imagining being the erotic target exemplar; frequency of engagement in dressing or behaving like their preferred target (0-4); strength of feeling that they would be better off as the target (0-4); and the frequency of consideration of making physical changes to look or function more like the target (0-4). RESULTS: Mild levels of reported sexual arousal to the idea of being the preferred erotic target were common among the 4 groups, characterizing about half of them. Gender identity discomfort was associated with autogynephilia, autoandrophilia, and autoanthropomorphozoophilia. Greater gender nonconformity was associated with autogynephilia, autoandrophilia, and autonepiophilia. Autism scores were associated with autoandrophilia and autonepiophilia. Masochism was not associated with ETII scores, but humiliation was. CLINICAL IMPLICATIONS: Findings suggest that it may be important to distinguish between subgroups of those with different levels and types of ETII arousal/expression. STRENGTHS & LIMITATIONS: Strengths of this study include the large, non-clinical sample of men and women for the investigation of ETIIs and the inclusion of measures of psychological correlates. The use of an Internet sample with self-report measures may be unrepresentative, although the Internet has the advantage of allowing recruitment from stigmatized or unusual groups. The cross-sectional nature limits our conclusions, as no causal inferences can be made. CONCLUSION: The results support the concept of ETIIs as a paraphilic dimension in non-clinical samples and the possible role of gender-related psychological factors. Brown A, Barker ED, Rahman Q. Erotic Target Identity Inversions Among Men and Women in an Internet Sample. J Sex Med 2020;17:99-110.