Faculty Bibliography

BACKGROUND/UNASSIGNED:Autism spectrum disorder (ASD) shows significant clinical variability, likely due to a combination of genetic and environmental factors. Preterm birth is a known risk factor for ASD, occurring in approximately 13% of diagnosed individuals. While genetic factors contribute to preterm birth in the general population, the relationship between genetic variation, preterm birth, and ASD heterogeneity remains unclear. METHODS/UNASSIGNED:We investigated the genetic factors associated with preterm birth in 31,947 autistic individuals using data from the SPARK (Simons Foundation Powering Autism Research for Knowledge) sample. We conducted 3 ancestry-specific genome-wide association studies for African/African American, admixed American, and non-Finnish European ancestries, followed by a meta-analysis of 3308 preterm cases and 28,639 controls using METAL. Functional mapping and gene-based analyses were performed using FUMA, and genetic correlations were estimated using LDSC and Popcorn. Polygenic risk scores (PRSs) were computed with BridgePRS, using PRS of preterm birth in the general population. RESULTS/UNASSIGNED:Our study identified ancestry-specific genetic loci associated with preterm birth in ASD cases. Although the meta-analysis results were not statistically significant, the estimated single nucleotide polymorphism heritability was 14%, indicating a meaningful contribution of common genetic variants. Across ancestry groups, preterm birth status was not significantly associated with PRSs for any psychiatric or medical conditions analyzed. However, polygenic liability to preterm birth in the general population was linked to several congenital anomalies after multiple testing adjustments. CONCLUSIONS/UNASSIGNED:These findings highlight the importance of diverse ancestries and early-life exposures in understanding ASD heterogeneity. Future research should replicate these findings in larger samples and explore rare variants associated with preterm birth to better understand the relationship between gestational duration and clinical and genetic differences in ASD.

Evidence from rodent studies highlights the mother as a safety cue that regulates fear and biology. However, when infant rats are exposed to rough maternal care (i.e., threat), their brains show atypical patterns of activity in response to maternal cues. In humans, childhood adversity (i.e., international adoption, involvement with Child Protective Services) is also associated with differential neural responses to caregiver cues. However, to date, no studies have tested the hypothesis that childhood adversity characterized by threat (e.g., physical abuse, domestic violence) influences neural responses to caregiver cues in children, as suggested by the rodent literature. This study investigates associations between threat experiences and neural responses to caregiver cues in young children using fMRI. The sample included 148 young children (52.02% Male; M_age = 6.45 years). Across the entire sample, children demonstrated heightened recruitment in regions associated with salience detection, visual processing, and social cognition in response to caregiver cues (relative to stranger cues). Moreover, threat experiences were associated with greater recruitment of the insula in response to caregiver cues (relative to stranger cues), even when controlling for deprivation experiences. The present findings contribute to a growing field of research linking childhood adversity to brain function, suggesting that experiences of threat may disrupt how children process caregiver cues at the neural level. Moreover, these results are in line with rodent studies that underscore threat as a potential disruptor of dyadic interaction between children and their caregivers. SUMMARY: Children demonstrate widespread brain activation in response to caregiver cues. Threat experiences are linked to heightened activation of the insula, a region implicated in salience detection and primary visceral processing, in response to caregiver cues. These findings suggest that caregiver cue processing might be a mechanism through which threat impacts the caregiver-child relationship, leading to cascading effects on mental health.

STUDY QUESTION/OBJECTIVE:Is there an association between infertility diagnosis and long-term adult-onset psychiatric conditions in women? SUMMARY ANSWER/CONCLUSIONS:Infertility diagnosis in women is linked to higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not schizophrenia or other psychotic disorders, particularly notable from 9 years after the first infertility diagnosis. WHAT IS KNOWN ALREADY/BACKGROUND:Infertility, especially in women, is associated with major mental health challenges around the time of diagnosis. However, the long-term connection with a wide range of psychiatric disorders is largely unknown. STUDY DESIGN, SIZE, DURATION/METHODS:This study employed a matched-pair design within the UK Biobank (UKB) cohort, including 3893 females with a diagnosis of infertility and 15 603 matched female controls, totaling 19 496 participants. PARTICIPANTS/MATERIALS, SETTING, METHODS/METHODS:Female UKB participants with a diagnosis of infertility were matched to females without the diagnosis in a 1:4 ratio based on year of birth, index of deprivation of their residency area, and primary care data linkage status. The diagnosis of female infertility was identified by the first occurrence of a primary or secondary diagnosis in either primary care or hospital records. Additional analyses explored interactions between infertility diagnosis and both miscarriage and childbearing status on psychiatric conditions. MAIN RESULTS AND THE ROLE OF CHANCE/RESULTS:Diagnosis of infertility was associated with higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not with schizophrenia or other psychotic disorders. The most notable increases in the risk of psychiatric diagnoses were observed 9 years after the first infertility diagnosis. No significant interactions were found between infertility diagnosis and either miscarriage or childbearing status on psychiatric conditions. Sensitivity analysis confirmed the robustness of these associations across different data sources for infertility diagnosis and psychiatric condition ascertainment. LIMITATIONS, REASONS FOR CAUTION/CONCLUSIONS:The study's limitations include the racial homogeneity and the overall healthier status of the UKB cohort compared to the general UK population and the potential underestimation of associations due to misclassification of subfecund women. WIDER IMPLICATIONS OF THE FINDINGS/CONCLUSIONS:These results emphasize the need for integrated mental health support in infertility care and long-term monitoring of infertility patients for psychiatric risks. STUDY FUNDING/COMPETING INTEREST(S)/BACKGROUND:None. No competing interests were declared. TRIAL REGISTRATION NUMBER/BACKGROUND:n/a.

This review showcases the ways that studying the neural basis of Behavioral Inhibition (BI) and maternal anxiety in infancy has advanced our understanding of the developmental pathophysiology of anxiety. We demonstrate that infants with BI and those who have been exposed to maternal anxiety/stress exhibit differences in neural processes associated with bottom-up attention and top-down control, both when we measure the brain at rest and when we measure the brain during stimulus processing. Differences in infant stimulus processing are particularly robust-not only do they emerge in at-risk infants, but they also shape risk trajectories from infancy through adolescence. Throughout this review, we underscore the value in a focus on infancy and early childhood. We also point to several key future directions for this work, including prioritizing a longitudinal, multi-modal approach for studying neurobehavioral profiles of early-life risk. Together, this work demonstrates that neural processes involved in attention and control are central to BI and early-life risk for anxiety across the lifespan.

Household chaos has been shown to be an important predictor across multiple domains of children's development, with both direct associations and indirect associations through changes in parenting practices. Yet, little is known about these associations among immigrant families. Data from the Children, Community, and Caregivers (C3) Study of the larger Together Growing Strong place-based initiative among predominantly Chinese and Latine immigrant families in the Sunset Park neighborhood of Brooklyn, New York were used to examine cross-sectional associations between household chaos and child behavior and receptive vocabulary at child ages 4 and 6 (N = 187). The STROBE checklist for cross-sectional research was adhered to. Linear regression models were used to examine unique contributions of variables, as well as structural equation modeling to examine mediation through parenting stress. As a supplemental exploratory analysis, differences in associations between household chaos and child behavior and language by race/ethnicity were further examined. There were significant positive associations between household chaos and parental reports of children's problem behavior (β = 0.21, 95% CI [0.07-0.35]) and significant negative associations between household chaos and direct assessments of children's receptive vocabulary (β=-0.21, 95% CI [-0.37 - -0.04]). Further, there were indirect associations of household chaos through parenting stress for child problem behavior only (β = 0.11, 95% CI [0.05-0.17]). The results for the main linear regression models and mediation models were primarily driven by Chinese families. Implications for predictors of child development in immigrant populations and the enduring salience of household chaos are discussed.

Our objective was to examine the role of structural racism and economic disadvantage in perinatal health inequities using the Environmental influences on Child Health Outcomes Cohort. Participants' addresses were linked to area-level measures of life expectancy, education, unemployment, health insurance, jail rate, segregation, and housing cost burden. We created absolute measures to represent economic disadvantage and relative measures comparing values for Black or Latinx people to White people in the same area to represent structural racism. We used quantile G-computation to estimate the effects of a one-quartile increase in all exposures simultaneously on fetal growth and gestational age measures. A one-quartile increase in economic disadvantage was associated with a reduction in birthweight [(-25.65 grams, 95% CI (-45.83, -5.48)], but not gestational age [-0.02 weeks, 95% CI (-0.13, 0.09)]. With a one-quartile increase in Latinx-White structural racism, we observed reductions in birthweight [-80.83, 95% CI (-143.42, -18.23)) among Latinx participants. A one-quartile increase in Black-White structural racism was weakly associated with lower birthweight among Black participants [-15.70, 95% CI (-82.89, 51.48)] but was associated with higher birthweight among White participants [57.47, 95% CI (13.26, 101.67)]. Our findings suggest co-occurring forms of structural inequity likely influence racialized disparities in fetal growth outcomes.

Clinical, neuroimaging and genomics evidence have increasingly underscored a degree of overlap between autism and attention-deficit/hyperactivity disorder (ADHD). This study explores the specific contribution of their core symptoms to shared biology in N = 166 verbal children (6-12 years) with rigorously-established primary diagnoses of either autism or ADHD (without autism). We investigated the associations between inter-individual differences in low motion whole-brain intrinsic functional connectivity (iFC) and dimensional measures of autism and ADHD symptoms indexed by clinician-based observation and parent interview, respectively. Additionally, we explored their linked gene expression patterns in silico. Whole-brain multivariate distance matrix regression revealed a transdiagnostic association between autism severity and iFC of two nodes primarily on the left hemisphere: the middle frontal gyrus of the frontoparietal network and the posterior cingulate cortex of the default mode network. Across children, the greater the iFC between these nodes, the more severe the autism symptoms, even after controlling for ADHD ratings. Results from secondary segregation analyses were consistent with primary findings, underscoring the significance of internetwork iFC for autism symptom severity across diagnoses. No statistically significant brain-behavior relationships were observed for ADHD symptoms. Genetic enrichment analyses of the iFC maps associated with autism symptoms implicated genes known to: (i) have greater rate of variance in autism and ADHD, and (ii) be involved in neuron projections, suggesting shared genetic mechanisms for this specific brain-clinical phenotype. These findings underscore the relevance of transdiagnostic dimensional approaches in linking clinically-defined and observation-based phenomena to shared presentations at the macroscale circuit- and genomic-levels across diagnoses.

In this Personal View, we address key questions to support evidence-based prevention and management of psychotic symptoms that might occur during ADHD pharmacotherapy. We begin by examining evidence showing a significantly increased occurrence of psychotic disorders in individuals with ADHD, independent of ADHD medications (pooled relative risk, odds ratio, or hazard ratio=4·74, 95% CI 4·11-5·46). We then examine whether ADHD medications play a causal role, noting that current evidence does not support such a causal link, at least for methylphenidate. We explore how vulnerability to psychosis varies across individuals with ADHD. Regarding the different steps involved in prescribing ADHD medications, we discuss the importance of balancing potential risks-such as emergence of psychotic symptoms-against the demonstrated benefits of pharmacological treatment for ADHD. Next, we present strategies for screening individuals for vulnerability to psychosis before initiating ADHD medication. We then offer guidance on the clinical management of psychotic symptoms that might arise during ADHD pharmacotherapy, including considerations of dosage and medication type. Finally, we identify key research priorities in this area. Overall, this paper provides an empirical framework, grounded in evidence and clinical practice, to guide the next steps in the field.

The transition from Child and Adolescent (CAMHS) to Adult Mental Health Services (AMHS) can be challenging. Drawing on the sample of the European MILESTONE project, we explored changes in clinical profiles and treatment outcomes in adolescents transitioning to AMHS over two years, focusing on different pharmacological treatment patterns. The sample (N = 690; mean age: 17.7 years; SD = 0.29) was categorised into three groups based on medication patterns: continuous (Group 1), intermittent (Group 2), and never medicated (Group 3). Participants underwent four evaluations over two years using tools measuring psychopathology and functioning, including the Health of the Nation Outcome Scale for Child and Adolescents (HoNOSCA) and ASEBA Battery. We employed repeated-measures models to analyse clinical rating changes and a two-way mixed ANOVA to assess interaction between time and groups. Group 3 had significantly lower mean HoNOSCA ratings than Groups 1 and 2 (p < 0.001), indicating better mental health. By the last time point (T4), the factors associated with a reduced risk of severe illness included an improvement in the risk of suicide attempts (p = 0.038), enhanced everyday functional skills (p = 0.008), higher quality of life (p = 0.001), and being male (p = 0.020). The ASEBA Battery showed Group 1 had more internalising symptoms, while Group 2 had more externalising symptoms than Group 3. During the transition from CAMHS to AMHS, continuous medication was associated with higher symptom severity than intermittent or no pharmacological treatment. This may reflect either a more severe initial symptomatology requiring sustained pharmacotherapy or a medication-related paradox, whereby symptoms persist or intensify owing to treatment resistance or side effects. TRIAL REGISTRATION: "MILESTONE study" registration: ISRCTN ISRCTN83240263 Registered 23 July 2015; ClinicalTrials.gov NCT03013595 Registered 6 January 2017.

Providing care to pediatric oncology patients involves delivering sensitive information to families, addressing diverse psychosocial needs, and navigating patient and family emotions. Psychosocial providers embedded within pediatric oncology clinics are uniquely qualified to address communication gaps between patients and providers, provide support to patients, and facilitate collaborative discussions between patients and the medical team. This quality improvement project aimed to describe the impact of including psychosocial providers in critical conversations between medical teams and families. Through conversation tracking, members of the psychosocial team recorded their involvement in thirty-six critical conversations. The psychosocial team offered various interventions including therapeutic processing, emotional assessment, medical translation, psychosocial support, child-focused support, and facilitation of discussions between families and medical providers. While challenges were identified including time and availability, physicians noted several benefits of psychosocial involvement, particularly in addressing emotional needs and enhancing communication with families. Psychosocial providers also noted benefits including demonstrating alignment with the medical team and enhancing the support that they are able to provide the family following the conversation. By integrating psychosocial support into critical conversations, medical providers can foster a patient-centered approach to care and optimize care delivery to effectively support families facing childhood cancer diagnoses.