Faculty Bibliography

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.

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.

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.

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.

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.

Accumulating evidence from neuroimaging studies has implicated widespread disruptions in brain connectivity in autism spectrum disorder (ASD), with altered connectivity patterns reported as early as infancy. However, it remains unexplored whether functional connectivity differences are evident prior to birth in the brain of fetuses who will later exhibit autistic traits in early childhood. In this study, we leveraged a longitudinal sample of 62 children with both quality-assured fetal brain resting-state MRI data and a parent-report measure of autistic traits at age 3 years. Enrichment analysis was employed to identify network pairs significantly correlated with autistic traits. Specificity analysis was conducted by additionally controlling for other childhood psychopathology. Our results demonstrated significant correlations between autistic traits and functional connectivity in the cingulate-left temporal and right prefrontal-left operculum network pairs in both the primary and specificity analyses. Visual network connectivity with prefrontal and opercular regions was also implicated. These network pairs demonstrated positive associations with autistic traits, indicating that stronger connectivity between these network pairs was associated with higher autistic traits. In contrast, weaker cerebellum-right operculum connectivity was associated with higher autistic traits, uniquely in the specificity analysis. This study provides the first in vivo evidence prospectively linking variation in functional network connectivity in the fetal brain to autistic traits in toddlerhood. These findings extend the current understanding of the prenatal brain origins of ASD and highlight the potential of fetal rs-fMRI as a tool to identify neural signatures related to social-emotional development and ASD likelihood.

BACKGROUND:Risky sexual behaviours (RSB) and attention deficit hyperactivity disorder (ADHD) are both major concerns among university students. However, their association remains insufficiently understood. This study aimed to evaluate the relationship between ADHD symptoms and a broad range of RSB in university students. METHODS:A total of 13 085 French students enrolled in the i-Share (Internet-based Students' Health Research Enterprise study (mean age: 20.6 years, SD=2.4) completed self-reported questionnaires assessing ADHD symptoms (Adult Self-Report Scale V.1.1), RSB, sociodemographic characteristics and alcohol and cannabis use. Logistic regression models were used to examine the cross-sectional associations between ADHD symptoms and RSB, adjusting for relevant confounders. RESULTS:A high level of ADHD symptoms was observed in 5.3% of students. In multivariate models, ADHD symptoms were associated with a wide range of RSB, including early first sexual intercourse (adjusted OR (aOR) 1.26; 95% CI 1.06 to 1.51), inconsistent condom use in the last 12 months (aOR 1.26; 95% CI 1.05 to 1.51), diagnosis of a sexually transmitted infection in the last 12 months (aOR 1.60; 95% CI 1.16 to 2.22) and having had multiple sexual partners in the last 12 months (adjusted incidence rate ratio 1.20; 95% CI 1.14 to 1.27). Among female students, ADHD symptoms were associated with lower current use of any form of contraception (aOR 0.59; 95% CI 0.48 to 0.71), and higher odds of having ever used emergency contraception (aOR 1.22; 95% CI 1.02 to 1.47), and having ever had an abortion (aOR 1.77; 95% CI 1.21 to 2.58). CONCLUSIONS:University students with a high level of ADHD symptoms are at increased risk of engaging in a wide range of RSB. Targeted preventive strategies may be particularly beneficial for this population.