Faculty Bibliography

OBJECTIVE:To assess associations between exposure to intrauterine SARS-CoV-2 and subsequent child neurodevelopment in a large, diverse cohort with confirmation of maternal SARS-CoV-2 status. STUDY DESIGN/METHODS:edition (ASQ-3) and at 18 months with the ASQ Social-Emotional (ASQ-SE) and the Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R). We compared exposed and unexposed infants' ASQ-3 total and subdomain scores, ASQ-SE and M-CHAT-R scores, and proportions meeting published referral thresholds, using multivariable linear and logistic regression. RESULTS:Among 1179 participants enrolled, 1008 (85.5%) had exposure, with 806 (80.0%) exposed during Omicron predominance. Of those with known timing, 349 (41.4%) and 295 (35.0%) were exposed in the second and third trimesters of pregnancy respectively. Exposure was not associated with differences in ASQ-3 (adjusted difference: -0.61, 95% CI: -10.03, 8.81) or ASQ-3 subdomains at 12 months, ASQ-SE at 18 months (adjusted difference: 0.19, 95% CI: -4.02, 4.41), or M-CHAT-R scores. Findings were similar for proportions meeting referral thresholds, and when stratified by variant or by trimester. CONCLUSIONS:In this multicenter cohort largely exposed since Omicron and in second or third trimester, intrauterine SARS-CoV-2 exposure was not associated with neurodevelopmental screening outcomes through 18 months of age. Further assessments of the impact of intrauterine SARS-CoV-2 on neurodevelopment beyond 18 months of age are needed.

BACKGROUND:Negative reactivity (NR) and behavioral inhibition (BI), temperamental traits characterized by novelty-evoked distress and avoidance respectively, represent risk markers for anxiety. However, not all infants with NR and BI develop anxiety. Pathways from infant temperament to anxiety remain underspecified. This study tests the hypothesis that heightened neural sensitivity to unexpected sensory stimuli in infancy moderates risk for anxiety. METHODS:Data from the Temperament Over Time Study (N=291) were utilized. Infants completed laboratory-based assessments of NR at 4 months (M) and BI at 2-3 years. BI was also assessed using parent-report. At 9 and 36M, electroencephalography was collected during a passive three-stimulus auditory oddball task, and the mismatch response (MMR) and novelty P3 were quantified. Adolescent anxiety was measured using parent- and self-reports, and clinical interviews at 13 and 15 years. Structural equational modeling analyses were applied to examine whether infants' MMR or novelty P3 at 9 and 36M modulate relations between NR, BI, and adolescent anxiety. RESULTS:The MMR at 9M moderated the relation between NR and BI, and the MMR at 36M moderated the relation between BI and 13-year anxiety. In both cases, a more negative MMR was associated with elevated risk. This association was not present for attention problems or externalizing outcomes. Additional exploratory analyses showed that the novelty P3 mediated pathways from NR to social anxiety. CONCLUSIONS:Individual differences in the infant's neural response to unexpected stimuli relate to temperamental risk for anxiety.

Pyramidal cells (PCs) of hippocampal area CA2 exhibit increased excitability in temporal lobe epilepsy (TLE) and in mouse models of TLE. In epileptic mice, selective inhibition of CA2 PCs reduces chronic seizures. Here we asked if activating CA2 PCs increases seizures. Mice expressing Cre recombinase in CA2 PCs (Amigo2-Cre mice) were injected with the convulsant pilocarpine to induce a period of severe seizures (status epilepticus, SE), which leads to chronic seizures after 3-4 weeks (epilepsy). Epileptic mice were injected with a Cre-dependent adeno-associated virus (AAV) to express an excitatory designer receptor exclusively activated by designer drug (eDREADD; hM3Dq) in dorsal CA2 bilaterally and implanted with subdural EEG electrodes. After recovery, mice were recorded continuously using video and EEG for 6 weeks, 3 weeks with drinking water containing the eDREADD activator clozapine-N-oxide (CNO) and 3 weeks without CNO. CA2 activation with CNO caused a significant increase in seizure frequency and duration. Seizures occurred in clusters (many seizures per day over several consecutive days) and mice given water with CNO had a greater maximum number of seizures per day during a cluster compared to water without CNO. CNO had no significant effect in control mice. In naïve Amigo2-Cre mice expressing hM3Dq, pre-treatment with CNO before pilocarpine administration shortened the latency to SE and increased EEG power at the start of SE. Taken together with prior findings, the results suggest that CA2 is a control point for regulating seizures in the pilocarpine mouse model of TLE.

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.

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:The obesity epidemic in the United States affects not only adults, but children and adolescents. SOURCES OF MATERIAL/UNASSIGNED:An extensive review of the literature including 85 articles has been completed with the aim of providing the most current definitions and recommendations for this chronic condition. ABSTACT OF FINDINGS/UNASSIGNED:This article reviews the definition of pediatric obesity, the increasing prevalence of obesity in children and adolescents, genetic and environmental risk factors, as well as the unique aspects and implications of this condition and its associated comorbidities for this population in comparison to adults. Current management recommendations are also discussed which include Intensive Health Behavioral and Lifestyle Treatment (IHBLT), metabolic surgery, and pharmacologic therapy including glucago-like peptide-1 receptor agonists (GLP-1RAs). CONCLUSION/CONCLUSIONS:Childhood obesity is a unique condition in its progression and management requirements, and should be approached with a focus on prevention as well as on the high-risk individual.

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.