Faculty Bibliography

OBJECTIVE:This study aimed at identifying moderators of efficacy of stimulants against placebo to inform personalized recommendations for treatment in preschool children (< 6 years) with attention-deficit/hyperactivity disorder (ADHD). METHOD/METHODS:We acquired individual-level participant data from two randomized placebo-controlled trials (RCTs) of preschool ADHD: MAPPA (8-week methylphenidate, 102 participants, Brazil) and SPD489-347 (6-week lisdexamfetamine, 148 participants, US). We evaluated the moderator and predictor effects of baseline demographic (age, sex, race, ethnicity, maternal educational level) and baseline clinical (ADHD symptom severity, intelligence quotient, number of psychiatric comorbidities) characteristics, as available, on endpoint ADHD symptom severity scores. Data from each study were analyzed separately with linear mixed-effects model for repeated measures. For categorical variables, we also computed treatment effects (i.e., stimulants versus placebo) within subgroups and, when possible, pooled them alongside subgroup data from PATS (5-week methylphenidate, 165 participants, US) in random-effects meta-analyses. RESULTS:Stimulants had greater efficacy against placebo in White children compared to Black children considering data from US studies. Older age was not a moderator of greater efficacy of stimulants against placebo, nor was it associated with worse ADHD symptom severity at endpoint. Greater baseline ADHD symptom severity was associated with higher ADHD symptom severity at endpoint independently of the assigned treatment group. CONCLUSION/CONCLUSIONS:Race, but not older age or baseline ADHD symptom severity, may moderate the efficacy of stimulants for preschool ADHD. Given the post hoc nature of subgroup analyses, the findings should be interpreted as exploratory and viewed as hypothesis for confirmation in future studies.

STUDY DESIGN/METHODS:Retrospective cohort study. OBJECTIVE:Due to proximity of the surgical site to important respiratory structures, patients may undergo delayed extubation after adult cervical deformity (ACD) surgery to manage postoperative airway edema/obstruction. Herein, we evaluate relevant relationships with delayed extubation. SUMMARY OF BACKGROUND DATA/BACKGROUND:Delayed extubation is an underreported perioperative occurrence, with only a few studies conducting case-by-case reviews of prolonged intubation. METHODS:Operative ACD patients with baseline (BL) were grouped based on whether they experienced delayed extubation (DE), or leaving the OR while still intubated, versus those who were extubated successfully in the OR (non-DE). Means comparison and regression analyses identified predictors of delayed extubation and associations with peri-operative complications and outcomes. RESULTS:82 patients met inclusion criteria (mean age 62.4±13.0 y, 52.4% female, Edmonton frailty score: 5.10±2.97, ACFI score: 0.30±0.16, CCI: 1.41±1.73). 14 patients left the OR intubated, and 1(1.2%) required reintubation. DE cohort demonstrated greater Edmonton frailty scores (P=0.017) and smoking histories (P=0.031). Intraoperatively, there was a significant difference EBL (P=0.021) and rate of transfusions (DE: 27.3% v non-DE: 4.8%, P=0.12). Upper instrumented vertebra (UIV) was not associated with DE, while lower LIV increased the likelihood of DE (OR 1.1, P=0.029). Post-operatively, as expected, there was a significant difference in rate of SICU admissions (DE: 90.9% v. non-DE: 49.2%, P=0.01), although no significant differences in LOS. Greater cSVA and MGS correction from baseline was associated with increased likelihood of delayed extubation (OR 1.1, CI 95% 1.05-1.17, P<.001; OR 1.14, CI 95% 1.05-1.24, P=0.003). Furthermore, delayed extubation was a significant predictor of increased VR-Physical Component Scores (P=0.013) at 6W, and DE cohort demonstrated significantly higher VR-PCS and VR-MCS Scores at 6W (P=0.01, both). CONCLUSIONS:Baseline frailty and larger radiographic correction can be associated with delayed extubation, which can impact quality of life perioperatively. Considerations like minimizing intraoperative blood loss and degree of correction could minimize delayed extubation.

BACKGROUND:Anxiety disorders may partly stem from altered neurodevelopment of attention-related networks. Neonatal alterations in resting-state functional connectivity (rsFC) among the dorsal attention (DAN); frontal parietal (FPN); salience (SN); and default mode networks (DMN)) relate to fearful temperament, a risk marker for anxiety. Nevertheless, little research examines development of these networks beyond the first months of life, particularly in fearful infants. This study examines how changes in these networks in the first two years of life relate to fearful temperament. METHODS:Using data from the Baby Connectome Project (from 180 infants across 396 sessions), we conducted independent components analysis to extract rsFC among the DMN, SN, DAN, and FPN. Longitudinal modeling characterized 1) age-related changes (slope) in rsFC through age two; 2) relations between rsFC change (slope) and fearfulness at age 2; 3) relations between rsFC and fearfulness trajectories (slope and intercept) over the first two years of life. RESULTS:Age-related decreases occurred in rsFC in DAN - FPN and DMN - SN. Smaller decreases in DAN - FPN rsFC over time related to greater fear at age 2, and to increases in fearfulness over time. High initial DAN-FPN rsFC and low initial DAN - SN rsFC also related to increasing fearfulness over time. CONCLUSION/CONCLUSIONS:This study provides the first evidence that changes in attention-related brain networks are related to early-life fearfulness, a robust early-life risk marker of anxiety.

OBJECTIVE:Childhood inhibited temperament (cIT) is associated with an increased risk for developing internalizing psychopathology. Neurobiological characteristics identified by structural magnetic resonance imaging (MRI) may elucidate the neural substrates for cIT, but studies are scarce and often focus on particular regions of interest. Moreover, current findings lack replication. This pre-registered analysis from the ENIGMA-Anxiety Working Group examined structural brain characteristics associated with cIT using a comprehensive whole-brain approach. METHOD/METHODS:Temperament assessments (behavioral observations, parental/teacher reports or self-reports on cIT before age 13) and MRI-data (age at scan: 6-25 years) from international research sites (Europe, North America, South America) were pooled for mega-analysis. Following image processing and quality control, associations between cIT and brain structure were examined in 3,803 participants. Subcortical volumes, cortical thickness and surface area (main analyses) and detailed subcortical characteristics (e.g. subnuclei, subfields, partial volume effects; exploratory analyses) were considered. RESULTS:= 0.029) in youth with parental/teacher reports on cIT-levels. Exploratory analyses revealed findings in hippocampus, putamen and caudate, but most did not survive statistical correction for multiple testing. CONCLUSION/CONCLUSIONS:This mega-analysis found no consistent associations between cIT and regional brain structure, although the role of parietal regions warrants further investigation. Future studies should consider brain function in cIT, preferably using longitudinal designs.

Sleep disturbances are prominent across neurodevelopmental disorders (NDDs) and may reflect specific abnormalities in brain development and function. Overnight polysomnography (PSG) allows for detailed investigation of sleep architecture, offering a unique window into neurocircuit function. Analysis of existing pediatric PSGs from clinical studies could enhance the availability of sleep studies in pediatric patients with NDDs towards a better understanding of mechanisms underlying abnormal development in NDDs. Here, we introduce and characterize a retrospective collection of 1527 clinical pediatric overnight PSGs across five different sites. We first developed an automated stager trained on independent pediatric sleep data, which yielded better performance compared to a generic stager trained primarily on adults. Using consistent staging across cohorts, we derived a panel of EEG micro-architectural features. This unbiased approach replicated broad trajectories previously described in typically developing sleep architecture. Further, we found sleep architecture disruptions in children with Down's Syndrome (DS) that were consistent across independent cohorts. Finally, we built and evaluated a model to predict age from sleep EEG metrics, which recapitulated our previous findings of younger predicted brain age in children with DS. Altogether, by creating a resource pooled from existing clinical data we expanded the available datasets and computational resources to study sleep in pediatric populations, specifically towards a better understanding of sleep in NDDs. This Retrospective Analysis of Sleep in Pediatric (RASP) cohorts dataset, including staging annotation derived from our automated stager, is deposited at https://sleepdata.org/datasets/rasp.

PURPOSE/OBJECTIVE:Our goals were to: 1) examine the occurrence of behavioral and emotional symptoms in children on the autism spectrum in a large national sample, stratifying by sex, and 2) evaluate whether children with increased autism-related social communication deficits also experience more behavioral and emotional problems. METHODS: Participants (n = 7,998) were from 37 cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program. Cross-sectional information on demographic factors, parent-report of an ASD diagnosis by clinician, Social Responsiveness Scale (SRS) scores, and Child Behavior Checklist (CBCL) scores were obtained for children aged 2.5-18 years by surveys. We examined mean differences in CBCL Total Problems and DSM-oriented subscale scores by autism diagnosis and by child sex. Analyses using logistic regression were conducted to examine whether autism was associated with higher CBCL scores. We further examined if these relationships differed by child age category (< 6 years, 6-11 years, 12 + years). The relationships between SRS score and CBCL total and subscale scores were examined using quantile regression models, with analyses adjusted for child sex and age. RESULTS: In ECHO, 553 youth were reported by a parent to have a clinician diagnosis of autism spectrum disorder (ASD) (432 [78%] boys and 121 [22%] girls). Youth on the spectrum had higher mean CBCL raw scores on Total Problems and all DSM-oriented subscales compared to those not on the spectrum (all p < 0.0001). Analyses adjusted for sex and stratified by age group indicated that higher odds of autism diagnosis were associated with total, depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD) scales in the top 30% of the CBCL score distribution. Autistic girls were more likely to have parent-reported depression and anxiety compared to autistic boys. In quantile regression analyses, we observed evidence of stronger associations between SRS and CBCL for those in higher quantiles of CBCL total problems scale score (beta representing 1-unit change in SRS associated with 1-unit increase in CBCL total problems scale score), among children in the 70-90th percentile (β = 1.60, p < 0.01), or top 10th percentile (β = 2.43, p < 0.01) of the CBCL total problems scale score distribution. Similar findings were seen for the DSM-oriented depression, anxiety, and ADHD subscales. CONCLUSION/CONCLUSIONS: Results from this large national sample suggest increased behavioral and emotional problems among autistic children compared to non-autistic children throughout early life. Among children on the spectrum this may warrant increased monitoring for co-occurring behavioral and emotional problems.

BACKGROUND/UNASSIGNED:Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with a multifactorial etiology, many aspects of which remain unclear. Emerging evidence suggests a potential association between ASD and clinical manifestations resulting from hormonal imbalances, henceforth named "steroidopathies." The present study aims to investigate the association between ASD, steroidopathies and altered steroid hormone levels. METHODS/UNASSIGNED:A cohort of 100 individuals aged 9-18 years was examined, comprising 50 autistic individuals (25 males, 25 females) compared to 50 individuals diagnosed with other neuropsychiatric disorders (20 males, 30 females). Data were collected on steroidopathies (including hirsutism, severe acne, irregular menstrual cycles, polycystic ovary syndrome, endometriosis, pubertal disorders) in participants and their first-degree relatives, as well as on maternal pregnancy and delivery complications. Blood samples were analyzed to assess hormonal profiles, including testosterone, estradiol, and vitamin D levels. A multivariate logistic regression analysis was conducted, with ASD status as the dependent variable and hormone levels, steroidopathies and other pregnancy-related conditions as independent variables. Sex and age were included as covariates. RESULTS/UNASSIGNED: = 0.0057). CONCLUSION/UNASSIGNED:These findings support the hypothesis of an association between steroidopathies and altered steroid hormone levels with ASD, suggesting that steroid hormone profiles could potentially serve as early biomarkers in future research. Furthermore, consideration of maternal endocrine health and prenatal exposures may contribute to a better understanding of ASD risk.

BACKGROUND/UNASSIGNED:Unaccompanied migrant youths are at elevated risk for exposure to trauma and related mental health challenges, but there is minimal evidence guiding best practices. We conducted a systematic review of quantitative studies that examined mental health evaluation and treatment services for unaccompanied migrant youths resettled in the United States (US). METHODS/UNASSIGNED:In accordance with the PRISMA 2020 statement, a literature search was conducted for empirical studies in nine databases and publicly available search engines. Citation tracking also assisted in identifying additional studies, including from the gray literature. The study protocol was pre-registered (PROSPERO ID: CRD42023396805). Inclusion criteria required that studies be published between January 1, 2000 and November 11, 2024 and report quantitative results that evaluate mental health status or mental health treatment outcomes for youths (younger than 18 years) who were unaccompanied when they arrived in the US. Descriptive, narrative synthesis was used for analysis of results. Mixed Method Appraisal Tool was used to appraise study quality. RESULTS/UNASSIGNED: = 1494 children)-six cohort studies (retrospective or prospective), five cross-sectional, one non-controlled trial, and one program evaluation-met inclusion criteria. Ten evaluated mental health using diverse questionnaires and most focused on trauma-related symptoms. Three focused on mental health treatment. Findings demonstrated heterogeneous methods of evaluating mental health symptoms and implementing treatment services for unaccompanied migrant youths, although many indicated high rates of reported traumatic exposure. Most reported higher rates of trauma-related and internalizing symptoms and all treatment studies demonstrated initial promise. Likely due to difficulty in accessing unaccompanied migrant youths, most studies used convenience samples limiting generalizability of findings. CONCLUSIONS/UNASSIGNED:Rigorous studies with comprehensive collection of sociodemographic characteristics are needed to inform the development of evidence-based services that accurately detect and effectively treat mental health challenges among unaccompanied migrant youths.