Faculty Bibliography

IMPORTANCE:Gender-diverse youths have higher rates of mental health problems compared with the general population, as shown in both clinical and nonclinical populations. Brain correlates of gender diversity, however, have been reported only among youths with gender dysphoria or in transgender individuals. OBJECTIVE:To examine brain morphologic correlates of gender diversity among adolescents from a general pediatric population who were assigned male or female at birth, separately. DESIGN, SETTING, AND PARTICIPANTS:This cross-sectional study was embedded in Generation R, a multiethnic population-based study conducted in Rotterdam, the Netherlands. Adolescents who were born between April 1, 2002, and January 31, 2006, and had information on self-reported or parent-reported gender diversity and structural neuroimaging at ages 13 to 15 years were included. Data analysis was performed from April 1 to July 31, 2022. EXPOSURES:Gender-diverse experiences among adolescents were measured with selected items from the Achenbach System of Empirically Based Assessment forms and the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults, as reported by adolescents and/or their parents. MAIN OUTCOMES AND MEASURES:High-resolution structural neuroimaging data were collected using a 3-T magnetic resonance imaging scanner (at a single site). We used linear regression models to examine differences in global brain volumetric measures between adolescents who reported gender diversity and those who did not. RESULTS:This study included 2165 participants, with a mean (SD) age of 13.8 (0.6) years at scanning. A total of 1159 participants (53.5%) were assigned female at birth and 1006 (46.5%) were assigned male at birth. With regard to maternal country of origin, 1217 mothers (57.6%) were from the Netherlands and 896 (42.4%) were from outside the Netherlands. Adolescents who reported gender diversity did not differ in global brain volumetric measures from adolescents who did not report gender diversity. In whole-brain, vertexwise analyses among adolescents assigned male at birth, thicker cortices in the left inferior temporal gyrus were observed among youths who reported gender diversity compared with those who did not. No associations were observed between gender diversity and surface area in vertexwise analyses. CONCLUSIONS AND RELEVANCE:The findings of this cross-sectional study suggest that global brain volumetric measures did not differ between adolescents who reported gender diversity and those who did not. However, these findings further suggest that gender diversity in the general population correlates with specific brain morphologic features in the inferior temporal gyrus among youths who are assigned male at birth. Replication of these findings is necessary to elucidate the potential neurobiological basis of gender diversity in the general population. Future longitudinal studies should also investigate the directionality of these associations.

IMPORTANCE:Autism spectrum disorder (ASD) is associated with significant clinical, neuroanatomical, and genetic heterogeneity that limits precision diagnostics and treatment. OBJECTIVE:To assess distinct neuroanatomical dimensions of ASD using novel semisupervised machine learning methods and to test whether the dimensions can serve as endophenotypes also in non-ASD populations. DESIGN, SETTING, AND PARTICIPANTS:This cross-sectional study used imaging data from the publicly available Autism Brain Imaging Data Exchange (ABIDE) repositories as the discovery cohort. The ABIDE sample included individuals diagnosed with ASD aged between 16 and 64 years and age- and sex-match typically developing individuals. Validation cohorts included individuals with schizophrenia from the Psychosis Heterogeneity Evaluated via Dimensional Neuroimaging (PHENOM) consortium and individuals from the UK Biobank to represent the general population. The multisite discovery cohort included 16 internationally distributed imaging sites. Analyses were performed between March 2021 and March 2022. MAIN OUTCOMES AND MEASURES:The trained semisupervised heterogeneity through discriminative analysis models were tested for reproducibility using extensive cross-validations. It was then applied to individuals from the PHENOM and the UK Biobank. It was hypothesized that neuroanatomical dimensions of ASD would display distinct clinical and genetic profiles and would be prominent also in non-ASD populations. RESULTS:Heterogeneity through discriminative analysis models trained on T1-weighted brain magnetic resonance images of 307 individuals with ASD (mean [SD] age, 25.4 [9.8] years; 273 [88.9%] male) and 362 typically developing control individuals (mean [SD] age, 25.8 [8.9] years; 309 [85.4%] male) revealed that a 3-dimensional scheme was optimal to capture the ASD neuroanatomy. The first dimension (A1: aginglike) was associated with smaller brain volume, lower cognitive function, and aging-related genetic variants (FOXO3; Z = 4.65; P = 1.62 × 10-6). The second dimension (A2: schizophrenialike) was characterized by enlarged subcortical volumes, antipsychotic medication use (Cohen d = 0.65; false discovery rate-adjusted P = .048), partially overlapping genetic, neuroanatomical characteristics to schizophrenia (n = 307), and significant genetic heritability estimates in the general population (n = 14 786; mean [SD] h2, 0.71 [0.04]; P < 1 × 10-4). The third dimension (A3: typical ASD) was distinguished by enlarged cortical volumes, high nonverbal cognitive performance, and biological pathways implicating brain development and abnormal apoptosis (mean [SD] β, 0.83 [0.02]; P = 4.22 × 10-6). CONCLUSIONS AND RELEVANCE:This cross-sectional study discovered 3-dimensional endophenotypic representation that may elucidate the heterogeneous neurobiological underpinnings of ASD to support precision diagnostics. The significant correspondence between A2 and schizophrenia indicates a possibility of identifying common biological mechanisms across the 2 mental health diagnoses.

Autism spectrum disorder (ASD), a heritable neurodevelopmental disorder, confers genetic liability that is often expressed among relatives through subclinical, genetically-meaningful traits, or endophenotypes. For instance, relative to controls, parents of individuals with ASD differ in language-related skills, with differences emerging in childhood. To examine ASD-related endophenotypes, this study investigated developmental academic profiles among clinically unaffected siblings of individuals with ASD (n = 29). Lower performance in language-related skills among siblings mirrored previously-reported patterns among parents, which were also associated with greater subclinical ASD-related traits in themselves and their parents, and with greater symptom severity in their sibling with ASD. Findings demonstrated specific phenotypes, derived from standardized academic testing, that may represent childhood indicators of genetic liability to ASD in first-degree relatives.

Fear conditioning is a widely used laboratory model to investigate learning, memory, and psychopathology across species. The quantification of learning in this paradigm is heterogeneous in humans and psychometric properties of different quantification methods can be difficult to establish. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values then serve as validity criterion to rank methods. Here, we develop a calibration protocol for human fear conditioning. Based on a literature review, series of workshops, and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of fear conditioning. Design variables were chosen to be as theory-free as possible and allow wide applicability in different experimental contexts. Besides establishing a specific calibration procedure, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of behavioral neuroscience that need measurement refinement.

INTRODUCTION/BACKGROUND:Interpretation of high-resolution CT images plays an important role in the diagnosis and management of interstitial lung diseases. However, interreader variation may exist due to varying levels of training and expertise. This study aims to evaluate interreader variation and the role of thoracic radiology training in classifying interstitial lung disease (ILD). METHODS:This is a retrospective study where seven physicians (radiologists, thoracic radiologists, and a pulmonologist) classified the subtypes of ILD of 128 patients from a tertiary referral center, all selected from the Interstitial Lung Disease Registry which consists of patients from November 2014 to January 2021. Each patient was diagnosed with a subtype of interstitial lung disease by a consensus diagnosis from pathology, radiology, and pulmonology. Each reader was provided with only clinical history, only CT images, or both. Reader sensitivity and specificity and interreader agreements using Cohen's κ were calculated. RESULTS:Interreader agreement based only on clinical history, only on radiologic information, or combination of both was most consistent amongst readers with thoracic radiology training, ranging from fair (Cohen's κ: 0.2-0.46), moderate to almost perfect (Cohen's κ: 0.55-0.92), and moderate to almost perfect (Cohen's κ: 0.53-0.91) respectively. Radiologists with any thoracic training showed both increased sensitivity and specificity for NSIP as compared to other radiologists and the pulmonologist when using only clinical history, only CT information, or combination of both (p < 0.05). CONCLUSIONS:Readers with thoracic radiology training showed the least interreader variation and were more sensitive and specific at classifying certain subtypes of ILD. SUMMARY SENTENCE/UNASSIGNED:Thoracic radiology training may improve sensitivity and specificity in classifying ILD based on HRCT images and clinical history.

Suicidal thoughts and behaviors (STB) and emergency department (ED) utilization are prevalent in autistic youth. The current study surveyed clinicians in a pediatric psychiatric ED to examine differences in attitudes on suicide-related care for autistic and non-autistic patient populations. While clinicians rated addressing STB in ASD as important and adaptations to care as necessary, less than half identified ASD as a suicide risk factor and confidence ratings were significantly lower for autistic patients. Previous ASD training predicted confidence and accounted for approximately 25% of the variance in confidence scores. Findings highlight the urgency to develop and disseminate ED clinician training, and address the lack of validated assessment tools, adapted suicide prevention practices, and evidence-based treatments for STB in autistic youth.

Perceived threat in youth's environments can elevate risk for mental health, social, and neurocognitive difficulties throughout the lifespan. However, few studies examine variability in youth's perceptions of threat across multiple contexts or evaluate outcomes across multiple domains, ultimately limiting our understanding of specific risks associated with perceived threats in different contexts. This study examined associations between perceived threat in youth's neighborhood, school, and family contexts at ages 9-10 and mental health, social, and neurocognitive outcomes at ages 11-12 within a large US cohort (N = 5525) enrolled in the Adolescent Brain Cognitive Development^SM Study (ABCD Study®). Latent profile analysis revealed four distinct profiles: Low Threat in all contexts, Elevated Family Threat, Elevated Neighborhood Threat, and Elevated Threat in all contexts. Mixed-effect models and post hoc pairwise comparisons showed that youth in Elevated Threat profile had poorer mental health and social outcomes 2 years later. Youth in the Elevated Family Threat profile uniquely showed increased disruptive behavior symptoms, whereas youth in the Elevated Neighborhood Threat profile predominantly displayed increased sleep problems and worse neurocognitive outcomes 2 years later. Together, findings highlight the importance of considering perceptions of threat across multiple contexts to achieve a more nuanced developmental picture.

PURPOSE/OBJECTIVE:Disruptive behavioral disorders (DBDs) are common among children/adolescents in sub-Saharan Africa. A 16-week manualized multiple family group (MFG) intervention called Amaka Amasanyufu designed to reduce DBDs among school-going children/adolescents in low-resource communities in Uganda was efficacious in reducing symptoms of poor mental health relative to usual care in the short-term (4 months post-intervention-initiation). We examined whether intervention effects are sustained 6 months postintervention. METHODS:We used longitudinal data from 636 children positive for DBDs: (1) Control condition, 10 schools, n = 243; (2) MFG delivered via parent peers (MFG-PP), eight schools, n = 194 and; (3) MFG delivered via community healthcare workers (MFG-CHW), eight schools, n = 199 from the SMART Africa-Uganda study (2016-2022). All participants were blinded. We estimated three-level linear mixed-effects models and pairwise comparisons at 6 months postintervention and time-within-group effects to evaluate the impact on Oppositional Defiant Disorder (ODD), impaired functioning, depressive symptoms, and self-concept. RESULTS:At 6 months postintervention, children in MFG-PP and MFG-CHW groups had significantly lower means for ODD (mean difference [MD] = -1.08 and -1.35) impaired functioning (MD = -1.19 and -1.16), and depressive symptoms (MD = -1.06 and -0.83), than controls and higher means for self-concept (MD = 3.81 and 5.14). Most outcomes improved at 6 months compared to baseline. There were no differences between the two intervention groups. DISCUSSION/CONCLUSIONS:The Amaka Amasanyufu intervention had sustained effects in reducing ODD, impaired functioning, and depressive symptoms and improving self-concept relative to usual care at 6 months postintervention. Our findings strengthen the evidence that the intervention effectively reduces DBDs and impaired functioning among young people in resource-limited settings and was sustained over time.

BACKGROUND:For some adults with Attention-Deficit/Hyperactivity Disorder (ADHD), nonstimulants need to be considered either as a monotherapy or as an adjunct to stimulants. OBJECTIVES:The objectives of this systematic review and meta-analysis were to assess the efficacy, acceptability, and tolerability of nonstimulants in adults with ADHD. METHODS:Data sources, searches, and study selection were based on a previously published network meta-analysis of randomized clinical trials (RCTs) by Cortese at al. (Lancet Psychiatry 5(9):727-738, 2018), which we updated in March 2022. Specifically, we searched PubMed, BIOSIS Previews, CINAHL, the Cochrane Central Register of Controlled Trials, EMBASE, ERIC, MEDLINE, PsycINFO, OpenGrey, Web of Science Core Collection, ProQuest Dissertations and Theses (UK and Ireland), ProQuest Dissertations and Theses (abstracts and international), and the WHO International Trials Registry Platform, including ClinicalTrials.gov for double-blind RCTs with a placebo arm, lasting at least one week, including adults with a diagnosis of ADHD based on DSM-III, DSM-III-R, DSM-IV(TR), DSM-5 or ICD-9- or 10, and reporting data on efficacy, tolerability (drop-out due to side effects) and acceptability (drop-out due to any cause) of guanfacine, clonidine, or atomoxetine. Additionally, we searched for RCTs of viloxazine extended release (ER), approved for ADHD in 2021. Random-effects meta-analyses were conducted, and the risk of bias for individual RCTs was assessed using the Cochrane Risk of Bias tool. RESULTS:We included 18 studies in the meta-analyses (4308 participants) plus one additional study in the narrative synthesis (374 participants). The meta-analysis showed that atomoxetine (15 RCTs) (Hedge's g = - 0.48, 95% CI [- 0.64; - 0.33]), guanfacine (two RCTs) (Hedge's g = - 0.66, 95% CI [- 0.94; - 0.38]) and viloxazine ER (one RCT) were significantly more efficacious than placebo. Atomoxetine was less well tolerated than placebo, while tolerability of guanfacine and viloxazine ER could not be meta-analysed, since only one study, for each medication, reported on it. CONCLUSIONS:All investigated nonstimulants were more efficacious in the treatment of ADHD in adults, than placebo, while the placebo had better acceptability and tolerability. PROTOCOL:https://osf.io/5vnmt/?view_only=2bf87ed12ba94645babedceeee4c0120 .