Faculty Bibliography

Prior research has identified epigenetic predictors of attention problems in school-aged children but has not yet investigated these in young children, or children at elevated risk of attention problems due to preterm birth. The current study evaluated epigenome-wide associations between neonatal DNA methylation and attention problems at age 2 years in children born very preterm. Participants included 441 children from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study, a multi-site study of infants born < 30 weeks gestational age. DNA methylation was measured from buccal swabs collected at NICU discharge using the Illumina MethylationEPIC Bead Array. Attention problems were assessed at 2 years of adjusted age using the attention problems subscale of the Child Behavior Checklist (CBCL). After adjustment for multiple testing, DNA methylation at 33 CpG sites was associated with child attention problems. Differentially methylated CpG sites were located in genes previously linked to physical and mental health, including several genes associated with ADHD in prior epigenome-wide and genome-wide association studies. Several CpG sites were located in genes previously linked to exposure to prenatal risk factors in the NOVI sample. Neonatal epigenetics measured at NICU discharge could be useful in identifying preterm children at risk for long-term attention problems and related psychiatric disorders, who could benefit from early prevention and intervention efforts.

We assessed the association between the use of medications for attention-deficit/hyperactivity disorder (ADHD) and the risk of all-cause mortality and unintentional injuries leading to emergency department (ED) or hospital admission in individuals aged ≤24 years with ADHD. We conducted a population-based retrospective cohort study between 2000 and 2021 using Quebec health administrative data. Individuals were followed from the first ADHD diagnosis or ADHD medication claim until turning 25, death, or study end. Exposure was defined as mutually exclusive episodes of ADHD medication use and/or coverage under the public provincial drug plan (PDP): 1) covered and not treated with ADHD medication; 2) covered and treated with ADHD medication; and 3) not covered under the PDP. The risk of all-cause mortality and unintentional injuries associated with exposure episodes was estimated using multivariable survival analyses. The cohort included n = 217 192 individuals aged 1-24 years with a male to female ratio of close to 2:1. Compared to non-medication use, episodes of ADHD medication use, overall, were associated with reduced all-cause mortality (adjusted hazard ratio, aHR 0.61, 95% CI 0.48-0.76) and unintentional injury leading to ED (0.75, 0.74-0.77) or hospitalisation (0.71, 0.68-0.75). Episodes of stimulants were associated with a lower risk of all-cause mortality and reduced risk of unintentional injuries, while episodes with non-stimulants and with both stimulants and non-stimulants concomitantly were associated with reduced risk of unintentional injuries, but not of all-cause mortality. Although residual confounding cannot be excluded, stimulants may have a protective effect in terms of risk of all-cause mortality and both stimulants and non-stimulants for ADHD may reduce the risk of unintentional injuries. The findings of the current study should inform clinical decision making on the choice of starting a pharmacological treatment for ADHD, when a balance needs to be struck between expected benefits and possible risks.

Attention-deficit/hyperactivity disorder (ADHD; also known as hyperkinetic disorder) is a common neurodevelopmental condition that affects children and adults worldwide. ADHD has a predominantly genetic aetiology that involves common and rare genetic variants. Some environmental correlates of the disorder have been discovered but causation has been difficult to establish. The heterogeneity of the condition is evident in the diverse presentation of symptoms and levels of impairment, the numerous co-occurring mental and physical conditions, the various domains of neurocognitive impairment, and extensive minor structural and functional brain differences. The diagnosis of ADHD is reliable and valid when evaluated with standard diagnostic criteria. Curative treatments for ADHD do not exist but evidence-based treatments substantially reduce symptoms and/or functional impairment. Medications are effective for core symptoms and are usually well tolerated. Some non-pharmacological treatments are valuable, especially for improving adaptive functioning. Clinical and neurobiological research is ongoing and could lead to the creation of personalized diagnostic and therapeutic approaches for this disorder.

People with schizophrenia die prematurely, yet regional differences are unclear. PRISMA 2020-compliant systematic review/random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) versus any control group, and moderators, in people with ICD/DSM-defined schizophrenia, comparing countries and continents. We conducted subgroup, meta-regression analyses, and quality assessment. The primary outcome was all-cause mortality. Secondary outcomes were suicide-, /natural-cause- and other-cause-related mortality. We included 135 studies from Europe (n = 70), North-America (n = 29), Asia (n = 33), Oceania (n = 2), Africa (n = 1). In incident plus prevalent schizophrenia, differences across continents emerged for all-cause mortality (highest in Africa, RR=5.98, 95 %C.I.=4.09-8.74, k = 1, lowest in North-America, RR=2.14, 95 %C.I.=1.92-2.38, k = 16), suicide (highest in Oceania, RR=13.5, 95 %C.I.=10.08-18.07, k = 1, lowest in North-America, RR=4.4, 95 %C.I.=4.07-4.76, k = 6), but not for natural-cause mortality. Europe had the largest association between antipsychotics and lower all-cause mortality/suicide (Asia had the smallest or no significant association, respectively), without differences for natural-cause mortality. Higher country socio-demographic index significantly moderated larger suicide-related and smaller natural-cause-related mortality risk in incident schizophrenia, with reversed associations in prevalent schizophrenia. Antipsychotics had a larger/smaller protective association in incident/prevalent schizophrenia regarding all-cause mortality, and smaller protective association for suicide-related mortality in prevalent schizophrenia. Additional regional differences emerged in incident schizophrenia, across countries, and secondary outcomes. Significant regional differences emerged for all-cause, cause-specific and suicide-related mortality. Natural-cause death was homogeneously increased globally. Moderators differed across countries. Global initiatives are needed to improve physical health in people with schizophrenia, local studies to identify actionable moderators.

Active avoidance responses (ARs) are instrumental behaviors that prevent harm. Adaptive ARs may contribute to active coping, whereas maladaptive avoidance habits are implicated in anxiety and obsessive-compulsive disorders. The AR learning mechanism has remained elusive, as successful avoidance trials produce no obvious reinforcer. We used a novel outcome-devaluation procedure in rats to show that ARs are positively reinforced by response-produced feedback (FB) cues that develop into safety signals during training. Males were sensitive to FB-devaluation after moderate training, but not overtraining, consistent with a transition from goal-directed to habitual avoidance. Using chemogenetics and FB-devaluation, we also show that goal-directed vs. habitual ARs depend on dorsomedial vs. dorsolateral striatum, suggesting a significant overlap between the mechanisms of avoidance and rewarded instrumental behavior. Females were insensitive to FB-devaluation due to a remarkable context-dependence of counterconditioning. However, degrading the AR-FB contingency suggests that both sexes rely on safety signals to perform goal-directed ARs.

BACKGROUND:Depression continues to be an ongoing threat to adolescent well-being with Black adolescents being particularly vulnerable to greater burdens of depression as well as lower mental health service utilization. Black adolescents are likely to have untreated depression due to social network influences, varied perceptions of services and providers, or self-stigma associated with experiencing depressive symptoms. Furthermore, if or when treatment is initiated, low engagement and early termination are common. To address this gap, a trial is being conducted to preliminarily test the effectiveness of an engagement intervention targeting Black adolescents with depression in school mental health services in New York City. METHODS:A total of 60 Black middle and high school adolescents displaying depressive symptoms are equally randomized (based on school site) to the treatment arms. Both trial arms deliver Interpersonal Psychotherapy for Depressed Adolescents (IPT-A), a time-limited, evidence-based treatment for depression. Additionally, one arm pairs IPT-A with a brief, multi-level engagement intervention, the Making Connections Intervention (MCI), involving adolescents, caregivers, and clinicians. Outcomes of interest are group differences in depression and suicide ideation, adolescent and caregiver engagement, and mental health service use. DISCUSSION/CONCLUSIONS:This trial will serve as an efficacy assessment of the MCI among a sample of Black adolescent students with depressive symptoms. Clinical and implementation results will be used to inform future research to further test the MCI intervention in a larger sample. TRIAL REGISTRATION/BACKGROUND:Registered by ClinicalTrials.gov on May 3, 2019, identifier: NCT03940508.

IMPORTANCE/UNASSIGNED:Few investigations have evaluated rates of brain-based magnetic resonance imaging (MRI) incidental findings (IFs) in large lifespan samples, their stability over time, or their associations with health outcomes. OBJECTIVES/UNASSIGNED:To examine rates of brain-based IFs across the lifespan, their persistence, and their associations with phenotypic indicators of behavior, cognition, and health; to compare quantified motion with radiologist-reported motion and evaluate its associations with IF rates; and to explore IF consistency across multiple visits. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cross-sectional study included participants from the Nathan Kline Institute-Rockland Sample (NKI-RS), a lifespan community-ascertained sample, and the Healthy Brain Network (HBN), a cross-sectional community self-referred pediatric sample focused on mental health and learning disorders. The NKI-RS enrolled participants (ages 6-85 years) between March 2012 and March 2020 and had longitudinal participants followed up for as long as 4 years. The HBN enrolled participants (ages 5-21 years) between August 2015 and October 2021. Clinical neuroradiology MRI reports were coded for radiologist-reported motion as well as presence, type, and clinical urgency (category 1, no abnormal findings; 2, no referral recommended; 3, consider referral; and 4, immediate referral) of IFs. MRI reports were coded from June to October 2021. Data were analyzed from November 2021 to February 2023. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Rates and type of IFs by demographic characteristics, health phenotyping, and motion artifacts; longitudinal stability of IFs; and Euler number in projecting radiologist-reported motion. RESULTS/UNASSIGNED:A total of 1300 NKI-RS participants (781 [60.1%] female; mean [SD] age, 38.9 [21.8] years) and 2772 HBN participants (976 [35.2%] female; mean [SD] age, 10.0 [3.5] years) had health phenotyping and neuroradiology-reviewed MRI scans. IFs were common, with 284 of 2956 children (9.6%) and 608 of 1107 adults (54.9%) having IFs, but rarely of clinical concern (category 1: NKI-RS, 619 [47.6%]; HBN, 2561 [92.4%]; category 2: NKI-RS, 647 [49.8%]; HBN, 178 [6.4%]; category 3: NKI-RS, 79 [6.1%]; HBN, 30 [1.1%]; category 4: NKI-RS: 12 [0.9%]; HBN, 6 [0.2%]). Overall, 46 children (1.6%) and 79 adults (7.1%) required referral for their IFs. IF frequency increased with age. Elevated blood pressure and BMI were associated with increased T2 hyperintensities and age-related cortical atrophy. Radiologist-reported motion aligned with Euler-quantified motion, but neither were associated with IF rates. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cross-sectional study, IFs were common, particularly with increasing age, although rarely clinically significant. While T2 hyperintensity and age-related cortical atrophy were associated with BMI and blood pressure, IFs were not associated with other behavioral, cognitive, and health phenotyping. Motion may not limit clinical IF detection.