Faculty Bibliography

IMPORTANCE/UNASSIGNED:Expectancy effects are significant confounding factors in psychiatric randomized clinical trials (RCTs), potentially affecting the interpretation of study results. This narrative review is the first, to our knowledge, to explore the relationship between expectancy effects, compromised blinding integrity, and the effects of active treatment/placebo in psychiatric RCTs. Additionally, we present statistical and experimental approaches that may help mitigate the confounding impact of expectancy effects. The review concludes with recommendations to enhance the reliability of RCTs in psychiatry. OBSERVATIONS/UNASSIGNED:The placebo response comprises both specific and nonspecific elements, with expectation being a key specific component. Evidence from experimental and clinical studies suggests that expectancy can influence treatment responses in RCTs. Blinding integrity may be compromised by perceived treatment efficacy and adverse effects, introducing bias into outcome assessments. Treatment expectations can lead to unblinding during RCTs, and meta-analytic data from studies in the fields of psychedelics and anxiety disorders indicate that this can influence effect sizes. Therefore, controlling for expectancy effects is essential when interpreting RCT results. Novel statistical methods, though still in need of further validation, offer strategies to address this issue. Another approach may involve experimental medicine models, which aim to develop objective improvement markers (readouts) less affected by expectancy effects. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Expectancy effects represent a significant confound in psychiatric RCTs. We recommend collecting data on treatment expectations alongside monitoring blinding integrity to more accurately interpret study results. Additionally, developing objective readouts that are less confounded by expectancy effects offers another promising avenue for mitigating these confounding influences in psychiatric RCTs.

BACKGROUND:Concerns about the cardiovascular safety of medications used for the treatment of attention-deficit hyperactivity disorder (ADHD) remain. We aimed to compare the effects of pharmacological treatments for ADHD on haemodynamic values and electrocardiogram (ECG) parameters in children, adolescents, and adults. METHODS:For this systematic review and network meta-analysis, we searched 12 electronic databases, including Cochrane CENTRAL, Embase, PubMed, and the WHO International Clinical Trials Registry Platform, from database inception to Jan 18, 2024, for published and unpublished randomised controlled trials comparing amphetamines, atomoxetine, bupropion, clonidine, guanfacine, lisdexamfetamine, methylphenidate, modafinil, or viloxazine against each other or placebo. Primary outcomes were change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), measured in mm Hg, and pulse, measured in beats per minute, at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. Summary data were extracted and pooled in random-effects network meta-analyses. Certainty of evidence was assessed with the Confidence in Network Meta-Analysis (CINeMA) framework. This study was registered with PROSPERO, CRD42021295352. Before study initiation, we contacted representatives of a UK-based charity of people with lived experience of ADHD-the ADHD Foundation-regarding the relevance of the topic and the appropriateness of the outcomes chosen. FINDINGS/RESULTS:102 randomised controlled trials with short-term follow-up (median 7 weeks [IQR 5-9]) were included, encompassing 13 315 children and adolescents (aged ≥5 years and <18 years; mean age 11 years [SD 3]; of available data, 9635 [73%] were male and 3646 [27%] were female; of available data, 289 [2%] were Asian, 1719 [15%] were Black, and 8303 [71%] were White) and 9387 adults (≥18 years, mean age 35 years [11]; of available data, 5064 [57%] were male and 3809 [43%] were female; of available data, 488 [6%] were Asian, 457 [6%] were Black, and 6372 [79%] were White). Amphetamines, atomoxetine, lisdexamfetamine, methylphenidate, and viloxazine led to increments in haemodynamic values in children and adolescents, adults, or both. In children and adolescents, mean increase against placebo ranged from 1·07 (95% CI 0·36-1·79; moderate CINeMA confidence) with atomoxetine to 1·81 (1·05-2·57; moderate) with methylphenidate for SBP; from 1·93 (0·74-3·11; high) with amphetamines to 2·42 (1·69-3·15; low) with methylphenidate for DBP; and from 2·79 (1·05-4·53; moderate) with viloxazine to 5·58 (4·67-6·49; high) with atomoxetine for pulse. In adults, mean increase against placebo ranged from 1·66 (95% CI 0·38-2·93; very low) with methylphenidate to 2·3 (0·66-3·94; very low) with amphetamines for SBP; from 1·60 (0·29-2·91; very low) with methylphenidate to 3·07 (0·69-5·45; very low) with lisdexamfetamine for DBP; and from 4·37 (3·16-5·59; very low) with methylphenidate to 5·8 (2·3-9·3; very low) with viloxazine for pulse. Amphetamines, lisdexamfetamine, or methylphenidate were not associated with larger increments in haemodynamic values compared with atomoxetine or viloxazine in either children and adolescents or adults. Guanfacine was associated with decrements in haemodynamic values in children and adolescents (mean decrease against placebo of -2·83 [95% CI -3·8 to -1·85; low CINeMA confidence] in SBP, -2·08 [-3 to -1·17; low] in DBP, and -4·06 [-5·45 -2·68; moderate] in pulse) and adults (mean decrease against placebo of -10·1 [-13·76 to -6·44; very low] in SBP, -7·73 [-11·88 to -3·58; very low] in DBP, and -6·83 [-10·85 to -2·81; very low] in pulse). Only four RCTs informed on effects in the medium term and none on the long term. INTERPRETATION/CONCLUSIONS:Practitioners should monitor blood pressure and pulse in patients with ADHD treated with any pharmacological intervention, and not stimulants only. Given the short duration of available randomised controlled trials, new research providing insights on the causal effects of ADHD medications on cardiovascular parameters in the longer term should be funded. FUNDING/BACKGROUND:National Institute for Health and Care Research.

Growing evidence suggests that infant attention may predict subsequent cognitive outcomes. However, prior studies have predominantly tested small samples of infants in tightly controlled laboratory settings that differ from the complex, visually rich environments that infants experience in their day-to-day lives. The present study addresses this gap by measuring infant sustained attention in the home using novel remote webcam eye tracking methodology. A large, demographically diverse sample of 3- to 12-month-old infants (N = 160; 49% = female; 65% from low- to extremely low-income households; 48% White, 18% Black, 16% Hispanic/Latine, 9% more than one race, 5% Asian, and 4% other) were recruited across the United States. Infants were remotely administered a free-viewing video task previously validated in lab-based studies, and infant look durations and gaze shifts were measured using remote webcam eye tracking. Our results revealed expected age-related changes in infant look durations and no effects of family demographics on variations in infant attention. Notably, we also found that variation in infant attention predicted emerging executive functions in a subset of infants (N = 78) who participated in a subsequent longitudinal assessment using the Early Executive Functions Questionnaire. This research adds to a growing literature validating the use of at-home remote assessments for objective measurement of infant cognition. This is a notable step toward advancing ecological validity and accessibility of developmental psychology studies in diverse samples. Ultimately, these findings may have important implications for characterizing normative developmental trajectories and for understanding how early sociocultural contexts shape these trajectories. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

BACKGROUND:To progress adolescent mental health research beyond our present achievements-a complex account of brain and environmental risk factors without understanding neurobiological embedding in the environment-we need methods to uncover relationships between the developing brain and real-world environmental experiences. METHODS:We investigated associations between brain function, environments, and emotional and behavioral problems using participants from the Adolescent Brain Cognitive Development (ABCD) Study (n = 2401 female). We applied manifold learning, a promising technique for uncovering latent structure from high-dimensional biomedical data such as functional magnetic resonance imaging. Specifically, we developed exogenous PHATE (potential of heat-diffusion for affinity-based trajectory embedding) (E-PHATE) to model brain-environment interactions. We used E-PHATE embeddings of participants' brain activation during emotional and cognitive processing tasks to predict individual differences in cognition and emotional and behavioral problems both cross-sectionally and longitudinally. RESULTS:E-PHATE embeddings of participants' brain activation and environments at baseline showed moderate-to-large associations with total, externalizing, and internalizing problems at baseline, across several subcortical regions and large-scale cortical networks, compared with the zero-to-small effects achieved by voxelwise data or common low-dimensional embedding methods. E-PHATE embeddings of the brain and environment at baseline were also related to emotional and behavioral problems 2 years later. These longitudinal predictions showed a consistent moderate effect in the frontoparietal and attention networks. CONCLUSIONS:The embedding of the adolescent brain in the environment yields enriched insight into emotional and behavioral problems. Using E-PHATE, we demonstrated how the harmonization of cutting-edge computational methods with longstanding developmental theories advances the detection and prediction of adolescent emotional and behavioral problems.

BACKGROUND:Children born preterm are at heightened risk for neurodevelopmental impairment, including specific deficits in attention. Few studies have investigated change over time in attention problems prior to school entry. The current study aims to describe trajectories of attention problems from age 2 through 5 years in a cohort of children born <30 weeks of gestational age (GA), identify sociodemographic, medical, and neurobehavioral characteristics associated with attention trajectories, and test whether attention problem trajectories predict the risk of a reported attention-deficit/hyperactivity disorder (ADHD) diagnosis. METHODS:We studied 608 infants from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study, a prospective, multisite study of infants born <30 weeks of GA. Parents reported on child attention problems at ages 2, 3, 4, and 5 years using the Child Behavior Checklist and the Behavior Assessment System for Children. Sociodemographic and medical characteristics were assessed via maternal interview and medical record review. Neurobehavioral characteristics were determined using neonatal and 2-year assessments. Parent report of child ADHD diagnosis was obtained. We used latent growth curve (LGC) modeling to test our study aims. RESULTS:A linear LGC model provided the best fit to the data. The average trajectory of attention problems evidenced low initial levels of symptoms and little change over time, yet there was significant heterogeneity in both initial levels and change over time. Individual differences in trajectory parameters were associated with sociodemographic, medical, environmental, and neurobehavioral characteristics. Children with higher initial levels of attention problems as well as steeper increases in attention problems over time were more likely to have a reported ADHD diagnosis. CONCLUSIONS:There is significant heterogeneity in trajectories of attention problems from age 2 to 5 in children born <30 weeks of GA and these differences have clinical relevance. These data could inform follow-up guidelines for preterm infants.

BACKGROUND:Autism spectrum disorder (ASD) is highly heritable and phenotypically variable. Neuroimaging markers reflecting variation in behavior will provide insights into circuitry subserving core features. We examined functional correlates of ASD symptomology at school-age, while accounting for associated behavioral and cognitive domains, in a longitudinal sample followed from infancy and enriched for those with a genetic liability for ASD. METHODS:Resting state functional connectivity MRIs (fcMRI) and behavioral data were analyzed from 97 school-age children (8.1-12.0 years, 55 males, 15 ASD) with (n = 63) or without (n = 34) a family history of ASD. fcMRI enrichment analysis (EA) was used to screen for associations between network-level functional connectivity and six behaviors of interest in a data-driven manner: social affect, restricted and repetitive behavior (RRB), generalized anxiety, inattention, motor coordination, and matrix reasoning. RESULTS:Functional connectivity between the visual and salience networks was significantly associated with social affect symptoms at school-age after accounting for all other behaviors. Results indicated that stronger connectivity was associated with higher social affect scores. No other behaviors were robustly associated with functional connectivity, though trends were observed between visual-salience connectivity and RRBs. CONCLUSIONS:Connectivity between the visual and salience networks may play an important role in social affect symptom variability among children with ASD and those with genetic liability for ASD. These findings align with and extend earlier reports in this sample of the central role of the visual system during infancy in ASD.

Cerebellar dysfunction affects socio-affective abilities beyond motor control. Recent studies suggest that non-invasive cerebellar neurostimulation can modulate social cognition networks, offering potential therapeutic benefits for children with autism, ADHD, and mood disorders. However, its application in pediatrics remains largely unexplored. This review summarizes emerging pediatric research on cerebellar transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). We discuss their mechanisms, potential benefits, and safety considerations, highlighting preliminary findings that suggest feasibility and effectiveness. Ethical concerns and technical challenges related to pediatric neuroanatomy and stimulation parameters are also addressed. While early results are promising, further clinical trials and neurophysiological studies are essential to optimize protocols and confirm long-term efficacy. Advancing our understanding of cerebellar involvement in socio-affective functions could lead to innovative rehabilitation strategies for neurodevelopmental disorders.

INTRODUCTION/BACKGROUND:People with low socioeconomic status (SES) or serious psychological distress (SPD) in the U.S. face ongoing and future disparities in tobacco smoking. We sought to estimate how smoking disparities contribute to disparities in life expectancy and aggregate life-years in these marginalized subpopulations. METHODS:We used the Simulation of Tobacco and Nicotine Outcomes and Policy (STOP) microsimulation model to project life expectancy as a function of subpopulation (low SES, higher SES, SPD, or non-SPD) and cigarette smoking status. Low SES was defined as having at least one of the following: income below poverty, less than high school education, or Medicaid insurance. Higher SES individuals belonged to none of these categories. SPD was defined as Kessler-6 score ≥ 13; non-SPD was a Kessler-6 score < 13. To project individual life expectancy losses from smoking, we simulated 40-year-olds stratified by gender, subpopulation (by SES or by SPD, with no change), and smoking status (current/never, with no change). To project time to reach 5% cigarette smoking prevalence (U.S.) - reflecting one tobacco "endgame" threshold - in each subpopulation, we simulated the entire subpopulations of people with low SES, higher SES, SPD, and non-SPD, incorporating corresponding distributions of gender, age, and smoking status and accounting for changes in smoking behaviors and secular smoking trends. We then estimated total life-years accumulated under status quo and alternate scenarios in which smoking dynamics in the marginalized subpopulations matched those of their less marginalized counterparts. RESULTS:The model showed that, for individuals with low SES or SPD, smoking is associated with substantial loss of life expectancy (9.8-11.5y). Marginalized subpopulations would reach 5% smoking prevalence 20y (low SES) and 17y (SPD) sooner if smoking trends mirrored their less marginalized counterparts; these differences result in 5.3 million (low SES) and 966,000 (SPD) excess life-years lost over 40y. CONCLUSIONS:Differences in cigarette smoking portend substantial ongoing and future disparities in life expectancy and time to reach 5% smoking prevalence. Reducing tobacco-related disparities in the U.S. will require an explicitly equity-focused vision, and the tobacco endgame will only be truly achieved when it includes all groups.